Genetics of Parkinson´s disease: Recessive forms

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The hospital symbol indicates the approximate location of the HGUB. The numbers in blue squares correspond to northern HDs and in orange squares to southern HDs. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "P. Ros Arlanzón, C. Aledo Sala, R. Hernández Lorido, I. Beltrán Blasco, N. López Hernández" "autores" => array:5 [ 0 => array:2 [ "nombre" => "P." "apellidos" => "Ros Arlanzón" ] 1 => array:2 [ "nombre" => "C." "apellidos" => "Aledo Sala" ] 2 => array:2 [ "nombre" => "R." "apellidos" => "Hernández Lorido" ] 3 => array:2 [ "nombre" => "I." "apellidos" => "Beltrán Blasco" ] 4 => array:2 [ "nombre" => "N." "apellidos" => "López Hernández" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2667049624000127?idApp=UINPBA00004N" "url" => "/26670496/0000000400000002/v1_202404250757/S2667049624000127/v1_202404250757/en/main.assets" ] "en" => array:18 [ "idiomaDefecto" => true "cabecera" => "Review ARTICLE" "titulo" => "Genetics of Parkinson´s disease: Recessive forms" "tieneTextoCompleto" => true "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "P.A. Salles, X. Pizarro-Correa, P. Chaná-Cuevas" "autores" => array:3 [ 0 => array:4 [ "nombre" => "P.A." "apellidos" => "Salles" "email" => array:1 [ 0 => "psalles@cetram.org" ] "referencia" => array:4 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "af0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "af0010" ] 2 => array:2 [ "etiqueta" => "c" "identificador" => "af0015" ] 3 => array:2 [ "etiqueta" => "*" "identificador" => "cr0005" ] ] ] 1 => array:3 [ "nombre" => "X." "apellidos" => "Pizarro-Correa" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "af0005" ] 1 => array:2 [ "etiqueta" => "d" "identificador" => "af0020" ] ] ] 2 => array:3 [ "nombre" => "P." "apellidos" => "Chaná-Cuevas" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "af0005" ] 1 => array:2 [ "etiqueta" => "e" "identificador" => "af0025" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "Centro de Trastornos del Movimiento (CETRAM), Santiago, Chile" "etiqueta" => "a" "identificador" => "af0005" ] 1 => array:3 [ "entidad" => "Sección de Trastornos del Movimiento, Departamento de Neurología, Clínica Alemana, Santiago, Chile" "etiqueta" => "b" "identificador" => "af0010" ] 2 => array:3 [ "entidad" => "Sección de Trastornos del Movimiento, Departamento de Neurociencias, Clínica Dávila, Santiago, Chile" "etiqueta" => "c" "identificador" => "af0015" ] 3 => array:3 [ "entidad" => "Servicio de Neurología, Clínica Universidad de Los Andes, Santiago, Chile" "etiqueta" => "d" "identificador" => "af0020" ] 4 => array:3 [ "entidad" => "Facultad de Ciencias Médicas, Universidad de Santiago de Chile, Santiago, Chile" "etiqueta" => "e" "identificador" => "af0025" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cr0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author at: Corporación CETRAM, Santiago, Chile." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Genética en la efermedad de Parkinson: Formas recesivas" ] ] "textoCompleto" => "IntroductionParkinson's disease (PD) is a progressive neurodegenerative disease characterised by such motor symptoms as bradykinesia and rigidity resulting from the progressive loss of dopaminergic neurons in the substantia nigra. Common non-motor signs include hyposmia, constipation, REM sleep behaviour disorder, and depression. Age and certain genetic and environmental factors are known risk factors for PD. Pathogenic variants with a demonstrated causal role are rare in the general population, although risk variants are more common. Study of genetic characteristics of PD sheds light on molecular and pathophysiological aspects of the disease and may lead to new therapeutic targets.PD is diagnosed before 40 years of age in 3%–5% of patients; this is the cut-off point used by some research groups to define early onset (other researchers use a cut-off point of 50 years). Genetics is thought to play a more significant role in early-onset PD.<a class="elsevierStyleCrossRef" href="#bb0005">1</a>Homozygous or compound heterozygous autosomal recessive genetic variants demonstrated to cause monogenic early-onset PD with typical or “pure” characteristics include: (1) parkin, or RBR E3 ubiquitin protein ligase (PRKN),<a class="elsevierStyleCrossRef" href="#bb0010">2</a> (2) PTEN-induced kinase 1 (PINK1),<a class="elsevierStyleCrossRef" href="#bb0015">3</a> and (3) parkinsonism-associated deglycase (PARK7, also known as DJ-1).<a class="elsevierStyleCrossRef" href="#bb0020">4</a> Although these genes are rare in the general population with PD, they explain approximately 13% of cases with onset before the age of 40–50 years.<a class="elsevierStyleCrossRef" href="#bb0025">5</a> Specifically, PRKN is considered the most common cause of monogenic early-onset parkinsonism.<a class="elsevierStyleCrossRef" href="#bb0025">5</a> In juvenile cases (onset before 21 years of age), variants of ATP13A2, FBXO7, PLA2G6, SYNJ1, and DNAJC6 may also play a role.This study reviews the basic molecular mechanisms and relevant clinical characteristics of autosomal recessive monogenic forms of PD.ReviewGenes associated with autosomal recessive early-onset Parkinson's disease with typical manifestationsPRKNFunction of the parkin proteinParkin belongs to a protein family with a preserved ubiquitin-like (UBL) domain and RING (“really interesting new gene”) finger motifs. Parkin functions as a multifunctional cytosolic E3 ubiquitin ligase, and catalyses the transfer of ubiquitinated molecules to multiple substrates. Through mono- and poly-ubiquitination chains linked by lysine-48 or lysine-63, the protein is involved in signalling protein degradation and in non-degradation processes. Parkin indirectly mediates PGC-1α, which regulates the expression of genes involved in mitochondrial biogenesis and antioxidant activity.PRKN and PINK1 encode proteins involved in a quality control system that “checks” the autophagy of depolarised and defective mitochondria (mitophagy). Parkin is self-inhibited in normal conditions, and is activated to induce mitophagy. This process is triggered by accumulation of PINK1, a serine–threonine kinase located on the mitochondrial outer membrane. PINK1 is involved in the phosphorylation of ubiquitin molecules, triggering the recruitment of parkin due to its affinity for phosphorylated ubiquitin. By binding to phosphorylated ubiquitin, PINK1 is able to phosphorylate parkin at the UBL domain, activating its catalytic action. The generation of new mitochondria-bound ubiquitin molecules and their phosphorylation by PINK1 results in a positive feedback mechanism, with further recruitment of parkin. Parkin-mediated ubiquitination of mitochondrial proteins leads to the recruitment of mitophagy receptors. PRKN and PINK1 have also been linked to processes other than autophagy, such as the production of mitochondrial-derived vesicles that transport damaged cargo, and the suppression of mitochondrial antigen presentation.<a class="elsevierStyleCrossRef" href="#bb0030">6</a>PRKN molecular mechanisms associated with Parkinson's diseaseThe simplest explanation of the pathophysiological mechanism associated with this gene is physiological loss of function of parkin, resulting in accumulation of substrates, and mitochondrial dysfunction due to the alteration of the genetic pathway shared with PINK1.<a class="elsevierStyleCrossRef" href="#bb0035">7</a>PRKN variantsPathological variants of PRKN include substitutions of individual base pairs, small deletions, splice-site mutations, and deletions of hundreds of nucleotides.<a class="elsevierStyleCrossRef" href="#bb0040">8</a>The penetrance of homozygous and heterozygous/compound heterozygous PRKN variants is estimated at 100% and 1%–25%, respectively<a class="elsevierStyleCrossRef" href="#bb0040">8</a>; these are considered the most common cause of early-onset PD, accounting for 4.6%–10.5% of cases, depending on the population studied.<a class="elsevierStyleCrossRef" href="#bb0045">9</a>PRKN-PD phenotypeMean age of onset of PRKN-PD is 31 years. Onset is early (20–40 years) in 62% of cases, late (>40 years) in 22%, and juvenile (<20 years) in 16%.<a class="elsevierStyleCrossRef" href="#bb0025">5</a>Generally, patients with PRKN-PD respond well to low doses of dopaminergic drugs.<a class="elsevierStyleCrossRef" href="#bb0050">10</a> A review found that 94% of patients respond well to levodopa.<a class="elsevierStyleCrossRef" href="#bb0025">5</a>Dystonia, dyskinesia, and motor fluctuations were reported in 18%, 19%, and 15% of cases, respectively. Strikingly, up to 46% presented dystonia not induced by levodopa.<a class="elsevierStyleCrossRef" href="#bb0025">5</a> However, dystonic gait disorders were reported as the initial symptom in 5 out of 18 patients.<a class="elsevierStyleCrossRef" href="#bb0055">11</a> Gait disturbances secondary to biphasic dyskinesia are also a more frequent initial symptom in PRKN-PD.<a class="elsevierStyleCrossRef" href="#bb0060">12</a> Levodopa-induced motor fluctuations and dystonia are more frequent in homozygous or compound heterozygous carriers than in heterozygous carriers of PRKN variants (94% vs 69% and 70% vs 40%, respectively).<a class="elsevierStyleCrossRef" href="#bb0065">13</a>In a review, tremor was reported in 31% of patients with PRKN-PD, and was absent in 3%. This information was not reported in the remaining 66%.<a class="elsevierStyleCrossRef" href="#bb0025">5</a> Postural instability is reported in 17%.<a class="elsevierStyleCrossRef" href="#bb0025">5</a> Atypical manifestations are rare, with antero-/retrocollis, pyramidal signs, spasticity, and alien hand syndrome being reported in only 3% of cases (n=32).<a class="elsevierStyleCrossRef" href="#bb0025">5</a>The prevalence of cognitive impairment is estimated at 1.5%–13%,<a class="elsevierStyleCrossRef" href="#bb0070">14</a> similar to the rate reported in the population aged over 65 years.<a class="elsevierStyleCrossRef" href="#bb0075">15</a>Psychotic symptoms are reported in 17/45 and depression in 48% of patients with PRKN-PD.<a class="elsevierStyleCrossRef" href="#bb0075">15</a>,<a class="elsevierStyleCrossRef" href="#bb0080">16</a> Presence of at least one symptom of impulse control disorder seems to appear at approximately the same rate as in idiopathic PD, although compulsive shopping, binge eating, and punding/hobbyism are more common in PRKN-PD.<a class="elsevierStyleCrossRef" href="#bb0085">17</a> Autonomic dysfunction occurs in 32% of patients with PRKN-PD.<a class="elsevierStyleCrossRef" href="#bb0075">15</a><a class="elsevierStyleCrossRef" href="#t0005">Table 1</a> summarises the phenotypes of autosomal recessive monogenic PD.<elsevierMultimedia ident="t0005"></elsevierMultimedia>PINK1Function of the PINK1 protein and molecular mechanisms associated with Parkinson's diseaseSee sections “Function of the parkin protein” and “PRKN molecular mechanisms associated with Parkinson's disease”.PINK1 variantsDozens of variants have been described, with the majority being nonsense point mutations. Penetrance is age-dependent, although, as with PRKN, it seems to be complete in carriers of biallelic pathogenic variants.The prevalence of these mutations is not known. They are thought to be the second most frequent cause of early-onset PD, and account for 3.7% of cases, ranging from 0.6% in European populations to 13.5% in Asian populations.<a class="elsevierStyleCrossRef" href="#bb0045">9</a>PINK1-PD phenotypeThe mean age of onset of PINK1-PD is 32 years (onset is early, late, and juvenile in 62%, 22%, and 15% of cases, respectively). Tremor is present in 51% of patients and absent in 9% (data not reported in 40%).<a class="elsevierStyleCrossRef" href="#bb0025">5</a> Postural instability is observed in 26%.<a class="elsevierStyleCrossRef" href="#bb0025">5</a>Ninety-nine percent of patients respond well to levodopa, with 39% presenting dyskinesia, 21% dystonia, and 34% motor fluctuations. Dyskinesia and dystonia are related to levodopa treatment in 85% and 24% of cases, respectively. Dystonia is not associated with levodopa in 59% of cases,<a class="elsevierStyleCrossRef" href="#bb0025">5</a> and was the initial symptom in 3 out of 4 patients with early-onset PD who were homozygous for PINK1 variants.<a class="elsevierStyleCrossRef" href="#bb0090">18</a>After exclusion of cases with missing data, patients with PINK1-PD presented cognitive impairment in 14%–33% of cases and psychotic symptoms in 2 out of 41 cases.<a class="elsevierStyleCrossRef" href="#bb0075">15</a>,<a class="elsevierStyleCrossRef" href="#bb0080">16</a> Depression was reported in 59%, and autonomic dysfunction in 46%.<a class="elsevierStyleCrossRef" href="#bb0075">15</a>DJ-1Function of the DJ-1 proteinDJ-1 encodes a small protein that is ubiquitously expressed as a homodimer in the cytoplasm, mitochondria, and nucleus. DJ-1 reacts to oxidative stress, sensing, and neutralising reactive oxygen species. It also has chaperone, protease, and glycosylase functions. Furthermore, it is a transcription regulator and RNA-binding protein, and regulates mitochondrial function, autophagy, and norepinephrine and dopamine homeostasis.<a class="elsevierStyleCrossRef" href="#bb0095">19</a>Molecular mechanisms associated with Parkinson's diseaseThe L166P variant is expressed as a monomer, losing its physiological functions and acquiring pro-apoptotic properties, with reduced lysosomal activity and mitochondrial damage.<a class="elsevierStyleCrossRef" href="#bb0095">19</a>DJ-1 variantsDJ-1 variants are rare, accounting for 1%–2% of sporadic cases of early-onset PD, although they are thought to represent approximately 5% of cases of early-onset PD in the Indian population.<a class="elsevierStyleCrossRef" href="#bb0100">20</a>DJ-1–PD phenotypeMean age of onset of DJ-1–PD is 27 years. Onset is early, juvenile, and late in 83%, 13%, and 4% of cases, respectively.Regarding motor symptoms, tremor is observed in 63% of patients, dystonia in 46% (induced by levodopa in 2/14 cases), dyskinesia in 23% (mostly induced by levodopa), and postural instability in 40%.<a class="elsevierStyleCrossRef" href="#bb0025">5</a> Hyperreflexia has been reported in at least 4 cases. Forty-five percent of patients respond well to levodopa.<a class="elsevierStyleCrossRef" href="#bb0025">5</a> Non-motor symptoms include psychotic symptoms in (3/4 cases), depression (66%), and autonomic dysfunction (28%).<a class="elsevierStyleCrossRef" href="#bb0075">15</a>Genes associated with autosomal recessive Parkinson's disease with atypical phenotypesATP13A2Function of the ATP13A2 proteinATP13A2 belongs to the P-type ATPase family of proteins, the majority of which are cation transporters. ATP13A2 regulates the metabolism and prevents the accumulation of divalent metals, preventing their cytotoxicity.<a class="elsevierStyleCrossRef" href="#bb0105">21</a> It has been suggested that it may also play a role in preventing intracellular accumulation of α-synuclein by modulating clearance via the autophagy–lysosomal pathway.<a class="elsevierStyleCrossRef" href="#bb0110">22</a>Molecular mechanisms associated with Parkinson's diseasePatient-derived cell models have shown low concentrations of intracellular free zinc ions, impaired expression of zinc transporters, and abnormal sequestering of zinc in vesicles associated with the autophagy–lysosomal pathway. This would have an impact on mitochondrial energy production and lysosomal proteolysis.<a class="elsevierStyleCrossRef" href="#bb0110">22</a>ATP13A2 variantsMore than 10 homozygous or compound heterozygous pathogenic variants have been reported to affect the protein's transmembrane domains.<a class="elsevierStyleCrossRef" href="#bb0105">21</a> These variants would result in loss of function of ATP13A2 through such mechanisms as nonsense-mediated mRNA decay, mislocalisation, and premature protein degradation by the proteasomal system.<a class="elsevierStyleCrossRef" href="#bb0110">22</a>Rare ATP13A2 variants have been associated with susceptibility to PD in exome sequencing studies.<a class="elsevierStyleCrossRef" href="#bb0115">23</a>ATP13A2-PD phenotypeDisorders related to ATP13A2, initially known as Kufor-Rakeb syndrome, have been assigned to various classifications: atypical parkinsonism (Kufor-Rakeb syndrome or ATP13A2-PD),<a class="elsevierStyleCrossRef" href="#bb0120">24</a> neuronal ceroid lipofuscinosis,<a class="elsevierStyleCrossRef" href="#bb0125">25</a> neurodegeneration with brain iron accumulation,<a class="elsevierStyleCrossRef" href="#bb0130">26</a> autosomal recessive spastic paraplegia-78,<a class="elsevierStyleCrossRef" href="#bb0135">27</a> and juvenile amyotrophic lateral sclerosis.<a class="elsevierStyleCrossRef" href="#bb0140">28</a>Symptoms generally appear before 20 years of age,<a class="elsevierStyleCrossRef" href="#bb0145">29</a>,<a class="elsevierStyleCrossRef" href="#bb0150">30</a> and the rate of progression is variable, ranging from relatively rapid deterioration over a space of months, to slower progression taking decades.<a class="elsevierStyleCrossRef" href="#bb0130">26</a>,<a class="elsevierStyleCrossRef" href="#bb0145">29</a>,<a class="elsevierStyleCrossRef" href="#bb0155">31</a> These diseases typically present with some degree of parkinsonism, with half of the cases presenting hand tremor,<a class="elsevierStyleCrossRef" href="#bb0110">22</a> which is more frequent in carriers of the T12M variant.<a class="elsevierStyleCrossRef" href="#bb0155">31</a> Postural reflexes are often absent.<a class="elsevierStyleCrossRef" href="#bb0160">32</a> Patients may initially respond well to levodopa, but soon develop peak dose dyskinesia and hallucinations, especially in cases associated with the G504R, T12M, or G533R variants<a class="elsevierStyleCrossRef" href="#bb0155">31</a>,<a class="elsevierStyleCrossRef" href="#bb0165">33</a> In other cases, levodopa is poorly tolerated.<a class="elsevierStyleCrossRef" href="#bb0120">24</a>,<a class="elsevierStyleCrossRef" href="#bb0160">32</a>Approximately, half of patients developed dystonia over the course of the disease, with limb involvement and in some cases risus sardonicus.<a class="elsevierStyleCrossRef" href="#bb0110">22</a>Pyramidal signs and spasticity, predominantly in the lower limbs, are also frequent. Vertical gaze palsy and facial–faucial–finger mini-myoclonus are common signs,<a class="elsevierStyleCrossRef" href="#bb0110">22</a> with other authors considering tongue tremor and chin trembling to be equivalent to the characteristic mini-myoclonus.<a class="elsevierStyleCrossRef" href="#bb0130">26</a>The clinical picture often includes dysarthria, dysphagia, cognitive impairment, behavioural alterations, psychosis, and hallucinations.<a class="elsevierStyleCrossRef" href="#bb0130">26</a>,<a class="elsevierStyleCrossRef" href="#bb0155">31</a>,<a class="elsevierStyleCrossRef" href="#bb0160">32</a> Ataxia and axonal sensorimotor neuropathy may also be present.<a class="elsevierStyleCrossRef" href="#bb0110">22</a>,<a class="elsevierStyleCrossRef" href="#bb0155">31</a><a class="elsevierStyleCrossRef" href="#t0005">Table 1</a> summarises the phenotypes of autosomal recessive monogenic PD.Neurodegeneration with brain iron accumulation/hereditary dystonia/PLA2G6-PDFunction of the phospholipase A2 group VI proteinThe PLA2G6 gene encodes phospholipase A2 group VI, a protein that plays a fundamental role in regulating inflammatory processes, the immune response, cell membrane homeostasis, mitochondrial function, and membrane remodelling. The protein protects mitochondria against apoptotic stimuli and has a neuroprotective effect in dopaminergic neurons.Molecular mechanisms associated with Parkinson's diseaseIt has been suggested that PLA2G6 may be involved in PD-associated neurodegeneration due to the excessive generation of reactive oxygen species and iron accumulation associated with dysfunction of the protein, a common finding in PD. PLA2G6 deficiency also results in elevated α-synuclein expression in neuronal mitochondria.<a class="elsevierStyleCrossRef" href="#bb0170">34</a>PLA2G6 variantsPLA2G6 variants include nonsense mutations, protein-truncating variants, fragment deletions, and copy number variants. The link between phenotypes and genotypes suggests that changes at specific sites have different effects on protein activity. Most studies find that frequent PLA2G6 variants appear not to constitute a risk factor for sporadic PD, with weak evidence of an association in Asian populations.<a class="elsevierStyleCrossRef" href="#bb0175">35</a>PLA2G6 parkinsonism phenotypePhospholipase A2 group VI-associated neurodegeneration (PLAN), an autosomal recessive syndrome of neurodegeneration with brain iron accumulation, is caused by PLA2G6 variants. This syndrome encompasses such phenotypes as classical infantile neuroaxonal dystrophy and atypical neuroaxonal dystrophy. Both phenotypes often present with ataxia, rigidity, spasticity, dystonia, myoclonic seizures, intellectual disability, and vision problems. In some cases, MRI reveals cerebellar atrophy and iron accumulation in the substantia nigra, the globus pallidus, and sometimes in the striatum (particularly in adult patients).<a class="elsevierStyleCrossRef" href="#bb0200">40</a>,<a class="elsevierStyleCrossRef" href="#bb0205">41</a>PLA2G6 was shown in 2008 to be the causal gene in adult-onset dystonia-parkinsonism (PARK14).<a class="elsevierStyleCrossRef" href="#bb0180">36</a>Age of onset of PLA2G6 parkinsonism is early (mean of 19±11 years), but the disease may appear at older ages.<a class="elsevierStyleCrossRef" href="#bb0145">29</a>,<a class="elsevierStyleCrossRef" href="#bb0185">37</a>,<a class="elsevierStyleCrossRef" href="#bb0190">38</a> Limb tremor has been described as an initial symptom.<a class="elsevierStyleCrossRef" href="#bb0195">39</a> Response to levodopa may be associated with early development of dyskinesia,<a class="elsevierStyleCrossRef" href="#bb0195">39</a> and treatment tends to lose its efficacy or to be associated with psychosis. These patients may present ataxia, dysarthria, dysphagia, and pyramidal signs.<a class="elsevierStyleCrossRef" href="#bb0190">38</a> Vertical gaze palsy, apraxia of eyelid opening,<a class="elsevierStyleCrossRef" href="#bb0145">29</a> and levodopa-associated oculogyric crises have also been reported.<a class="elsevierStyleCrossRef" href="#bb0190">38</a>,<a class="elsevierStyleCrossRef" href="#bb0195">39</a> Cognitive impairment, psychosis, and psychiatric complaints are also frequent.<a class="elsevierStyleCrossRef" href="#bb0185">37</a>,<a class="elsevierStyleCrossRef" href="#bb0190">38</a>FBXO7Function of the FBXO7 proteinFBXO7 belongs to the F-box family of proteins, interchangeable subunits on the Skp, Cullin, F-box containing (SCF) E3 complex. By binding to cullin-1 and RING-box, it forms a multimeric E3 ubiquitin ligase in which FBXO7 acts as the ubiquitin-recruiting unit. FBXO7 has recently been reported to play a role in the autophagy of damaged mitochondria in PINK1-PD, promoting the recruitment and ubiquitination of parkin.<a class="elsevierStyleCrossRef" href="#bb0210">42</a>,<a class="elsevierStyleCrossRef" href="#bb0215">43</a>Molecular mechanisms associated with FBXO7 and Parkinson's diseaseLoss of FBXO7 expression results in inhibition of the recruitment of parkin to depolarised mitochondria, leading to dysfunction in the mitophagy process.<a class="elsevierStyleCrossRef" href="#bb0215">43</a>FBXO7 variantsSeveral FBXO7 variants have been described. For instance, the R498X variant, reported in multiple cases of familial PD, reduces the protein's capacity to recruit parkin, and the T22M and R378G variants affect binding sites; no functional studies have yet been performed for the I87T, D328R, or R481C variants. The non-coding IVS-329C>T variant has been linked to moderate risk of PD.<a class="elsevierStyleCrossRef" href="#bb0220">44</a>FBXO7 parkinsonism phenotypePatients display heterogeneous phenotypes, mostly presenting with parkinsonism and signs of pyramidal involvement.Symptoms usually appear between 10 and 30 years of age,<a class="elsevierStyleCrossRef" href="#bb0145">29</a> although late onset (41–52 years) has also been reported.<a class="elsevierStyleCrossRef" href="#bb0150">30</a>,<a class="elsevierStyleCrossRef" href="#bb0225">45</a> Levodopa was effective in 81.3% of cases (13/16), and was frequently associated with dyskinesia, motor fluctuations, and behavioural problems.<a class="elsevierStyleCrossRef" href="#bb0145">29</a>,<a class="elsevierStyleCrossRef" href="#bb0155">31</a>,<a class="elsevierStyleCrossRef" href="#bb0230">46</a>,<a class="elsevierStyleCrossRef" href="#bb0235">47</a> Dystonic characteristics are observed in more than half of patients.<a class="elsevierStyleCrossRef" href="#bb0155">31</a> Ten (10) out of 16 cases of FBXO7 parkinsonism presented action tremor.<a class="elsevierStyleCrossRef" href="#bb0145">29</a>,<a class="elsevierStyleCrossRef" href="#bb0235">47</a> Pyramidal signs are reported in over 56% of patients,<a class="elsevierStyleCrossRef" href="#bb0235">47</a> and are frequently associated with spasticity and talipes equinovarus from childhood.<a class="elsevierStyleCrossRef" href="#bb0230">46</a> Oculomotor apraxia and vertical gaze palsy are common, as are psychiatric disorders. Cognitive impairment is reported in over 43% of patients.<a class="elsevierStyleCrossRef" href="#bb0235">47</a> Tics and chorea have also been described.DNAJC6Function of the DNAJC6 proteinDNAJC6 encodes auxilin, which is expressed selectively in neurons. Auxilin acts as a co-chaperone to recruit HSC70 to clathrin-coated vesicles. Its main function is in endocytosis, which is crucial in regulating signalling pathways via receptor and ligand internalisation, which is necessary for axon and dendrite growth. It is also involved in post-endocytic recycling of synaptic vesicles, and stimulates ATPase activity in many cell processes.Molecular mechanisms associated with DNAJC6 and Parkinson's diseaseExperimental models have demonstrated an association between degeneration of dopaminergic neurons, pathological α-synuclein aggregation, increased intrinsic neuronal firing frequency, and mitochondrial and lysosomal dysfunction.<a class="elsevierStyleCrossRef" href="#bb0240">48</a> Evidence from affected patients suggests dyshomeostasis downstream from auxilin, GAK, and dopaminergic proteins.<a class="elsevierStyleCrossRef" href="#bb0245">49</a>DNAJC6 variantsHomozygous or compound heterozygous DNAJC6 variants result in loss of function of the protein. The variants reported to date include splice site mutations, large multi-exon deletions, protein-truncating variants, and nonsense mutations.DNAJC6 parkinsonism phenotypeThese patients develop parkinsonism at an early age (10–42 years),<a class="elsevierStyleCrossRef" href="#bb0150">30</a> presenting rapid progression associated with resting and postural tremor.<a class="elsevierStyleCrossRef" href="#bb0250">50</a> Some respond well to levodopa, but present motor and psychiatric adverse effects. Patients eventually present ataxia and postural instability, reaching a stage where they need a wheelchair or are unable to leave bed, with anarthria and global akinesia at 10–15 years of progression.<a class="elsevierStyleCrossRef" href="#bb0250">50</a> Some patients present generalised or intermittent dystonia.<a class="elsevierStyleCrossRef" href="#bb0190">38</a>,<a class="elsevierStyleCrossRef" href="#bb0250">50</a> Carriers of the D331Y variant present PD, although tremor is less frequent.<a class="elsevierStyleCrossRef" href="#bb0190">38</a> Reported symptoms include intellectual disability, pyramidal signs, severe dysarthria, and epilepsy.<a class="elsevierStyleCrossRef" href="#bb0250">50</a> The D331Y and M358I variants are associated with autonomic dysfunction.<a class="elsevierStyleCrossRef" href="#bb0190">38</a>VPS13CFunction of the VPS13C proteinVPS13C belongs to a family of large VPS13 proteins (VPS13A–D), which are essential in vesicular transport. Early studies linked VPS13 with delivery of proteins to the lysosome. It has been suggested that the protein may also play a role in PINK1/parkin transport, delivering damaged mitochondrial cargo directly to lysosomes in response to mitochondrial stress. Several other reports suggest that, like PINK1 and PRKN, VPS13C is involved in mitochondrial maintenance.<a class="elsevierStyleCrossRef" href="#bb0255">51</a>Molecular mechanisms associated with VPS13C and Parkinson's diseaseLoss of function of VPS13C would cause perinuclear redistribution of mitochondria, mitochondrial fragmentation, and a reduction in mitochondrial transmembrane potential, increasing mitophagy in response to mitochondrial damage, mediated by PINK1/parkin.VPS13C variantsNonsense variants, splice site mutations, and structural variations have been reported in 6 individuals from France and Turkey.<a class="elsevierStyleCrossRef" href="#bb0260">52</a> Such polymorphisms as rs2414739 may act as genetic risk factors for PD.<a class="elsevierStyleCrossRef" href="#bb0265">53</a>VPS13C parkinsonism phenotypeParkinsonism associated with VPS13C variants manifests early (25–46 years of age) and responds to levodopa. However, progression is particularly aggressive, frequently with loss of treatment response,<a class="elsevierStyleCrossRef" href="#bb0150">30</a>,<a class="elsevierStyleCrossRef" href="#bb0270">54</a> and some patients present motor fluctuations and dystonia. Limb tremor, axial symptoms, cognitive impairment, dysautonomia, pyramidal signs, and weakness are reported in 2/3 patients. The majority of patients are unable to leave bed by 15 years after symptom onset.<a class="elsevierStyleCrossRef" href="#bb0270">54</a>ConclusionsThe causal genes involved in recessive forms of parkinsonism participate in various pathways and cell processes fundamental to PD pathophysiology. Specifically, pathogenic PRKN and PINK1 variants are associated with dysfunctional mitophagy. Such other genes as DJ-1, PLA2G6, VPS13C, and ATP13A2 are related to mitochondrial homeostasis. Others, such as DNAJC6, are involved in vesicle trafficking, and especially endocytosis. From a clinical perspective, patients with PRKN-PD present a classical early-onset phenotype, as do those with PINK1-PD and DJ-1–PD, who rarely present atypical symptoms. On the other hand, the remaining genetic forms addressed in this review manifest with complex phenotypes and atypical characteristics including pyramidal signs, dystonia (constituting the so-called pallido-pyramidal syndrome), ataxia, myoclonus, oculomotor alterations, epilepsy, and psychiatric disorders. Establishing phenotype–genotype relationships and identifying the molecular pathways involved in autosomal recessive PD constitute the groundwork for advancing towards precision medicine.Data protectionThe authors declare that no patient data appear in this article.FundingThis study has received no specific funding from any public, commercial, or non-profit organisation." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres2134712" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "as0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1812709" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2134711" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "as0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1812708" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "s0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "s0010" "titulo" => "Review" "secciones" => array:2 [ 0 => array:3 [ "identificador" => "s0015" "titulo" => "Genes associated with autosomal recessive early-onset Parkinson's disease with typical manifestations" "secciones" => array:3 [ 0 => array:3 [ "identificador" => "s0020" "titulo" => "PRKN" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "s0025" "titulo" => "Function of the parkin protein" ] 1 => array:2 [ "identificador" => "s0030" "titulo" => "PRKN molecular mechanisms associated with Parkinson's disease" ] 2 => array:2 [ "identificador" => "s0035" "titulo" => "PRKN variants" ] 3 => array:2 [ "identificador" => "s0040" "titulo" => "PRKN-PD phenotype" ] ] ] 1 => array:3 [ "identificador" => "s0045" "titulo" => "PINK1" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "s0050" "titulo" => "Function of the PINK1 protein and molecular mechanisms associated with Parkinson's disease" ] 1 => array:2 [ "identificador" => "s0055" "titulo" => "PINK1 variants" ] 2 => array:2 [ "identificador" => "s0060" "titulo" => "PINK1-PD phenotype" ] ] ] 2 => array:3 [ "identificador" => "s0065" "titulo" => "DJ-1" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "s0070" "titulo" => "Function of the DJ-1 protein" ] 1 => array:2 [ "identificador" => "s0075" "titulo" => "Molecular mechanisms associated with Parkinson's disease" ] 2 => array:2 [ "identificador" => "s0080" "titulo" => "DJ-1 variants" ] 3 => array:2 [ "identificador" => "s0085" "titulo" => "DJ-1–PD phenotype" ] ] ] ] ] 1 => array:3 [ "identificador" => "s0090" "titulo" => "Genes associated with autosomal recessive Parkinson's disease with atypical phenotypes" "secciones" => array:5 [ 0 => array:3 [ "identificador" => "s0095" "titulo" => "ATP13A2" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "s0100" "titulo" => "Function of the ATP13A2 protein" ] 1 => array:2 [ "identificador" => "s0105" "titulo" => "Molecular mechanisms associated with Parkinson's disease" ] 2 => array:2 [ "identificador" => "s0110" "titulo" => "ATP13A2 variants" ] 3 => array:2 [ "identificador" => "s0115" "titulo" => "ATP13A2-PD phenotype" ] ] ] 1 => array:3 [ "identificador" => "s0120" "titulo" => "Neurodegeneration with brain iron accumulation/hereditary dystonia/PLA2G6-PD" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "s0125" "titulo" => "Function of the phospholipase A2 group VI protein" ] 1 => array:2 [ "identificador" => "s0130" "titulo" => "Molecular mechanisms associated with Parkinson's disease" ] 2 => array:2 [ "identificador" => "s0135" "titulo" => "PLA2G6 variants" ] 3 => array:2 [ "identificador" => "s0140" "titulo" => "PLA2G6 parkinsonism phenotype" ] ] ] 2 => array:3 [ "identificador" => "s0145" "titulo" => "FBXO7" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "s0150" "titulo" => "Function of the FBXO7 protein" ] 1 => array:2 [ "identificador" => "s0155" "titulo" => "Molecular mechanisms associated with FBXO7 and Parkinson's disease" ] 2 => array:2 [ "identificador" => "s0160" "titulo" => "FBXO7 variants" ] 3 => array:2 [ "identificador" => "s0165" "titulo" => "FBXO7 parkinsonism phenotype" ] ] ] 3 => array:3 [ "identificador" => "s0170" "titulo" => "DNAJC6" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "s0175" "titulo" => "Function of the DNAJC6 protein" ] 1 => array:2 [ "identificador" => "s0180" "titulo" => "Molecular mechanisms associated with DNAJC6 and Parkinson's disease" ] 2 => array:2 [ "identificador" => "s0185" "titulo" => "DNAJC6 variants" ] 3 => array:2 [ "identificador" => "s0190" "titulo" => "DNAJC6 parkinsonism phenotype" ] ] ] 4 => array:3 [ "identificador" => "s0195" "titulo" => "VPS13C" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "s0200" "titulo" => "Function of the VPS13C protein" ] 1 => array:2 [ "identificador" => "s0205" "titulo" => "Molecular mechanisms associated with VPS13C and Parkinson's disease" ] 2 => array:2 [ "identificador" => "s0210" "titulo" => "VPS13C variants" ] 3 => array:2 [ "identificador" => "s0215" "titulo" => "VPS13C parkinsonism phenotype" ] ] ] ] ] ] ] 6 => array:2 [ "identificador" => "s0220" "titulo" => "Conclusions" ] 7 => array:2 [ "identificador" => "s6075" "titulo" => "Data protection" ] 8 => array:2 [ "identificador" => "s6080" "titulo" => "Funding" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2022-09-23" "fechaAceptado" => "2023-08-01" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1812709" "palabras" => array:6 [ 0 => "Parkinson's disease" 1 => "Genetics" 2 => "PRKN" 3 => "PINK1" 4 => "DJ-1" 5 => "Autosomal recessive" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1812708" "palabras" => array:6 [ 0 => "Enfermedad de Parkinson" 1 => "genética" 2 => "PRKN" 3 => "PINK1" 4 => "DJ-1" 5 => "Autosómico Recesivo" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "The genes associated with autosomal recessive Parkinson's disease (PD) include the PRKN, PINK1, and DJ-1 genes. Homozygous and compound heterozygous carriers of pathogenic variants of these genes tend to display typical characteristics of PD at early ages.On the other hand, the ATP13A2, FBXO7, PLA2G6, SYNJ1, and DNAJC6 genes are associated with early-onset recessive forms that frequently present with pyramidal signs, ataxia, and oculomotor alterations, with early appearance of levodopa-induced motor fluctuations and dyskinesia. Such non-motor symptoms as depression, psychiatric disorders, hallucinations, and epilepsy are also more frequent in this group.Among multiple molecular mechanisms involved in these cases, key examples are the dysfunction of mitochondrial and lysosomal processes.This article presents a brief review intended to inform clinicians about the basic molecular mechanisms and phenotype–genotype relationship of these monogenic forms of PD." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Los genes asociados a enfermedad de Parkinson (EP) de herencia mendeliana autosómica recesiva incluyen PRKN, PINK1 y DJ-1. Los individuos portadores homocigotos o heterocigotos compuestos de variantes patogénicas en estos genes tienden a manifestar características típicas de la enfermedad de EP a edad temprana.Por otro lado, los genes ATP13A2, FBXO7, PLA2G6, SYNJ1, y DNAJC6, se asocian a formas recesivas de manifestación precoz, presentan con frecuencia signos piramidales, ataxia y alteraciones oculomotoras, y desarrollan tempranamente, fluctuaciones motoras y disquinesias inducidas por levodopa. Alteraciones no motoras como depresión, alteraciones psiquiátricas, alucinaciones y epilepsia son también más frecuentes en este grupo.Entre los múltiples aspectos moleculares comprometidos en estos casos, destacan la disfunción de procesos mitocondriales y lisosomales.En este artículo presentamos una breve revisión orientada al clínico sobre los aspectos moleculares básicos y relación fenotipo-genotipo de estas formas monogénicas de la EP." ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "<elsevierMultimedia ident="ec0005"></elsevierMultimedia>" "etiqueta" => "Appendix A" "titulo" => "Supplementary data" "identificador" => "s0225" ] ] ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "t0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0005" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "+: expected in this disease. BIA: brain iron accumulation; FFF: facial–faucial–finger; LL: lower limbs; OA: oculomotor apraxia; OC: oculogyric crises; SP: spastic paraparesis; TEV: talipes equinovarus; VGP: vertical gaze palsy.*** This table is based on the authors' interpretation of the literature." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Gene \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">PRKN \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">PINK1 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">DJ-1 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">ATP13A2 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">PLA2G6 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">FBXO7 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">DNAJC6 \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">VPS13C \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Locus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PARK2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PARK6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PARK7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PARK9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PARK14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PARK15 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Early onset \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Juvenile onset \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Response to levodopa \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+∼50% \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+At onset \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+At onset \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Motor fluctuations/early dyskinesia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+Early \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+Early \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+Early \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+Early \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dystonia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+LL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+TEV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tremor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Postural instability \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pyramidal signs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+SP phenotype \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neuropathy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ataxia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Myoclonus/mini-myoclonus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+FFF mini-myoclonus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oculomotor alterations \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+VGP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+OC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+OA, VGP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Epilepsy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Early-onset dementia/intellectual disability \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Severe neuropsychiatric disorders/early-onset psychosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+Psychosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+Psychosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Autonomic dysfunction \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+Early \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+Early \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Early dysarthria/dysphagia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+Anarthria \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Abnormal neuroimaging findings \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+Atrophy, BIA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t">+Cerebellar atrophy, BIA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3519380.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Summary of the phenotypes of different forms of autosomal recessive monogenic parkinsonism." ] ] 1 => array:7 [ "identificador" => "ec0005" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => false "mostrarDisplay" => true "detalles" => array:1 [ 0 => array:3 [ "identificador" => "al0010" "detalle" => "Image " "rol" => "short" ] ] "Ecomponente" => array:2 [ "fichero" => "mmc1.pdf" "ficheroTamanyo" => 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Review ARTICLE

Genética en la efermedad de Parkinson: Formas recesivas

P.A. Sallesa,b,c,

Corresponding author

psalles@cetram.org

Corresponding author at: Corporación CETRAM, Santiago, Chile.

, X. Pizarro-Correaa,d, P. Chaná-Cuevasa,e

a Centro de Trastornos del Movimiento (CETRAM), Santiago, Chile

b Sección de Trastornos del Movimiento, Departamento de Neurología, Clínica Alemana, Santiago, Chile

c Sección de Trastornos del Movimiento, Departamento de Neurociencias, Clínica Dávila, Santiago, Chile

d Servicio de Neurología, Clínica Universidad de Los Andes, Santiago, Chile

e Facultad de Ciencias Médicas, Universidad de Santiago de Chile, Santiago, Chile

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            "etiqueta" => "e"
            "identificador" => "af0025"
          ]
        ]
        "correspondencia" => array:1 [
          0 => array:3 [
            "identificador" => "cr0005"
            "etiqueta" => "&#8270;"
            "correspondencia" => "Corresponding author at&#58; Corporaci&#243;n CETRAM&#44; Santiago&#44; Chile&#46;"
          ]
        ]
      ]
    ]
    "titulosAlternativos" => array:1 [
      "es" => array:1 [
        "titulo" => "Gen&#233;tica en la efermedad de Parkinson&#58; Formas recesivas"
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="s0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0025">Introduction</span><p id="p0005" class="elsevierStylePara elsevierViewall">Parkinson&#39;s disease &#40;PD&#41; is a progressive neurodegenerative disease characterised by such motor symptoms as bradykinesia and rigidity resulting from the progressive loss of dopaminergic neurons in the substantia nigra&#46; Common non-motor signs include hyposmia&#44; constipation&#44; REM sleep behaviour disorder&#44; and depression&#46; Age and certain genetic and environmental factors are known risk factors for PD&#46; Pathogenic variants with a demonstrated causal role are rare in the general population&#44; although risk variants are more common&#46; Study of genetic characteristics of PD sheds light on molecular and pathophysiological aspects of the disease and may lead to new therapeutic targets&#46;</p><p id="p0010" class="elsevierStylePara elsevierViewall">PD is diagnosed before 40&#8239;years of age in 3&#37;&#8211;5&#37; of patients&#59; this is the cut-off point used by some research groups to define early onset &#40;other researchers use a cut-off point of 50&#8239;years&#41;&#46; Genetics is thought to play a more significant role in early-onset PD&#46;<a class="elsevierStyleCrossRef" href="#bb0005"><span class="elsevierStyleSup">1</span></a></p><p id="p0015" class="elsevierStylePara elsevierViewall">Homozygous or compound heterozygous autosomal recessive genetic variants demonstrated to cause monogenic early-onset PD with typical or &#8220;pure&#8221; characteristics include&#58; &#40;1&#41; parkin&#44; or RBR E3 ubiquitin protein ligase &#40;<span class="elsevierStyleItalic">PRKN</span>&#41;&#44;<a class="elsevierStyleCrossRef" href="#bb0010"><span class="elsevierStyleSup">2</span></a> &#40;2&#41; PTEN-induced kinase 1 &#40;<span class="elsevierStyleItalic">PINK1</span>&#41;&#44;<a class="elsevierStyleCrossRef" href="#bb0015"><span class="elsevierStyleSup">3</span></a> and &#40;3&#41; parkinsonism-associated deglycase &#40;<span class="elsevierStyleItalic">PARK7</span>&#44; also known as <span class="elsevierStyleItalic">DJ-1</span>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bb0020"><span class="elsevierStyleSup">4</span></a> Although these genes are rare in the general population with PD&#44; they explain approximately 13&#37; of cases with onset before the age of 40&#8211;50&#8239;years&#46;<a class="elsevierStyleCrossRef" href="#bb0025"><span class="elsevierStyleSup">5</span></a> Specifically&#44; <span class="elsevierStyleItalic">PRKN</span> is considered the most common cause of monogenic early-onset parkinsonism&#46;<a class="elsevierStyleCrossRef" href="#bb0025"><span class="elsevierStyleSup">5</span></a> In juvenile cases &#40;onset before 21&#8239;years of age&#41;&#44; variants of <span class="elsevierStyleItalic">ATP13A2</span>&#44; <span class="elsevierStyleItalic">FBXO7</span>&#44; <span class="elsevierStyleItalic">PLA2G6</span>&#44; <span class="elsevierStyleItalic">SYNJ1</span>&#44; and <span class="elsevierStyleItalic">DNAJC6</span> may also play a role&#46;</p><p id="p0020" class="elsevierStylePara elsevierViewall">This study reviews the basic molecular mechanisms and relevant clinical characteristics of autosomal recessive monogenic forms of PD&#46;</p></span><span id="s0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0030">Review</span><span id="s0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0035">Genes associated with autosomal recessive early-onset Parkinson&#39;s disease with typical manifestations</span><span id="s0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0040">PRKN</span><span id="s0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0045">Function of the parkin protein</span><p id="p0025" class="elsevierStylePara elsevierViewall">Parkin belongs to a protein family with a preserved ubiquitin-like &#40;UBL&#41; domain and RING &#40;&#8220;really interesting new gene&#8221;&#41; finger motifs&#46; Parkin functions as a multifunctional cytosolic E3 ubiquitin ligase&#44; and catalyses the transfer of ubiquitinated molecules to multiple substrates&#46; Through mono- and poly-ubiquitination chains linked by lysine-48 or lysine-63&#44; the protein is involved in signalling protein degradation and in non-degradation processes&#46; Parkin indirectly mediates PGC-1&#945;&#44; which regulates the expression of genes involved in mitochondrial biogenesis and antioxidant activity&#46;</p><p id="p0030" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">PRKN</span> and <span class="elsevierStyleItalic">PINK1</span> encode proteins involved in a quality control system that &#8220;checks&#8221; the autophagy of depolarised and defective mitochondria &#40;mitophagy&#41;&#46; Parkin is self-inhibited in normal conditions&#44; and is activated to induce mitophagy&#46; This process is triggered by accumulation of PINK1&#44; a serine&#8211;threonine kinase located on the mitochondrial outer membrane&#46; PINK1 is involved in the phosphorylation of ubiquitin molecules&#44; triggering the recruitment of parkin due to its affinity for phosphorylated ubiquitin&#46; By binding to phosphorylated ubiquitin&#44; PINK1 is able to phosphorylate parkin at the UBL domain&#44; activating its catalytic action&#46; The generation of new mitochondria-bound ubiquitin molecules and their phosphorylation by PINK1 results in a positive feedback mechanism&#44; with further recruitment of parkin&#46; Parkin-mediated ubiquitination of mitochondrial proteins leads to the recruitment of mitophagy receptors&#46; <span class="elsevierStyleItalic">PRKN</span> and <span class="elsevierStyleItalic">PINK1</span> have also been linked to processes other than autophagy&#44; such as the production of mitochondrial-derived vesicles that transport damaged cargo&#44; and the suppression of mitochondrial antigen presentation&#46;<a class="elsevierStyleCrossRef" href="#bb0030"><span class="elsevierStyleSup">6</span></a></p></span><span id="s0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0050"><span class="elsevierStyleItalic">PRKN</span> molecular mechanisms associated with Parkinson&#39;s disease</span><p id="p0035" class="elsevierStylePara elsevierViewall">The simplest explanation of the pathophysiological mechanism associated with this gene is physiological loss of function of parkin&#44; resulting in accumulation of substrates&#44; and mitochondrial dysfunction due to the alteration of the genetic pathway shared with <span class="elsevierStyleItalic">PINK1</span>&#46;<a class="elsevierStyleCrossRef" href="#bb0035"><span class="elsevierStyleSup">7</span></a></p></span><span id="s0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0055"><span class="elsevierStyleItalic">PRKN</span> variants</span><p id="p0040" class="elsevierStylePara elsevierViewall">Pathological variants of <span class="elsevierStyleItalic">PRKN</span> include substitutions of individual base pairs&#44; small deletions&#44; splice-site mutations&#44; and deletions of hundreds of nucleotides&#46;<a class="elsevierStyleCrossRef" href="#bb0040"><span class="elsevierStyleSup">8</span></a></p><p id="p0045" class="elsevierStylePara elsevierViewall">The penetrance of homozygous and heterozygous&#47;compound heterozygous <span class="elsevierStyleItalic">PRKN</span> variants is estimated at 100&#37; and 1&#37;&#8211;25&#37;&#44; respectively<a class="elsevierStyleCrossRef" href="#bb0040"><span class="elsevierStyleSup">8</span></a>&#59; these are considered the most common cause of early-onset PD&#44; accounting for 4&#46;6&#37;&#8211;10&#46;5&#37; of cases&#44; depending on the population studied&#46;<a class="elsevierStyleCrossRef" href="#bb0045"><span class="elsevierStyleSup">9</span></a></p></span><span id="s0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0060"><span class="elsevierStyleItalic">PRKN</span>-PD phenotype</span><p id="p0050" class="elsevierStylePara elsevierViewall">Mean age of onset of <span class="elsevierStyleItalic">PRKN</span>-PD is 31&#8239;years&#46; Onset is early &#40;20&#8211;40&#8239;years&#41; in 62&#37; of cases&#44; late &#40;&#62;<span class="elsevierStyleHsp" style=""></span>40&#8239;years&#41; in 22&#37;&#44; and juvenile &#40;&#60;<span class="elsevierStyleHsp" style=""></span>20&#8239;years&#41; in 16&#37;&#46;<a class="elsevierStyleCrossRef" href="#bb0025"><span class="elsevierStyleSup">5</span></a></p><p id="p0055" class="elsevierStylePara elsevierViewall">Generally&#44; patients with <span class="elsevierStyleItalic">PRKN</span>-PD respond well to low doses of dopaminergic drugs&#46;<a class="elsevierStyleCrossRef" href="#bb0050"><span class="elsevierStyleSup">10</span></a> A review found that 94&#37; of patients respond well to levodopa&#46;<a class="elsevierStyleCrossRef" href="#bb0025"><span class="elsevierStyleSup">5</span></a></p><p id="p0060" class="elsevierStylePara elsevierViewall">Dystonia&#44; dyskinesia&#44; and motor fluctuations were reported in 18&#37;&#44; 19&#37;&#44; and 15&#37; of cases&#44; respectively&#46; Strikingly&#44; up to 46&#37; presented dystonia not induced by levodopa&#46;<a class="elsevierStyleCrossRef" href="#bb0025"><span class="elsevierStyleSup">5</span></a> However&#44; dystonic gait disorders were reported as the initial symptom in 5 out of 18 patients&#46;<a class="elsevierStyleCrossRef" href="#bb0055"><span class="elsevierStyleSup">11</span></a> Gait disturbances secondary to biphasic dyskinesia are also a more frequent initial symptom in <span class="elsevierStyleItalic">PRKN</span>-PD&#46;<a class="elsevierStyleCrossRef" href="#bb0060"><span class="elsevierStyleSup">12</span></a> Levodopa-induced motor fluctuations and dystonia are more frequent in homozygous or compound heterozygous carriers than in heterozygous carriers of <span class="elsevierStyleItalic">PRKN</span> variants &#40;94&#37; vs 69&#37; and 70&#37; vs 40&#37;&#44; respectively&#41;&#46;<a class="elsevierStyleCrossRef" href="#bb0065"><span class="elsevierStyleSup">13</span></a></p><p id="p0065" class="elsevierStylePara elsevierViewall">In a review&#44; tremor was reported in 31&#37; of patients with <span class="elsevierStyleItalic">PRKN</span>-PD&#44; and was absent in 3&#37;&#46; This information was not reported in the remaining 66&#37;&#46;<a class="elsevierStyleCrossRef" href="#bb0025"><span class="elsevierStyleSup">5</span></a> Postural instability is reported in 17&#37;&#46;<a class="elsevierStyleCrossRef" href="#bb0025"><span class="elsevierStyleSup">5</span></a> Atypical manifestations are rare&#44; with antero-&#47;retrocollis&#44; pyramidal signs&#44; spasticity&#44; and alien hand syndrome being reported in only 3&#37; of cases &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>32&#41;&#46;<a class="elsevierStyleCrossRef" href="#bb0025"><span class="elsevierStyleSup">5</span></a></p><p id="p0070" class="elsevierStylePara elsevierViewall">The prevalence of cognitive impairment is estimated at 1&#46;5&#37;&#8211;13&#37;&#44;<a class="elsevierStyleCrossRef" href="#bb0070"><span class="elsevierStyleSup">14</span></a> similar to the rate reported in the population aged over 65&#8239;years&#46;<a class="elsevierStyleCrossRef" href="#bb0075"><span class="elsevierStyleSup">15</span></a></p><p id="p0075" class="elsevierStylePara elsevierViewall">Psychotic symptoms are reported in 17&#47;45 and depression in 48&#37; of patients with <span class="elsevierStyleItalic">PRKN</span>-PD&#46;<a class="elsevierStyleCrossRef" href="#bb0075"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0080"><span class="elsevierStyleSup">16</span></a> Presence of at least one symptom of impulse control disorder seems to appear at approximately the same rate as in idiopathic PD&#44; although compulsive shopping&#44; binge eating&#44; and punding&#47;hobbyism are more common in <span class="elsevierStyleItalic">PRKN</span>-PD&#46;<a class="elsevierStyleCrossRef" href="#bb0085"><span class="elsevierStyleSup">17</span></a> Autonomic dysfunction occurs in 32&#37; of patients with <span class="elsevierStyleItalic">PRKN</span>-PD&#46;<a class="elsevierStyleCrossRef" href="#bb0075"><span class="elsevierStyleSup">15</span></a><a class="elsevierStyleCrossRef" href="#t0005">Table 1</a> summarises the phenotypes of autosomal recessive monogenic PD&#46;</p><elsevierMultimedia ident="t0005"></elsevierMultimedia></span></span><span id="s0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0065">PINK1</span><span id="s0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0070">Function of the PINK1 protein and molecular mechanisms associated with Parkinson&#39;s disease</span><p id="p0080" class="elsevierStylePara elsevierViewall">See sections &#8220;Function of the parkin protein&#8221; and &#8220;PRKN molecular mechanisms associated with Parkinson&#39;s disease&#8221;&#46;</p></span><span id="s0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0075"><span class="elsevierStyleItalic">PINK1</span> variants</span><p id="p0085" class="elsevierStylePara elsevierViewall">Dozens of variants have been described&#44; with the majority being nonsense point mutations&#46; Penetrance is age-dependent&#44; although&#44; as with <span class="elsevierStyleItalic">PRKN</span>&#44; it seems to be complete in carriers of biallelic pathogenic variants&#46;</p><p id="p0090" class="elsevierStylePara elsevierViewall">The prevalence of these mutations is not known&#46; They are thought to be the second most frequent cause of early-onset PD&#44; and account for 3&#46;7&#37; of cases&#44; ranging from 0&#46;6&#37; in European populations to 13&#46;5&#37; in Asian populations&#46;<a class="elsevierStyleCrossRef" href="#bb0045"><span class="elsevierStyleSup">9</span></a></p></span><span id="s0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0080"><span class="elsevierStyleItalic">PINK1</span>-PD phenotype</span><p id="p0095" class="elsevierStylePara elsevierViewall">The mean age of onset of <span class="elsevierStyleItalic">PINK1</span>-PD is 32&#8239;years &#40;onset is early&#44; late&#44; and juvenile in 62&#37;&#44; 22&#37;&#44; and 15&#37; of cases&#44; respectively&#41;&#46; Tremor is present in 51&#37; of patients and absent in 9&#37; &#40;data not reported in 40&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bb0025"><span class="elsevierStyleSup">5</span></a> Postural instability is observed in 26&#37;&#46;<a class="elsevierStyleCrossRef" href="#bb0025"><span class="elsevierStyleSup">5</span></a>Ninety-nine percent of patients respond well to levodopa&#44; with 39&#37; presenting dyskinesia&#44; 21&#37; dystonia&#44; and 34&#37; motor fluctuations&#46; Dyskinesia and dystonia are related to levodopa treatment in 85&#37; and 24&#37; of cases&#44; respectively&#46; Dystonia is not associated with levodopa in 59&#37; of cases&#44;<a class="elsevierStyleCrossRef" href="#bb0025"><span class="elsevierStyleSup">5</span></a> and was the initial symptom in 3 out of 4 patients with early-onset PD who were homozygous for <span class="elsevierStyleItalic">PINK1</span> variants&#46;<a class="elsevierStyleCrossRef" href="#bb0090"><span class="elsevierStyleSup">18</span></a></p><p id="p0100" class="elsevierStylePara elsevierViewall">After exclusion of cases with missing data&#44; patients with <span class="elsevierStyleItalic">PINK1</span>-PD presented cognitive impairment in 14&#37;&#8211;33&#37; of cases and psychotic symptoms in 2 out of 41 cases&#46;<a class="elsevierStyleCrossRef" href="#bb0075"><span class="elsevierStyleSup">15</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0080"><span class="elsevierStyleSup">16</span></a> Depression was reported in 59&#37;&#44; and autonomic dysfunction in 46&#37;&#46;<a class="elsevierStyleCrossRef" href="#bb0075"><span class="elsevierStyleSup">15</span></a></p></span></span><span id="s0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0085">DJ-1</span><span id="s0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0090">Function of the DJ-1 protein</span><p id="p0105" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">DJ-1</span> encodes a small protein that is ubiquitously expressed as a homodimer in the cytoplasm&#44; mitochondria&#44; and nucleus&#46; DJ-1 reacts to oxidative stress&#44; sensing&#44; and neutralising reactive oxygen species&#46; It also has chaperone&#44; protease&#44; and glycosylase functions&#46; Furthermore&#44; it is a transcription regulator and RNA-binding protein&#44; and regulates mitochondrial function&#44; autophagy&#44; and norepinephrine and dopamine homeostasis&#46;<a class="elsevierStyleCrossRef" href="#bb0095"><span class="elsevierStyleSup">19</span></a></p></span><span id="s0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0095">Molecular mechanisms associated with Parkinson&#39;s disease</span><p id="p0110" class="elsevierStylePara elsevierViewall">The L166P variant is expressed as a monomer&#44; losing its physiological functions and acquiring pro-apoptotic properties&#44; with reduced lysosomal activity and mitochondrial damage&#46;<a class="elsevierStyleCrossRef" href="#bb0095"><span class="elsevierStyleSup">19</span></a></p></span><span id="s0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0100"><span class="elsevierStyleItalic">DJ-1</span> variants</span><p id="p0115" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">DJ-1</span> variants are rare&#44; accounting for 1&#37;&#8211;2&#37; of sporadic cases of early-onset PD&#44; although they are thought to represent approximately 5&#37; of cases of early-onset PD in the Indian population&#46;<a class="elsevierStyleCrossRef" href="#bb0100"><span class="elsevierStyleSup">20</span></a></p></span><span id="s0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0105"><span class="elsevierStyleItalic">DJ-1</span>&#8211;PD phenotype</span><p id="p0120" class="elsevierStylePara elsevierViewall">Mean age of onset of <span class="elsevierStyleItalic">DJ-1</span>&#8211;PD is 27&#8239;years&#46; Onset is early&#44; juvenile&#44; and late in 83&#37;&#44; 13&#37;&#44; and 4&#37; of cases&#44; respectively&#46;</p><p id="p0125" class="elsevierStylePara elsevierViewall">Regarding motor symptoms&#44; tremor is observed in 63&#37; of patients&#44; dystonia in 46&#37; &#40;induced by levodopa in 2&#47;14 cases&#41;&#44; dyskinesia in 23&#37; &#40;mostly induced by levodopa&#41;&#44; and postural instability in 40&#37;&#46;<a class="elsevierStyleCrossRef" href="#bb0025"><span class="elsevierStyleSup">5</span></a> Hyperreflexia has been reported in at least 4 cases&#46; Forty-five percent of patients respond well to levodopa&#46;<a class="elsevierStyleCrossRef" href="#bb0025"><span class="elsevierStyleSup">5</span></a> Non-motor symptoms include psychotic symptoms in &#40;3&#47;4 cases&#41;&#44; depression &#40;66&#37;&#41;&#44; and autonomic dysfunction &#40;28&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bb0075"><span class="elsevierStyleSup">15</span></a></p></span></span></span><span id="s0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0110">Genes associated with autosomal recessive Parkinson&#39;s disease with atypical phenotypes</span><span id="s0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0115">ATP13A2</span><span id="s0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0120">Function of the ATP13A2 protein</span><p id="p0130" class="elsevierStylePara elsevierViewall">ATP13A2 belongs to the P-type ATPase family of proteins&#44; the majority of which are cation transporters&#46; ATP13A2 regulates the metabolism and prevents the accumulation of divalent metals&#44; preventing their cytotoxicity&#46;<a class="elsevierStyleCrossRef" href="#bb0105"><span class="elsevierStyleSup">21</span></a> It has been suggested that it may also play a role in preventing intracellular accumulation of &#945;-synuclein by modulating clearance via the autophagy&#8211;lysosomal pathway&#46;<a class="elsevierStyleCrossRef" href="#bb0110"><span class="elsevierStyleSup">22</span></a></p></span><span id="s0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0125">Molecular mechanisms associated with Parkinson&#39;s disease</span><p id="p0135" class="elsevierStylePara elsevierViewall">Patient-derived cell models have shown low concentrations of intracellular free zinc ions&#44; impaired expression of zinc transporters&#44; and abnormal sequestering of zinc in vesicles associated with the autophagy&#8211;lysosomal pathway&#46; This would have an impact on mitochondrial energy production and lysosomal proteolysis&#46;<a class="elsevierStyleCrossRef" href="#bb0110"><span class="elsevierStyleSup">22</span></a></p></span><span id="s0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0130"><span class="elsevierStyleItalic">ATP13A2</span> variants</span><p id="p0140" class="elsevierStylePara elsevierViewall">More than 10 homozygous or compound heterozygous pathogenic variants have been reported to affect the protein&#39;s transmembrane domains&#46;<a class="elsevierStyleCrossRef" href="#bb0105"><span class="elsevierStyleSup">21</span></a> These variants would result in loss of function of ATP13A2 through such mechanisms as nonsense-mediated mRNA decay&#44; mislocalisation&#44; and premature protein degradation by the proteasomal system&#46;<a class="elsevierStyleCrossRef" href="#bb0110"><span class="elsevierStyleSup">22</span></a></p><p id="p0145" class="elsevierStylePara elsevierViewall">Rare <span class="elsevierStyleItalic">ATP13A2</span> variants have been associated with susceptibility to PD in exome sequencing studies&#46;<a class="elsevierStyleCrossRef" href="#bb0115"><span class="elsevierStyleSup">23</span></a></p></span><span id="s0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0135"><span class="elsevierStyleItalic">ATP13A2</span>-PD phenotype</span><p id="p0150" class="elsevierStylePara elsevierViewall">Disorders related to <span class="elsevierStyleItalic">ATP13A2</span>&#44; initially known as Kufor-Rakeb syndrome&#44; have been assigned to various classifications&#58; atypical parkinsonism &#40;Kufor-Rakeb syndrome or <span class="elsevierStyleItalic">ATP13A2</span>-PD&#41;&#44;<a class="elsevierStyleCrossRef" href="#bb0120"><span class="elsevierStyleSup">24</span></a> neuronal ceroid lipofuscinosis&#44;<a class="elsevierStyleCrossRef" href="#bb0125"><span class="elsevierStyleSup">25</span></a> neurodegeneration with brain iron accumulation&#44;<a class="elsevierStyleCrossRef" href="#bb0130"><span class="elsevierStyleSup">26</span></a> autosomal recessive spastic paraplegia-78&#44;<a class="elsevierStyleCrossRef" href="#bb0135"><span class="elsevierStyleSup">27</span></a> and juvenile amyotrophic lateral sclerosis&#46;<a class="elsevierStyleCrossRef" href="#bb0140"><span class="elsevierStyleSup">28</span></a></p><p id="p0155" class="elsevierStylePara elsevierViewall">Symptoms generally appear before 20&#8239;years of age&#44;<a class="elsevierStyleCrossRef" href="#bb0145"><span class="elsevierStyleSup">29</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0150"><span class="elsevierStyleSup">30</span></a> and the rate of progression is variable&#44; ranging from relatively rapid deterioration over a space of months&#44; to slower progression taking decades&#46;<a class="elsevierStyleCrossRef" href="#bb0130"><span class="elsevierStyleSup">26</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0145"><span class="elsevierStyleSup">29</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0155"><span class="elsevierStyleSup">31</span></a> These diseases typically present with some degree of parkinsonism&#44; with half of the cases presenting hand tremor&#44;<a class="elsevierStyleCrossRef" href="#bb0110"><span class="elsevierStyleSup">22</span></a> which is more frequent in carriers of the T12M variant&#46;<a class="elsevierStyleCrossRef" href="#bb0155"><span class="elsevierStyleSup">31</span></a> Postural reflexes are often absent&#46;<a class="elsevierStyleCrossRef" href="#bb0160"><span class="elsevierStyleSup">32</span></a> Patients may initially respond well to levodopa&#44; but soon develop peak dose dyskinesia and hallucinations&#44; especially in cases associated with the G504R&#44; T12M&#44; or G533R variants<a class="elsevierStyleCrossRef" href="#bb0155"><span class="elsevierStyleSup">31</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0165"><span class="elsevierStyleSup">33</span></a> In other cases&#44; levodopa is poorly tolerated&#46;<a class="elsevierStyleCrossRef" href="#bb0120"><span class="elsevierStyleSup">24</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0160"><span class="elsevierStyleSup">32</span></a></p><p id="p0160" class="elsevierStylePara elsevierViewall">Approximately&#44; half of patients developed dystonia over the course of the disease&#44; with limb involvement and in some cases risus sardonicus&#46;<a class="elsevierStyleCrossRef" href="#bb0110"><span class="elsevierStyleSup">22</span></a></p><p id="p0165" class="elsevierStylePara elsevierViewall">Pyramidal signs and spasticity&#44; predominantly in the lower limbs&#44; are also frequent&#46; Vertical gaze palsy and facial&#8211;faucial&#8211;finger mini-myoclonus are common signs&#44;<a class="elsevierStyleCrossRef" href="#bb0110"><span class="elsevierStyleSup">22</span></a> with other authors considering tongue tremor and chin trembling to be equivalent to the characteristic mini-myoclonus&#46;<a class="elsevierStyleCrossRef" href="#bb0130"><span class="elsevierStyleSup">26</span></a></p><p id="p0170" class="elsevierStylePara elsevierViewall">The clinical picture often includes dysarthria&#44; dysphagia&#44; cognitive impairment&#44; behavioural alterations&#44; psychosis&#44; and hallucinations&#46;<a class="elsevierStyleCrossRef" href="#bb0130"><span class="elsevierStyleSup">26</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0155"><span class="elsevierStyleSup">31</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0160"><span class="elsevierStyleSup">32</span></a> Ataxia and axonal sensorimotor neuropathy may also be present&#46;<a class="elsevierStyleCrossRef" href="#bb0110"><span class="elsevierStyleSup">22</span></a><span class="elsevierStyleSup"><span class="elsevierStyleBold">&#44;</span></span><a class="elsevierStyleCrossRef" href="#bb0155"><span class="elsevierStyleSup">31</span></a><a class="elsevierStyleCrossRef" href="#t0005">Table 1</a> summarises the phenotypes of autosomal recessive monogenic PD&#46;</p></span></span><span id="s0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0140">Neurodegeneration with brain iron accumulation&#47;hereditary dystonia&#47;<span class="elsevierStyleItalic">PLA2G6</span>-PD</span><span id="s0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0145">Function of the phospholipase A2 group VI protein</span><p id="p0175" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">PLA2G6</span> gene encodes phospholipase A2 group VI&#44; a protein that plays a fundamental role in regulating inflammatory processes&#44; the immune response&#44; cell membrane homeostasis&#44; mitochondrial function&#44; and membrane remodelling&#46; The protein protects mitochondria against apoptotic stimuli and has a neuroprotective effect in dopaminergic neurons&#46;</p></span><span id="s0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0150">Molecular mechanisms associated with Parkinson&#39;s disease</span><p id="p0180" class="elsevierStylePara elsevierViewall">It has been suggested that <span class="elsevierStyleItalic">PLA2G6</span> may be involved in PD-associated neurodegeneration due to the excessive generation of reactive oxygen species and iron accumulation associated with dysfunction of the protein&#44; a common finding in PD&#46; <span class="elsevierStyleItalic">PLA2G6</span> deficiency also results in elevated &#945;-synuclein expression in neuronal mitochondria&#46;<a class="elsevierStyleCrossRef" href="#bb0170"><span class="elsevierStyleSup">34</span></a></p></span><span id="s0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0155"><span class="elsevierStyleItalic">PLA2G6</span> variants</span><p id="p0185" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">PLA2G6</span> variants include nonsense mutations&#44; protein-truncating variants&#44; fragment deletions&#44; and copy number variants&#46; The link between phenotypes and genotypes suggests that changes at specific sites have different effects on protein activity&#46; Most studies find that frequent <span class="elsevierStyleItalic">PLA2G6</span> variants appear not to constitute a risk factor for sporadic PD&#44; with weak evidence of an association in Asian populations&#46;<a class="elsevierStyleCrossRef" href="#bb0175"><span class="elsevierStyleSup">35</span></a></p></span><span id="s0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0160"><span class="elsevierStyleItalic">PLA2G6</span> parkinsonism phenotype</span><p id="p0190" class="elsevierStylePara elsevierViewall">Phospholipase A2 group VI-associated neurodegeneration &#40;PLAN&#41;&#44; an autosomal recessive syndrome of neurodegeneration with brain iron accumulation&#44; is caused by <span class="elsevierStyleItalic">PLA2G6</span> variants&#46; This syndrome encompasses such phenotypes as classical infantile neuroaxonal dystrophy and atypical neuroaxonal dystrophy&#46; Both phenotypes often present with ataxia&#44; rigidity&#44; spasticity&#44; dystonia&#44; myoclonic seizures&#44; intellectual disability&#44; and vision problems&#46; In some cases&#44; MRI reveals cerebellar atrophy and iron accumulation in the substantia nigra&#44; the globus pallidus&#44; and sometimes in the striatum &#40;particularly in adult patients&#41;&#46;<a class="elsevierStyleCrossRef" href="#bb0200"><span class="elsevierStyleSup">40</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0205"><span class="elsevierStyleSup">41</span></a></p><p id="p0195" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">PLA2G6</span> was shown in 2008 to be the causal gene in adult-onset dystonia-parkinsonism &#40;PARK14&#41;&#46;<a class="elsevierStyleCrossRef" href="#bb0180"><span class="elsevierStyleSup">36</span></a></p><p id="p0200" class="elsevierStylePara elsevierViewall">Age of onset of <span class="elsevierStyleItalic">PLA2G6</span> parkinsonism is early &#40;mean of 19<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&#8239;years&#41;&#44; but the disease may appear at older ages&#46;<a class="elsevierStyleCrossRef" href="#bb0145"><span class="elsevierStyleSup">29</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0185"><span class="elsevierStyleSup">37</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0190"><span class="elsevierStyleSup">38</span></a> Limb tremor has been described as an initial symptom&#46;<a class="elsevierStyleCrossRef" href="#bb0195"><span class="elsevierStyleSup">39</span></a> Response to levodopa may be associated with early development of dyskinesia&#44;<a class="elsevierStyleCrossRef" href="#bb0195"><span class="elsevierStyleSup">39</span></a> and treatment tends to lose its efficacy or to be associated with psychosis&#46; These patients may present ataxia&#44; dysarthria&#44; dysphagia&#44; and pyramidal signs&#46;<a class="elsevierStyleCrossRef" href="#bb0190"><span class="elsevierStyleSup">38</span></a> Vertical gaze palsy&#44; apraxia of eyelid opening&#44;<a class="elsevierStyleCrossRef" href="#bb0145"><span class="elsevierStyleSup">29</span></a> and levodopa-associated oculogyric crises have also been reported&#46;<a class="elsevierStyleCrossRef" href="#bb0190"><span class="elsevierStyleSup">38</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0195"><span class="elsevierStyleSup">39</span></a> Cognitive impairment&#44; psychosis&#44; and psychiatric complaints are also frequent&#46;<a class="elsevierStyleCrossRef" href="#bb0185"><span class="elsevierStyleSup">37</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0190"><span class="elsevierStyleSup">38</span></a></p></span></span><span id="s0145" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0165">FBXO7</span><span id="s0150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0170">Function of the FBXO7 protein</span><p id="p0205" class="elsevierStylePara elsevierViewall">FBXO7 belongs to the F-box family of proteins&#44; interchangeable subunits on the Skp&#44; Cullin&#44; F-box containing &#40;SCF&#41; E3 complex&#46; By binding to cullin-1 and RING-box&#44; it forms a multimeric E3 ubiquitin ligase in which FBXO7 acts as the ubiquitin-recruiting unit&#46; <span class="elsevierStyleItalic">FBXO7</span> has recently been reported to play a role in the autophagy of damaged mitochondria in <span class="elsevierStyleItalic">PINK1</span>-PD&#44; promoting the recruitment and ubiquitination of parkin&#46;<a class="elsevierStyleCrossRef" href="#bb0210"><span class="elsevierStyleSup">42</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0215"><span class="elsevierStyleSup">43</span></a></p></span><span id="s0155" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0175">Molecular mechanisms associated with <span class="elsevierStyleItalic">FBXO7</span> and Parkinson&#39;s disease</span><p id="p0210" class="elsevierStylePara elsevierViewall">Loss of <span class="elsevierStyleItalic">FBXO7</span> expression results in inhibition of the recruitment of parkin to depolarised mitochondria&#44; leading to dysfunction in the mitophagy process&#46;<a class="elsevierStyleCrossRef" href="#bb0215"><span class="elsevierStyleSup">43</span></a></p></span><span id="s0160" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0180"><span class="elsevierStyleItalic">FBXO7</span> variants</span><p id="p0215" class="elsevierStylePara elsevierViewall">Several <span class="elsevierStyleItalic">FBXO7</span> variants have been described&#46; For instance&#44; the R498X variant&#44; reported in multiple cases of familial PD&#44; reduces the protein&#39;s capacity to recruit parkin&#44; and the T22M and R378G variants affect binding sites&#59; no functional studies have yet been performed for the I87T&#44; D328R&#44; or R481C variants&#46; The non-coding IVS-329C<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>T variant has been linked to moderate risk of PD&#46;<a class="elsevierStyleCrossRef" href="#bb0220"><span class="elsevierStyleSup">44</span></a></p></span><span id="s0165" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0185"><span class="elsevierStyleItalic">FBXO7</span> parkinsonism phenotype</span><p id="p0220" class="elsevierStylePara elsevierViewall">Patients display heterogeneous phenotypes&#44; mostly presenting with parkinsonism and signs of pyramidal involvement&#46;</p><p id="p0225" class="elsevierStylePara elsevierViewall">Symptoms usually appear between 10 and 30&#8239;years of age&#44;<a class="elsevierStyleCrossRef" href="#bb0145"><span class="elsevierStyleSup">29</span></a> although late onset &#40;41&#8211;52&#8239;years&#41; has also been reported&#46;<a class="elsevierStyleCrossRef" href="#bb0150"><span class="elsevierStyleSup">30</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0225"><span class="elsevierStyleSup">45</span></a> Levodopa was effective in 81&#46;3&#37; of cases &#40;13&#47;16&#41;&#44; and was frequently associated with dyskinesia&#44; motor fluctuations&#44; and behavioural problems&#46;<a class="elsevierStyleCrossRef" href="#bb0145"><span class="elsevierStyleSup">29</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0155"><span class="elsevierStyleSup">31</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0230"><span class="elsevierStyleSup">46</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0235"><span class="elsevierStyleSup">47</span></a> Dystonic characteristics are observed in more than half of patients&#46;<a class="elsevierStyleCrossRef" href="#bb0155"><span class="elsevierStyleSup">31</span></a> Ten &#40;10&#41; out of 16 cases of <span class="elsevierStyleItalic">FBXO7</span> parkinsonism presented action tremor&#46;<a class="elsevierStyleCrossRef" href="#bb0145"><span class="elsevierStyleSup">29</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0235"><span class="elsevierStyleSup">47</span></a> Pyramidal signs are reported in over 56&#37; of patients&#44;<a class="elsevierStyleCrossRef" href="#bb0235"><span class="elsevierStyleSup">47</span></a> and are frequently associated with spasticity and talipes equinovarus from childhood&#46;<a class="elsevierStyleCrossRef" href="#bb0230"><span class="elsevierStyleSup">46</span></a> Oculomotor apraxia and vertical gaze palsy are common&#44; as are psychiatric disorders&#46; Cognitive impairment is reported in over 43&#37; of patients&#46;<a class="elsevierStyleCrossRef" href="#bb0235"><span class="elsevierStyleSup">47</span></a> Tics and chorea have also been described&#46;</p></span></span><span id="s0170" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0190">DNAJC6</span><span id="s0175" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0195">Function of the DNAJC6 protein</span><p id="p0230" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">DNAJC6</span> encodes auxilin&#44; which is expressed selectively in neurons&#46; Auxilin acts as a co-chaperone to recruit HSC70 to clathrin-coated vesicles&#46; Its main function is in endocytosis&#44; which is crucial in regulating signalling pathways via receptor and ligand internalisation&#44; which is necessary for axon and dendrite growth&#46; It is also involved in post-endocytic recycling of synaptic vesicles&#44; and stimulates ATPase activity in many cell processes&#46;</p></span><span id="s0180" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0200">Molecular mechanisms associated with <span class="elsevierStyleItalic">DNAJC6</span> and Parkinson&#39;s disease</span><p id="p0235" class="elsevierStylePara elsevierViewall">Experimental models have demonstrated an association between degeneration of dopaminergic neurons&#44; pathological &#945;-synuclein aggregation&#44; increased intrinsic neuronal firing frequency&#44; and mitochondrial and lysosomal dysfunction&#46;<a class="elsevierStyleCrossRef" href="#bb0240"><span class="elsevierStyleSup">48</span></a> Evidence from affected patients suggests dyshomeostasis downstream from auxilin&#44; GAK&#44; and dopaminergic proteins&#46;<a class="elsevierStyleCrossRef" href="#bb0245"><span class="elsevierStyleSup">49</span></a></p></span><span id="s0185" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0205"><span class="elsevierStyleItalic">DNAJC6</span> variants</span><p id="p0240" class="elsevierStylePara elsevierViewall">Homozygous or compound heterozygous <span class="elsevierStyleItalic">DNAJC6</span> variants result in loss of function of the protein&#46; The variants reported to date include splice site mutations&#44; large multi-exon deletions&#44; protein-truncating variants&#44; and nonsense mutations&#46;</p></span><span id="s0190" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0210"><span class="elsevierStyleItalic">DNAJC6</span> parkinsonism phenotype</span><p id="p0245" class="elsevierStylePara elsevierViewall">These patients develop parkinsonism at an early age &#40;10&#8211;42&#8239;years&#41;&#44;<a class="elsevierStyleCrossRef" href="#bb0150"><span class="elsevierStyleSup">30</span></a> presenting rapid progression associated with resting and postural tremor&#46;<a class="elsevierStyleCrossRef" href="#bb0250"><span class="elsevierStyleSup">50</span></a> Some respond well to levodopa&#44; but present motor and psychiatric adverse effects&#46; Patients eventually present ataxia and postural instability&#44; reaching a stage where they need a wheelchair or are unable to leave bed&#44; with anarthria and global akinesia at 10&#8211;15&#8239;years of progression&#46;<a class="elsevierStyleCrossRef" href="#bb0250"><span class="elsevierStyleSup">50</span></a> Some patients present generalised or intermittent dystonia&#46;<a class="elsevierStyleCrossRef" href="#bb0190"><span class="elsevierStyleSup">38</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0250"><span class="elsevierStyleSup">50</span></a> Carriers of the D331Y variant present PD&#44; although tremor is less frequent&#46;<a class="elsevierStyleCrossRef" href="#bb0190"><span class="elsevierStyleSup">38</span></a> Reported symptoms include intellectual disability&#44; pyramidal signs&#44; severe dysarthria&#44; and epilepsy&#46;<a class="elsevierStyleCrossRef" href="#bb0250"><span class="elsevierStyleSup">50</span></a> The D331Y and M358I variants are associated with autonomic dysfunction&#46;<a class="elsevierStyleCrossRef" href="#bb0190"><span class="elsevierStyleSup">38</span></a></p></span></span><span id="s0195" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0215">VPS13C</span><span id="s0200" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0220">Function of the VPS13C protein</span><p id="p0250" class="elsevierStylePara elsevierViewall">VPS13C belongs to a family of large VPS13 proteins &#40;VPS13A&#8211;D&#41;&#44; which are essential in vesicular transport&#46; Early studies linked VPS13 with delivery of proteins to the lysosome&#46; It has been suggested that the protein may also play a role in PINK1&#47;parkin transport&#44; delivering damaged mitochondrial cargo directly to lysosomes in response to mitochondrial stress&#46; Several other reports suggest that&#44; like <span class="elsevierStyleItalic">PINK1</span> and <span class="elsevierStyleItalic">PRKN</span>&#44; <span class="elsevierStyleItalic">VPS13C</span> is involved in mitochondrial maintenance&#46;<a class="elsevierStyleCrossRef" href="#bb0255"><span class="elsevierStyleSup">51</span></a></p></span><span id="s0205" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0225">Molecular mechanisms associated with <span class="elsevierStyleItalic">VPS13C</span> and Parkinson&#39;s disease</span><p id="p0255" class="elsevierStylePara elsevierViewall">Loss of function of VPS13C would cause perinuclear redistribution of mitochondria&#44; mitochondrial fragmentation&#44; and a reduction in mitochondrial transmembrane potential&#44; increasing mitophagy in response to mitochondrial damage&#44; mediated by PINK1&#47;parkin&#46;</p></span><span id="s0210" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0230"><span class="elsevierStyleItalic">VPS13C</span> variants</span><p id="p0260" class="elsevierStylePara elsevierViewall">Nonsense variants&#44; splice site mutations&#44; and structural variations have been reported in 6 individuals from France and Turkey&#46;<a class="elsevierStyleCrossRef" href="#bb0260"><span class="elsevierStyleSup">52</span></a> Such polymorphisms as rs2414739 may act as genetic risk factors for PD&#46;<a class="elsevierStyleCrossRef" href="#bb0265"><span class="elsevierStyleSup">53</span></a></p></span><span id="s0215" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0235"><span class="elsevierStyleItalic">VPS13C</span> parkinsonism phenotype</span><p id="p0265" class="elsevierStylePara elsevierViewall">Parkinsonism associated with <span class="elsevierStyleItalic">VPS13C</span> variants manifests early &#40;25&#8211;46&#8239;years of age&#41; and responds to levodopa&#46; However&#44; progression is particularly aggressive&#44; frequently with loss of treatment response&#44;<a class="elsevierStyleCrossRef" href="#bb0150"><span class="elsevierStyleSup">30</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bb0270"><span class="elsevierStyleSup">54</span></a> and some patients present motor fluctuations and dystonia&#46; Limb tremor&#44; axial symptoms&#44; cognitive impairment&#44; dysautonomia&#44; pyramidal signs&#44; and weakness are reported in 2&#47;3 patients&#46; The majority of patients are unable to leave bed by 15&#8239;years after symptom onset&#46;<a class="elsevierStyleCrossRef" href="#bb0270"><span class="elsevierStyleSup">54</span></a></p></span></span></span></span><span id="s0220" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0240">Conclusions</span><p id="p0270" class="elsevierStylePara elsevierViewall">The causal genes involved in recessive forms of parkinsonism participate in various pathways and cell processes fundamental to PD pathophysiology&#46; Specifically&#44; pathogenic <span class="elsevierStyleItalic">PRKN</span> and <span class="elsevierStyleItalic">PINK1</span> variants are associated with dysfunctional mitophagy&#46; Such other genes as <span class="elsevierStyleItalic">DJ-1</span>&#44; <span class="elsevierStyleItalic">PLA2G6</span>&#44; <span class="elsevierStyleItalic">VPS13C</span>&#44; and <span class="elsevierStyleItalic">ATP13A2</span> are related to mitochondrial homeostasis&#46; Others&#44; such as <span class="elsevierStyleItalic">DNAJC6</span>&#44; are involved in vesicle trafficking&#44; and especially endocytosis&#46; From a clinical perspective&#44; patients with <span class="elsevierStyleItalic">PRKN</span>-PD present a classical early-onset phenotype&#44; as do those with <span class="elsevierStyleItalic">PINK1</span>-PD and <span class="elsevierStyleItalic">DJ-1</span>&#8211;PD&#44; who rarely present atypical symptoms&#46; On the other hand&#44; the remaining genetic forms addressed in this review manifest with complex phenotypes and atypical characteristics including pyramidal signs&#44; dystonia &#40;constituting the so-called pallido-pyramidal syndrome&#41;&#44; ataxia&#44; myoclonus&#44; oculomotor alterations&#44; epilepsy&#44; and psychiatric disorders&#46; Establishing phenotype&#8211;genotype relationships and identifying the molecular pathways involved in autosomal recessive PD constitute the groundwork for advancing towards precision medicine&#46;</p></span><span id="s6075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st6135">Data protection</span><p id="p6340" class="elsevierStylePara elsevierViewall">The authors declare that no patient data appear in this article&#46;</p></span><span id="s6080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st6140">Funding</span><p id="p6345" class="elsevierStylePara elsevierViewall">This study has received no specific funding from any public&#44; commercial&#44; or non-profit organisation&#46;</p></span></span>"
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          "titulo" => "Introduction"
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          "titulo" => "Review"
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            0 => array:3 [
              "identificador" => "s0015"
              "titulo" => "Genes associated with autosomal recessive early-onset Parkinson&#39;s disease with typical manifestations"
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                  "identificador" => "s0020"
                  "titulo" => "PRKN"
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                      "titulo" => "Function of the parkin protein"
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                      "titulo" => "PRKN molecular mechanisms associated with Parkinson&#39;s disease"
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                      "titulo" => "PRKN-PD phenotype"
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              "identificador" => "s0090"
              "titulo" => "Genes associated with autosomal recessive Parkinson&#39;s disease with atypical phenotypes"
              "secciones" => array:5 [
                0 => array:3 [
                  "identificador" => "s0095"
                  "titulo" => "ATP13A2"
                  "secciones" => array:4 [
                    0 => array:2 [
                      "identificador" => "s0100"
                      "titulo" => "Function of the ATP13A2 protein"
                    ]
                    1 => array:2 [
                      "identificador" => "s0105"
                      "titulo" => "Molecular mechanisms associated with Parkinson&#39;s disease"
                    ]
                    2 => array:2 [
                      "identificador" => "s0110"
                      "titulo" => "ATP13A2 variants"
                    ]
                    3 => array:2 [
                      "identificador" => "s0115"
                      "titulo" => "ATP13A2-PD phenotype"
                    ]
                  ]
                ]
                1 => array:3 [
                  "identificador" => "s0120"
                  "titulo" => "Neurodegeneration with brain iron accumulation&#47;hereditary dystonia&#47;PLA2G6-PD"
                  "secciones" => array:4 [
                    0 => array:2 [
                      "identificador" => "s0125"
                      "titulo" => "Function of the phospholipase A2 group VI protein"
                    ]
                    1 => array:2 [
                      "identificador" => "s0130"
                      "titulo" => "Molecular mechanisms associated with Parkinson&#39;s disease"
                    ]
                    2 => array:2 [
                      "identificador" => "s0135"
                      "titulo" => "PLA2G6 variants"
                    ]
                    3 => array:2 [
                      "identificador" => "s0140"
                      "titulo" => "PLA2G6 parkinsonism phenotype"
                    ]
                  ]
                ]
                2 => array:3 [
                  "identificador" => "s0145"
                  "titulo" => "FBXO7"
                  "secciones" => array:4 [
                    0 => array:2 [
                      "identificador" => "s0150"
                      "titulo" => "Function of the FBXO7 protein"
                    ]
                    1 => array:2 [
                      "identificador" => "s0155"
                      "titulo" => "Molecular mechanisms associated with FBXO7 and Parkinson&#39;s disease"
                    ]
                    2 => array:2 [
                      "identificador" => "s0160"
                      "titulo" => "FBXO7 variants"
                    ]
                    3 => array:2 [
                      "identificador" => "s0165"
                      "titulo" => "FBXO7 parkinsonism phenotype"
                    ]
                  ]
                ]
                3 => array:3 [
                  "identificador" => "s0170"
                  "titulo" => "DNAJC6"
                  "secciones" => array:4 [
                    0 => array:2 [
                      "identificador" => "s0175"
                      "titulo" => "Function of the DNAJC6 protein"
                    ]
                    1 => array:2 [
                      "identificador" => "s0180"
                      "titulo" => "Molecular mechanisms associated with DNAJC6 and Parkinson&#39;s disease"
                    ]
                    2 => array:2 [
                      "identificador" => "s0185"
                      "titulo" => "DNAJC6 variants"
                    ]
                    3 => array:2 [
                      "identificador" => "s0190"
                      "titulo" => "DNAJC6 parkinsonism phenotype"
                    ]
                  ]
                ]
                4 => array:3 [
                  "identificador" => "s0195"
                  "titulo" => "VPS13C"
                  "secciones" => array:4 [
                    0 => array:2 [
                      "identificador" => "s0200"
                      "titulo" => "Function of the VPS13C protein"
                    ]
                    1 => array:2 [
                      "identificador" => "s0205"
                      "titulo" => "Molecular mechanisms associated with VPS13C and Parkinson&#39;s disease"
                    ]
                    2 => array:2 [
                      "identificador" => "s0210"
                      "titulo" => "VPS13C variants"
                    ]
                    3 => array:2 [
                      "identificador" => "s0215"
                      "titulo" => "VPS13C parkinsonism phenotype"
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
        6 => array:2 [
          "identificador" => "s0220"
          "titulo" => "Conclusions"
        ]
        7 => array:2 [
          "identificador" => "s6075"
          "titulo" => "Data protection"
        ]
        8 => array:2 [
          "identificador" => "s6080"
          "titulo" => "Funding"
        ]
        9 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2022-09-23"
    "fechaAceptado" => "2023-08-01"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1812709"
          "palabras" => array:6 [
            0 => "Parkinson&#39;s disease"
            1 => "Genetics"
            2 => "<span class="elsevierStyleItalic">PRKN</span>"
            3 => "<span class="elsevierStyleItalic">PINK1</span>"
            4 => "<span class="elsevierStyleItalic">DJ-1</span>"
            5 => "Autosomal recessive"
          ]
        ]
      ]
      "es" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1812708"
          "palabras" => array:6 [
            0 => "Enfermedad de Parkinson"
            1 => "gen&#233;tica"
            2 => "<span class="elsevierStyleItalic">PRKN</span>"
            3 => "<span class="elsevierStyleItalic">PINK1</span>"
            4 => "<span class="elsevierStyleItalic">DJ-1</span>"
            5 => "Autos&#243;mico Recesivo"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="as0005" class="elsevierStyleSection elsevierViewall"><p id="sp0020" class="elsevierStyleSimplePara elsevierViewall">The genes associated with autosomal recessive Parkinson&#39;s disease &#40;PD&#41; include the <span class="elsevierStyleItalic">PRKN</span>&#44; <span class="elsevierStyleItalic">PINK1</span>&#44; and <span class="elsevierStyleItalic">DJ-1</span> genes&#46; Homozygous and compound heterozygous carriers of pathogenic variants of these genes tend to display typical characteristics of PD at early ages&#46;</p><p id="sp0025" class="elsevierStyleSimplePara elsevierViewall">On the other hand&#44; the <span class="elsevierStyleItalic">ATP13A2</span>&#44; <span class="elsevierStyleItalic">FBXO7</span>&#44; <span class="elsevierStyleItalic">PLA2G6</span>&#44; <span class="elsevierStyleItalic">SYNJ1</span>&#44; and <span class="elsevierStyleItalic">DNAJC6</span> genes are associated with early-onset recessive forms that frequently present with pyramidal signs&#44; ataxia&#44; and oculomotor alterations&#44; with early appearance of levodopa-induced motor fluctuations and dyskinesia&#46; Such non-motor symptoms as depression&#44; psychiatric disorders&#44; hallucinations&#44; and epilepsy are also more frequent in this group&#46;</p><p id="sp0030" class="elsevierStyleSimplePara elsevierViewall">Among multiple molecular mechanisms involved in these cases&#44; key examples are the dysfunction of mitochondrial and lysosomal processes&#46;</p><p id="sp0035" class="elsevierStyleSimplePara elsevierViewall">This article presents a brief review intended to inform clinicians about the basic molecular mechanisms and phenotype&#8211;genotype relationship of these monogenic forms of PD&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="as0010" class="elsevierStyleSection elsevierViewall"><p id="sp0040" class="elsevierStyleSimplePara elsevierViewall">Los genes asociados a enfermedad de Parkinson &#40;EP&#41; de herencia mendeliana autos&#243;mica recesiva incluyen PRKN&#44; PINK1 y DJ-1&#46; Los individuos portadores homocigotos o heterocigotos compuestos de variantes patog&#233;nicas en estos genes tienden a manifestar caracter&#237;sticas t&#237;picas de la enfermedad de EP a edad temprana&#46;</p><p id="sp0045" class="elsevierStyleSimplePara elsevierViewall">Por otro lado&#44; los genes ATP13A2&#44; FBXO7&#44; PLA2G6&#44; SYNJ1&#44; y DNAJC6&#44; se asocian a formas recesivas de manifestaci&#243;n precoz&#44; presentan con frecuencia signos piramidales&#44; ataxia y alteraciones oculomotoras&#44; y desarrollan tempranamente&#44; fluctuaciones motoras y disquinesias inducidas por levodopa&#46; Alteraciones no motoras como depresi&#243;n&#44; alteraciones psiqui&#225;tricas&#44; alucinaciones y epilepsia son tambi&#233;n m&#225;s frecuentes en este grupo&#46;</p><p id="sp0050" class="elsevierStyleSimplePara elsevierViewall">Entre los m&#250;ltiples aspectos moleculares comprometidos en estos casos&#44; destacan la disfunci&#243;n de procesos mitocondriales y lisosomales&#46;</p><p id="sp0055" class="elsevierStyleSimplePara elsevierViewall">En este art&#237;culo presentamos una breve revisi&#243;n orientada al cl&#237;nico sobre los aspectos moleculares b&#225;sicos y relaci&#243;n fenotipo-genotipo de estas formas monog&#233;nicas de la EP&#46;</p></span>"
      ]
    ]
    "apendice" => array:1 [
      0 => array:1 [
        "seccion" => array:1 [
          0 => array:4 [
            "apendice" => "<p id="p0280" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="ec0005"></elsevierMultimedia></p>"
            "etiqueta" => "Appendix A"
            "titulo" => "Supplementary data"
            "identificador" => "s0225"
          ]
        ]
      ]
    ]
    "multimedia" => array:2 [
      0 => array:8 [
        "identificador" => "t0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "al0005"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">&#43;&#58; expected in this disease&#46; BIA&#58; brain iron accumulation&#59; FFF&#58; facial&#8211;faucial&#8211;finger&#59; LL&#58; lower limbs&#59; OA&#58; oculomotor apraxia&#59; OC&#58; oculogyric crises&#59; SP&#58; spastic paraparesis&#59; TEV&#58; talipes equinovarus&#59; VGP&#58; vertical gaze palsy&#46;</p><p id="sp0015" class="elsevierStyleSimplePara elsevierViewall">&#42;&#42;&#42; This table is based on the authors&#39; interpretation of the literature&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Gene&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">PRKN</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">PINK1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">DJ-1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">ATP13A2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">PLA2G6</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">FBXO7</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">DNAJC6</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">VPS13C</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Locus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PARK2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PARK6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PARK7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PARK9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PARK14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">PARK15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Early onset&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Juvenile onset&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Response to levodopa&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&#8764;50&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;<span class="elsevierStyleHsp" style=""></span>At onset&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;<span class="elsevierStyleHsp" style=""></span>At onset&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Motor fluctuations&#47;early dyskinesia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;<span class="elsevierStyleHsp" style=""></span>Early&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;<span class="elsevierStyleHsp" style=""></span>Early&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;<span class="elsevierStyleHsp" style=""></span>Early&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;<span class="elsevierStyleHsp" style=""></span>Early&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dystonia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;<span class="elsevierStyleHsp" style=""></span>LL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;<span class="elsevierStyleHsp" style=""></span>TEV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tremor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Postural instability&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pyramidal signs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;<span class="elsevierStyleHsp" style=""></span>SP phenotype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Neuropathy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ataxia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Myoclonus&#47;mini-myoclonus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;<span class="elsevierStyleHsp" style=""></span>FFF mini-myoclonus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Oculomotor alterations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;<span class="elsevierStyleHsp" style=""></span>VGP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;<span class="elsevierStyleHsp" style=""></span>OC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;<span class="elsevierStyleHsp" style=""></span>OA&#44; VGP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Epilepsy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Early-onset dementia&#47;intellectual disability&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Severe neuropsychiatric disorders&#47;early-onset psychosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;<span class="elsevierStyleHsp" style=""></span>Psychosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;<span class="elsevierStyleHsp" style=""></span>Psychosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Autonomic dysfunction&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;<span class="elsevierStyleHsp" style=""></span>Early&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;<span class="elsevierStyleHsp" style=""></span>Early&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Early dysarthria&#47;dysphagia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;<span class="elsevierStyleHsp" style=""></span>Anarthria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Abnormal neuroimaging findings&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;<span class="elsevierStyleHsp" style=""></span>Atrophy&#44; BIA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#43;<span class="elsevierStyleHsp" style=""></span>Cerebellar atrophy&#44; BIA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "identificador" => "bs0005"
          "bibliografiaReferencia" => array:54 [
            0 => array:3 [
              "identificador" => "bb0005"
              "etiqueta" => "1&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Epidemiological&#44; clinical&#44; and genetic characteristics of early-onset parkinsonism"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "A&#46; Schrag"
                            1 => "J&#46;M&#46; Schott"
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                    0 => array:2 [
                      "doi" => "10.1016/S1474-4422(06)70411-2"
                      "Revista" => array:7 [
                        "tituloSerie" => "Lancet Neurol"
                        "fecha" => "2006"
                        "volumen" => "5"
                        "numero" => "4"
                        "paginaInicial" => "355"
                        "paginaFinal" => "363"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16545752"
                            "web" => "Medline"
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              "identificador" => "bb0010"
              "etiqueta" => "2&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "T&#46; Kitada"
                            1 => "S&#46; Asakawa"
                            2 => "N&#46; Hattori"
                            3 => "H&#46; Matsumine"
                            4 => "Y&#46; Yamamura"
                            5 => "S&#46; Minoshima"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/33416"
                      "Revista" => array:7 [
                        "tituloSerie" => "Nature&#46;"
                        "fecha" => "1998"
                        "volumen" => "392"
                        "numero" => "6676"
                        "paginaInicial" => "605"
                        "paginaFinal" => "608"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9560156"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
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            ]
            2 => array:3 [
              "identificador" => "bb0015"
              "etiqueta" => "3&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hereditary early-onset Parkinson&#39;s disease caused by mutations in PINK1"
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Article information

ISSN: 26670496
Original language: English

DOI:10.1016/j.neurop.2024.100147

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