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Fuente: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred Reporting Items For Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med. 2009;6:e1000097. doi:10.1371/journal.pmed1000097.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Ignacio Santandreu-Morales, Eduardo Redondo-Cerezo, David Martín-Enguix" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Ignacio" "apellidos" => "Santandreu-Morales" ] 1 => array:2 [ "nombre" => "Eduardo" "apellidos" => "Redondo-Cerezo" ] 2 => array:2 [ "nombre" => "David" "apellidos" => "Martín-Enguix" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2387020623000566" "doi" => "10.1016/j.medcle.2022.11.003" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020623000566?idApp=UINPBA00004N" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775322005607?idApp=UINPBA00004N" "url" => "/00257753/0000016000000005/v3_202304070253/S0025775322005607/v3_202304070253/es/main.assets" ] "en" => array:17 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Special article</span>" "titulo" => "Follow-up regimens for carriers of hereditary transthyretin variants" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "213" "paginaFinal" => "217" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Inés Asunción Losada-López, Solange Kapetanovic-García, Teresa Sevilla-Mantecón, Francisco Muñoz-Beamud" "autores" => array:4 [ 0 => array:4 [ "nombre" => "Inés Asunción" "apellidos" => "Losada-López" "email" => array:1 [ 0 => "ialosada@hsll.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff1" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Solange" "apellidos" => "Kapetanovic-García" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Teresa" "apellidos" => "Sevilla-Mantecón" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "Francisco" "apellidos" => "Muñoz-Beamud" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Internal Medicine Service, Hospital Universitario Son Llátzer, Palma, Spain; Balearic Research Group in Genetic Cardiopathies, Sudden Death and TTR Amyloidosis, Instituto de Investigación Sanitaria de las Islas Baleares (IdISBa), Palma, Spain" "etiqueta" => "a" "identificador" => "aff1" ] 1 => array:3 [ "entidad" => "Unidad de ELA y neuromuscular, Hospital Universitario Basurto, Bilbao, Spain" "etiqueta" => "b" "identificador" => "aff0005" ] 2 => array:3 [ "entidad" => "Hospital Universitari i Politècnic La Fe & IIS La Fe, Neuromuscular Diseases Unit, Department of Neurology, Valencia, Spain; Universitat de València, Valencia, Spain; Biomedical Research Network Center in Rare Diseases (CIBERER); Member of the European Reference Network for Rare Neuromuscular Diseases (ERN EURO-NMD), Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Facultativo Especialista de Área de Medicina Interna, Unidad de Enfermedades Autoinmunes, Minoritarias y Trombosis, Coordinador Unidad Multidisciplinar de Amiloidosis Hereditaria, Servicio de Medicina Interna, Hospital Juan Ramón Jiménez, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Seguimiento de portadores asintomáticos de variantes hereditarias de la transtirretina" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1555 "Ancho" => 2341 "Tamanyo" => 260233 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Follow-up strategy for TTR variant carriers. COMPASS-31: Composite Autonomic Symptom Score-31; Norfolk QOL-DN: Norfolk Quality of Life-Diabetic Neuropathy; QST: quantitative sensory thermotest; SSR: sympathetic skin response (SSR).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Hereditary transthyretin (ATTRv) amyloidosis is a rare and fatal disease caused by misfolded transthyretin (TTR) variants, which are deposited as amyloid fibrils in multiple tissues and organs, including the nerves and heart.<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">1,2</span></a> This multisystem disease exhibits a wide range of clinical manifestations, including peripheral neuropathy, autonomic dysfunction, gastrointestinal manifestations, ocular impairment, nephropathy, and/or cardiomyopathy.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">More than 120 different variants have been described in the <span class="elsevierStyleItalic">TTR</span> gene, with the Val50Met (V50M) variant the most prevalent worldwide and the most common in endemic regions.<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">2–4</span></a> The disease severity and life expectancy of patients with ATTRv amyloidosis depend on the type of <span class="elsevierStyleItalic">TTR</span> variant, with some, such as T60A, S77Y, I107V, and late-onset V30M, associated with worse prognosis.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Although some <span class="elsevierStyleItalic">TTR</span> variants are associated with predominantly neurological or predominantly cardiac phenotypes, many variants present with mixed phenotypes of both polyneuropathy and cardiomyopathy or as a completely systemic disease.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">3</span></a> In addition, the clinical phenotype may differ among carriers of the same <span class="elsevierStyleItalic">TTR</span> variant based on geographical origin, variant penetrance, age at onset, and epigenetic factors.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">2</span></a> Therefore, the highly heterogeneous and multisystemic nature of the disease poses a diagnostic challenge.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">1</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The identification of an index patient with this autosomal dominant disorder should be followed by genetic testing to detect other family members who have inherited the pathogenic <span class="elsevierStyleItalic">TTR</span> variant. Any asymptomatic <span class="elsevierStyleItalic">TTR</span> variant carriers should then be monitored to ensure the early diagnosis of ATTRv amyloidosis in a multidisciplinary unit.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">5</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Newly approved TTR-stabilizing and <span class="elsevierStyleItalic">TTR</span> gene-silencing therapies can modify the course of this rapidly progressive disease but are more effective in early disease stages.<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">6–8</span></a> This illustrates the importance of appropriate follow-up approaches for asymptomatic <span class="elsevierStyleItalic">TTR</span> variant carriers that enable the identification of the earliest detectable sign or symptom and the implementation of timely interventions to prevent or at least delay disease progression. However, the development of standardized guidelines for the follow-up of asymptomatic <span class="elsevierStyleItalic">TTR</span> variant carriers is hampered by the heterogeneity of genotypes/phenotypes, the reduced penetrance of some <span class="elsevierStyleItalic">TTR</span> variants, the anticipation phenomenon, and the incomplete understanding of the factors contributing to the variability of disease onset in <span class="elsevierStyleItalic">TTR</span> variant carriers.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Furthermore, the right time for treatment initiation in individuals without symptoms of neuropathy or cardiomyopathy remains to be defined. There is thus a need for a consensus on the minimum criteria for treatment initiation in <span class="elsevierStyleItalic">TTR</span> variant carriers who are exhibiting the first manifestations of ATTRv amyloidosis.</p><p id="par0035" class="elsevierStylePara elsevierViewall">In this publication, we provide an overview of the current methods for evaluating ATTRv amyloidosis development and present advice on the follow-up regimens for the early diagnosis and timely treatment of <span class="elsevierStyleItalic">TTR</span> variant carriers with the initial manifestations of ATTRv amyloidosis.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Methodology</span><p id="par0040" class="elsevierStylePara elsevierViewall">Key opinion leaders in ATTRv amyloidosis met to discuss the current strategies for the follow-up of <span class="elsevierStyleItalic">TTR</span> variant carriers and define the minimum set of clinical findings for confirming the onset of symptomatic disease and the need for treatment. Based on a literature review and the clinical experience of the experts, this publication provides guidance on the optimal frequency of follow-up of <span class="elsevierStyleItalic">TTR</span> variant carriers and the most appropriate tests. The aim is to outline the most useful tests for the early diagnosis of ATTRv amyloidosis in previously identified <span class="elsevierStyleItalic">TTR</span> variant carriers, define the clinical thresholds confirming the onset of symptomatic disease, and achieve consensus on the clinical findings indicating the right time to initiate treatment for the optimal clinical outcome.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Results</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Identification of asymptomatic <span class="elsevierStyleItalic">TTR</span> variant carriers</span><p id="par0045" class="elsevierStylePara elsevierViewall">After the diagnosis of an index patient with ATTRv amyloidosis, a phylogenetic study should be conducted to identify family members at risk of having also inherited the <span class="elsevierStyleItalic">TTR</span> variant. Genetic testing to identify asymptomatic <span class="elsevierStyleItalic">TTR</span> variant carriers should then be offered to at-risk relatives from the age of 18 onward.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">9</span></a> Because the symptoms of ATTRv amyloidosis do not usually appear until late adulthood and there is no preventive treatment, genetic testing is not recommended in people under the age of 18 years to avoid emotional distress in <span class="elsevierStyleItalic">TTR</span> variant carriers.<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">9,10</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Follow-up of asymptomatic <span class="elsevierStyleItalic">TTR</span> variant carriers</span><p id="par0050" class="elsevierStylePara elsevierViewall">The identification of asymptomatic <span class="elsevierStyleItalic">TTR</span> variant carriers at risk of developing ATTRv amyloidosis allows the establishment of regular follow-up regimens for the early diagnosis of active disease, prompting early treatment initiation. During the first follow-up visit, <span class="elsevierStyleItalic">TTR</span> variant carriers should be informed of the nature and symptoms of the disease. The education of <span class="elsevierStyleItalic">TTR</span> variant carriers is crucial to facilitate the early recognition of certain symptoms that otherwise might not be associated with the disease. Genetic counseling should be offered at the first visit. Patients’ degree of understanding and acceptance of being a carrier of a pathogenic <span class="elsevierStyleItalic">TTR</span> variant should be evaluated.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">9</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Because ATTRv amyloidosis is a multisystem disease, the periodic follow-up of assessments should be performed by a multidisciplinary team and should cover the diverse signs and symptoms of the disease onset.<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">5,10</span></a> Importantly, the baseline for the follow-up tests and investigations should be established once asymptomatic <span class="elsevierStyleItalic">TTR</span> variant carriers are identified to have a reference value for successive assessments.</p><p id="par0060" class="elsevierStylePara elsevierViewall">The differences in the initial manifestations observed among specific <span class="elsevierStyleItalic">TTR</span> variants, and even within the same variant depending on the geographical origin, have led to the establishment of different follow-up approaches for <span class="elsevierStyleItalic">TTR</span> variant carriers that aim to identify the earliest signs and symptoms of disease onset. For instance, the early-onset V50M variant is the most common variant in endemic areas and is more frequently associated with sensorimotor and autonomic neuropathy.<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">1,10</span></a> Hence, follow-up strategies in endemic areas should consider small-fiber and autonomic neuropathies because they often appear as one of the first signs of active disease.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">5</span></a> In contrast, the autonomic symptoms associated with the V50M variant and late-onset ATTRv amyloidosis are mild and generally appear later in the course of the disease.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">1</span></a> Many other non-V50M variants are associated with mixed phenotypes involving both cardiac and neurological impairment, whereas other less represented non-V50M variants such as V122I, T60A, L111M, and I68L are associated with cardiac impairment as the predominant phenotype; although, evidence is emerging to suggest many of these patients also experience neuropathy symptoms. Thus, tailored follow-up approaches for <span class="elsevierStyleItalic">TTR</span> variant carriers should be based on the clinical phenotype associated with their specific <span class="elsevierStyleItalic">TTR</span> variant and the clinical findings at disease onset to identify the earliest manifestation of active ATTRv amyloidosis.</p><p id="par0065" class="elsevierStylePara elsevierViewall">Follow-up assessments should mainly evaluate neuropathy, autonomic dysfunction, cardiovascular impairment, ocular manifestations, and renal dysfunction. However, the systemic nature of the disease should always be taken into account.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">11</span></a> Therefore, the first tool is a structured medical anamnesis asking about red flag symptoms. A clinical questionnaire such as the Small-fiber Neuropathy-Symptom Inventory Questionnaire (SFN-SIQ) could be also useful to evaluate neuropathic symptoms.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Neurological evaluation</span><p id="par0070" class="elsevierStylePara elsevierViewall">Because no specific biomarkers of ATTRv amyloidosis with polyneuropathy have been described, the neurological evaluation should include various tests and investigations. The Neuropathy Impairment Score (NIS) is a composite score of polyneuropathy that combines different measurements, such as weakness, reflexes, and sensation.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">12</span></a> An increase in the NIS score from baseline could be indicative of the development and progression of ATTRv amyloidosis polyneuropathy. Along with the NIS, the neurological assessments should evaluate the changes in nerve conduction studies, which confirm the onset of neuropathic manifestations.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">13</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Small-fiber neuropathy, which may affect both somatic and autonomic fibers, could be the first sign of the disease. Therefore, its evaluation is crucial mainly in early onset V50M ATTRv amyloidosis. Due to the low sensitivity and specificity of the different test available for the diagnosis of small fiber neuropathy, several tests must be conducted for its diagnosis.<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">14,15</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Orthostatic blood pressure and heart rate variability (R–R interval) are common methods for assessing autonomic function.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">16</span></a> Orthostatic hypotension, which is defined as a drop of 20<span class="elsevierStyleHsp" style=""></span>mmHg or more in systolic blood pressure or 10<span class="elsevierStyleHsp" style=""></span>mmHg or more in diastolic blood pressure upon standing,<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">17,18</span></a> and the diminished variability of heart rate R–R intervals in the electrocardiogram are indicative of cardiac autonomic dysfunction in ATTRv amyloidosis.<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">2,17</span></a> The sensitivities of the R–R interval and the orthostatic hypotension test are both 80%.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">19</span></a> Other tests, such as the Sudoscan®, sympathetic skin response (SSR), and the quantitative sensory thermotest (QST) should also be performed if available. Both the Sudoscan® and SSR assess sympathetic cholinergic sudomotor function, which is one of the earliest indicators of distal small-fiber neuropathy.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">20</span></a> The Sudoscan® measures the electrochemical skin conductance, which depends on sweat chloride production and may be reduced in individuals with sudomotor dysfunction.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">20</span></a> The SSR is based on changes in the skin potential caused by sweat glands after the application of a stimulus, whereas the QST measures sensitivity to thermal stimuli.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">15</span></a> The sensitivities of the Sudoscan and QST are 60% and 80%, respectively.<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">15,20,21</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Based on the literature, several different small-fiber neuropathy tests can be performed, depending on hospital availability.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Patient self-rating questionnaires</span><p id="par0090" class="elsevierStylePara elsevierViewall">Patient questionnaires are a useful tool for understanding the development and progression of neuropathic symptoms and should always be completed during annual visits. For instance, the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) is a 35-item, self-rating questionnaire that can be used to assess the progression of polyneuropathy and its impact on quality of life.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">22</span></a> The Norfolk QOL-DN score is based on the evaluation of symptoms, activities of daily living, and small-fiber, large-fiber, and autonomic neuropathies. An increase in the score indicates a worsening condition; the maximum impairment score is 136 points.</p><p id="par0095" class="elsevierStylePara elsevierViewall">The Composite Autonomic Symptom Score (COMPASS-31) is another self-rating questionnaire that should be completed by <span class="elsevierStyleItalic">TTR</span> variant carriers during follow-up. This 31-item questionnaire was designed to evaluate symptoms of autonomic dysfunction, which usually occurs at early stages of ATTRv amyloidosis before motor impairment.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">16</span></a> With a maximum impairment score of 100 points, an increase in the COMPASS-31 score indicates progression of autonomic impairment in <span class="elsevierStyleItalic">TTR</span> variant carriers.</p><p id="par0100" class="elsevierStylePara elsevierViewall">Other self-rating questionnaires validated for ATTRv amyloidosis could also be performed. However, those mentioned above, are the ones most commonly used in clinical trials.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Cardiac evaluation</span><p id="par0105" class="elsevierStylePara elsevierViewall">Cardiovascular function should be assessed by electrocardiography (ECG), Holter ECG, and echocardiography, along with analysis of the plasma levels of both N-terminal pro-B-type natriuretic peptide (NT-proBNP) and troponin. Whereas ECG and Holter ECG allow the detection of rhythm and disturbances, echocardiography assesses cardiac structure and function. ECG is also used to evaluate heart rate variability (R–R interval).<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">23,24</span></a> In the presence of abnormal results, cardiovascular impairment should be further evaluated by nuclear scintigraphy and cardiac magnetic resonance imaging, which may provide more detailed information on cardiac morphology and function.<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">23,24</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Ophthalmological and renal assessments</span><p id="par0110" class="elsevierStylePara elsevierViewall">Ophthalmological assessments are important because ocular complications, such as dry eye, vitreous deposits, and secondary glaucoma, are common manifestations of ATTRv amyloidosis.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">1</span></a> Such examinations should particularly be considered in carriers of the V50M variant, in whom ocular impairment may develop, although infrequently, at disease onset.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">1</span></a> Similarly, assessment of renal function by serum creatinine, glomerular filtration rate, and urinary microalbumin should be considered in <span class="elsevierStyleItalic">TTR</span> variant carriers at risk of developing renal impairment. Importantly, microalbuminuria can precede the onset of neuropathy<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">1</span></a> and may be a useful indicator for the early detection of disease onset. Structural follow-up is presented in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Minimum criteria for the diagnosis and treatment of ATTRv amyloidosis</span><p id="par0115" class="elsevierStylePara elsevierViewall">Because novel therapies for ATTRv amyloidosis are most effective at early disease stages, the follow-up of <span class="elsevierStyleItalic">TTR</span> variant carriers should aim to detect the first detectable sign or symptom of disease. Whereas a clinical approach to establish the onset of ATTRv amyloidosis in <span class="elsevierStyleItalic">TTR</span> variant carriers has recently been published,<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">10</span></a> the minimum criteria for treatment initiation are less well defined.</p><p id="par0120" class="elsevierStylePara elsevierViewall">According to the proposed diagnostic approach, the onset of symptomatic ATTRv amyloidosis in <span class="elsevierStyleItalic">TTR</span> variant carriers can be established in the presence of at least one symptom or sign definitely related to disease onset, including sensory loss, spontaneous and evoked pain, alternating episodes of constipation/diarrhea, orthostatic syncope, unintentional weight loss, dyspnea, orthopnea, or syncope.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">10</span></a> Alternatively, disease onset should be established when two abnormal test results are found in the absence of symptoms or when one abnormal test result is found in the presence of at least one potential symptom of disease onset, including nonpainful sensations (e.g., paresthesia and restless leg syndrome), early satiety, dizziness, palpitations, episodes of diarrhea, or leg edema.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">10</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">However, because TTR stabilizers and <span class="elsevierStyleItalic">TTR</span> gene silencers are prescribed for the treatment of polyneuropathy and cardiomyopathy in patients with ATTRv amyloidosis, treatment initiation in the absence of symptoms may be difficult to justify. We thus first need to define the key signs and symptoms of the clinical presentation of polyneuropathy, which can affect both large and small nerve fibers. Whereas large-fiber polyneuropathy can be easily detected by electromyography with nerve conduction studies, small-fiber damage is difficult to assess due to the lack of a specific and sensitive test for the diagnosis of small-fiber neuropathy. We therefore propose that polyneuropathy be diagnosed in the presence of symptoms of large- or small-fiber neuropathy or autonomic dysfunction along with abnormal nerve conduction studies compatible with large-fiber neuropathy or with at least three abnormal results from the small-fiber tests (Sudoscan, R–R interval, QST, and SSR).</p><p id="par0130" class="elsevierStylePara elsevierViewall">On the other hand, the diagnosis of amyloid cardiomyopathy in ATTRv amyloidosis patients should also be defined to enable the prompt initiation of treatment in those countries where is it available. For the diagnosis of ATTRv amyloidosis cardiomyopathy, patients must be a carrier of a <span class="elsevierStyleItalic">TTR</span> gene variant and have negative serum free light chains and negative serum and urine immunofixation, the presence of cardiac ultrasound or magnetic resonance neurography (MRN) criteria for amyloid cardiomyopathy, and either a positive cardiac biopsy or a positive grade 2 or 3 cardiac bisphosphonate scintigraphy. Moreover, the diagnosis can be established in the presence of a positive amyloid extracardiac biopsy and cardiac ultrasound or MRN criteria for amyloid cardiomyopathy.</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Discussion</span><p id="par0135" class="elsevierStylePara elsevierViewall">Despite the lack of prophylactic treatment for preventing ATTRv amyloidosis development, the identification of asymptomatic <span class="elsevierStyleItalic">TTR</span> variant carriers by genetic testing allows regular follow-up and offers the possibility of an early diagnosis that ensures timely interventions for optimal outcomes.</p><p id="par0140" class="elsevierStylePara elsevierViewall">After genetic testing identifies a pathogenic <span class="elsevierStyleItalic">TTR</span> variant in an asymptomatic carrier, the clinical phenotype associated with the specific variant and the family history should be considered to determine the most appropriate follow-up strategy. The baseline for the periodic tests and investigations should be properly established to detect changes from baseline with regular follow-up.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">10</span></a> In addition, <span class="elsevierStyleItalic">TTR</span> variant carriers should be informed about all potential signs and symptoms of ATTRv amyloidosis to facilitate their rapid recognition and the early identification of disease onset.</p><p id="par0145" class="elsevierStylePara elsevierViewall">Typically, follow-up visits are scheduled on an annual basis, although the monitoring frequency should be adapted according to the typical progression of the specific <span class="elsevierStyleItalic">TTR</span> variant and the family history. For instance, more intensive follow-up is required for <span class="elsevierStyleItalic">TTR</span> variants with high penetrance and rapid progression rates.</p><p id="par0150" class="elsevierStylePara elsevierViewall">Annual follow-up assessments of the neurological function of <span class="elsevierStyleItalic">TTR</span> variant carriers should include clinical history, physical examination, and a clinical questionnaire, along with the NIS test, which has proved useful to detect polyneuropathy over a broad range of clinical manifestations and severities.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">12</span></a> Nerve conduction studies, which can detect a decreased amplitude of sensory nerve action potentials before the development of neurological symptoms, should be performed every year or every other year.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">13</span></a> Autonomic function should also be evaluated annually using the orthostatic hypotension test.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">10</span></a> During the annual follow-up visits, <span class="elsevierStyleItalic">TTR</span> variant carriers should complete the Norfolk QOL-DN and COMPASS-31 self-rating questionnaires, which provide further clues for early diagnoses or for the detection of disease progression.</p><p id="par0155" class="elsevierStylePara elsevierViewall">In addition to the NIS, other neurophysiological tests should be applied to ensure the often challenging early diagnosis of small-fiber neuropathy.<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">25</span></a> We propose the use of the Sudoscan test because it provides a simple and noninvasive approach to sudomotor function.<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">25</span></a> Moreover, we suggest that the QST and the R–R interval and the SSR tests be performed. We thus propose inclusion of the NIS and the small fiber neuropathy test in the baseline screening. If no alterations are found, in-depth assessments of neuropathic function can be performed every 2 years to avoid unnecessary distress to asymptomatic <span class="elsevierStyleItalic">TTR</span> variant carriers.</p><p id="par0160" class="elsevierStylePara elsevierViewall">The frequency of cardiac assessments may vary depending on the specific <span class="elsevierStyleItalic">TTR</span> variant and the expected clinical phenotype. In endemic areas where early-onset V50M is the main variant and the neuropathic phenotype predominates, cardiac evaluation of <span class="elsevierStyleItalic">TTR</span> variant carriers with cardiac ultrasound and Holter ECG can be performed every 2–3 years if the baseline assessment is normal, with ECG being performed at every visit. However, in nonendemic areas with genetic heterogeneity, in-depth assessment of the cardiac function of <span class="elsevierStyleItalic">TTR</span> variant carriers should be performed annually, especially when they carry variants associated with a more predominant cardiac phenotype.<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">24</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">In the absence of signs and symptoms of ATTRv amyloidosis, the presence of two abnormal test results is the minimum criterion to establish disease onset according to the consensual approach published by Conceição et al.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">10</span></a> However, these two abnormal findings may be insufficient to justify treatment initiation in the absence of other symptoms. There is therefore a need for a consensus on the minimal evidence of neurological impairment defining the need for treatment to facilitate treatment decision-making. We propose that treatment begin immediately as indicated above. The quantification of nerve fibers by skin biopsy can also be used to confirm small-fiber neuropathy because it provides pathological evidence of small-fiber damage<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">25</span></a>; its sensitivity is 88–90% and its specificity is 89–97%.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">21</span></a> However, skin biopsy is not widely available, which, along with the invasive nature of the technique, limits its application. Other new screening tools may contribute to the diagnostic work-up. For instance, corneal confocal microscopy can identify a reduced corneal nerve fiber length, which correlates with autonomic small-fiber neuropathy<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">26</span></a>; however, this non-invasive imaging technique is only available in some laboratories. Furthermore, the development of new diagnostic tools to improve the diagnosis of small-fiber damage should help physicians to diagnose polyneuropathy at the initial stages, leading to early interventions capable of modifying the course of the ATTRv amyloidosis.</p><p id="par0170" class="elsevierStylePara elsevierViewall">As has already been reported, we recommend a combination of autonomic tests in a screening battery for the diagnosis of autonomic neuropathy.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">10</span></a> This permits a more accurate measurement of autonomic function.</p><p id="par0175" class="elsevierStylePara elsevierViewall">Moreover, regarding amyloid cardiomyopathy we also propose that treatment begins immediately after the diagnosis, as discussed previously<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">24</span></a>; however, treatment in this setting is only available in some countries.</p><p id="par0180" class="elsevierStylePara elsevierViewall">The performance of a tissue biopsy for identifying amyloid deposits is not routinely recommended in the follow up of asymptomatic carriers of the genetic mutations associated with ATTRv amyloidosis.<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">27</span></a> It has a sensitivity of 60–80% for amyloid detection and its results vary highly depending on the pathologist's experience and expertise. Moreover, it is invasive and time consuming, and a negative result does not exclude the diagnosis of amyloidosis<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">27</span></a> while a positive one does not necessarily determine a specific treatment choice.</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusions</span><p id="par0185" class="elsevierStylePara elsevierViewall">Given the advent of novel ATTRv amyloidosis treatment options able to slow or reverse disease progression,<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">1,3,4</span></a> the follow-up of asymptomatic <span class="elsevierStyleItalic">TTR</span> variant carriers should be aimed at detecting the initial manifestation of the disease and at promoting early treatment initiation for optimal clinical outcomes. Hence, the design and frequency of the follow-up regimens should consider the specific <span class="elsevierStyleItalic">TTR</span> variant and the family history to ensure detection of the earliest sign or symptom of disease onset.</p><p id="par0190" class="elsevierStylePara elsevierViewall">Minimum criteria to establish the onset of symptomatic ATTRv amyloidosis in the absence of signs and symptoms of active disease may be insufficient to justify treatment initiation. Treatment decision-making should be based on the existence of polyneuropathy, which, in the presence of symptoms, should be established when nerve conduction studies are altered or when at least three abnormal findings are found among the follow-up tests assessing small-fiber/dysautonomic neuropathy.</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Funding</span><p id="par0195" class="elsevierStylePara elsevierViewall">This study was funded by Alnylam Pharmaceuticals Spain S.L. Editorial support was provided by Kevin Clayton and Josep Solanes (blueBOARD), funded by Alnylam Pharmaceuticals Spain S.L.</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conflict of interest</span><p id="par0200" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Inés Losada</span> has received research grants and honoraria as speaker from Alnylam, Pfizer and Sobi.</p><p id="par0205" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Solange Kapetanovic-García</span> declares that she does not have known competing financial interests.</p><p id="par0210" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Teresa Sevilla-Mantecón</span> declares that she does not have known competing financial interests.</p><p id="par0215" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Francisco Muñoz-Beamud</span> has received research grants and honoraria as speaker and advisor from Alnylam, Pfizer, and Sobi.</p><p id="par0220" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Lucía Galán-Dávila</span> has received honoraria as advisor and speaker from Alnylam, Akcea, Sobi, and Pfizer.</p><p id="par0225" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Carlos Casasnovas-Pons</span> declares that he does not have known competing financial interests.</p><p id="par0230" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Marta de Andrés-Dosouto</span> is a full-time employee of Alnylam and holds stock and/or stock options.</p><p id="par0235" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">María García-Álvaro</span> is a full-time employee of Alnylam and holds stock and/or stock options.</p><p id="par0240" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Manuel Romero-Acebal</span> has received research grants and honoraria as speaker and advisor from Alnylam and Pfizer.</p><p id="par0245" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Ferran Martínez-Valle</span> has received travel bursaries and sponsored talks from Alnylam and Pfizer.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Methodology" ] 2 => array:3 [ "identificador" => "sec0015" "titulo" => "Results" "secciones" => array:7 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Identification of asymptomatic TTR variant carriers" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Follow-up of asymptomatic TTR variant carriers" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Neurological evaluation" ] 3 => array:2 [ "identificador" => "sec0035" "titulo" => "Patient self-rating questionnaires" ] 4 => array:2 [ "identificador" => "sec0040" "titulo" => "Cardiac evaluation" ] 5 => array:2 [ "identificador" => "sec0045" "titulo" => "Ophthalmological and renal assessments" ] 6 => array:2 [ "identificador" => "sec0050" "titulo" => "Minimum criteria for the diagnosis and treatment of ATTRv amyloidosis" ] ] ] 3 => array:2 [ "identificador" => "sec0055" "titulo" => "Discussion" ] 4 => array:2 [ "identificador" => "sec0060" "titulo" => "Conclusions" ] 5 => array:2 [ "identificador" => "sec0065" "titulo" => "Funding" ] 6 => array:2 [ "identificador" => "sec0070" "titulo" => "Conflict of interest" ] 7 => array:2 [ "identificador" => "xack660143" "titulo" => "Acknowledgements" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2022-04-12" "fechaAceptado" => "2022-10-18" "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1555 "Ancho" => 2341 "Tamanyo" => 260233 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Follow-up strategy for TTR variant carriers. COMPASS-31: Composite Autonomic Symptom Score-31; Norfolk QOL-DN: Norfolk Quality of Life-Diabetic Neuropathy; QST: quantitative sensory thermotest; SSR: sympathetic skin response (SSR).</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:27 [ 0 => array:3 [ "identificador" => "bib0140" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "D. Adams" 1 => "H. Koike" 2 => "M. Slama" 3 => "T. 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Barcelona), Marta de Andrés (Alnylam Pharmaceuticals Spain S.L.) and María García-Álvaro (Alnylam Pharmaceuticals Spain S.L.).</p>" "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/00257753/0000016000000005/v3_202304070253/S0025775322005310/v3_202304070253/en/main.assets" "Apartado" => array:4 [ "identificador" => "64288" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Artículo especial" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/00257753/0000016000000005/v3_202304070253/S0025775322005310/v3_202304070253/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0025775322005310?idApp=UINPBA00004N" ]
Journal Information
Special article
Follow-up regimens for carriers of hereditary transthyretin variants
Seguimiento de portadores asintomáticos de variantes hereditarias de la transtirretina
Inés Asunción Losada-Lópeza,
, Solange Kapetanovic-Garcíab, Teresa Sevilla-Mantecónc, Francisco Muñoz-Beamudd
Corresponding author
a Internal Medicine Service, Hospital Universitario Son Llátzer, Palma, Spain; Balearic Research Group in Genetic Cardiopathies, Sudden Death and TTR Amyloidosis, Instituto de Investigación Sanitaria de las Islas Baleares (IdISBa), Palma, Spain
b Unidad de ELA y neuromuscular, Hospital Universitario Basurto, Bilbao, Spain
c Hospital Universitari i Politècnic La Fe & IIS La Fe, Neuromuscular Diseases Unit, Department of Neurology, Valencia, Spain; Universitat de València, Valencia, Spain; Biomedical Research Network Center in Rare Diseases (CIBERER); Member of the European Reference Network for Rare Neuromuscular Diseases (ERN EURO-NMD), Spain
d Facultativo Especialista de Área de Medicina Interna, Unidad de Enfermedades Autoinmunes, Minoritarias y Trombosis, Coordinador Unidad Multidisciplinar de Amiloidosis Hereditaria, Servicio de Medicina Interna, Hospital Juan Ramón Jiménez, Spain