Letter to the Editor
A Spanish family with a compound heterozygous mutation in SPG7: From uncertainty to clinical reality
Familia española portadora de una mutación en heterocigosis compuesta en el gen SPG7: de la incertidumbre a la realidad clínica
M.C. Fernández-Morenoa,
, C. Castro-Fernándezb, M.M. Viloria-Peñasc, L. Castilla-Guerrad
Corresponding author
a Servicio de Neurología, Hospital Universitario Virgen de Valme, Universidad de Sevilla, Sevilla, Spain
b Grupo Neurogenetica, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, La Coruña, Spain
c Servicio de Bioquímica Clínica, Hospital Universitario Virgen de Valme, Sevilla, Spain
d Servicio de Medicina Interna, Hospital Universitario Virgen Macarena, Universidad de Sevilla, Sevilla, Spain
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"apellidos" => "Castilla-Guerra" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Servicio de Neurología, Hospital Universitario Virgen de Valme, Universidad de Sevilla, Sevilla, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Grupo Neurogenetica, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, La Coruña, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Servicio de Bioquímica Clínica, Hospital Universitario Virgen de Valme, Sevilla, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Servicio de Medicina Interna, Hospital Universitario Virgen Macarena, Universidad de Sevilla, Sevilla, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Familia española portadora de una mutación en heterocigosis compuesta en el gen <span class="elsevierStyleItalic">SPG7</span>: de la incertidumbre a la realidad clínica" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 654 "Ancho" => 750 "Tamanyo" => 55530 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">T1-weighted sagittal brain MRI scan showing cerebellar atrophy.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Spastic paraplegia type 7 (SPG7; OMIM #607259) is an autosomal recessive disorder caused by mutations in the <span class="elsevierStyleItalic">SPG7</span> gene, which encodes the mitochondrial metalloprotease paraplegin.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> It accounts for approximately 5%-12% of all autosomal recessive forms and up to 7% of sporadic cases in adults. It has also been associated with symptoms of cerebellar ataxia,<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> which may constitute the most relevant clinical manifestation. However, phenotypic variations are more complex; the literature includes cases of chronic progressive external ophthalmoplegia,<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> primary lateral sclerosis,<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> and parkinsonism.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Over 131 pathogenic variants have been described (Human Gene Mutation Database, accessed 14 July 2019). We report the cases of 3 sisters from a Spanish family, who presented ataxia and spasticity and were carriers of 2 single nucleotide variants of uncertain significance in the <span class="elsevierStyleItalic">SPG7</span> gene.</p><p id="par0015" class="elsevierStylePara elsevierViewall">We studied a family of 7 siblings born to non-consanguineous parents and with no family history of neurological disease. Three of them (3 women) reported progressive difficulty walking, with instability and dysarthria appearing in the third decade of life. A clinical examination performed after 20 years of disease progression revealed multidirectional nystagmus, dysarthria, global hyperreflexia with bilateral extensor plantar reflex, and marked spasticity of the lower limbs, with the patients requiring bilateral support to walk. The eldest of the 3 sisters also presented cognitive impairment, ophthalmoparesis, upper limb dysmetria, and wide-based gait. All 3 showed cerebellar atrophy on MR images (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). The remaining siblings were not affected (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">After ruling out secondary causes and the mutations most frequently associated with ataxia and spastic paraparesis in the proband, we conducted a genetic study of the <span class="elsevierStyleItalic">SPG7</span> gene. We detected 2 missense mutations, and decided to perform the genetic study in the remaining siblings.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Peripheral blood samples were collected and we performed DNA amplification by PCR and traditional DNA sequencing with the ABI 3730® analyser (Applied Biosystems; Foster City, CA, USA). We studied all coding exons and exon-intron boundaries. We also analysed small deletions/insertions and point mutations in the coding regions and splice sites of <span class="elsevierStyleItalic">SPG7</span>.</p><p id="par0030" class="elsevierStylePara elsevierViewall">We detected 2 compound missense mutations (NM_003119.3:c.1982T>C:p.Met661Thr and NM_003119.3:c.1948G>A:p.Asp650Asn) in heterozygosis in the 3 siblings affected. Two unaffected siblings carried one of the mutations each, and another carried neither (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>B).</p><p id="par0035" class="elsevierStylePara elsevierViewall">The clinical and genetic significance of the variants was established by studying population frequencies, conservation scores (GERP, Phylophen, SiPhy), and prediction scores (SIFT, Polyphen, Mutation Taster, Mutation Assessor, LRT, CADD, DANN) for each variant. We reviewed the available information on <span class="elsevierStyleItalic">SPG7</span> variants previously associated with the disease (published articles, OMIM®, GeneReviews®, ClinVar, Human Gene Mutation Database). We also studied family segregation, although no samples were available from either of the parents.</p><p id="par0040" class="elsevierStylePara elsevierViewall">In silico predictions and the clinical and genetic criteria studied support the pathogenic potential of both variants. Variant p.Met661Thr is not included in population frequency databases, and was found in compound heterozygosity in a patient with suspected pure spastic paraparesis.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Variant p.Asp650Asn, in turn, presents a population frequency of 0.001% and had previously been detected in a sporadic case in a patient with ataxia as the main symptom and who also presented symptoms of upper motor neuron involvement.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> In both cases, all conservation and prediction algorithms signalled a functional impact on the protein.</p><p id="par0045" class="elsevierStylePara elsevierViewall">The patients presented here show the characteristic clinical features, with some exceptions. The patient with the longest disease progression time presented more severe ataxia and less common symptoms, including ophthalmoparesis and cognitive impairment.</p><p id="par0050" class="elsevierStylePara elsevierViewall">These phenotypic differences may be explained by the accumulation of symptoms over the period of disease progression; however, we lack prospective follow-up data.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Both mutations have been classified as variants of uncertain significance, and have previously been described in only 2 cases. The clinical and genetic data presented here support the pathogenic role of these mutations. However, further research is necessary to evaluate their pathogenicity.</p><p id="par0060" class="elsevierStylePara elsevierViewall">To our knowledge, this is the first study to report the occurrence of both variants in a single family with spastic ataxia. Although no samples were available from the parents, the segregation of both variants in different affected and non-affected siblings suggests that each variant comes from one parent.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2020-01-23" "NotaPie" => array:1 [ 0 => array:1 [ "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Fernández-Moreno MC, Castro-Fernández C, Viloria-Peñas MM, Castilla-Guerra L. Familia española portadora de una mutación en heterocigosis compuesta en el gen <span class="elsevierStyleItalic">SPG7</span>: de la incertidumbre a la realidad clínica. Neurología. 2020;35:694–696.</p>" ] ] "multimedia" => array:2 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 654 "Ancho" => 750 "Tamanyo" => 55530 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">T1-weighted sagittal brain MRI scan showing cerebellar atrophy.</p>" ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Fig 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2351 "Ancho" => 1847 "Tamanyo" => 393173 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">SPG7</span> mutations and clinical correlations. (A) Pedigree chart of the family. CA: cerebellar atrophy; CI: cognitive impairment; LL S/H: lower limb spasticity/hyperreflexia; NN: neurologically normal; OPH: ophthalmoparesis; +: present; –: absent. (B) Sanger sequencing of the <span class="elsevierStyleItalic">SPG7</span> gene. Heterozygous mutations are indicated with arrows.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:7 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Spastic paraplegia and OXPHOS impairment caused by mutations in Paraplegin, a nuclear-encoded mitochondrial metalloprotease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. Casari" 1 => "M. De Fusco" 2 => "S. Ciarmatori" 3 => "M. Zeviani" 4 => "M. Mora" 5 => "P. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 October | 13 | 2 | 15 |
| 2024 September | 39 | 4 | 43 |
| 2024 August | 32 | 5 | 37 |
| 2024 July | 29 | 8 | 37 |
| 2024 June | 31 | 10 | 41 |
| 2024 May | 19 | 8 | 27 |
| 2024 April | 28 | 7 | 35 |
| 2024 March | 25 | 4 | 29 |
| 2024 February | 29 | 8 | 37 |
| 2024 January | 35 | 4 | 39 |
| 2023 December | 32 | 4 | 36 |
| 2023 November | 23 | 9 | 32 |
| 2023 October | 36 | 14 | 50 |
| 2023 September | 26 | 7 | 33 |
| 2023 August | 16 | 12 | 28 |
| 2023 July | 23 | 13 | 36 |
| 2023 June | 38 | 11 | 49 |
| 2023 May | 51 | 9 | 60 |
| 2023 April | 38 | 5 | 43 |
| 2023 March | 14 | 12 | 26 |
| 2023 February | 11 | 3 | 14 |
| 2023 January | 17 | 11 | 28 |
| 2022 December | 19 | 8 | 27 |
| 2022 November | 20 | 19 | 39 |
| 2022 October | 19 | 16 | 35 |
| 2022 September | 14 | 22 | 36 |
| 2022 August | 19 | 25 | 44 |
| 2022 July | 8 | 12 | 20 |
| 2022 June | 17 | 25 | 42 |
| 2022 May | 13 | 17 | 30 |
| 2022 April | 18 | 13 | 31 |
| 2022 March | 16 | 11 | 27 |
| 2022 February | 24 | 10 | 34 |
| 2022 January | 29 | 10 | 39 |
| 2021 December | 17 | 8 | 25 |
| 2021 November | 36 | 9 | 45 |
| 2021 October | 48 | 15 | 63 |
| 2021 September | 34 | 11 | 45 |
| 2021 August | 33 | 6 | 39 |
| 2021 July | 9 | 11 | 20 |
| 2021 June | 15 | 10 | 25 |
| 2021 May | 20 | 10 | 30 |
| 2021 April | 45 | 17 | 62 |
| 2021 March | 25 | 15 | 40 |
| 2021 February | 15 | 17 | 32 |
| 2021 January | 13 | 11 | 24 |
| 2020 December | 9 | 6 | 15 |
| 2020 November | 1 | 2 | 3 |
| 2020 October | 2 | 5 | 7 |
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