Adult-onset non-5q proximal spinal muscular atrophy: a comprehensive review

Pinto, Wladimir Bocca Vieira de Rezende; Souza, Paulo Victor Sgobbi de; Badia, Bruno Mattos Lombardi; Farias, Igor Braga; Filho, José Laredo; Gonçalves, Eduardo Augusto; Machado, Roberta Ismael Lacerda; Oliveira, Acary Souza Bullé

doi:10.1590/0004-282x-anp-2020-0429

Cited by 5 publications

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“…Unfortunately, although some reviews of non-5q SMA patients have been published, 4 , 14 clinical series of patients are lacking and the value of routine neuropathy next-generation sequencing (NGS) gene panels is largely unknown. The aim of this study was to describe the clinical and genetic landscape of a large multicentric series of patients with non-5q SMA and evaluate the performance of neuropathy gene panels in these patients.…”

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Phenotype Presentation and Molecular Diagnostic Yield in Non-5q Spinal Muscular Atrophy

et al. 2023

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Background and ObjectivesSpinal muscular atrophy (SMA) is mainly caused by homozygousSMN1gene deletions on 5q13. Non-5q SMA patients’ series are lacking, and the diagnostic yield of next-generation sequencing (NGS) is largely unknown. The aim of this study was to describe the clinical and genetic landscape of non-5q SMA and evaluate the performance of neuropathy gene panels in these disorders.MethodsDescription of patients with non-5q SMA followed in the different neuromuscular reference centers in France as well as in London, United Kingdom. Patients without a genetic diagnosis had undergone at least a neuropathy or large neuromuscular gene panel.ResultsSeventy-one patients from 65 different families were included, mostly sporadic cases (60.6%). At presentation, 21 patients (29.6%) showed exclusive proximal weakness (P-SMA), 35 (49.3%) showed associated distal weakness (PD-SMA), and 15 (21.1%) a scapuloperoneal phenotype (SP-SMA). Thirty-two patients (45.1%) had a genetic diagnosis:BICD2(n = 9),DYNC1H1(n = 7),TRPV4(n = 4),VCP,HSBP1,AR(n = 2),VRK1,DNAJB2,MORC2,ASAH1,HEXB, and unexpectedly,COL6A3(n = 1). The genetic diagnostic yield was lowest in P-SMA (6/21, 28.6%) compared with PD-SMA (16/35, 45.7%) and SP-SMA (10/15, 66.7%). An earlier disease onset and a family history of the disease or consanguinity were independent predictors of a positive genetic diagnosis. Neuropathy gene panels were performed in 59 patients with a 32.2% diagnostic yield (19/59). In 13 additional patients, a genetic diagnosis was achieved through individual gene sequencing or an alternative neuromuscular NGS.DiscussionNon-5q SMA is genetically heterogeneous, and neuropathy gene panels achieve a molecular diagnosis in one-third of the patients. The diagnostic yield can be increased by sequencing of other neuromuscular and neurometabolic genes. Nevertheless, there is an unmet need to cluster these patients to aid in the identification of new genes.

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Phenotype Presentation and Molecular Diagnostic Yield in Non-5q Spinal Muscular Atrophy

et al. 2023

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“…A total of 16,582 variants remained after the application of these filters. Genes known to be associated with non-5q proximal SMA [ 7 , 8 ] or amyotrophic lateral sclerosis (ALS) [ 9 ], another disease affecting motoneurons, were individually checked (Supplementary Table 2 ). The two other patients benefited either directly from WES (patient 10) or from WGS (patient 4) after a negative panel analysis of genes associated with myopathy (initial suspicion of myopathy).…”

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confidence: 99%

“…6 Centre de Biotechnologie Cellulaire, CBC Biotec, Hospices Civils de Lyon, Groupement Est, Bron, France. 7 Hôpital de la Timone, Maladies Neuromusculaires et SMA, Assistance Publique des Hôpitaux de Marseille, Marseille, France. 8 Centre de Référence des Maladies Neuromusculaires Nord/Est/Ile-de-France, Service de Neurologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.…”

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Genetic characterization of non-5q proximal spinal muscular atrophy in a French cohort: the place of whole exome sequencing

et al. 2023

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Proximal spinal muscular atrophy (SMA) is defined by a degeneration of the anterior horn cells resulting in muscle weakness predominantly in the proximal lower limbs. While most patients carry a biallelic deletion in the SMN1 gene (localized in chromosome 5q), little is known regarding patients without SMN1-mutation, and a genetic diagnosis is not always possible. Here, we report a cohort of 24 French patients with non-5q proximal SMA from five neuromuscular centers who all, except two, had next-generation sequencing (NGS) gene panel, followed by whole exome sequencing (WES) if gene panel showed a negative result. The two remaining patients benefited directly from WES or whole genome sequencing (WGS). A total of ten patients with causative variants were identified, nine of whom were index cases (9/23 families = 39%). Eight variants were identified by gene panel: five variants in DYNC1H1, and three in BICD2. Compound heterozygous causative variants in ASAH1 were identified directly by WES, and one variant in DYNC1H1 was identified directly by WGS. No causative variant was found using WES in patients with a previous panel with negative results (14 cases). We thus recommend using primarily NGS panels in patients with non-5q-SMA and using WES, especially when several members of the same family are affected and/or when trio analyses are possible, or WGS as second-line testing if available.

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“…4,13 Nevertheless, around 70% or more of non-5q SMA patients do not have a definitive molecular diagnosis. 6 Unfortunately, although some reviews of non-5q SMA patients have been published, 4,14 clinical series of patients are lacking and the value of routine neuropathy next-generation sequencing (NGS) gene panels is largely unknown. The aim of this study was to describe the clinical and genetic landscape of a large multicentric series of patients with non-5q SMA and evaluate the performance of neuropathy gene panels in these patients.…”

mentioning

confidence: 99%

Phenotype Presentation and Molecular Diagnostic Yield in Non-5q Spinal Muscular Atrophy

2024

Neurol Genet

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Background and ObjectivesSpinal muscular atrophy (SMA) is mainly caused by homozygous SMN1 gene deletions on 5q13. Non-5q SMA patients' series are lacking, and the diagnostic yield of next-generation sequencing (NGS) is largely unknown. The aim of this study was to describe the clinical and genetic landscape of non-5q SMA and evaluate the performance of neuropathy gene panels in these disorders. MethodsDescription of patients with non-5q SMA followed in the different neuromuscular reference centers in France as well as in London, United Kingdom. Patients without a genetic diagnosis had undergone at least a neuropathy or large neuromuscular gene panel. ResultsSeventy-one patients from 65 different families were included, mostly sporadic cases (60.6%). At presentation, 21 patients (29.6%) showed exclusive proximal weakness (P-SMA), 35 (49.3%) showed associated distal weakness (PD-SMA), and 15 (21.1%) a scapuloperoneal phenotype (SP-SMA). Thirty-two patients (45.1%) had a genetic diagnosis: BICD2 (n = 9), DYNC1H1 (n = 7), TRPV4 (n = 4), VCP, HSBP1, AR (n = 2), VRK1, DNAJB2, MORC2, ASAH1, HEXB, and unexpectedly, COL6A3 (n = 1). The genetic diagnostic yield was lowest in P-SMA (6/21, 28.6%) compared with PD-SMA (16/35, 45.7%) and SP-SMA (10/15, 66.7%). An earlier disease onset and a family history of the disease or consanguinity were independent predictors of a positive genetic diagnosis. Neuropathy gene panels were performed in 59 patients with a 32.2% diagnostic yield (19/59). In 13 additional patients, a genetic diagnosis was achieved through individual gene sequencing or an alternative neuromuscular NGS. DiscussionNon-5q SMA is genetically heterogeneous, and neuropathy gene panels achieve a molecular diagnosis in one-third of the patients. The diagnostic yield can be increased by sequencing of other neuromuscular and neurometabolic genes. Nevertheless, there is an unmet need to cluster these patients to aid in the identification of new genes.

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Adult-onset non-5q proximal spinal muscular atrophy: a comprehensive review

Cited by 5 publications

References 68 publications

Phenotype Presentation and Molecular Diagnostic Yield in Non-5q Spinal Muscular Atrophy

Phenotype Presentation and Molecular Diagnostic Yield in Non-5q Spinal Muscular Atrophy

Genetic characterization of non-5q proximal spinal muscular atrophy in a French cohort: the place of whole exome sequencing

Phenotype Presentation and Molecular Diagnostic Yield in Non-5q Spinal Muscular Atrophy

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