A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases

Objective: to identify causative mutations in a patient affected by ataxia and spastic paraplegia. Methods: whole-exome sequencing (WES) and whole-genome sequencing (WGS) were performed using patient's DNA sample. RT-PCR and cDNA Sanger sequencing were performed on RNA extracted from patient's fibroblasts, as well as western blot. Results: a novel missense variant in SPG7 (c.2195T> C; p.Leu732Pro) was first found by whole-exome sequencing (WES), while the second, also unreported, deep intronic variant (c.286 + 853A>G) was identified by whole-genome sequencing (WGS). RT-PCR confirmed the in silico predictions showing that this variant activated a cryptic splice site, inducing the inclusion of a pseudoexon into the mRNA sequence, which encoded a premature stop codon. Western blot showed decreased SPG7 levels in patient's fibroblasts. Interpretation: identification of a deep intronic variant in SPG7, which could only have been detected by performing WGS, led to a diagnosis in this HSP patient. This case challenges the notion of an autosomal dominant inheritance for SPG7, and illustrates the importance of performing WGS subsequently or alternatively to WES to find additional mutations, especially in patients carrying one variant in a gene causing a predominantly autosomal recessive disease

Phenotypic correlations in a large single center cohort of patients with BSCL2 nerve disorders: a clinical, neurophysiological and muscle MRI study

Background: BSCL2 heterozygote mutations are a common cause of distal hereditary motor neuropathies (dHMN). We present a series of BSCL2 patients and correlate clinical, neurophysiological and muscle-MRI findings. Methods: 26 patients from 5 families carrying the p.N88S mutation were ascertained. Age of onset, clinical phenotype (dHMN, Charcot-Marie-Tooth/CMT, spastic paraplegia), physical examination, disability measured as modified Rankin score (mRS) and neurophysiological findings were collected. A whole body muscle-MRI had been performed in 18 patients. We analyzed the pattern of muscle involvement on T1-weighted and STIR sequences. Hierarchical analysis using heatmaps and a MRI Composite Score (MRI CS) were generated. Statistical analysis was carried out with STATA SE v.15. Results Mean age was 51.54+/-19.94 years and 14 patients were males. dHMN was the most common phenotype (50%) and 5 patients (19.23%) showed no findings on examination. Disease onset was commonly in childhood and disability was low (mRS=1.34+/-1.13) although median time since onset of disease was 32 years (range=10-47). CMT-like patients were more disabled and disability correlated with age. On muscle-MRI, thenar eminence, soleus and tibialis anterior were most frequently involved, irrespective of clinical phenotype. MRI CS was strongly correlated with disability. Conclusion: Patients with the p.N88S BSCL2 gene mutation are phenotypically variable, although dHMN is most frequent and generally slowly progressive. Muscle-MRI pattern is consistent regardless of phenotype and correlates with disease severity, probably serving as a reliable outcome measure for future clinical trials

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

BACKGROUND AND OBJECTIVES: Spinal 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. METHODS: Description 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. RESULTS: Seventy-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. DISCUSSION: Non-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

Neuropathie héréditaire associée au gène SORD

International audienceMutations in the SORD gene have recently been identified as a cause of autosomal Charcot-Marie-Tooth disease as well as the underlying defect in some cases of hereditary distal motoneuronopathies. Patients may be amenable to therapies in a near future

Les sarcoglycanopathies

Les sarcoglycanopathies font partie des dystrophies musculaires des ceintures (LGMD) autosomiques récessives et représentent la troisième cause la plus fréquente d’entre elles. Elles sont consécutives à un déficit d’un des sarcoglycanes α, β, γ, ou δ. La présentation clinique habituelle est celle d’une atteinte symétrique des muscles des ceintures pelvienne et scapulaire ainsi que du tronc, associée à une atteinte cardiorespiratoire plus ou moins sévère et une élévation franche des créatine-phospho-kinases (CPK). Les premiers symptômes apparaissent au cours de la première décennie, la perte de la marche survenant souvent au cours de la deuxième décennie. Les lésions sont de type dystrophique sur la biopsie musculaire. Il s’y associe une diminution ou une absence d’immunomarquage du sarcoglycane correspondant au gène muté, et dans une moindre mesure des trois autres sarcoglycanes associés. De nombreuses mutations ont été rapportées dans les quatre gènes impliqués et quelques-unes d’entre elles sont prépondérantes dans certaines populations. à ce jour, il n’existe pas de traitement curatif ce qui n’empêche pas de voir se développer de nombreux essais cliniques, notamment en thérapie génique

Sjögren syndrome and RFC1-CANVAS sensory ganglionopathy: co-occurrence or misdiagnosis?

International audienc

RFC1 repeat expansions: A recurrent cause of sensory and autonomic neuropathy with cough and ataxia

BACKGROUND: Ataxia and cough are rare features in hereditary sensory and autonomic neuropathies (HSAN), a group of diseases of mostly unknown genetic cause. Biallelic repeat expansions in RFC1 are associated with cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). METHODS: After unremarkable whole-exome sequencing (WES) analysis, we performed a repeat-primed PCR to detect intronic RFC1 expansions in 12 HSAN families, which all presented with chronic cough. RESULTS: In these patients, 75% carried biallelic expansions of the pathogenic AAGGG motif. Compared to RFC1-/- cases, RFC1+/+ patients presented more consistently with positive sensory and autonomic symptoms. Afferent ataxia was more severe in the RFC1+/+ cohort and cerebellar ataxia was a common feature (21%). CONCLUSIONS: We demonstrate that RFC1 is a frequent cause of (WES-negative) HSAN with chronic cough and ataxia. The diagnostic yield of RFC1 repeat-primed PCR was surprisingly high, given that HSAN is genetically poorly understood. This combination of symptoms HSAN, ataxia, and chronic cough symptoms represents a new nosological entity within the neuropathy-ataxia spectrum

RFC1 repeat expansions: A recurrent cause of sensory and autonomic neuropathy with cough and ataxia

Ataxia and cough are rare features in hereditary sensory and autonomic neuropathies (HSAN), a group of diseases of mostly unknown genetic cause. Biallelic repeat expansions in RFC1 are associated with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS). This study aimed to investigate the prevalence of RFC1 repeat expansions in a cohort of HSAN patients