Implication of the SH3TC2 gene in Charcot-Marie-Tooth disease associated with deafness and/or scoliosis: Illustration with four new pathogenic variants

Lerat, J.; Magdelaine, Corinne; Lunati, Ariane; Dzugan, Hélène; Dejoie, C.; Rêgo, M. J. B. M.; Beyrie, P. Beze; Bieth, Éric; Calvas, Patrick; Pascal, Pierre; Delaubrier, A.; Démurger, Florence; Gilbert‐Dussardier, Brigitte; Goizet, Cyril; Journel, Hubert; Laffargue, Fanny; Magy, Laurent; Taithe, F.; Toutain, Annick; Urtizberea, Jon Andoni; Sturtz, Franck; Lia, Anne‐Sophie

doi:10.1016/j.jns.2019.06.027

Cited by 7 publications

(1 citation statement)

References 15 publications

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“…It is quite difficult in clinical practice to suggest a gene that might have pathogenic variants causing peripheral neuropathy without molecular tests. Some distinct clinical signs are associated with certain neuropathy-like stroke-like episodes and white matter alterations in CMT1X ( GJB1 ), early scoliosis in CMT4C ( SH3TC2 ), or neuromyotonic discharges recorded by electromyography in axonal neuropathy with neuromyotonia ( HINT1 ) [ 2 , 3 ]. Nevertheless, despite all these helpful clinical correlations, diagnostic strategies are being replaced by a targeted next-generation sequencing (NGS) as the most effective and economical approach.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Pathogenicity and Causativity of Variants in the MPZ and SH3TC2 Genes in a Family Case of Hereditary Peripheral Neuropathy

Щагина

Orlova

Муртазина

et al. 2023

IJMS

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The implementation of NGS methods into clinical practice allowed researchers effectively to establish the molecular cause of a disorder in cases of a genetically heterogeneous pathology. In cases of several potentially causative variants, we need additional analysis that can help in choosing a proper causative variant. In the current study, we described a family case of hereditary motor and sensory neuropathy (HMSN) type 1 (Charcot–Marie–Tooth disease). DNA analysis revealed two variants in the SH3TC2 gene (c.279G>A and c.1177+5G>A), as well as a previously described variant c.449−9C>T in the MPZ gene, in a heterozygous state. This family segregation study was incomplete because of the proband’s father's unavailability. To evaluate the variants’ pathogenicity, minigene splicing assay was carried out. This study showed no effect of the MPZ variant on splicing, but the c.1177+5G>A variant in the SH3TC2 gene leads to the retention of 122 nucleotides from intron 10 in the RNA sequence, causing a frameshift and an occurrence of a premature stop codon (NP_078853.2:p.Ala393GlyfsTer2).

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Section: Introductionmentioning

confidence: 99%

Evaluation of Pathogenicity and Causativity of Variants in the MPZ and SH3TC2 Genes in a Family Case of Hereditary Peripheral Neuropathy

Щагина

Orlova

Муртазина

et al. 2023

IJMS

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Neuropathy due to bi-allelic SH3TC2 variants: genotype-phenotype correlation and natural history

Rehbein

Treidler

et al. 2023

Brain

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Recessive SH3TC2 variants cause Charcot-Marie-Tooth disease type 4C (CMT4C). CMT4C is typically a sensorimotor demyelinating polyneuropathy, marked by early onset spinal deformities, but its clinical characteristics and severity are quite variable. Clear relationships between pathogenic variants and the spectrum of disease manifestations are to date lacking. Gene replacement therapy has been shown to ameliorate the phenotype in a mouse model of CMT4C, emphasizing the need for natural history studies to inform clinical trial readiness. Data, including both genetic information and clinical characteristics, were compiled from the longitudinal, prospective dataset of the Inherited Neuropathy Consortium, a member of the Rare Diseases Clinical Research Network (INC-RDCRN). The Charcot Marie Tooth Neuropathy Score (CMTNS), Examination Score (CMTES) and the Rasch-weighted CMTES (CMTES-R) were used to describe symptoms, neurologic examinations, and neurophysiologic characteristics. Standardized response means were calculated at yearly intervals and a mixed model for repeated measures was used to estimate the change in CMTES and CMTES-R over time. 56 individuals (59% female), median age 27 years (range 2–67 years) with homozygous or compound heterozygous variants in SH3TC2 were identified, including 34 unique variants, 14 of which have not previously been published. 28 participants had longitudinal data available. While there was not a significant difference in the CMTES in those with protein-truncating versus non-protein-truncating variants, there were significant differences in the mean ulnar nerve compound muscle action potential amplitude, the mean radial sensory nerve action potential amplitude, and in the prevalence of scoliosis, suggesting the possibility of a milder phenotype in individuals with one or two non-protein-truncating variants. Overall, the mean value of the CMTES was 13, reflecting moderate clinical severity. There was a high rate of scoliosis (81%), scoliosis surgery (36%), and walking difficulty (94%) among study participants. The CMTES and CMTES-R appeared moderately responsive to change over extended follow-up, demonstrating a standardized response mean of 0.81 standard deviation units or 0.71 standard deviation units respectively, over 3 years. Our analysis represents the largest cross-sectional and only longitudinal study to date, of the clinical phenotype of both adults and children with CMT4C. With the promise of upcoming genetic treatments, this data will further define the natural history of the disease and inform study design in preparation for clinical trials.

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A Search for Undiagnosed Charcot-Marie-Tooth Disease Among Patients Registered with Unspecified Polyneuropathy in the Danish National Patient Registry

Vaeth

Andersen

Christensen

et al. 2021

CLEP

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Purpose In a recent study based on data from the Danish National Patients Registry (DNPR), we reported the prevalence of Charcot-Marie-Tooth disease (CMT) in Denmark to be 22.5 per 100.000. This prevalence is most likely a minimum estimate, as many cases of CMT may be misdiagnosed or remain undiagnosed due to the heterogeneous nature of the disorder. The aim of this study was to investigate the possible number of undiagnosed CMT cases among patients registered with unspecified polyneuropathy (UP) diagnoses in the DNPR. Patients and Methods From the DNPR we extracted data on all patients given an UP diagnosis in the period 1977 to 2012. We selected all patients diagnosed with a primary UP diagnosis before age 40 at a department of neurology, neurophysiology, clinical genetics or pediatrics, and excluded all patients with a specified polyneuropathy diagnosis or with diagnostic codes related to alcohol and diabetes mellitus. To assess the proportion of possible CMT patients, we performed medical record review in a random sample of patients diagnosed in the Central Denmark Region. To further investigate the possible overlap between UP and CMT in the DNPR, we performed a series of searches for ICD-8 and ICD-10 codes related to CMT. Results Between 1977 and 2012, 30.903 patients were diagnosed with UP without also being diagnosed with CMT. A total of 940 patients fulfilled the selection criteria. We found that 21.5% (95% CI 13.1%–32.2%) of the cases in the random sample fulfilled our criteria for CMT. This estimate increases the prevalence of CMT in Denmark with 3.6 per 100,000 (95% CI 2.4%–5.5%). Conclusion This study illustrates how hitherto undiagnosed CMT patients may be identified in the DNPR and further reports the number of possible CMT cases. Our results support the hypothesis that the true prevalence of CMT is higher than recently reported.

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Implication of the SH3TC2 gene in Charcot-Marie-Tooth disease associated with deafness and/or scoliosis: Illustration with four new pathogenic variants

Cited by 7 publications

References 15 publications

Evaluation of Pathogenicity and Causativity of Variants in the MPZ and SH3TC2 Genes in a Family Case of Hereditary Peripheral Neuropathy

Evaluation of Pathogenicity and Causativity of Variants in the MPZ and SH3TC2 Genes in a Family Case of Hereditary Peripheral Neuropathy

Neuropathy due to bi-allelic SH3TC2 variants: genotype-phenotype correlation and natural history

A Search for Undiagnosed Charcot-Marie-Tooth Disease Among Patients Registered with Unspecified Polyneuropathy in the Danish National Patient Registry

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