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Eur J Hum Genet. 2019 Apr 17. doi: 10.1038/s41431-019-0403-8. [Epub ahead of print]

LRSAM1 variants and founder effect in French families with ataxic form of Charcot-Marie-Tooth type 2.

Author information

1
AP-HP, G-H Pitié-Salpêtrière, Centre de Référence des Maladies neuromusculaires, Paris Nord/Est/Ile de france, Paris, France. alessia.peretti@libero.it.
2
Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy. alessia.peretti@libero.it.
3
Service de Neurologie CHU Gabriel Montpied, Clermont Ferrand, France.
4
Service de Neurologie, Groupe Hospitalier La Rochelle-Ré-Aunis, La Rochelle, France.
5
Hôpital Neurologique Pierre Wertheimer, Service d'ENMG-Pathologies Neuromusculaires, Lyon-Bron, France.
6
Service de Génétique Clinique, Hôpital Couple Enfant, CHU Grenoble Alpes, Grenoble, France.
7
Centre de Compétences des Maladies Neuro Musculaires, CHU Grenoble Alpes, Grenoble, France.
8
Département de Neurologie, CHU Bordeaux (Pellegrin Hospital), Bordeaux, France.
9
Centre de Référence neurogénétique, Hôpital Pellegrin, CHU Bordeaux, Bordeaux, France.
10
Laboratoire MRGM, INSERM U1211, Univ. Bordeaux, Bordeaux, France.
11
Département de Neurologie, CHU de Montpellier, Montpellier, France.
12
Service et Laboratoire de Neurologie, Centre de Référence Neuropathies Périphériques rares, CHU Limoges, Limoges, France.
13
Service Explorations et Pathologies Neuromusculaires, CHRU Besançon, Besançon, France.
14
AP-HP, Service de Neurologie, CHU Bicêtre, Le Kremlin-Bicêtre, France.
15
Centre de Référence national des Neuropathies amyloïdes familiales et Autres Neuropathies périphériques rares (NNERF), Le Kremlin-Bicêtre, France.
16
AP-HP, G-H Pitié-Salpêtrière, Centre de Référence des Maladies neuromusculaires, Paris Nord/Est/Ile de france, Paris, France.
17
AP-HP, Bicêtre Paris Sud Hospital, Service Génétique moléculaire pharmacogénétique et Hormonologie, Le Kremlin-Bicêtre, France.
18
Département de Génétique, AP-HP, Sorbonne Université, Paris, France.
19
Hôpital Pitié-Salpêtrière, Paris, France.
20
Univ. Limoges, CHU Limoges, Limoges, France.
21
Service de Biochimie et Biologie moléculaire Grand Est, Unité Médicale Pathologies neurologiques et cardiologiques, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Bron, France.

Abstract

Currently only 25-30% of patients with axonal forms of Charcot-Marie-Tooth disease (CMT) receive a genetic diagnosis. We aimed to identify the causative gene of CMT type 2 in 8 non-related French families with a distinct clinical phenotype. We collected clinical, electrophysiological, and laboratory findings and performed genetic analyses in four different French laboratories. Seventy-two patients with autosomal dominant inheritance were identified. The disease usually started in the fourth decade and the clinical picture was dominated by sensory ataxia (80%), neuropathic pain (38%), and length-dependent sensory loss to all modalities. Electrophysiological studies showed a primarily axonal neuropathy, with possible isolated sensory involvement in milder phenotypes. Disease severity varied greatly but the clinical course was generally mild. We identified 2 novel variants in LRSAM1 gene: a deletion of 4 amino acids, p.(Gln698_Gln701del), was found in 7 families and a duplication of a neighboring region of 10 amino acids, p.(Pro702_Gln711dup), in the remaining family. A common haplotype of ~450 kb suggesting a founder effect was noted around LRSAM1 in 4 families carrying the first variant. LRSAM1 gene encodes for an E3 ubiquitin ligase important for neural functioning. Our results confirm the localization of variants in its catalytic C-terminal RING domain and broaden the phenotypic spectrum of LRSAM1-related neuropathies, including painful and predominantly sensory ataxic forms.

PMID:
30996334
DOI:
10.1038/s41431-019-0403-8

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