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

Alessia Peretti, Maud Perie, Didier Vincent, Françoise Bouhour, Klaus Dieterich, Martial Mallaret, Fanny Duval, Cyril Goizet, Raul Juntas-Morales, Laurent Magy, Guilhem Solé, Sylvain Nollet, Adeline Not, Sarah Léonard-Louis, Bruno Francou, Eric Leguern, Anne-Sophie Lia, Corinne Magdelaine, Philippe Latour, Tanya Stojkovic
Eur J Hum Genet. 2019-04-17; 27(9): 1406-1418
DOI: 10.1038/s41431-019-0403-8

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1. Eur J Hum Genet. 2019 Sep;27(9):1406-1418. doi: 10.1038/s41431-019-0403-8. Epub
2019 Apr 17.

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

Peretti A(1)(2), Perie M(3), Vincent D(4), Bouhour F(5), Dieterich K(6), Mallaret
M(7), Duval F(8), Goizet C(9)(10), Juntas-Morales R(11), Magy L(12), Solé G(8),
Nollet S(13), Not A(14)(15), Léonard-Louis S(16), Francou B(17), Leguern
E(18)(19), Lia AS(20), Magdelaine C(20), Latour P(21), Stojkovic T(16).

Author information:
(1)AP-HP, G-H Pitié-Salpêtrière, Centre de Référence des Maladies
neuromusculaires, Paris Nord/Est/Ile de france, Paris, France.
.
(2)Department of Neurosciences, Biomedicine and Movement Sciences, University of
Verona, Verona, Italy. .
(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.

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.

DOI: 10.1038/s41431-019-0403-8
PMCID: PMC6777460
PMID: 30996334 [Indexed for MEDLINE]

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