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A Novel Mutation in a Large French-Canadian Family with LGMD1B

Published online by Cambridge University Press:  02 December 2014

Nicolas Chrestian ,
Paul N. Valdmanis ,
Najmeddine Echahidi ,
Denis Brunet ,
Jean-Pierre Bouchard ,
Peter Gould ,
Guy A. Rouleau ,
Jean Champagne  and
Nicolas Dupré
Nicolas Chrestian
Affiliation:
Faculty of Medicine, Laval University, Department of Neurological Sciences, CHAUQ - Enfant-JJésussus, Quebec City
Paul N. Valdmanis
Affiliation:
Centre d’excellence en neuromique de l’Université de Montréal, CHUM Research Center - Notre-Dame Hospital, J.A. de Sève Pavilion, Montreal, QC, Canada
Najmeddine Echahidi
Affiliation:
Faculty of Medicine, Laval University, Institut Universitaire de cardiologie et pneumologie de l’Université Laval, Laval Hospital, Quebec City
Denis Brunet
Affiliation:
Faculty of Medicine, Laval University, Department of Neurological Sciences, CHAUQ - Enfant-JJésussus, Quebec City
Jean-Pierre Bouchard
Affiliation:
Faculty of Medicine, Laval University, Department of Neurological Sciences, CHAUQ - Enfant-JJésussus, Quebec City
Peter Gould
Affiliation:
Faculty of Medicine, Laval University, Department of Neurological Sciences, CHAUQ - Enfant-JJésussus, Quebec City
Guy A. Rouleau
Affiliation:
Centre d’excellence en neuromique de l’Université de Montréal, CHUM Research Center - Notre-Dame Hospital, J.A. de Sève Pavilion, Montreal, QC, Canada
Jean Champagne
Affiliation:
Faculty of Medicine, Laval University, Institut Universitaire de cardiologie et pneumologie de l’Université Laval, Laval Hospital, Quebec City
Nicolas Dupré
Affiliation:
Faculty of Medicine, Laval University, Department of Neurological Sciences, CHAUQ - Enfant-JJésussus, Quebec City Centre d’excellence en neuromique de l’Université de Montréal, CHUM Research Center - Notre-Dame Hospital, J.A. de Sève Pavilion, Montreal, QC, Canada
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abstract

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Background:

Limb girdle muscular dystrophy type 1B is an autosomal dominant disease characterized by late onset proximal muscle involvement associated with cardiac complications such as atrioventricular conduction blocks, dilated cardiomyopathy, and sudden death.

Objective:

Define the full phenotypic spectrum of a new mutation in the LMNA gene causing limb girdle muscular dystrophy type 1B.

Methods:

We identified a large French Canadian family with the LGMD 1B phenotype and a cardiac conduction disease phenotype that carried a new mutation in the LMNA gene and sought to define its full phenotypic spectrum by performing complete neurological and cardiac evaluations, muscle biopsy, RNA and DNA studies.

Results:

The proband and 12 living at risk relatives were tested. In total, we identified seven carriers of a new (IVS9-3C>G) LMNA gene mutation. Of the three symptomatic patients, all had cardiac involvement, but only two presented proximal limb weakness. The one available muscle biopsy demonstrated a normally expressed lamin A/C protein, localized at the nuclear envelope. RNA study revealed a loss of exon 10 transcription caused by the IVS9-3C to G splicing mutation.

Conclusions:

We have identified a new mutations in the LMNA gene in a French-Canadian family. This diagnosis has important implications for affected patients and their siblings since they may eventually require pacemaker implantation.

Résumé:

RÉSUMÉ: <span class='bold'> <span class='italic'>Contexte:</span></span>

La dystrophie musculaire des ceintures type 1 B est une maladie autosomique dominante caractérisée par un début tardif, une atteinte des muscles proximaux associée à des complications cardiaques comme des blocs de conduction auriculo-ventriculaires, une cardiomyopathie congestive et une mort subite.

<span class='bold'> <span class='italic'>Objectif:</span></span>

Le but de cette étude était de définir l’expression phénotypiques d’une nouvelle mutation du gène LMNA qui cause la dystrophie musculaire des ceintures de type 1B.

<span class='bold'> <span class='italic'>Méthodes:</span></span>

Nous avons identifié une grande famille canadienne-française présentant le phénotype LGMD 1B accompagné d’un trouble de conduction cardiaque, qui était porteuse d’une nouvelle mutation du gène LMNA. Nous définissons le spectre de ses variations phénotypiques dans cette famille au moyen d’une évaluation neurologique et cardiaque complète, d’une biopsie musculaire et d’études de l’ARN et de l’ADN.

<span class='bold'> <span class='italic'>Résultats:</span></span>

Les trois patients qui présentaient des symptômes avaient tous une atteinte cardiaque, mais seulement deux présentaient une faiblesse proximale. La seule biopsie musculaire disponible a montré une expression normale de la lamine A/C localisée à l’enveloppe nucléaire. L’étude de l’ARN a montré une perte de transcription de l’exon 10 causée par une mutation d’épissage IVS9-3C à G.

<span class='bold'> <span class='italic'>Conclusions:</span></span>

Ce diagnostic a des implications importantes pour les patients atteints et leur fratrie parce qu’ils peuvent éventuellement avoir besoin d’un stimulateur cardiaque.

Type
Original Articles
Information
Canadian Journal of Neurological Sciences , Volume 35 , Issue 3 , July 2008 , pp. 331 - 334
Copyright
Copyright © The Canadian Journal of Neurological 2008

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