Clinical and Electrophysiological Study in French-Canadian Population with Charcot-Marie-Tooth Disease Type 1A Associated with 17pll.2 Duplication

Background: The aim of the present study was to examine the frequency and the phenotypic manifestations in a FrenchCanadian population with a chromosome 17pl 1.2 duplication (Charcot-Marie-Tooth type 1A, CMT-1 A). Methods: Molecular analysis were performed by Southern blot using pVAW409R3a probe. Clinical evaluation was carried out according to the scale defined by the European HMSN Consortium. Results: The frequency of duplication was found to be similar in the adult (70.8%) and pediatric (72.7%) populations. Onset of symptoms occurred before 20 years of age in 85.7% of adult cases and before the age of 5 in 80% of the pediatric cases. The classical CMT syndrome was observed in 77% of the cases and the syndrome was associated with additional features in 15% of cases in the adult population. All the children presented with classical CMT syndrome with no additional features. There was a significant correlation between the disability score and the duration of the disease but no correlation was found between median nerve conduction velocity and the functional handicap, the age at onset or the duration of the disease. In one family, there was a very conspicuous anticipation over five observed generations. Conclusion: This study reveals that the age at onset, the clinical and electrophysiological variability as well as the functional disability variations in a French-Canadian population did not differ from those reported in other populations. RESUME: Etude clinique et electrophysiologique, dans la population canadienne franchise, de la maladie de Charcot-Marie-Tooth de type 1A associee a une duplication en 17pll.2. Introduction: Le but de cette etude etait d'examiner la frequence et les manifestations phenotypiques de la maladie de Charcot-Marie-Tooth de type 1A (CMT-1 A) associee a une duplication en 17pl 1.2 dans la population canadienne francaise. Methodes: Une analyse moleculaire a 6t6 faite par buvardage de Southern au moyen de la sonde pVAW409R3a. Une evaluation clinique a 6te faite selon I'echelle deTinie par le Consortium European sur la neuropathie sensitivomotrice hereditaire. Resultats: La frequence de la duplication etait la meme chez les adultes (70.8%) et chez les enfants (72.7%). Le debut des symptomes etait survenu avant l'age de 20 ans chez 85.7% des adultes et avant l'age de 5 ans chez 80% des enfants. Le syndrome classique du CMT a etfi observe dans 77% des cas et ce syndrome etait associe a des manifestations additionnelles chez 15% des cas adultes. Tous les enfants presentaient le syndrome CMT classique sans manifestations additionnelles. II existait une correlation significative entre le score a I'echelle d'invalidite et la duree de la maladie, mais aucune correlation entre la vitesse de conduction dans le nerf median et I'invalidite fonctionnelle, l'age de debut ou la dur£e de la maladie. Dans une famille, nous avons observe une anticipation evidente d'une generation a l'autre sur cinq generations. Conclusion: Cette etude revele que l'age de debut, la variabilite clinique et electrophysiologique ainsi que les variations de l'invalidite fonctionnelle sont les memes dans la population canadienne francaise que ce qui a ete rapporte dans d'autres populations. Can. J. Neurol. Sci. 1999; 26: 196-200 Hereditary sensory and motor neuropathies are a clinically and genetically heterogeneous group of neuromuscular disorders. The most common types, the hypertrophic type, are denominated type I hereditary motor and sensory neuropathy (HMSN-I) or type 1 Charcot-Marie-Tooth (CMT-I). Inheritance is usually autosomal dominant although sporadic cases have been reported. HMSN-I is itself genetically heterogeneous, with at least two chromosomal loci involved. The most common form, type la, is due to a dominant allele mapping on chromosome 17 associated with either a 1.5 Mb DNA duplication in 17pl 1.2-pl2, including the peripheral myelin protein-22 (PMP-22) geneor a point mutation of the PMP-22 gene." A much rarer form, type lb, is mapped at lq22-23 and is associated with point mutations in the myelin Po gene;" two more families in which the disease was From the Laboratoire de Recherche en Genetique Humaine, CHU Laval, Quebec, Canada (N.P., L.C., J.P.), Departement des Sciences Neurologiques, Hopital EnfantJesus, Quebec, Canada (J.-P.B., D.B.), Service de Pediatrie, Hopital Marie-Enfant, Montreal, Canada (M.V.), Service de Neurologie Pediatrique, CHU Sherbrooke, Canada (B.L.), Service de Rhumatologie, CHU Laval, Quebec, Canada (G.M.) RECEIVED DECEMBER 1 5 , 1 9 9 8 . ACCEPTED IN FINAL FORM APRIL 7 , 1 9 9 9 . Reprint requests to: Dr Jack Puymirat, Laboratoire de Recherche en Genetique Humaine, CHU Laval, 2705 Blvd Laurier, Ste-Foy, Quebec, Canada Gl V 4G2