Phenotypic expression of a Pro 87 to Leu mutation in the connexin 32 gene in a large Swiss family with Charcot–Marie–Tooth neuropathy

• Published in: Journal of the neurological sciences 2003-03, Vol.207 (1), p.77-86
• Main Authors: Kuntzer, Thierry, Dunand, Murielle, Schorderet, Daniel F, Vallat, Jean-Michel, Hahn, Angelika F, Bogousslavsky, Julien
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Amino Acid Substitution - genetics; Biological and medical sciences; Charcot-Marie-Tooth Disease - genetics; Charcot-Marie-Tooth Disease - physiopathology; Child; Child, Preschool; CMTX; Connexin 32 mutation; Connexins - genetics; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Female; Gap Junction beta-1 Protein; Hereditary motor and sensory neuropathies; Humans; Leucine - genetics; Male; Medical sciences; Middle Aged; Neural Conduction - genetics; Neurology; Pedigree; Phenotype; Point Mutation; Statistics, Nonparametric; X-linked Charcot–Marie–Tooth
• ISSN: 0022-510X; 1878-5883
• DOI: 10.1016/S0022-510X(02)00394-5

Background: The clinical manifestations of CMTX have been well described but the natural history has not yet been studied in detail. We studied phenotype variability in a family with a Pro 87 to Leu mutation of the connexin 32 (Cx32) gene. Methods: A total of 32 family members, of which 19 patients were affected, underwent clinical, electrophysiological, and genetic studies. Results: Onset was in the second decade. Clinical features were similar in both sexes when quantitative scores were compared, but more males had a steppage gait and skeletal deformities. All adult patients had a predominant involvement of the thenar muscles. The median values of nerve conduction velocities (NCVs) were not statistically different in men and in women. The correlation coefficients were low between motor NCVs within the same extremities, indicating nonuniform slowing between nerves, the ulnar nerve being the least affected. When disability was rated, a strong correlation was seen in male patients between severity of motor axonal loss and duration of the disease. The main pathological features were axonal loss, clusters of regenerating fibers and paranodal demyelination, the hallmark of a Schwann cell pathology. Conclusions: Our data support the hypothesis that clinical disability in CMTX is caused by loss of large myelinated axons in men. Furthermore, this study shows that the nerves are not uniformly affected in terms of axonal loss. Preventing axonal degeneration and promoting axonal regeneration in the most affected nerves might be the best therapeutic approaches to ameliorate disability in CMTX.