Phenotypic expression of a Pro 87 to Leu mutation in the connexin 32 gene in a large Swiss family with Charcot-Marie-Tooth neuropathy.
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.
Kuntzer
Thierry
T
Service de Neurologie, Centre Hospitalier Universitaire Vaudois, BH 7/306, 1011, Lausanne, Switzerland. thierry.kuntzer@chuv.hospvd.ch
Dunand
Murielle
M
Schorderet
Daniel F
DF
Vallat
Jean Michel
JM
Hahn
Angelika F
AF
Bogousslavsky
Julien
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution / Q000235:genetics*; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D017630:Connexins / Q000235:genetics*; D005260:Female; D006801:Humans; D007930:Leucine / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009431:Neural Conduction / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D018709:Statistics, Nonparametric; D000097002:Gap Junction beta-1 Protein
D017630:Connexins; D007930:Leucine; D000097002:Gap Junction beta-1 Protein