Clinical and molecular studies in a family with probable X-linked dominant Charcot-Marie-Tooth disease involving the central nervous system.
OBJECTIVE
To investigate the clinical and molecular characteristics of an apparently X-linked dominant form of Charcot-Marie-Tooth (CMT) disease in a family with central nervous system involvement and additional features.


BACKGROUND
Charcot-Marie-Tooth disease may be inherited as an autosomal dominant, autosomal recessive, or X-linked trait. In the X-linked dominant form of CMT, females demonstrate milder clinical and electrophysiological features compared with their male relatives.


METHODS
Clinical and related examinations were performed in 4 affected individuals from a family with a novel form of CMT affecting males more severely than females. DNA analysis of the connexin 32 (Cx32) gene and proteolipid protein (PLP) gene was performed. We genotyped 3 members of the family to determine which regions of the X chromosome were inherited discordantly in the affected and unaffected brothers.


RESULTS
Clinical studies revealed significant spasticity, hyperreflexia, and delayed central conduction, in addition to peripheral neuropathy. Nerve conduction velocities were slower in the affected males than in the affected females. Direct DNA sequencing of the Cx32 coding region and neural-specific promoter were normal. A PLP null mutation was excluded. Levels of very long chain fatty acids were normal. Genotyping studies of the X chromosome supported X-linked inheritance of the neuropathy.


CONCLUSIONS
This family differs from others with hereditary motor and sensory neuropathic diseases by the presence of upper motor neuron signs and additional features. The clinical features and inheritance pattern are consistent with X-linked dominant inheritance or autosomal dominant inheritance.
Hisama
F M
FM
Neurogenetics Program, Department of Neurology, Yale University School of Medicine, LCI 1000, PO Box 208018, New Haven, CT 06520-8018, USA. fuki.hisama@yale.edu
Lee
H H
HH
Vashlishan
A
A
Tekumalla
P
P
Russell
D S
DS
Auld
E
E
Goldstein
J M
JM
D000328:Adult; D001927:Brain Diseases / Q000235:genetics* / Q000503:physiopathology; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000503:physiopathology; D002675:Child, Preschool; D017630:Connexins / Q000235:genetics; D016057:Evoked Potentials, Auditory, Brain Stem; D005074:Evoked Potentials, Visual; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D018991:Myelin Proteolipid Protein / Q000235:genetics; D009431:Neural Conduction; D010375:Pedigree; D014960:X Chromosome / Q000235:genetics*; D000097002:Gap Junction beta-1 Protein
D017630:Connexins; D018991:Myelin Proteolipid Protein; D000097002:Gap Junction beta-1 Protein