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.