Phenotype-genotype correlations in a CMT2B family with refined 3q13-q22 locus

Objective: To perform genotype-phenotype correlation and genetic linkage an alysis in a family with axonal Charcot-Marie-Tooth (CMT) syndrome and ulcer o-mutilating features. Background: CMT2B is a rare disorder belonging to th e group of axonal CMT syndromes that is clinically characterized by marked distal muscle weakness and wasting as well as a high frequency of foot ulce rs, infections, and amputations. So far only two families with this disorde r have been described in which molecular genetic studies have shown evidenc e of autosomal dominant inheritance with linkage to chromosome 3q13-q22. Me thods: The authors report a large Austrian family presenting with the typic al clinical features of CMT2B. Detailed clinical and electrophysiologic dat a were obtained in 15 at-risk individuals and DNA samples from 19 family me mbers were collected for genetic linkage studies. Results: Eight; family me mbers were definitely affected upon clinical and electrophysiologic examina tion and the majority revealed pronounced distal muscle wasting and weaknes s as well as prominent sensory abnormalities, which were frequently complic ated by infections and amputations. Electrophysiologic studies showed norma l or slightly to moderately slowed motor nerve conduction velocities, marke dly reduced compound motor action potential amplitudes with chronodispersio n, and absent or reduced amplitudes of sensory nerve action potentials. The molecular genetic study demonstrates linkage to chromosome 3q13-q22. Haplo type analysis in affected individuals indicates that the CMT2B locus is loc ated between the flanking markers D3S1589 and D3S1549, representing a regio n of 10 cM. Conclusions: This family is the third CMT2B family reported so far and confirms the existence of the CMT2B locus on chromosome 3q13-q22, w hich is responsible for a clinically and electrophysiologically homogeneous disorder with prominent distal muscle weakness and wasting, and ulcero-mut ilating features. Marked sensory disturbances and the high frequency of foo t ulcers, infections, and amputations in our patients seem to be typical fo r CMT2B. Recombination events in affected individuals reduce the CMT2B cand idate gene interval considerably from 25 to 10 cM.