In a man with Charcot-Marie-Tooth disease type 1B (CMT1B; 118200), Schiavon et al. (1998) identified a 371C-T transition in exon 3 of the MPZ gene, resulting in a thr124-to-met (T124M) substitution. The patient had a relatively mild clinical course, with onset of generalized asthenia at age 42 years and a slightly decreased motor NCV of 37 m/s.
In 7 Charcot-Marie-Tooth families and in 2 isolated CMT patients of Belgian ancestry, De Jonghe et al. (1999) found the T124M mutation. Allele-sharing analysis of markers flanking the MPZ gene indicated that all patients with the T124M mutation had 1 common ancestor. The mutation was associated with a clinically distinct phenotype characterized by axonal involvement, late onset, marked sensory abnormalities, and, in some families, deafness and pupillary abnormalities (CMT2J; 607736). Nerve conduction velocities of the motor median nerve varied from less than 38 m/s to normal values in these patients. Clusters of remyelinating axons in the sural nerve biopsy demonstrated an axonal involvement, with axonal regeneration. Phenotype/genotype correlations in 30 patients with the mutation indicated that, based on nerve conduction velocity criteria, these patients were difficult to classify as CMT1 or CMT2. De Jonghe et al. (1999) concluded that CMT patients with slightly reduced or nearly normal nerve conduction velocity should be screened for MPZ mutations, particularly when additional clinical features such as marked sensory disturbances, pupillary abnormalities, or deafness are also present.
Chapon et al. (1999) and Misu et al. (2000) likewise found a distinct CMT type 2 axonal phenotype with pupillary anomalies, deafness, and sensory abnormalities associated with the T124M mutation.
Senderek et al. (2000) suggested that T124M reflects a mutation hotspot.
Baloh et al. (2004) reported a family in which multiple members spanning 3 generations had severe chronic recurring coughing spasms, beginning in their teens and lasting for 20 to 30 minutes and ending in retching or vomiting. All affected members had tonic pupils and most developed late-onset axonal peripheral neuropathy. The features resembled CMT with hearing loss and pupillary abnormalities reported by De Jonghe et al. (1999) and Misu et al. (2000), but hearing loss was not a feature in this family. The proband also reported gastrointestinal symptoms diagnosed as irritable bowel syndrome, occasional urinary incontinence, and erectile dysfunction. The proband and his affected sister and mother were heterozygous for the T124M mutation; 4 unaffected family members tested did not have the mutation. Baloh et al. (2004) concluded that the T124M mutation results in dysfunction of the autonomic nervous system.
Triggs et al. (2006) described a family with the characteristic features of CMT2J and the T124M mutation.
