A number sign (#) is used with this entry because of evidence that axonal Charcot-Marie-Tooth disease type 2HH (CMT2HH) is caused by heterozygous mutation in the JAG1 gene (601920) on chromosome 20p12.

Axonal Charcot-Marie-Tooth disease type 2HH (CMT2HH) is an autosomal dominant peripheral neuropathy characterized predominantly by onset of vocal cord weakness resulting in stridor in infancy or early childhood. The vocal cord paresis remains throughout life and may be severe enough to require tracheostomy. Additional features of the disorder usually include pes cavus and scoliosis. Some patients have mild distal muscle weakness and atrophy primarily affecting the lower limbs, although the upper limbs may also be involved, and distal sensory impairment, often with hyporeflexia (Sullivan et al., 2020).

For a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210).

Sullivan et al. (2020) reported 9 patients from 2 unrelated families with a peripheral neuropathy associated with vocal cord paresis. Eight patients ranged in age from 33 to 73 years; the ninth was 19 years old. All presented at birth or in early childhood with notable stridor, although it was not properly diagnosed for many until adult life. The vocal cord paresis was severe, necessitating tracheostomy in 4 patients. Additional features were more variable. The patients in family 1 had mild distal limb weakness affecting the upper and lower limbs with mild distal sensory loss and areflexia. Hand weakness was slowly progressive. Most had pes cavus and scoliosis. The patients in the second family did not have significant weakness or sensory loss, although 2 had decreased reflexes in the lower limbs. They also had tremor, fasciculations of the periorbital region and limbs, abnormal hand posturing, periorbital twitching, and polyminimyoclonus in the fingers. Two patients in family 2 had poor circulation with lower limb edema and discoloration, and 2 had kyphoscoliosis. All had pes cavus. One patient had high-normal serum creatine kinase. Nerve conduction studies in all patients were consistent with an axonal peripheral neuropathy.

The transmission pattern of CMT2HH in the families reported by Sullivan et al. (2020) was consistent with autosomal dominant inheritance.

In 9 affected individuals from 2 unrelated families with CMT2HH, Sullivan et al. (2020) identified heterozygous missense mutations in the JAG1 gene (S577R, 601920.0015 and S650P, 601920.0016). Both mutations occurred at highly conserved residues in the extracellular domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Neither was present in the gnomAD database. In vitro expression studies showed that the mutations impaired protein glycosylation and reduced JAG1 surface expression compared to controls. Mutant JAG1 was partially retained in the endoplasmic reticulum. Homozygous expression of the S577R mutation in mice was embryonic lethal. Heterozygous S577R mice showed impaired performance in a test of limb strength compared to wildtype, but were able to perform in the accelerating rotarod test. Electrophysiologic studies showed reduced compound muscle action potentials (CMAPs). Examination of the recurrent laryngeal nerve did not show significant axonal abnormalities, but there was some focally folded myelin. Sullivan et al. (2020) noted that none of the patients had features of Alagille syndrome (118450). The findings implicated JAG1 in the maintenance of peripheral nerve integrity and suggested that the neuropathy may result from altered Notch (190198) signaling.