Charcot-Marie-Tooth Disease, Axonal, Type 2j

A number sign (#) is used with this entry because CMT2 with hearing loss and pupillary abnormalities (CMT2J) is caused by heterozygous mutation in the myelin protein-zero gene (MPZ; 159440) on chromosome 1q23.

Description

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

Clinical Features

De Jonghe et al. (1999) reported 7 Charcot-Marie-Tooth families and 2 isolated CMT2 patients of Belgian ancestry with a clinically distinct phenotype characterized by late onset (fourth to fifth decade), marked sensory abnormalities, deafness, and pupillary abnormalities. 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.

Chapon et al. (1999) reported a French family in which 7 members of 3 generations had a type of CMT2 characterized by Argyll-Robertson-like pupils, dysphagia, and deafness. Electrophysiologic studies and nerve biopsy defined the neuropathy as axonal type. Age of onset ranged from 18 to 50 years.

Misu et al. (2000) reported 7 families with axonal CMT characterized by relatively late onset (37 to 61 years), marked sensory impairment, and distal muscle atrophy and weakness. Pupillary abnormalities and deafness were often present.

Seeman et al. (2004) reported a Czech family in which 3 members spanning 3 generations had a phenotype consistent with CMT2J. The 2 older members developed progressive hearing impairment in their late teens and distal muscle atrophy and weakness at least 10 years later. Both had slow or absent pupillary reactions, and both showed mildly decreased motor nerve conduction velocities (NCV) and extremely low compound muscle action potentials (CMAP), suggesting progressive axonal loss with secondary demyelination. Sural nerve biopsy of 1 patient showed profound loss of large myelinated fibers, multiple clusters of regenerated axonal sprouts, and no onion bulb formations. The youngest patient was a 13-year-old boy with mild hearing impairment and very slow pupillary reaction in the right eye. He had no symptoms of CMT. All 3 patients had a mutation in the MPZ gene (159440.0030). Seeman et al. (2004) emphasized that hearing loss was the presenting feature in this family.

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 had a heterozygous thr124-to-met mutation in the MPZ gene (T124M; 159440.0016); 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) discussed the case of a 57-year-old woman with numbness and weakness of the feet and legs. In adolescence, she had noted that her pupils were dilated, fixed, and unequal in size. In her early thirties, numbness developed over the anterior surfaces of her shins and ankles. In her early to mid-forties, she became unsteady when using the stairs or walking in the dark. Numbness in her legs increased and dysesthetic sensations developed in her feet. Examination at 47 years of age showed fixed, dilated pupils. Other cranial nerves were normal. There was atrophy of the intrinsic foot muscles but not of the legs. There was no orthostatic hypotension. Ankle jerks were absent; deep tendon reflexes were diminished in the arms and knees. There was reduced sensation to pinprick, light touch, vibration, and joint position in both legs below the knees and in both feet. Romberg sign was present. During the next 10 years her gait difficulty progressed gradually. She had occasional difficulty with bladder emptying. At the age of 57 years, the proband stated that she had some hearing loss. The father of the patient had had high-arched feet, poor balance, and dilated pupils all his life. In his fifties, numbness and weakness developed in his toes and feet, gradually spreading to his knees and affecting his hands; hearing loss, orthostatic hypotension, and impotence developed. Two of the 5 sibs of the proband had polyneuropathy. Her 33-year-old son had dilated pupils and a 27-year daughter had anisocoria. The patient was found to have the T124M mutation of the MPZ gene. The pupillary dysfunction in this family represents Adie pupil (103100), which is characterized by a poor pupillary light reaction, reduced accommodation, sector palsies of the iris, and enhanced pupillary response to near effort.

Kabzinska et al. (2007) reported a 2-generation family with late-onset axonal CMT associated with hearing loss. The proband presented at age 54 with clumsy gait and sensory loss in the distal parts of the upper and lower limbs since the age of 46. Neurologic examination showed weakness of the distal muscles of the lower limbs and hypertrophy of calf muscles with absent Achilles tendon reflexes. Audiometry showed left-sided severe sensorineural hearing loss of 20 to 60 dB in the high frequencies. The proband's brother had similar gait and sensory problems and, in spite of denying any hearing loss, his audiometry showed symmetric sensorineural hearing loss of 30 to 80 dB in the middle and high frequencies. Their mother and maternal aunt were also affected. Nerve conduction velocities in the proband corresponded to chronic axonal neuropathy with secondary demyelination. Although these patients did not present with hearing problems, Kabzinska et al. (2007) recommended performance of audiometry in the patients with late-onset CMT. Pupillary abnormalities were not observed.

Molecular Genetics

In 7 CMT2 families and 2 isolated CMT patients with the unique CMT2 phenotype, De Jonghe et al. (1999) identified a T124M mutation in the MPZ gene (159440.0016). 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. The affected family reported by Chapon et al. (1999) had the same T124M mutation in the MPZ gene.

All of the families reported by Misu et al. (2000) had a mutation in the MPZ gene: 4 families carried the T124M mutation and 3 carried a D75V mutation (159440.0019).

In affected members of a family with late-onset axonal CMT and progressive hearing loss, Kabzinska et al. (2007) identified a heterozygous mutation in the MPZ gene (159440.0034).

Nomenclature

In keeping with the most common designations used in the medical community, 'CMT1' referring to autosomal dominant demyelinating CMT and 'CMT2' referring to axonal CMT, we have chosen to designate this form of axonal CMT with hearing loss and pupillary abnormalities caused by mutation in the MPZ gene as 'CMT2J.'