Myelin protein zero mutation His39Pro: hereditary motor and sensory neuropathy with variable onset, hearing loss, restless legs and multiple sclerosis

Background

Mutations of myelin protein zero (MPZ) may cause inherited neuropathy with variable expression.

Objective

To report phenotypic variability in a large American kindred with MPZ mutation His39Pro.

Patients

Genetic testing was performed on 77 family members and 200 controls. Clinical and electrophysiological field study assessments were available for review in 47 family members.

Results

His39Pro was found in all 10 individuals prospectively identified with neuropathy. 200 normal controls were without mutation. Symptoms of neuropathy began in adulthood and were slowly progressive except for one acute-onset painful sensory neuropathy. Associated features included premature hearing loss (n  =  7), nocturnal restless leg symptoms (n = 8) and multiple sclerosis in one.

Conclusions

MPZ mutation His39Pro may be associated with acute-onset neuropathy, early‐onset hearing loss and restless legs. The relationship with multiple sclerosis in the proband remains uncertain. Among inherited neuropathies, attempts at correlating phenotype with genotype have met with variable success. Success depends on the specific gene, number of patients studied and the methods by which clinical involvement was ascertained. Of the different genetic causes of hereditary motor and sensory neuropathies, myelin protein zero (MPZ) mutations account for considerable variability, with more than 90 mutations described.¹ Variable degrees of hearing loss,^2,3 pupillary areflexia to light and accommodation,³ and diaphragmatic weakness⁴ or chronic cough⁵ have been reported. Frequent association with restless‐leg‐like symptoms has not been established. The clinical and electrophysiological variability in patients with MPZ mutations may be seen even among monozygotic twins.⁶ Previous studies on families with MPZ mutations were usually carried out on a small number of people. In the kinship reported here, many family members and other controls were studied.On the basis of multiple lines of evidence, changes in immunity represent an attractive potential modifying mechanism for the varied presentations of MPZ mutations.^7,8,9 Rare mutations of the peripheral myelin proteins (PMP22) and connexin 32 have been associated with changes in the central nervous system (CNS) on imaging, characteristic of multiple sclerosis and acute disseminated encephalomyelitis, respectively.^{10,11,12,13,14} In this report, we present data on a large family with the MPZ mutation His39Pro and describe the varied phenotypes seen in the kindred, including one case of acute‐onset painful neuropathy, hearing loss, restless legs and relapsing remitting multiple sclerosis.