Congenital hearing impairment associated with peripheral cochlear nerve dysmyelination in glycosylation-deficient muscular dystrophy.

Author summary Hearing loss (HL) is one of the most common sensory impairments and heterogeneous disorders in humans. Up to 60% of HL cases are caused by genetic factors, and approximately 30% of genetic HL cases are syndromic. Although 400-700 genetic syndromes are associated with sensorineural HL (SNHL), caused due to problems in the nerve pathways from the cochlea to the brain, only about 45 genes are known to be associated with syndromic HL. Muscular dystrophies (MDs) are neuromuscular disorders characterized by progressive degeneration of skeletal muscle accompanied by non-muscular symptoms. MD-dystroglycanopathy (MD-DG), caused by aberrant glycosylation of alpha-dystroglycan, is an MD subtype with a wide spectrum of non-muscular symptoms. Despite a growing number of MD-DG subtypes (at least 18), no comprehensive study has investigated SNHL in MD-DG. Here, we found that hearing impairment was associated with abnormal myelination of the peripheral segment of the cochlear nerve caused by impaired dystrophin-dystroglycan complex in two mouse models (type 3 and 6) of MD-DG and in patients (type 4) with MD-DG. This is the first comprehensive study investigating SNHL in MD-DG. Our findings may provide new insights into understanding the pathogenic characteristics and mechanisms underlying inherited syndromic hearing impairment. Hearing loss (HL) is one of the most common sensory impairments and etiologically and genetically heterogeneous disorders in humans. Muscular dystrophies (MDs) are neuromuscular disorders characterized by progressive degeneration of skeletal muscle accompanied by non-muscular symptoms. Aberrant glycosylation of alpha-dystroglycan causes at least eighteen subtypes of MD, now categorized as MD-dystroglycanopathy (MD-DG), with a wide spectrum of non-muscular symptoms. Despite a growing number of MD-DG subtypes and increasing evidence regarding their molecular pathogeneses, no comprehensive study has investigated sensorineural HL (SNHL) in MD-DG. Here, we found that two mouse models of MD-DG, Large(myd/myd) and POMGnT1-KO mice, exhibited congenital, non-progressive, and mild-to-moderate SNHL in auditory brainstem response (ABR) accompanied by extended latency of wave I. Profoundly abnormal myelination was found at the peripheral segment of the cochlear nerve, which is rich in the glycosylated alpha-dystroglycan-laminin complex and demarcated by "the glial dome." In addition, patients with Fukuyama congenital MD, a type of MD-DG, also had latent SNHL with extended latency of wave I in ABR. Collectively, these findings indicate that hearing impairment associated with impaired Schwann cell-mediated myelination at the peripheral segment of the cochlear nerve is a notable symptom of MD-DG.