Deafness, X-Linked 5

A number sign (#) is used with this entry because of evidence that X-linked deafness-5 (DFNX5) is caused by hemizygous mutation in the AIFM1 gene (300169) on chromosome Xq26.

Description

X-linked deafness-5 is a neurologic disorder characterized by childhood onset of auditory neuropathy and later onset of distal sensory impairment affecting the peripheral nervous system (summary by Zong et al., 2015).

Clinical Features

Wang et al. (2006) studied an extended 5-generation Chinese family with a form of deafness referred to as auditory neuropathy. The family had originally been described by Wang et al. (2003). Auditory neuropathy is a type of hearing disorder defined by the preservation of outer hair cell function with abnormal or absent auditory brainstem responses and mild to profound hearing loss (Starr et al., 2000; Starr et al., 2004; Wang et al., 2003). Affected members in the family reported by Wang et al. (2006) had type I auditory neuropathy involving primary degeneration of the auditory nerve (i.e., axons) accompanied by late-onset peripheral neuropathy. Neurologic examination revealed diffuse peripheral sensory neuropathy. Nerve conduction evaluation showed that the sensory nerve potential was not induced in the bilateral median, ulnar, peroneal, tibial, and sural nerves in 1 patient, in the left median and ulnar nerves in a second, and in the right median and bilateral sural nerves in a third. Motor nerve conduction was normal in all 3 affected individuals tested. Wang et al. (2006) noted that the combination of auditory neuropathy and peripheral sensory neuropathy had been reported before (Satya-Murti et al., 1979).

Zong et al. (2015) reported 14 patients from 4 Chinese families with childhood-onset auditory neuropathy and delayed peripheral sensory neuropathy presenting as extremity numbness, unsteadiness, and areflexia. Electrophysiologic studies performed in some patients showed reduced or absent sural, median, and ulnar sensory nerve conduction velocities and sensory action potential amplitudes (SNAPs), whereas motor nerve results were normal. Both the hearing impairment and sensory neuropathy were slowly progressive. Brain imaging of the internal auditory canals showed bilateral cochlear nerve hypoplasia. All patients had normal cognitive function, and none had muscle weakness or atrophy. Eleven Chinese patients with sporadic occurrence of the disorder were also reported; the phenotype was similar to the familial cases, although not all patients had symptoms of peripheral neuropathy.

Inheritance

The transmission pattern of deafness in the family reported by Wang et al. (2006) was consistent with X-linked recessive inheritance.

Mapping

By linkage analysis, Wang et al. (2006) mapped a locus for a form of auditory and peripheral neuropathy in a Chinese family to Xq23-q27.3; both the maximum 2-point and multipoint lod scores were 2.41. Haplotype analysis confirmed this localization between markers DXS1220 and DXS8084. Wang et al. (2006) identified no causative mutations in a candidate gene in this region, SLCA14 (300444).

In a review of sex-linked deafness, Petersen et al. (2008) noted that the AUNX1 locus overlaps with CMTX4 (310490) and CMTX5 (311070), both of which also show hearing loss and peripheral neuropathy.

Molecular Genetics

In affected male members of 5 unrelated Chinese families with X-linked deafness-5, Zong et al. (2015) identified 5 different hemizygous missense mutations in the AIFM1 gene (300169.0003-300169.0007). Mutations in the first 2 families, including the family originally reported by Wang et al. (2006), were found by whole-exome sequencing and confirmed by Sanger sequencing. Screening of this gene identified the same or additional hemizygous mutations in 11 (10%) of 93 men with sporadic auditory sensory disorder. The mutations segregated with the disorder in the families, and female carriers were unaffected. Of the 11 different missense variants identified, most occurred in the NADH and second FAD domains of the protein, which are essential for FAD-dependent NADH oxidoreductase. Functional studies of the variants were not performed.

Nomenclature

Petersen et al. (2008) suggested that the designation AUNX1 was not accurate since the disorder is not a nonsyndromic form of auditory neuropathy as patients also develop diffuse peripheral neuropathy. Petersen et al. (2008) proposed the designation DFNX5.