Auditory Neuropathy And Optic Atrophy

A number sign (#) is used with this entry because of evidence that auditory neuropathy and optic atrophy (ANOA) is caused by homozygous or compound heterozygous mutation in the FDXR gene (103270) on chromosome 17q25.

Description

ANOA is an autosomal recessive neurologic disorder characterized by onset of visual and hearing impairment in the first or second decades (summary by Paul et al., 2017).

Clinical Features

Paul et al. (2017) reported 8 patients from 4 unrelated families with sensorineural neuropathies affecting vision and hearing. The families were of various ethnicities, including Tunisian, Algerian, French, and Russian. The patients had onset of hearing loss and visual impairment in the first or second decades. Acoustic workup showed auditory neuropathy, based on severe impaired auditory brainstem responses (ABRs), discrepancies between tonal and vocal audiometry, and the presence of otoacoustic emissions in both ears. Ophthalmologic workup showed variable abnormalities, including optic atrophy, decreased visual evoked potentials, and papilledema with disc pallor. All had normal psychomotor development except 1 patient who had slight language delay. One patient was diagnosed with retinitis pigmentosa at 2 years of age because of low vision and nystagmus; electroretinogram (ERG) waves were undetectable and the fundus was altered. At age 20 years, this patient developed auditory neuropathy and showed complete ophthalmoplegia with retinitis pigmentosa and optic atrophy.

Inheritance

The transmission pattern of ANOA in the families reported by Paul et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 8 patients from 4 unrelated families with ANOA, Paul et al. (2017) identified homozygous or compound heterozygous mutations in the FDXR gene (103270.0001-103270.0004). The mutation in the first family was found by exome sequencing and confirmed by Sanger sequencing; mutations in subsequent patients were found by direct sequencing of the FDXR gene. Fibroblasts derived from patients in 2 of the families showed decreased levels of FDXR compared to controls. Activity of iron-sulfur cluster (ISC)-containing enzymes (e.g., SDHB, 185470) and levels of heme oxygenase (see HMOX1, 141250) were decreased; decreased activities of mitochondrial complexes I and III, and variable decreases of complex IV and V were also observed. Patient cells showed increased iron uptake and increased mitochondrial oxidative stress, consistent with a defect in iron homeostasis. Expression of some of the mutations failed to fully rescue growth defects in yeast with deletion of the FDXR ortholog arh1, whereas wildtype FDXR was able to rescue the defect. The findings indicated that the mutations are deleterious to FDXR function.