Leber Congenital Amaurosis With Early-Onset Deafness

A number sign (#) is used with this entry because of evidence that Leber congenital amaurosis with early-onset deafness (LCAEOD) is caused by heterozygous mutation in the TUBB4B gene (602660) on chromosome 9q34.

Description

Leber congenital amaurosis with early-onset deafness is an autosomal dominant syndrome manifesting as early-onset and severe photoreceptor and cochlear cell loss. Some patients show extinguished responses on electroretinography and moderate to severe hearing loss at birth (Luscan et al., 2017).

Clinical Features

Luscan et al. (2017) studied 4 families in which 5 affected individuals exhibited early-onset retinal degeneration and hearing loss. Diagnosis of eye disease occurred by age 3 years, with 3 of the 5 patients showing no responses on electroretinography (ERG) at birth. Funduscopy showed features of advanced retinitis pigmentosa in a 34-year-old affected French woman (family 1), who had marked reduction in caliber of retinal vessels, generalized choroid atrophy, marked macular rearrangement, and numerous peripheral pigmentary deposits. Her 5.5-year-old affected son showed similar abnormalities, although to a much lesser extent. Hearing loss in the 5 patients was diagnosed within the first decade of life, and ranged from mild to severe. Vocal audiograms of the affected mother and son from family 1 were consistent with pure-tone traces, suggesting endocochlear deafness. The maternal grandmother from family 1, who developed hearing loss in her fourth decade and reported no vision problems, had retinal degeneration on fundus examination and optical coherence tomography, but photopic and scotopic ERGs were normal. All patients had normal neurologic and psychomotor development, and brain MRI was normal in an affected Danish boy (family 4) at age 2 months. The authors designated the severe and early-onset retinal degeneration seen in these patients to be consistent with advanced Leber congenital amaurosis type 2 (see LCA2, 204100), although they noted that all 5 had high hypermetropia, which was atypical for LCA2.

Molecular Genetics

By whole-exome sequencing in 3 affected members of a family (family 1) with early-onset retinal degeneration and hearing loss, Luscan et al. (2017) identified heterozygosity for a missense mutation in the TUBB4B gene (R391H; 602660.0001) in the affected mother and son. The maternal grandmother, who had milder symptoms, was found to be mosaic for the mutation, which was present in 29% of reads and had arisen de novo. Analysis of an in-house whole-exome sequencing database identified 3 more probands with LCAEOD and mutations in TUBB4B, 2 with the same R391H mutation, and 1 with an R391C substitution (602660.0002). In 2 of the families, the mutation was shown to have arisen de novo, but in the third family (family 2), the mutation was inherited from an unaffected mosaic father, in whom the variant was present in only 13% of reads.