Optic Atrophy 7 With Or Without Auditory Neuropathy

A number sign (#) is used with this entry because of evidence that optic atrophy-7 with or without auditory neuropathy (OPA7) is caused by homozygous mutation in the TMEM126A gene (612988) on chromosome 11q14.

For a discussion of genetic heterogeneity of optic atrophy, see OPA1 (165500).

Clinical Features

In a large multiplex inbred Algerian family and subsequently in 3 other Maghreb families, Hanein et al. (2009) identified an autosomal recessive juvenile-onset optic atrophy characterized by severe bilateral deficiency in visual acuity, optic disc pallor, and central scotoma. Onset was between 4 and 6 years of age. The peripheral visual field was strictly normal in all but the oldest patient, who lost it between the ages of 30 and 37 years. Polarographic tests and spectrophotometric assays on cultured skin fibroblasts showed normal respiratory chain function in a patient from one family but partial deficiency of complex I in a patient from another family. The latter patient presented with normal brain MRI but moderate hypertrophic cardiomyopathy. These features, along with the minor brain MRI alterations and mild hearing loss in the former patient, were suggestive of a mitochondrial dysfunction as previously noted in patients with Leber hereditary optic neuropathy (LHON; see 535000) or optic atrophy-1 (OPA1; 165500).

Meyer et al. (2010) described a sister and brother from a consanguineous family of Algerian origin who had poor vision from birth with progressive visual loss over time. Examination at ages 19 years and 17 years, respectively, showed visual acuity ranging from 20/200 to 20/400. The brother had right exotropia and bilateral horizontal nystagmus. Neither patient had any evidence of residual color vision, and Goldmann perimetry testing identified bilateral visual field constriction in both. Funduscopy revealed bilateral temporal optic nerve pallor with otherwise normal retinal findings. Full-field electroretinography (ERG) was normal in both patients, but the pattern ERG N95:P50 ratio was subnormal, with the P50 showing shortened peak time bilaterally in both patients. Optical coherence tomography (OCT) showed a marked global reduction in the retinal nerve fiber layer (RNFL) thickness. The electrophysiologic findings were consistent with bilateral retinal ganglion cell/optic nerve cell dysfunction. In addition, audiologic investigation in both sibs revealed abnormalities falling within the auditory neuropathy/dysynchrony spectrum. The patients reported no auditory or vestibular symptoms; there was good outer hair cell function, but inner hair cell/neural function was impaired, with abnormal stapedial reflex thresholds and abnormal or absent auditory brainstem-evoked responses.

Desir et al. (2012) studied a consanguineous Moroccan family in which 3 sibs were affected with optic atrophy. The proband had sudden bilateral loss of vision at age 16, at which time visual acuity was less than 20/400 bilaterally and was associated with severe dyschromatopsia, bilateral optic disc pallor, and absolute central scotoma. The standard ERG was normal, but OCT showed thinning of all RNFLs. At 33 years of age, he developed bilateral weakness of foot dorsiflexion with gait disturbance; peripheral neuropathy was suspected, and his symptoms improved with intravenous immunoglobulin. Brain CT scan was normal. Electrophysiologic evaluation at 36 years of age was suggestive of sensory-motor axonal neuropathy with focal demyelinating abnormalities. A 30-year-old brother and 20-year-old sister had visual complaints since childhood; examination revealed bilateral mild decreased vision, temporal pallor of discs, relative scotoma in the papillomacular area bilaterally, and dyschromatopsia. OCT scan in the brother showed temporal thinning of the RNFL. Another brother exhibited mild symptoms, consisting of transient partial loss of vision after exercise (Uhthoff phenomenon). Examination at age 28 years showed normal visual acuity and color vision, with no disc pallor on funduscopy.

Mapping

Using homozygosity mapping in a consanguineous multiplex family of Algerian ancestry with nonsyndromic autosomal recessive optic atrophy, Hanein et al. (2009) identified a unique region of homozygosity on chromosome 11q14.1-q21. The critical interval spanned 14.4 Mb and contained 40 known genes (maximum lod score Zmax = 3.73 with no recombination event at the D11S4187 locus).

In 2 affected and 2 unaffected sibs from a consanguineous family of Algerian origin with optic atrophy and auditory neuropathy, Meyer et al. (2010) performed genomewide SNP microarray genotyping and identified a 24.17-Mb region of homozygosity on chromosome 11, from SNPs rs10793396 to rs10895556. Analysis of microsatellite markers within the candidate region at 11q14.1-q22.3 confirmed that the affected sibs were homozygous and unaffected sibs were heterozygous.

In a consanguineous Moroccan family with optic atrophy, Desir et al. (2012) performed a genomewide search for homozygosity-by-descent and identified a 10.8-Mb homozygous region between SNPs rs2226615 and rs2048973 on chromosome 11q13.5-q14.2 that was concordant; analysis of microsatellite markers confirmed homozygosity in the 3 affected sibs.

Molecular Genetics

Because all optic atrophy genes known to that time encode mitochondrial proteins, Hanein et al. (2009) selected 3 genes from the OPA7 critical region predicted to encode mitochondrial proteins for mutation analysis. Hanein et al. (2009) identified a homozygous arg55-to-ter (R55X) mutation in the TMEM126A gene (612988.0001) in all affected family members of a large Algerian family as well as in 3 additional autosomal recessive optic atrophy families of Maghrebian origin (1 from Tunisia and 2 from Morocco). Haplotype analysis was consistent with a founder effect, and suggested that the R55X mutation originated approximately 2,400 years ago.

In a consanguineous family of Algerian origin with optic atrophy and auditory neuropathy mapping to chromosome 11q14.1-q22.3, Meyer et al. (2010) directly sequenced the candidate gene TMEM126A and identified homozygosity for the R55X mutation in the 2 affected sibs; the unaffected parents were heterozygous for the mutation. The authors suggested that auditory neuropathy might be a key feature of TMEM126A-associated optic neuropathy.

In 3 affected sibs from a consanguineous Moroccan family with optic atrophy mapping to 11q13.5-q14.2, Desir et al. (2012) identified homozygosity for the R55X mutation in the TMEM126A gene. The unaffected parents were heterozygous for R55X, as was a brother who had transient partial vision loss with exercise. The mutation was not found in 100 ethnically matched controls. Desir et al. (2012) noted that their patients had no hearing complaints but were not tested for auditory neuropathy.