Optic Atrophy 10 With Or Without Ataxia, Mental Retardation, And Seizures

A number sign (#) is used with this entry because of evidence that optic atrophy-10 (OPA10) with or without ataxia, mental retardation, and seizures can be caused by homozygous or compound heterozygous mutation in the RTN4IP1 gene (610502) on chromosome 6q21.

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

Clinical Features

Angebault et al. (2015) studied a consanguineous Moroccan family in which a brother and sister, aged 52 years and 41 years, respectively, had low vision from early childhood without any other symptoms. Fundus examination showed moderate bilateral optic disc pallor, and optical coherence tomography (OCT) revealed a marked decrease in the thickness of the retinal nerve fiber layer temporally, suggestive of mitochondrial hereditary optic atrophy. Angebault et al. (2015) also studied 2 sisters, born of nonconsanguineous parents, who were 14 and 12 years old, respectively, and had severe bilateral optic neuropathy associated with nystagmus as well as a mild statokinetic cerebellar syndrome and learning disabilities. The older sister was more severely affected, with mild mental retardation and generalized seizures that began at age 3 years. Fundus examination in both sisters showed abnormal optic discs, which appeared to be small, with horizontal orientation, and pale over the entire surface, suggestive of hypoplasia. The thickness of the retinal nerve fiber layer was dramatically reduced in all quadrants. There was no detectable visual evoked potential, and optic tracts were thin on brain MRI, indicating severe alteration of the optic path. The brain was otherwise normal, as were cardiac and neuromuscular examinations.

Mapping

In a consanguineous Moroccan family in which 2 sibs had optic atrophy, Angebault et al. (2015) performed SNP genotyping and identified 4 homozygous regions, on chromosomes 1, 6, 18, and 22.

Molecular Genetics

In a consanguineous Moroccan family in which 2 sibs had optic atrophy, Angebault et al. (2015) performed exome sequencing and identified a homozygous missense mutation in the RTN4IP1 gene (R103H; 610502.0001) that segregated with disease. Screening of RTN4IP1 in a cohort of 240 European probands with inherited optic neuropathy revealed 2 simplex-case individuals of Roma origin who were homozygous for the same R103H mutation on the same haplotype, suggesting a founder effect. In addition, 2 sisters from a nonconsanguineous family who had optic neuropathy associated with ataxia, mental retardation, and seizures were compound heterozygous for R103H and a nonsense mutation in RTN4IP1 (K201X; 610502.0002).