Progressive External Ophthalmoplegia With Mitochondrial Dna Deletions, Autosomal Dominant 5

A number sign (#) is used with this entry because autosomal dominant progressive external ophthalmoplegia (adPEO) with mitochondrial DNA (mtDNA) deletions-5 (PEOA5) is caused by heterozygous mutation in the nuclear-encoded RRM2B gene (604712) on chromosome 8q23.1.

For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant progressive external ophthalmoplegia, see PEOA1 (157640).

See also autosomal recessive mitochondrial DNA depletion syndrome (612075), which is caused by homozygous or compound heterozygous mutations in the RRM2B gene.

Clinical Features

Tyynismaa et al. (2009) reported a large 4-generation North American family of European origin in which 13 individuals had autosomal dominant progressive external ophthalmoplegia. The diagnosis was based on the finding of ophthalmoparesis and ptosis with onset late in the second decade or in adult life. Some patients had restricted eye movements without ptosis. In addition, some patients experienced easy muscle fatigue with exercise. Skeletal muscle biopsies showed fibers deficient in cytochrome c oxidase activity and multiple mtDNA deletions. In a second family of Hungarian origin, the proband was a 40-year-old man who had exercise intolerance and bilateral ptosis since his twenties. Neurologic exam revealed external ophthalmoplegia, hypoacusis, decreased reflexes, and mild gait ataxia. He also had depressive mood, anxiety, moderate cognitive dysfunction, and alcohol abuse. His brother, mother, and maternal uncle also had external ophthalmoplegia.

Fratter et al. (2011) reported 7 unrelated patients with PEOA5 confirmed by genetic analysis (see, e.g., 604712.0010 and 604712.0011). All had a family history of the disorder. All 7 patients had PEO with variable additional features, including ptosis (6), fatigue (5), dysphagia (4), proximal myopathy (2), dysarthria (2), ataxia (2), and gastrointestinal symptoms (2). One patient had diabetes. Skeletal muscle biopsy showed a mosaic defect of cytochrome c oxidase activity and multiple mtDNA deletions.

Inheritance

The transmission pattern of PEO in the families reported by Tyynismaa et al. (2009) was consistent with autosomal dominant inheritance.

Recessive inheritance of this disorder due to homozygous or compound heterozygous missense variations in the RRM2B gene has been suggested (Takata et al., 2011; Fratter et al., 2011).

Molecular Genetics

By linkage analysis followed by candidate gene sequencing in a large North American family with autosomal dominant PEO, Tyynismaa et al. (2009) identified a heterozygous mutation in the RRM2B gene (R327X; 604712.0001) that segregated with the disorder. Affected members of an unrelated Hungarian family carried the same mutation, but there was no evidence of a common origin.

By direct sequencing of the RRM2B gene in 75 unrelated probands with PEO in whom mutations in other known genes had been excluded, Fratter et al. (2011) identified 3 different heterozygous truncating mutations in the RRM2B gene (see, e.g., 604712.0010 and 604712.0011) in 7 (9.3%) patients. The findings suggested that RRM2B mutations are rather frequent in familial PEO with mtDNA deletions. Three additional patients were found to carry 3 different heterozygous missense variants, but the pathogenicity of the variants was considered provisional in the absence of further supporting evidence.