Progressive External Ophthalmoplegia With Mitochondrial Dna Deletions, Autosomal Recessive 3

A number sign (#) is used with this entry because of evidence that autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions-3 (PEOB3) is caused by compound heterozygous mutation in the mitochondrial thymidine kinase gene (TK2; 188250) on chromosome 16q21. One such family has been reported.

For a discussion of genetic heterogeneity of autosomal recessive PEO, see PEOB1 (258450).

Clinical Features

Tyynismaa et al. (2012) reported 2 Finnish sisters, born of unrelated parents, with adult-onset progressive external ophthalmoplegia beginning in their forties. Both also developed progressive proximal muscle weakness associated with muscle atrophy. One had scapular winging and 1 developed dysarthria; both patients reported dysphagia. Each patient died of nonneurologic causes. Muscle biopsy indicated a mitochondrial myopathy with up to 10% COX-negative ragged-red fibers. MtDNA copy number analyzed in 1 patient (60% of control mean) did not fulfill criteria for mtDNA depletion (less that 40% of control mean).

Inheritance

The transmission pattern of PEOB3 in the family reported by Tyynismaa et al. (2012) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 Finnish sisters with adult-onset PEOB, Tyynismaa et al. (2012) identified compound heterozygous missense mutations in the TK2 gene (R225W, 188250.0007 and T230A, 188250.0008). The mutations were found by whole-exome sequencing. In vitro functional expression assays showed that these mutations carried some residual enzymatic activity, which correlated with the relatively mild phenotype in these patients. Tyynismaa et al. (2012) noted that disorders with mtDNA depletion or mtDNA deletion form a continuum of manifestations depending on the severity of the functional defect, and concluded that mutations in the TK2 gene may also cause adult-onset autosomal recessive PEO.