Progressive External Ophthalmoplegia With Mitochondrial Dna Deletions, Autosomal Dominant 4

A number sign (#) is used with this entry because autosomal dominant progressive external ophthalmoplegia (adPEO) with mitochondrial DNA (mtDNA) deletions-4 (PEOA4) is caused by heterozygous mutation in the nuclear-encoded DNA polymerase gamma-2 gene (POLG2; 604983) on chromosome 17q.

Description

Progressive external ophthalmoplegia-4 is an autosomal dominant form of mitochondrial disease that variably affects skeletal muscle, the nervous system, the liver, and the gastrointestinal tract. Age at onset ranges from infancy to adulthood. The phenotype ranges from relatively mild, with adult-onset skeletal muscle weakness and weakness of the external eye muscles, to severe, with a multisystem disorder characterized by delayed psychomotor development, lactic acidosis, constipation, and liver involvement (summary by Young et al., 2011).

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

Clinical Features

Longley et al. (2006) described a female patient with late-onset progressive external ophthalmoplegia (PEO) caused by heterozygous mutation in the gene encoding the catalytic subunit of DNA polymerase gamma (POLG2; 604983). The patient, aged 60 years, developed exercise intolerance and muscle pain by age 40, followed by ptosis, progressive external ophthalmoplegia, and mild weakness of the facial and limb muscles. She had impaired glucose tolerance, evidence of a cardiac conduction defect (left bundle branch block and intermittent bigeminy), and elevated serum creatine kinase. Her similarly affected mother was deceased; 2 sisters were unaffected. Skeletal muscle histochemistry revealed a mosaic cytochrome c oxidase (COX; see 123864) defect with 6% COX-negative fibers. Biochemical analysis of a skeletal muscle homogenate revealed normal respiratory chain complex activity. Southern blot analysis and long-range PCR of skeletal muscle mitochondrial DNA (mtDNA) revealed multiple mtDNA deletions. Real-time PCR of single muscle fibers detected high percentage levels of deleted mtDNA in the majority of COX-defective muscle fibers, typical of a multiple mtDNA deletion disorder. Longley et al. (2006) remarked that the patient had no specific clinical features that were different from 100 other PEO patients who were screened for mutations in POLG2 but had no mutation in the gene.

Young et al. (2011) reported 3 unrelated patients with PEOA4. There was large variability in clinical features and in severity. A 6-month-old boy was irritable and showed failure to thrive, lethargy, hypotonia, liver disease, and refractory seizures. A 19-year-old woman had progressive external ophthalmoplegia, exercise intolerance, easy fatigability, gastroesophageal reflux, delayed gastric emptying, respiratory insufficiency, lactic acidosis, and a history of failure to thrive. Muscle biopsy showed abnormal mitochondria. The third patient was an 8-year-old boy with neonatal hypotonia, developmental delay, seizures, constipation, abnormal liver enzymes, ketosis, cortical blindness, and cerebellar atrophy.

Molecular Genetics

Longley et al. (2006) screened for mutation in the POLG2 gene (604983) in 101 patients with PEO and multiple mtDNA deletions in skeletal muscle in whom no mutations in genes known to be associated with autosomal dominant PEO were found. They identified a heterozygous POLG2 mutation, G451E (604983.0001), in 1 patient. The smaller 55-kD accessory subunit (p55) of DNA polymerase gamma, encoded by the POLG2 gene, confers high processivity on the DNA polymerase gamma protein complex by increasing its affinity to DNA. Although G451E p55 retained a wildtype ability to bind DNA, it failed to enhance DNA-binding strength of the DNA polymerase gamma protein complex. The disorder was thought most likely to have arisen through haploinsufficiency or heterodimerization of the mutated and wildtype proteins, which promote mtDNA deletions by stalling the DNA replication fork. The progressive accumulation of mtDNA deletions causes cytochrome c oxidase (COX) deficiency in muscle fibers and results in the clinical phenotype.

Young et al. (2011) sequenced the POLG2 gene in 112 samples from patients suspected of having a defect in mtDNA replication, but who did not have mutations in the POLG gene (174763). Eight heterozygous POLG2 variants were identified in 8 patients and in 1 unaffected control. Detailed in vitro functional expression studies indicated that only 3 of the 7 novel variants, P205R (604983.0003), R369G (604983.0004), and a 2-bp deletion (1423delTT; 604983.0005), were functionally pathogenic. These mutant proteins showed variable defects in DNA binding, binding to the p140 catalytic component of mtDNA polymerase, and ability to stimulate p140-induced primer extension, indicating an impairment in processivity. The other variants identified, G103S, L153V, D386E, and S423Y, were believed to be polymorphisms because they showed activity similar to the wildtype protein in functional assays. The study emphasized the need to characterize biochemical consequences of variants quantitatively before classifying them as pathogenic.