POLG – Autosomal Recessive Progressive External Ophthalmoplegia

Autosomal recessive progressive external ophthalmoplegia (arPEO) is a mitochondrial disorder characterized by chronic ophthalmoparesis, dysarthria, and sensory ataxic neuropathy. The nuclear-encoded DNA polymerase gamma, POLG, is essential for mitochondrial DNA replication and repair. Pathogenic variants in POLG disrupt enzyme activity, leading to accumulation of mtDNA deletions and depletion, hallmarks of arPEO.

Initial case reports described two nuclear families and one sporadic patient presenting with the clinical triad of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO). All carried compound heterozygous POLG missense alleles, including the novel c.1879C>T (p.Arg627Trp) identified in the sporadic case (PMID:12565911). The common c.1399G>A (p.Ala467Thr) allele co-segregated in Belgian families at a carrier frequency of 0.6%.

A subsequent family study with features overlapping mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) but without TP mutations reported two affected siblings harboring three POLG missense substitutions: c.752C>T (p.Thr251Ile), c.1760C>T (p.Pro587Leu), and a previously described c.2591A>G (p.Asn864Ser), implicating POLG in arPEO phenotypes (PMID:12825077). This underscores the allelic heterogeneity and expands the phenotypic spectrum.

In total, at least 5 probands from 3 unrelated families have been described with arPEO and compound heterozygous POLG variants, with segregation in 4 additional affected relatives. These findings demonstrate autosomal recessive inheritance and consistent co-segregation of POLG alleles with disease.

Functional assays reveal that the A467T mutant polymerase retains only 4% of wild-type activity and fails to engage the accessory subunit, compromising processivity and catalytic efficiency (PMID:16024923). Structure–function studies of polymerase-domain variants (e.g., Y955C, R943H) show 0.03–30% residual activity and altered nucleotide selectivity, correlating with clinical severity (PMID:15258572). These data support a loss-of-function mechanism via haploinsufficiency.

Together, robust genetic segregation and concordant biochemical defects provide strong evidence that recessive POLG mutations cause arPEO. Clinical testing of POLG should be prioritized in patients with unexplained ophthalmoparesis and associated neuropathic features. Key Take-home: POLG variant analysis is clinically actionable for diagnosis and genetic counseling in arPEO.

References

• Neuromuscular Disorders • 2003 • Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia. PMID:12565911
• European Journal of Human Genetics • 2003 • Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy. PMID:12825077
• Nature Structural & Molecular Biology • 2004 • Structure-function defects of human mitochondrial DNA polymerase in autosomal dominant progressive external ophthalmoplegia. PMID:15258572
• The Journal of Biological Chemistry • 2005 • The common A467T mutation in the human mitochondrial DNA polymerase (POLG) compromises catalytic efficiency and interaction with the accessory subunit. PMID:16024923

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