POLG – Spinocerebellar Ataxia with Epilepsy

Molecular screening of genes affecting mitochondrial DNA stability in 15 unrelated patients with multiple mtDNA deletions or depletion identified six recessive mutations in POLG in individuals presenting with cerebellar ataxia and epilepsy (PMID:16639411). These six probands harbor three novel missense variants among others, including c.2740A>C (p.Thr914Pro). Further biochemical characterization demonstrated that the p.Thr914Pro substitution compromises initiation of lagging-strand DNA synthesis, leading to mtDNA deletions and accumulation of neuronal dysfunction consistent with the spinocerebellar ataxia with epilepsy phenotype (PMID:23446635). Collectively, these data provide limited but emerging evidence for an autosomal recessive association between POLG and spinocerebellar ataxia with epilepsy. Regular POLG genotyping should be considered in unexplained ataxia-epilepsy cases to support diagnosis and genetic counselling.

References

• European journal of human genetics • 2006 • Molecular analysis of ANT1, TWINKLE and POLG in patients with multiple deletions or depletion of mitochondrial DNA by a dHPLC-based assay. PMID:16639411
• Human molecular genetics • 2013 • Subnormal levels of POLγA cause inefficient initiation of light-strand DNA synthesis and lead to mitochondrial DNA deletions and progressive external ophthalmoplegia PMID:23446635

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