POLG R964C and GBA L444P mutations in familial Parkinson's disease: Case report and literature review

Polymerase gamma (POLG) is an enzyme responsible for the replication and repair of mitochondrial DNA. Mutations in POLG may cause variable clinical manifestations, including parkinsonism, epilepsy, cerebellar ataxia, neuropathy, and progressive external ophthalmoplegia. However, mutations of this gene are rare in patients with typical Parkinson's disease (PD). We report a man (current age: 59 years) without any underlying disease presenting with right-hand tremor at the age of 39 years, followed by slow movement, rigidity, and postural instability. He developed motor fluctuation and levodopa-induced dyskinesia 8 years later. At the age of 58 years, cognitive decline and visual hallucination ensued; he was institutionalized thereafter. We used multiplex ligation-dependent probe amplification, which demonstrated no large deletions or duplications of relevant PD genes. Next, targeted sequencing panel covering 51 genes causative for PD was applied for the proband; it revealed a heterozygous missense substitution R964C in POLG and a heterozygous missense substitution L444P in GBA. The patient's father, who had been diagnosed as having PD and type 2 diabetes mellitus at the age of 70 years, demonstrated identical mutations. This is the first report of familial PD combined with POLG R964C and GBA L444P mutations. Two pathogenic gene mutations potentially cause double hit in pathological neurodegeneration. This finding extends our understanding of the PD genotype–phenotype correlation.