Polg Mutation–Related Mitochondrial Disease Presenting With Progressive Cerebellar Ataxia: A Case Report and Review of The Literature
Keywords:
POLG; mitochondrial disease; W748S; cerebellar ataxia; sensory neuropathy; mitochondrial DNA polymerase gamma; whole-exome sequencing; neuroimaging.Abstract
Background
POLG-related mitochondrial disorders are a heterogeneous group of inherited diseases caused by pathogenic variants in the POLG gene, which encodes the catalytic subunit of mitochondrial DNA polymerase gamma. Neurological manifestations range from developmental regression and epilepsy to cerebellar ataxia, peripheral neuropathy, cognitive impairment, and progressive neurological decline.
Case Presentation
A 28-year-old woman presented with approximately 9 years of progressive giddiness, recurrent falls, gait imbalance, sensory symptoms involving both lower limbs, headache, behavioral abnormalities, and developmental regression. She was born to second-degree consanguineous parents and had a history of delayed speech followed by poor scholastic performance and cognitive decline. Neurological examination revealed an MMSE score of 13/30, scanning speech, impaired multiple sensory modalities in both lower limbs, limb incoordination, positive Romberg sign, stance and gait ataxia, and reeling gait. Brain MRI demonstrated symmetrical T2/FLAIR hyperintensities involving the bilateral thalami, midbrain tegmentum, pons, and cerebellar hemispheres, with sparing of the dentate nuclei and basal ganglia. There was no significant enhancement or definite spinal cord involvement. Whole-exome sequencing identified a homozygous POLG p.Trp748Ser (W748S) missense variant.
Conclusion
This case highlights the clinical and radiological heterogeneity of POLG-related mitochondrial disease. Progressive cerebellar ataxia associated with sensory dysfunction, cognitive/developmental regression, characteristic bilateral MRI abnormalities, consanguinity, and a biallelic pathogenic POLG variant should prompt consideration of a POLG-related disorder. Molecular genetic testing is particularly useful when clinical and radiological findings overlap with other inherited metabolic and neurodegenerative disorders.
