Phenotypic Variability of Polymerase Gamma–Associated Ataxia

Abstract Objective: Mutations in the mitochondrial DNA polymerase gamma (POLG) are causing a wide spectrum of overlapping disorders, including ataxia as one of the most common presentations. Our study was to determine the clinical, electrophysiological, neuroimaging, and genetic characteristics of the POLG-associated ataxias (POLG-A). Methods: We assessed 3 adult ataxia patients with biallelic POLG mutations for exhaustive phenotypes, follow-up data, and accessory investigations, consisting of blood chemistry, metabolic survey, cerebral fluid analysis, electromyography (EMG), nerve conduction velocity (NCV), electroencephalogram (EEG), brain MRI, muscle biopsy, and gene sequencing. Results: In these 3 POLG-A patients, ataxia was one of the first and dominant presentations, and aggravated gradually. Significant proprioceptive loss caused by sensory neuropathy indicated that sensory ataxias prevailed over cerebellar ones. Clusters of non-ataxia phenotypes consisted of ophthalmoplegia, ptosis, dysarthria, dysphagia and exercise intolerance in Patient2 and Patient3, epileptic seizures in Patient1. Consequently, Patient2 and Patient3 were identified as sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO), while Patient 1 conformed to spinal cerebellar ataxia with epilepsy (SCAE). Brain imaging seemed noncontributory. The final diagnosis relies on the molecular finding of deleterious mutations in POLG. Conclusions: We confirm that the presence of prominent ataxia, mainly due to sensory neuropathy, especially when companied by diverse associations of muscle weakness involving ocular and pharyngeal muscle, epilepsy, exercise intolerance, hearing loss, should guide clinicians towards POLG-A.