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Background: Variants in POLG are one of the most common causes of inherited mitochondrial disease. Phenotypic classification of POLG disease has evolved haphazardly making it complicated and difficult to implement in everyday clinical practise. The aim of our study was to simplify the classification and facilitate better clinical recognition. Methods: A multinational, retrospective study using data from 155 patients with POLG variants recruited from seven European countries. Results: We describe the spectrum of clinical features associated with POLG variants in the largest known cohort of patients. While clinical features clearly form a continuum, stratifying patients simply according to age of onset—onset prior to age 12 years; onset between 12 and 40 years and onset after the age of 40 years, permitted us to identify clear phenotypic and prognostic differences. Prior to 12 years of age, liver involvement (87%), seizures (84%), and feeding difficulties (84%) were the major features. For those with onset between 12 and 40 years, ataxia (90%), peripheral neuropathy (84%), and seizures (71%) predominated, while for those with onset over 40 years, ptosis (95%), progressive external ophthalmoplegia (89%), and ataxia (58%) were the major clinical features. The earlier the onset the worse the prognosis. Patients with epilepsy and those with compound heterozygous variants carried significantly worse prognosis. Conclusion: Based on our data, we propose a simplified POLG disease classification, which can be used to guide diagnostic investigations and predict disease course.

Objective: To study the impact of gender, puberty, and pregnancy on the expression of POLG disease, one of the most common mitochondrial diseases known. Methods: Clinical, laboratory, and genetic data were collected retrospectively from 155 patients with genetically confirmed POLG disease recruited from seven European countries. We used the available data to study the impact of gender, puberty, and pregnancy on disease onset and deterioration. Results: We found that disease onset early in life was common in both sexes but there was also a second peak in females around the time of puberty. Further, pregnancy had a negative impact with 10 of 14 women (71%) experiencing disease onset or deterioration during pregnancy. Interpretation: Gender clearly influences the expression of POLG disease. While onset very early in life was common in both males and females, puberty in females appeared associated both with disease onset and increased disease activity. Further, both disease onset and deterioration, including seizure aggravation and status epilepticus, appeared to be associated with pregnancy. Thus, whereas disease activity appears maximal early in life with no subsequent peaks in males, both menarche and pregnancy appear associated with disease onset or worsening in females. This suggests that hormonal changes may be a modulating factor.