The phenotypic spectrum of polymerase gamma (POLG) disease from birth to late adulthood

Variants in POLG, the gene encoding the catalytic subunit of DNA-polymerase gamma (polγ), the enzyme that replicates and repairs the mitochondrial genome, are among the most common causes of inherited mitochondrial disease. The clinical phenotypes of POLG disease are overlapping and extremely heterogeneous, making early clinical recognition challenging. The aim of my PhD project was to study the clinical spectrum and natural course of POLG disease in a large cohort of patients in order to provide a reliable clinical classification that was useful in both paediatric and adult populations, and to identify robust diagnostic and prognostic biomarkers which could facilitate early diagnosis and/or predict the prognosis. Multinational, retrospective studies of individuals recruited from 13 centres in seven European countries (Norway, Sweden, Denmark, Finland, Netherlands, Spain and the United Kingdom) were performed. Clinical, laboratory, neurophysiological, neuro-imaging, and genetic data were systematically collected using a standardized electronic, web-based clinical record form. The results of this project provide clear evidence that the clinical features of POLG disease are a continuum, i.e. the same spectrum of symptoms/features is found in all age groups. This allowed us to classify POLG disease more simply than the earlier attempts which only generated a plethora of syndromes with overlapping features. The project provides also an extensive phenotypic characterisation of patients with early onset disease and demonstrated the breadth of clinical manifestations and natural history of the disease in this age group. Highlighting the existence of POLG disease without seizures will improve diagnosis of those with early onset disease. The study cohort included individuals with disease onset from birth to late adulthood; this enabled us to study the clinical spectrum of the disease through all the ages. We could identify clear phenotypic and prognostic differences by grouping the patients simply using age of onset to: early onset, juvenile and adult, and late onset disease. We believe that our simplified classification will facilitate early clinical recognition, guide the investigation and predict the prognosis of the disease. Further, the results of this project showed that POLG disease is associated with blood brain barrier dysfunction and that the presence of raised cerebrospinal fluid protein/albumin can be used as a biomarker both for early diagnosis and to predict those who will be at risk to develop epilepsy. Moreover, the project revealed, for the first time, that anaemia is a feature of POLG disease, and the presence of anaemia is associated with significantly worse survival and can be used as a predictor for poor prognosis