The wide POLG-related spectrum: An integrated view

The aims of this study were to describe the spectrum of recessively inherited POLG-related disorders, to report new POLG mutations and to discuss genotype-phenotype correlations in order to propose a strategy for diagnosis. Twenty eight patients diagnosed with two POLG mutations at 12 tertiary European centers of adult neurology were studied. Exhaustive phenotypic data, brain MRI, muscle analysis, mitochondrial DNA and POLG analysis findings were collected. Five distinct phenotypes were observed: Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoparesis (SANDO), autosomal recessive Progressive External Ophthalmoplegia (arPEO), Spino Cerebellar Ataxia with Epilepsy (SCAE), Mitochondrial Neuro Gastro Intestinal Encephalopathy (MNGIE)-like phenotype and Sensory Ataxic Neuropathy with Ophthalmoparesis but without dysarthria which we propose to name SANG. An increasing gradient of functional severity was appreciated from PEO with the best prognosis, to SANG, SANDO and finally SCAE respectively. Four new missense mutations were found. Regarding genotype/phenotype correlations, P587L mutation was associated with SANG rather than with SANDO (p < 0.005) and W748S mutation was associated with SANDO or SCAE (with more severe disease progression), rather than with SANG or PEO (p < 0.004). Distinguishing between various phenotypes can have important diagnosis and prognosis implications. POLG mutations should be priority searched for in cases of SANDO or SANG. Mitochondrial respiratory chain and mitochondrial DNA studies should be considered in the case of negative POLG analysis or other phenotypes. (C) 2016 Elsevier B.V. All rights reserved.