Molecular and clinical genetics of mitochondrial diseases due toPOLGmutations

Abstract

Mutations in the POLG gene have emerged as one of the most common causes of inherited mitochondrial disease in children and adults. They are responsible for a heterogeneous group of at least 6 major phenotypes of neurodegenerative disease that include: 1) childhood Myocerebrohepatopathy Spectrum disorders (MCHS), 2) Alpers syndrome, 3) Ataxia Neuropathy Spectrum (ANS) disorders, 4) Myoclonus Epilepsy Myopathy Sensory Ataxia (MEMSA), 5) autosomal recessive Progressive External Ophthalmoplegia (arPEO), and 6) autosomal dominant Progressive External Ophthalmoplegia (adPEO). Due to the clinical heterogeneity, time-dependent evolution of symptoms, overlapping phenotypes, and inconsistencies in muscle pathology findings, definitive diagnosis relies on the molecular finding of deleterious mutations. We sequenced the exons and flanking intron region from approximately 350 patients displaying a phenotype consistent with POLG related mitochondrial disease and found informative mutations in 61 (17%). Two mutant alleles were identified in 31 unrelated index patients with autosomal recessive POLG-related disorders. Among them, 20 (67%) had Alpers syndrome, 4 (13%) had arPEO, and 3 (10%) had ANS. In addition, 30 patients carrying one altered POLG allele were found. A total of 25 novel alterations were identified, including 6 null mutations. We describe the predicted structural/functional and clinical importance of the previously unreported missense variants and discuss their likelihood of being pathogenic. In conclusion, sequence analysis allows the identification of mutations responsible for POLG-related disorders and, in most of the autosomal recessive cases where two mutant alleles are found in trans, finding deleterious mutations can provide an unequivocal diagnosis of the disease.

Mitochondrial Disease in Childhood: Nuclear Encoded

“…It presents with developmental delay, encephalopathy, dementia, myopathy, and hypotonia. Other features include failure to thrive, lactic acidosis, liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss [67]. Similar to the presentation of AHS, MCHS presents early in life with hepatopathy, encephalopathy, and a fatal outcome.…”

“…This disorder was previously referred to as sensory ataxia, neuropathy, dysarthria and ophthalmoplegia. In contrast to myoclonic epilepsy myopathy sensory ataxia, it is characterized by the presence of PEO and absence of significant myopathy [66,67]. Muscle pathology is often normal.…”

“…Psychiatric disturbance is a common feature. Other features include myoclonus, blindness, hearing loss, and a varying degree of liver failure [67].…”

Quantitative multiplex PCR of short fluorescent fragments for the detection of large intragenic POLG rearrangements in a large French cohort

“…The catalytic subunit contains three different domains: a 3 0 -5 0 exonuclease domain, a 'linker' domain and a highly conserved polymerase domain. 1 Mutations in POLG have been identified in severe mtDNA depletion syndromes, such as Alpers syndrome, as well as in mtDNA multiple deletion disorders such as ataxia, chronic progressive external ophthalmoplegia (CPEO), mitochondrial recessive ataxia syndrome, sensory ataxic neuropathy with dysarthria and ophthalmoparesis (SANDO) and spinocerebellar ataxia with epilepsy (SCAE) [2][3][4][5] (http://tools.niehs.nih.gov/polg/). Most of these mutations were missense mutations.…”

“…Nonsense mutations, splice-site mutations, small deletions and insertions have also been described. 5 To date, only one large-scale rearrangement involving POLG has been identified by array-CGH, but in most laboratories, the detection of large-scale rearrangements is not performed as a routine analysis. 6,7 In this study, we performed POLG sequencing in 160 French patients presenting a phenotype compatible with POLG deficiency.…”