Mitochondrial DNA polymerase   mutations: an ever expanding molecular and clinical spectrum

Abstract

Mutations in the POLG gene have emerged as one of the most common causes of inherited mitochondrial diseases in children and adults. This study sequenced the exons and flanking intronic regions of the POLG gene from 2697 unrelated patients with clinical presentations suggestive of POLG deficiency. Informative mutations have been identified in 136 unrelated individuals (5%), including 92 patients with two recessive pathogenic alleles and three patients harbouring a dominant mutation. Twenty-four novel recessive mutations and a novel possible dominant mutation, p.Y951N, were identified. All missense mutations occurred at evolutionarily conserved amino acids within functionally important regions identified by molecular modelling analyses. Oligonucleotide array comparative genomic hybridisation analyses performed on DNA samples from 81 patients with one mutant POLG allele identified a large intragenic deletion in only one patient, suggesting that large deletions in POLG are rare. The 92 patients with two mutant alleles exhibited a broad spectrum of disease. Almost all patients in all age groups had some degree of neuropathy. Seizures, hepatopathy, and lactic acidaemia were predominant in younger patients. By comparison, patients who developed symptoms in adulthood had a higher percentage of myopathy, sensory ataxia, and chronic progressive external ophthalmoplegia (CPEO)/ptosis. In conclusion, POLG mutations account for a broad clinical spectrum of mitochondrial disorders. Sequence analysis of the POLG gene should be considered as a part of routine screening for mitochondrial disorders, even in the absence of apparent mitochondrial DNA abnormalities.

Mitochondrial Disease in Childhood: Nuclear Encoded

“…An updated map for these mutations is available at http://tools.niehs.nih.gov/polg/ [57]. POLG-related disorders are categorized into 6 recognizable phenotypes; however, the 2 PEO phenotypes are typically adult-onset disorders [58][59][60]. Childhood-onset manifestations of POLG include the following.…”

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

“…7 Children (age of onset 15 months-10 years) presented seizures, developmental delay and hepatopathy, whereas peripheral neuropathy, ataxia, myopathy and CPEO/ptosis were found in adult individuals (age of onset 15-63 years). Five patients presented with a refractory EPC or recurrent status epilepticus, among which only one had hepatic involvement.…”

“…She was heterozygous for the p.Pro1073Leu mutation, previously described in recessive hepatic encephalopathy. 7,16 Patient 15 was a 14-year-old boy born of healthy consanguineous parents. He presented delayed psychomotor development and muscular weakness associated with hepatopathy.…”

“…Patients were diagnosed in French referral centers and presented a phenotype compatible with POLG mutations. 7 mtDNA molecular analysis Total DNA was extracted using standard phenol-chloroform procedure. Long-range PCR was performed as described previously 8 and Southern blot was used when deletions were detected by PCR method.…”

“…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. We describe clinical and molecular data for 22 patients from 18 kindreds harboring POLG variants including two patients with unusual clinical presentations.…”