Subsequent Sanger sequencing of POLG in a further 275 unrelated probands with genetically unconfirmed mitochondrial disease revealed a third unrelated proband with a similar phenotype harboring homozygous c.1879C>T; p.R627W mutations and a fourth patient, with a milder clinical disorder, harboring compound heterozygous POLG c.1879C>T; p.R627W and c.2341G>A; p.A781T mutations.
PurposeMutations in POLG, the most common single-gene cause of inherited mitochondrial disease, are diagnostically challenging owing to clinical heterogeneity and overlap between syndromes.
POLG1 encodes mitochondrial DNA polymerase and is one of the causative genes for a Mendelian-inheritance mitochondrial disease, which is occasionally accompanied by mood disorders.
Normal muscle and fibroblast studies do no exclude the diagnosis of POLG-related mitochondrial disease and direct sequencing of the POLG gene should be the gold standard when investigating suspected cases.
Diseases due to mutations of POLG gene, encoding the mitochondrial DNA polymerase, are reputed to have very diverse clinical presentations and have been proposed to cause up to 25% adult mitochondrial diseases.
We identified a mitochondrial disease causing missense variation in polymerase domain of POLG1 protein at amino acid 1143 (E1143G) to be 25 times more prevalent in European-Americans (allele frequency 0.03777) when compared to African-American (allele frequency 0.00151) population.
Clinical diagnosis of POLG-related disorders can be challenging because the phenotypic spectrums are heterogeneous which can mimic different types of mitochondrial disorders.
An analysis of the POLG1 gene should be performed for all patients with suspected mitochondrial disease before the introduction of valproate therapy, and treatment with valproic acid should be avoided in these patients.
Genes encoding the DNA helicase TWINKLE (C10orf2) or the two subunits of mtDNA polymerase γ (POLγ) (POLG1 and POLG2) have a direct effect on the mitochondrial DNA replication machinery and were reported in many mitochondrial disorders.
Our clustering method provides a powerful tool to predict the pathogenic potential and predicted disease phenotype of novel variants and mutations in POLG, the most common nuclear gene underlying mitochondrial disorders.
Distal upper limb myopathy/cachexia is not previously described with dominant POLG mutations and our observations further highlight the diverse clinical spectrum of POLG-related mitochondrial disorders.
The aim of this study was to determine the prevalence of POLG mutations in an adult population of Australian patients with mitochondrial disease, displaying symptoms commonly associated with POLG-related diseases.
Our findings suggest that the presence of HOD, in the appropriate clinical setting, should alert the clinician to the possibility of a mitochondrial disorder and the need to screen for mutations in POLG and SURF1 genes.
The combinatorial analyses of mtDNA and POLG revealed a diagnostic yield of 6.7% in patients with suspected mitochondrial disorders but no recognizable syndromes.
Many mutations in POLG, the gene that encodes pol γ, have been associated with mitochondrial diseases such as myocerebrohepatopathy spectrum (MCHS) disorders, Alpers-Huttenlocher syndrome, myoclonic epilepsy myopathy sensory ataxia (MEMSA), ataxia neuropathy spectrum (ANS), and progressive external ophthalmoplegia (PEO).
(1) Mitochondrial disorders(2) are a well-recognized cause; however, to our knowledge this is the first time that such extensive intracranial calcium deposits have been described in a patient with a POLG1 mutation.
Alpers syndrome is one of the most common phenotypes of mitochondrial disorders in early childhood and has been associated with pathogenic mutations in POLG1.