MUTATION REPORTS

The unfolding clinical spectrum of POLG mutations

M J Blok¹, B J van den Bosch^1,2, E Jongen¹, A Hendrickx¹, C E de Die-Smulders¹, J E Hoogendijk³, E Brusse⁴, M de Visser⁵, B T Poll-The⁶, J Bierau¹, I F de Coo⁷, H J Smeets^1,2

¹ Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands
² Department of Genetics and Cell Biology, Maastricht University Medical Centre, Maastricht, The Netherlands
³ Department of Neurology, University Medical Center Utrecht, Rudolf Magnus Institute of Neuroscience Utrecht, The Netherlands
⁴ Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
⁵ Department of Neurology, Academic Medical Centre, University of Amsterdam, The Netherlands
⁶ Department of Pediatrics, Emma’s Children Hospital, University of Amsterdam, Amsterdam, The Netherlands
⁷ Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands

^{Correspondence to} Dr B J van den Bosch, Department of Clinical Genetics, Maastricht University Medical Centre, PO Box 5800, 6202 AZ Maastricht, The Netherlands; bianca.vandenbosch{at}gen.unimaas.nl

Background: Mutations in the DNA polymerase- (POLG) gene are a major cause of clinically heterogeneous mitochondrial diseases, associated with mtDNA depletion and multiple deletions.

Objective: To determine the spectrum of POLG mutations in our Dutch patient cohort, to evaluate the pathogenicity of novel mutations, and to establish genotype–phenotype correlations.

Results: The authors identified 64 predominantly recessive mutations in 37 patients from a total of 232 patients, consisting of 23 different mutations. The substitution p.A467T was most frequently observed (n = 23), but was as frequent in childhood cases as in adult cases. Five new pathogenic recessive mutations, p.Lys925ArgfsX42, p.R275X, p.G426S, p.A804T and p.R869Q were identified. The known dominant chronic progressive external ophthalmoplegia (CPEO) mutation p.R943H was for the first time associated with premature ovarian failure as well. In 19 patients the authors identified only a single recessive mutation, or a sequence variant with unclear clinical significance. The data substantiate earlier observations that in POLG patients a fatal status epilepticus and liver failure can be triggered by sodium valproate. It is therefore important to exclude POLG mutations before administering this treatment.

Conclusion: The clinical features of the patient are the most important features to select putative POLG mutation carriers and not the presence of mtDNA deletions or OXPHOS (oxidative phosphorylation) activity. The authors conclude that POLG mutations are an important cause of heterogeneous mitochondrial pathology and that more accurate genotype–phenotype correlations allow a more rapid genetic diagnosis and improved prognosis for mutation carriers.

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