Elsevier

Genetics in Medicine

Volume 19, Issue 11, November 2017, Pages 1217-1225
Genetics in Medicine

Original Research Article
The clinical spectrum and natural history of early-onset diseases due to DNA polymerase gamma mutations

https://doi.org/10.1038/gim.2017.35Get rights and content
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Abstract

Purpose

Mutations in POLG,the most common single-gene cause of inherited mitochondrial disease, are diagnostically challenging owing to clinical heterogeneity and overlap between syndromes. We aimed to improve the clinical recognition of POLG-related disorders in the pediatric population.

Methods

We performed a multinational, phenotype: genotype study using patients from three centers, two Norwegian and one from the United Kingdom. Patients with age at onset <12 years and confirmed pathogenic biallelic POLGmutations were considered eligible.

Results

A total of 27 patients were identified with a median age at onset of 11 months (range 0.6–80.4). The majority presented with global developmental delay (n=24/24, 100%), hypotonia (n=22/23, 96%) and faltering growth (n=24/27, 89%). Epilepsy was common, but notably absent in patients with the myocerebrohepatopathy spectrum phenotype. We identified two novel POLGgene mutations.

Conclusion

Our data suggest that POLG-related disease should be suspected in any child presenting with diffuse neurological symptoms. Full POLGsequencing is recommended since targeted screening may miss mutations. Finally, we simplify the classification of POLG-related disease in children using epilepsy as the crucial defining element; we show that Alpers and myocerebrohepatopathy spectrum follow different outcomes and that they manifest different degrees of respiratory chain dysfunction.

Keywords

Alpers
infantile hepatocerebral syndromes
mitochondrial disease
mtDNA depletion
myocerebrohepatopathy syndrome

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