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

Abstract

PurposeMutations 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.MethodsWe 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 POLG mutations were considered eligible.ResultsA 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 POLG gene mutations.ConclusionOur data suggest that POLG-related disease should be suspected in any child presenting with diffuse neurological symptoms. Full POLG sequencing 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.

• Authors: Omar Hikmat, Charalampos Tzoulis, Wui K Chong, Latifa Chentouf, Claus Klingenberg, Carl Fratter, Lucinda J Carr, Prab Prabhakar, Nandhini Kumaraguru, Paul Gissen, J Helen Cross, Thomas S Jacques, Jan-Willem Taanman, Laurence A Bindoff, Shamima Rahman
• Journal: Genetics in medicine : official journal of the American College of Medical Genetics (Genet Med) Vol. 19 Issue 11 Pg. 1217-1225 (11 2017) ISSN: 1530-0366 [Electronic] United States
• PMID: 28471437 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Polymerase gamma
• POLG protein, human

Topics

• Child
• Child, Preschool
• DNA Polymerase gamma (genetics)
• Developmental Disabilities (genetics, physiopathology)
• Female
• Genotype
• Humans
• Infant
• Magnetic Resonance Imaging
• Male
• Mitochondrial Diseases (enzymology, genetics, pathology, physiopathology)
• Muscle, Skeletal (pathology)
• Mutation
• Phenotype
• Retrospective Studies