Normal biochemical analysis of the oxidative phosphorylation (OXPHOS) system in a child with POLG mutations: a
M C de Vries1, R J Rodenburg, E Morava
1Nijmegen Centre for Mitochondrial Disorders at Department of Pediatrics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. m.devries@cukz.umcn.nl
Insights
This study details a child with polymerase gamma (POLG1) mutations presenting normal mitochondrial function. This finding expands the understanding of POLG1-related disorders in children.
Area of Science:
- Genetics
- Mitochondrial Biology
- Pediatric Neurology
Background:
- Mutations in polymerase gamma (POLG1) are typically associated with severe mitochondrial oxidative phosphorylation (OXPHOS) deficiencies and Alpers-Huttenlocher syndrome in children.
- The classical presentation involves combined OXPHOS deficiencies, often with significant neurological and hepatic involvement.
Observation:
- A 5-year-old child with POLG1 mutations exhibited delayed psychomotor development, ataxia, epilepsy, visual impairment, and sensorineural deafness.
- Despite severe neurological symptoms and a family history of OXPHOS deficiencies, muscle, fibroblast, and liver analyses revealed normal mitochondrial energy-generating system (MEGS) capacity.
- Cerebrospinal fluid showed elevated lactic acid and protein levels, common in mitochondrial disorders.
Findings:
- Genetic analysis identified compound heterozygosity for two known POLG1 mutations (A467T and G848S).
- Strikingly, comprehensive analysis of the mitochondrial energy-generating system (MEGS) in muscle, fibroblasts, and liver was normal, contradicting the expected severe OXPHOS deficiency.
- This case highlights a phenotypic variant of POLG1-related disorders where neurological symptoms manifest despite preserved mitochondrial function.
Implications:
- The normal MEGS capacity in this POLG1-mutated patient underscores the heterogeneity and complexity of childhood mitochondrial diseases.
- These findings suggest that POLG1 mutation analysis should be considered even in the absence of detectable OXPHOS deficiencies.
- A liberal approach to genetic testing for POLG1 mutations is warranted in pediatric cases with neurological presentations suggestive of mitochondrial dysfunction, given the high frequency of these mutations.
Abstract:
We report a 5-year-old child carrying polymerase gamma (POLG1) mutations, but strikingly normal oxidative phosphorylation analysis in muscle, fibroblasts and liver. Mutations in POLG1 have so far been described in children with severe combined oxidative phosphorylation (OXPHOS) deficiencies and with the classical Alpers-Huttenlocher syndrome. The patient presented with a delayed psychomotor development and ataxia during the first two years of life. From the third year of life he developed epilepsy and regression in development, together with symptoms of visual impairment and sensorineuronal deafness. Cerebrospinal fluid showed elevated lactic acid and protein concentrations. An elder brother had died due to combined OXPHOS deficiencies. Despite the clinical similarity with the elder brother, except for liver involvement, the OXPHOS system analysis in a frozen muscle biopsy was normal. For this reason a fresh muscle biopsy was performed, which has the advantage of the possibility of measuring the substrate oxidation rates and ATP production, part of the mitochondrial energy-generating system (MEGS). During the same session, biopsies of liver and fibroblasts were taken. These three tissues showed normal measurements of the MEGS capacity. Based on the phenotype of Alpers-Huttenlocher syndrome in the elder brother, we decided to screen the POLG1 gene. Mutation analysis showed compound heterozygosity with two known mutations, A467T and G848S. The normal MEGS capacity in this patient expands the already existing complexity and heterogeneity of the childhood POLG1 patients and, on the basis of the high frequency of POLG1 mutations in childhood, warrants a liberal strategy with respect to mutation analysis.
