Summary
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.
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Abbreviations
- ATP:
-
adenosine triphosphate
- COX:
-
cytochrome C oxidase
- CS:
-
citrate synthase
- CSF:
-
cerebrospinal fluid
- ECG:
-
electrocardiography
- EEG:
-
electroencephalography
- EPC:
-
epilepsia partialis continua
- MEGS:
-
mitochondrial energy-generating system
- MRI:
-
magnetic resonance imaging
- MRS:
-
magnetic resonance spectroscopy
- mtDNA:
-
mitochondrial DNA
- OXPHOS:
-
oxidative phosphorylation system
- PDHc:
-
pyruvate dehydrogenase complex
- POLG:
-
polymerase gamma
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Acknowledgements
Research at the NCMD is funded by the Radboud University Nijmegen Medical Centre, the Prinses Beatrix Fonds, the Dutch Scientific Organization, the Ministry of Economic Affairs and the European Community’s sixth Framework Programme for Research, Priority 1 ‘Life sciences, genomics and biotechnology for health’, contract number LSHM-CT-2004–503116.
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Communicating editor: John Christodoulou
JIMD Short Report #108 (2008) Online
Competing interests: None declared
References to electronic databases: Alpers–Huttenlocher syndrome (OMIM #203700).
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de Vries, M.C., Rodenburg, R.J., Morava, E. et al. Normal biochemical analysis of the oxidative phosphorylation (OXPHOS) system in a child with POLG mutations: A cautionary note. J Inherit Metab Dis 31 (Suppl 2), 299–302 (2008). https://doi.org/10.1007/s10545-008-0871-4
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DOI: https://doi.org/10.1007/s10545-008-0871-4