Multiple oxidative phosphorylation deficiencies in severe childhood multi-system disorders due to polymerase gamma
Maaike C de Vries1, Richard J Rodenburg, Eva Morava
1Nijmegen Centre for Mitochondrial Disorders, Departments of Pediatrics, Laboratory of Pediatrics and Neurology and Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. m.devries@cukz.umcn.nl
Insights
Mutations in the polymerase gamma (POLG1) gene cause combined oxidative phosphorylation deficiencies in children, leading to severe symptoms like epilepsy and liver dysfunction. POLG1 analysis is recommended even without Alpers syndrome presentation.
Area of Science:
- Biochemistry
- Genetics
- Pediatrics
Background:
- Combined oxidative phosphorylation (OXPHOS) enzyme complex deficiencies are rare genetic disorders affecting cellular energy production.
- Mutations in the polymerase gamma (POLG1) gene are known causes of mitochondrial DNA (mtDNA) depletion and related disorders.
Observation:
- Eight children presented with failure to thrive, feeding difficulties, infantile epilepsy, psychomotor delay, and hypotonia.
- Five patients developed severe liver dysfunction, with three meeting criteria for Alpers syndrome.
- Muscle biopsies revealed deficiencies in OXPHOS enzyme complexes (I, III, II, IV, PDHc), while fibroblast studies showed normal enzyme activities.
Findings:
- All eight children harbored homozygous or compound heterozygous mutations in the POLG1 gene.
- Two novel POLG1 mutations were identified, associated with mtDNA depletion.
- Muscle-specific OXPHOS deficiencies despite normal fibroblast enzyme activities suggest tissue-specific effects of POLG1 mutations.
Implications:
- POLG1 mutation analysis should be considered in children with unexplained combined OXPHOS deficiencies, particularly when muscle biopsies show abnormalities.
- Early diagnosis through genetic testing can facilitate timely management and genetic counseling for affected families.
- This study highlights the phenotypic variability of POLG1-related disorders beyond classic Alpers syndrome.
Abstract:
Failure to thrive, feeding difficulties, variable forms of infantile epilepsy or psychomotor developmental delay and hypotonia were the most frequent clinical disease presentations in eight children with combined oxidative phosphorylation enzyme complex deficiencies carrying mutations in the polymerase gamma (POLG1) gene. Five out of eight patients developed severe liver dysfunction during the course of the disease. Three of these patients fulfilled the disease criteria for Alpers syndrome. Most children showed deficiencies of respiratory chain enzyme complexes I and III, in combination with complex II, complex IV and/or PDHc in muscle, whereas in fibroblasts normal enzyme activities were measured. All children carried homozygous or compound heterozygous mutations in the POLG1 gene, including two novel mutations in association with mtDNA depletion. Conclusion We suggest performing POLG1 mutation analysis in children with combined oxidative phosphorylation deficiencies in muscle, even if the clinical picture is not Alpers syndrome.
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