Multiple oxidative phosphorylation deficiencies in severe childhood multi-system disorders due to polymerase gamma (POLG1) mutations.
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.
de Vries
Maaike C
MC
Nijmegen 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
Rodenburg
Richard J
RJ
Morava
Eva
E
van Kaauwen
Edwin P M
EP
ter Laak
Henk
H
Mullaart
Reinier A
RA
Snoeck
Irina N
IN
van Hasselt
Peter M
PM
Harding
Peter
P
van den Heuvel
Lambert P W
LP
Smeitink
Jan A M
JA
D004252:DNA Mutational Analysis; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D002549:Diffuse Cerebral Sclerosis of Schilder / Q000235:genetics* / Q000503:physiopathology; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000503:physiopathology
D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human