Brain Advance Access published online on November 16, 2008
Brain, doi:10.1093/brain/awn296
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Biochemical and genetic analysis of 3-methylglutaconic aciduria type IV: a diagnostic strategy
1Nijmegen Center for Mitochondrial Disorders, Department of Paediatrics, 2Laboratory of Paediatrics and Neurology, Radboud University Medical Center Nijmegen, The Netherlands, 3National Human Genome Research Institute, National Institutes of Health, Bethesda, USA and 4Department of General Paediatrics, University Children's Hospital, Düsseldorf, Germany
Correspondence to:
Eva Morava, Radboud University Nijmegen Medical Centre, Nijmegen Center for Mitochondrial Disorders at the Department of Paediatrics, PO Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: e.morava{at}cukz.umcn.nl
The heterogeneous group of 3-methylglutaconic aciduria type IV consists of patients with various organ involvement and mostly progressive neurological impairment in combination with 3-methylglutaconic aciduria and biochemical features of dysfunctional oxidative phosphorylation. Here we describe the clinical and biochemical phenotype in 18 children and define 4 clinical subgroups (encephalomyopathic, hepatocerebral, cardiomyopathic, myopathic). In the encephalomyopathic group with neurodegenerative symptoms and respiratory chain complex I deficiency, two of the children, presenting with mild Methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness, harboured SUCLA2 mutations. In children with a hepatocerebral phenotype most patients presented with complex I deficiency and mtDNA-depletion, three of which carried POLG1-mutations. In the cardiomyopathic subgroup most patients had complex V deficiency and an overlapping phenotype with that previously described in isolated complex V deficiency, in three patients a TMEM70 mutation was confirmed. In one male with a pure myopathic form and severe combined respiratory chain disorder, based on the pathogenomic histology of central core disease, RYR1 mutations were detected. In our patient group the presence of the biochemical marker 3-methylglutaconic acid was indicative for nuclear coded respiratory chain disorders. By delineating patient-groups we elucidated the genetic defect in 10 out of 18 children. Depending on the clinical and biochemical phenotype we suggest POLG1, SUCLA2, TMEM70 and RYR1 sequence analysis and mtDNA-depletion studies in children with 3-methylglutaconic aciduria type IV.
Key Words: 3-methylglutaconic aciduria; deafness; cardiomyopathy; cataract; mtDNA depletion; mitochondrial encephalomyopathy; TMEM70
Abbreviations: BN-PAGE, Blue native-polyacrylamide gel electrophoresis; CM, cardiomyopathy; DCMA, Dilatative cardiomyopathy and ataxia; FTT, failure to thrive; HCM, hypertrophic cardiomyopathy; 3-MGA-uria, 3-methylglutaconic aciduria; 3-MGA, 3-methylglutaconic acid; OXPHOS, oxidative phosphorylation
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Received July 11, 2008. Revised August 28, 2008. Accepted October 10, 2008.
*These authors contributed equally to this work.