Case reportMitochondrial myopathy associated with a novel mutation in mtDNA
Introduction
The mitochondrial encephalomyopathies are a diverse group of disorders often caused by defects in mitochondrial DNA (mtDNA). Hundreds of large-scale mtDNA rearrangements and over 150 mtDNA point mutations have been associated with disease [1]. Patients harboring these mutations usually have multisystem disorders, but phenotypic expression can vary in different families and even in different members of the same family. This complex genotype-phenotype correlation is due to many factors, including the abundance of mutant mDNA and its tissue distribution. Most pathogenic point mutations occur in tRNA genes, are heteroplasmic, and are maternally inherited.
Here, we report a patient with weakness and hypotonia, who harbors a previously undescribed and apparently de novo G-to-A mutation at nucleotide position 10406 in the tRNA arginine (tRNAArg) gene.
Section snippets
Case Report
A 6-year-old boy was the third child of non-consanguineous parents. He had normal birth and early development, but showed emotional problems and, at age 4, was given the diagnosis of Asperger syndrome. At the same age, the mother also noted motor problems: the child could not walk long distances, required a walker or a wheelchair for family outings, and needed a handrail to push himself up stairs. The condition did not seem to progress significantly. At age 7, he has occasional dysphagia for
Histochemistry and biochemistry
Histochemical study of muscle using 8-um-thick frozen sections was carried out as described [2]. Biochemical analysis was performed in 10% muscle homogenates as previously described [3].
Molecular analysis
Total DNA was extracted by standard protocol (PUREGENE, Gentra System, Inc, Minneapolis, Minn) following the manufacturer’s instructions. Protocols used for blood, urine, hair roots, and cheek mucosa were as described [4].
Direct sequencing of the 22 tRNA genes of mtDNA was performed in an ABI Prism 310 Genetic
Results
Histochemical analysis of the muscle biopsy showed frequent ragged-red fibers (RRF) and cytochrome c oxidase (COX)-deficient fibers. In keeping with the mitochondrial proliferation shown by histochemistry, biochemical analysis revealed markedly increased citrate synthase and succinate dehydrogenase (SDH) activities. In contrast, activities of respiratory chain complexes I+III, II+III, and especially IV (COX) were decreased (Table 1). When normalized to either citrate synthase or SDH, the
Discussion
We describe a novel mutation, a G10406A in the tRNAArg gene, which appears to have arisen de novo in the proband, a 6-year-old boy with proximal myopathy and Asperger syndrome. We believe that this mutation is pathogenic for several reasons. First, it is heteroplasmic, and heteroplasmy is a common feature of pathogenic mtDNA mutations. Second, it has not been previously reported and was not detected by us in a group of 100 controls. Third, the point mutation that we encountered in a tRNA gene
Acknowledgement
This work has been supported by NIH grant HD32062, a grant from the Muscular Dystrophy Association, and the Marriott Mitochondrial Disorders Clinical Research Fund (MMDCRF).
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