Case reportSevere encephalomyopathy in a patient with homoplasmic A5814G point mutation in mitochondrial tRNACys gene
Introduction
Mitochondrial encephalomyopathies are a heterogeneous group of diseases often associated with multisystemic presentations [1]. The most severely affected organs are those with high oxidative metabolism, such as brain, skeletal and cardiac muscle, and kidney [1]. Diseases due to mutations in mitochondrial DNA (mtDNA) are usually transmitted by maternal inheritance and are heteroplasmic, i.e., mutant and wild-type mtDNAs coexist in tissues.
Since 1988, over 150 point mutations in mitochondrial DNA have been associated with human diseases, many involving mitochondrial tRNA genes [1]. Pathogenic tRNA mutations typically impair mtDNA translation, resulting in disruption of protein synthesis and reduction in the activities of respiratory chain complexes containing mtDNA-encoded polypeptides.
Here, we describe a woman with severe encephalomyopathy and her oligosymptomatic relatives, who harbor an apparently homoplasmic A5814G mutation in the tRNACys gene of mtDNA.
Section snippets
Case report
The family tree is shown in Fig. 1A. The proband (III-1) was a 30-year-old woman, born at term by normal delivery and after an uneventful pregnancy. In the first months of life, the mother noted that she did not follow objects and interacted poorly with the environment. She controlled her head at 2 years of age, sat without support at 4, but could never stand without support or walk, and she never learned to speak. At age 8 years, she developed hand tremor and at age 17 she manifested
Morphologic and biochemical analysis
Muscle specimens of the right quadriceps from the proband and her mother were immediately frozen in liquid nitrogen-cooled isopentane. Cryostat sections were stained using hematoxylin and eosin and by a battery of standard histochemical stains.
Mitochondrial enzyme activities in muscle extracts were determined by standardized techniques.
Molecular genetic analysis
Samples of total genomic DNA isolated from frozen muscle specimens of the proband and her mother were screened for mtDNA large-scale rearrangements by Southern
Results
The proband’s muscle biopsy showed variation in fiber size, rare central nuclei, some esterase-positive hypotrophic fibers, type 2 fiber predominance and hypotrophy, some lipid accumulation, and a few fibers staining weakly with the cytochrome c oxidase (COX) reaction. The mother’s biopsy showed slight variation in fiber size, and modest fiber type 2 predominance and grouping.
Biochemical analysis of muscle showed decreased activities of complexes I and IV of the respiratory chain in the patient
Discussion
The clinical presentation of our patient did not correspond to any defined syndrome, but was highly suggestive of a mitochondrial encephalomyopathy because of the complex neurological picture, which included mental retardation, epilepsy, tetraplegia, cerebellar and extrapyramidal signs, and muscle atrophy. In addition, this patient showed deafness, retinal dystrophy, short stature, microcephaly, dysmorphic features, recurrent vomiting, and bladder dysfunction. Brain MRI showed non-specific
Acknowledgements
This work was supported by NIH Grants HD32062 and NS11766, by a grant from the Muscular Dystrophy Association, and by the Marriott Mitochondrial Disorder Clinical Research Fund (MMDCRF).
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