Point Mutation tRNASer(UCN) in a Child With Hearing Loss and Myoclonus Epilepsy

Abstract

We report on a family with a 12-year-old boy who suffered from a maternally inherited syndrome characterized by a combination of sensorineural hearing loss, myoclonus epilepsy, ataxia, severe psychomotor retardation, short stature, and diabetes mellitus. First, he showed a muscular hypotonia with hearing loss; later, he developed a myoclonus epilepsy, growth failure, and severe psychomotor retardation. At the age of 10 years, he developed diabetes mellitus. After initiation of combined ubiquinone and vitamin C treatment, we observed a progression in psychomotor development. Lactate and pyruvate levels in blood and cerebrospinal fluid were normal. No ragged red fibers or ultrastructural abnormalities were seen in a skeletal muscle biopsy. Biochemical assays of respiratory chain complex activities revealed decreased activity of complexes I and IV. By sequence analysis of mitochondrial DNA encoding transfer ribonucleic acids (RNAs), a homoplasmic T to C substitution at nucleotide position 7512 was found affecting a highly conserved base pair in the tRNAser(UCN) acceptor stem. Asymptomatic family members of the maternal line were heteroplasmic for the mutation in blood samples. Analysis of mitochondrial DNA in patients with hearing loss and myoclonus epilepsy is recommended, even in the absence of laboratory findings. Therapeutically, ubiquinone and antioxidants can be beneficial. (J Child Neurol 2006;21:253—255; DOI 10.2310/7010.2006.00047).

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References

Goto VI , Matsuoka T. , Horai S. : A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalopathies. Nature 1990 ;348:651—653.

Shoffner JM , Lott MT , Lezza Ams , et al: Myoclonic epilepsy and ragged red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA mutation. Cell 1990;61:931—937.

Wallace DC , Lott MT , Brown MD , et al: Report of the Committee on Human Mitochondrial DNA, in Cuticcia AJ (ed): Human Gene Mapping, 1995: A Compendium. Baltimore, Johns Hopkins University Press, 1995, 910—954.

Munnich A. , Rötig A. , Chretien D. , et al: Clinical presentations and laboratory investigations in respiratory chain deficiency. Eur J Paediatr 1996;155:262—274.

Sarvidei S. : Mithocondrial encephalopathies: Gene mutation. Neuromuscul Disord 1996;6:11—14.

Jaksch M. , Klopstock T. , Kurlemann G. , et al: Progressive myoclonus epilepsy and mitochondrial myopathy associated with mutations in the tRNASer(UCN) gene. Ann Neurol 1998;44:635—640.

Kleinle S. , Schneider V. , Moosmann P. , et al: A novel mitochondrial tRNA(Phe) mutation inhibiting anticodon stem formation associated with a muscle disease. Biochem Biophys Res Commun 1998;247:112—115.

Liechti-Gallati S. , Schneider V. , Neeser D. , Kraemer R. : Two buffer PAGE system-based SSCP/HD analysis: A general protocol for rapid and sensitive mutation screening in cystic fibrosis and any other human genetic disease . Eur J Hum Genet 1999;7:590—598.

Nakamura M. , Nakano S. , Goto Y. , et al: A novel point mutation in the mitochondrial tRNASer(UCN) gene detected in a family with MERRF/MELAS overlap syndrome. Biochem Biophys Res Commun 1995;214:86—93.

10.

Tiranti V. , Chariot P. , Carella F. , et al: Maternally inherited hearing loss, ataxia and myoclonus associated with a novel point mutation in mitochondrial tRNASer(UCN) gene. Hum Mol Genet 1995;4:1421—1427.

11.

Bresolin N. , Doriguzzi C. , Ponzetto C. , et al: Ubidecarenone in the treatment of mitochondrial myopathies: A multi-center double-blind trial. J Neurol Sci 1990;100:70—78.

12.

Matthews PM , Ford B. , Dandurand RJ , et al: Coenzyme Q10 with multiple vitamins is generally ineffective in treatment of mitochondrial disease. Neurology 1993;43:884—890.

13.

Ikejiri Y. , Mori E. , Ishii K. , et al: Idebenone improves mitochondrial oxidative metabolism in a patient with MELAS. Neurology 1996;47:583—585.

14.

Krähenbühl S. , Schäfer T. , Wiesmann U. : Determination of the activities of the enzyme complexes of the electron transport chain in human fibroblasts. Clin Chim Acta 1996;253:79—90.