Exercise Intolerance, Muscle Pain and Lactic Acidaemia Associated with a 7497G>A Mutation in the TRNASer(UCN) Gene

Overview

Journal J Inherit Metab Dis

Publisher Wiley

Date 2003 Nov 8

PMID 14605505

Citations 7

Authors

O Grafakou

F A Hol

K Otfried Schwab

M H Siers

H Ter Laak

F Trijbels

R Ensenauer

C Boelen

J Smeitink

Affiliations

Soon will be listed here.

Abstract

A 13-year-old girl with non-familial exercise intolerance, muscle pain and lactic acidaemia underwent a muscle biopsy for suspected mitochondrial disease. Muscle morphology showed 25% ragged-red fibres and 80% COX-negative staining. Enzymatic activities of mitochondrially co-encoded respiratory chain enzymes (complexes I, III, and IV) were decreased in muscle but normal in cultured skin fibroblasts. mtDNA analysis revealed the presence of the 7497G>A mutation in the tRNASer(UCN) gene, homoplasmic in skeletal muscle and 90% in leukocytes. Analysis of the mother's mtDNA showed 10% heteroplasmy in blood. It may be concluded that the 7497G>A mutation is associated with a muscle-only disease presentation for which high levels of mutated mtDNA are required. Exercise intolerance and muscle pain in otherwise normal children warrants further mitochondrial evaluation.

Citing Articles

The Mitochondrial tRNA Gene: A Novel m.7484A>G Mutation Associated with Mitochondrial Encephalomyopathy and Literature Review.

Borgione E, Lo Giudice M, Santa Paola S, Giuliano M, Di Blasi F, Di Stefano V Life (Basel). 2023; 13(2).

PMID: 36836911 PMC: 9963529. DOI: 10.3390/life13020554.

Genetic etiology study of four Chinese families with two nonsyndromic deaf children in succession by targeted next-generation sequencing.

Xiao C, Liu S, Wang H, Ding Y, Chen Y, Liu H Mol Genet Genomic Med. 2021; 9(4):e1634.

PMID: 33638616 PMC: 8123758. DOI: 10.1002/mgg3.1634.

Muscle pain in mitochondrial diseases: a picture from the Italian network.

Filosto M, Piccinelli S, Lamperti C, Mongini T, Servidei S, Musumeci O J Neurol. 2019; 266(4):953-959.

PMID: 30710167 DOI: 10.1007/s00415-019-09219-x.

Clinically proven mtDNA mutations are not common in those with chronic fatigue syndrome.

Schoeman E, van der Westhuizen F, Erasmus E, van Dyk E, Knowles C, Al-Ali S BMC Med Genet. 2017; 18(1):29.

PMID: 28302057 PMC: 5356238. DOI: 10.1186/s12881-017-0387-6.

Genomics and genetics in the biology of adaptation to exercise.

Bouchard C, Rankinen T, Timmons J Compr Physiol. 2013; 1(3):1603-48.

PMID: 23733655 PMC: 3938186. DOI: 10.1002/cphy.c100059.

References

COOPERSTEIN S, LAZAROW A . A microspectrophotometric method for the determination of cytochrome oxidase. J Biol Chem. 1951; 189(2):665-70. View

Sternberg D, Danan C, Lombes A, Laforet P, Girodon E, Goossens M . Exhaustive scanning approach to screen all the mitochondrial tRNA genes for mutations and its application to the investigation of 35 independent patients with mitochondrial disorders. Hum Mol Genet. 1998; 7(1):33-42. DOI: 10.1093/hmg/7.1.33. View

Kleinle S, Schneider V, Moosmann P, Brandner S, Krahenbuhl S . A novel mitochondrial tRNA(Phe) mutation inhibiting anticodon stem formation associated with a muscle disease. Biochem Biophys Res Commun. 1998; 247(1):112-5. DOI: 10.1006/bbrc.1998.8729. View

Fischer J, Ruitenbeek W, Gabreels F, Janssen A, Renier W, Sengers R . A mitochondrial encephalomyopathy: the first case with an established defect at the level of coenzyme Q. Eur J Pediatr. 1986; 144(5):441-4. DOI: 10.1007/BF00441735. View

Fischer J, Ruitenbeek W, Berden J, Trijbels J, Veerkamp J, STADHOUDERS A . Differential investigation of the capacity of succinate oxidation in human skeletal muscle. Clin Chim Acta. 1985; 153(1):23-36. DOI: 10.1016/0009-8981(85)90135-4. View

Nishigaki Y, Bonilla E, Shanske S, Gaskin D, DiMauro S, Hirano M . Exercise-induced muscle "burning," fatigue, and hyper-CKemia: mtDNA T10010C mutation in tRNA(Gly). Neurology. 2002; 58(8):1282-5. DOI: 10.1212/wnl.58.8.1282. View

Kleinle S, Wiesmann U, Superti-Furga A, Krahenbuhl S, Boltshauser E, Reichen J . Detection and characterization of mitochondrial DNA rearrangements in Pearson and Kearns-Sayre syndromes by long PCR. Hum Genet. 1997; 100(5-6):643-50. DOI: 10.1007/s004390050567. View

van Laack H, Ruitenbeek W, Trijbels J, Sengers R, Gabreels F, Janssen A . Estimation of pyruvate dehydrogenase (E1) activity in human skeletal muscle; three cases with E1 deficiency. Clin Chim Acta. 1988; 171(1):109-18. DOI: 10.1016/0009-8981(88)90296-3. View

Sue C, Tanji K, Hadjigeorgiou G, Andreu A, Nishino I, Krishna S . Maternally inherited hearing loss in a large kindred with a novel T7511C mutation in the mitochondrial DNA tRNA(Ser(UCN)) gene. Neurology. 1999; 52(9):1905-8. DOI: 10.1212/wnl.52.9.1905. View

10.

Hutchin T, Parker M, Young I, Davis A, Pulleyn L, Deeble J . A novel mutation in the mitochondrial tRNA(Ser(UCN)) gene in a family with non-syndromic sensorineural hearing impairment. J Med Genet. 2000; 37(9):692-4. PMC: 1734692. DOI: 10.1136/jmg.37.9.692. View

11.

Fischer J, Ruitenbeek W, Trijbels J, Veerkamp J, STADHOUDERS A, Sengers R . Estimation of NADH oxidation in human skeletal muscle mitochondria. Clin Chim Acta. 1986; 155(3):263-73. DOI: 10.1016/0009-8981(86)90246-9. View

12.

Smeitink J, van den Heuvel L, DiMauro S . The genetics and pathology of oxidative phosphorylation. Nat Rev Genet. 2001; 2(5):342-52. DOI: 10.1038/35072063. View

13.

Bentlage H, Wendel U, Schagger H, ter Laak H, Janssen A, Trijbels J . Lethal infantile mitochondrial disease with isolated complex I deficiency in fibroblasts but with combined complex I and IV deficiencies in muscle. Neurology. 1996; 47(1):243-8. DOI: 10.1212/wnl.47.1.243. View

14.

Ionasescu V, Hart M, DiMauro S, Moraes C . Clinical and morphologic features of a myopathy associated with a point mutation in the mitochondrial tRNA(Pro) gene. Neurology. 1994; 44(5):975-7. DOI: 10.1212/wnl.44.5.975. View

15.

Verhoeven K, Ensink R, Tiranti V, Huygen P, Johnson D, Schatteman I . Hearing impairment and neurological dysfunction associated with a mutation in the mitochondrial tRNASer(UCN) gene. Eur J Hum Genet. 1999; 7(1):45-51. DOI: 10.1038/sj.ejhg.5200247. View

16.

Jaksch M, Klopstock T, Kurlemann G, Dorner M, Hofmann S, Kleinle S . Progressive myoclonus epilepsy and mitochondrial myopathy associated with mutations in the tRNA(Ser(UCN)) gene. Ann Neurol. 1998; 44(4):635-40. DOI: 10.1002/ana.410440409. View

17.

Reid F, Rovio A, Holt I, Jacobs H . Molecular phenotype of a human lymphoblastoid cell-line homoplasmic for the np 7445 deafness-associated mitochondrial mutation. Hum Mol Genet. 1997; 6(3):443-9. DOI: 10.1093/hmg/6.3.443. View

18.

Jaksch M, Hofmann S, Kleinle S, Pongratz D, Muller-Hocker J, Jedele K . A systematic mutation screen of 10 nuclear and 25 mitochondrial candidate genes in 21 patients with cytochrome c oxidase (COX) deficiency shows tRNA(Ser)(UCN) mutations in a subgroup with syndromal encephalopathy. J Med Genet. 1998; 35(11):895-900. PMC: 1051480. DOI: 10.1136/jmg.35.11.895. View

19.

Andreu A, Hanna M, Reichmann H, Bruno C, Penn A, Tanji K . Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA. N Engl J Med. 1999; 341(14):1037-44. DOI: 10.1056/NEJM199909303411404. View

20.

McFarland R, Clark K, Morris A, Taylor R, Macphail S, Lightowlers R . Multiple neonatal deaths due to a homoplasmic mitochondrial DNA mutation. Nat Genet. 2002; 30(2):145-6. DOI: 10.1038/ng819. View