Mitochondrial Myopathy,Sideroblastic Anemia,and Lactic Acidosis: An Autosomal Recessive Syndrome in Persian Jews Caused by a Mutation in the PUS1 Gene

Abstract

We report the seventh case of autosomal recessive inherited mitochondrial myopathy, lactic acidosis, and sideroblastic anemia. The patient, a product of consanguineous Persian Jews, had the association of mental retardation, dysmorphic features, lactic acidosis, myopathy, and sideroblastic anemia. Muscle biopsy demonstrated low activity of complexes 1 and 4 of the respiratory chain. Electron microscopy revealed paracrystalline inclusions in most mitochondria. Southern blot of the mitochondrial DNA did not show any large-scale rearrangements. The patient was found to be homozygous for the 656C→T mutation in the pseudouridine synthase 1 gene (PUS1). Mitochondrial myopathy, lactic acidosis, and sideroblastic anemia is an oxidative phosphorylation disorder causing sideroblastic anemia, myopathy, and, in some cases, mental retardation that is due to mutations in the nuclear-encoded PUS1 gene. This finding provides additional evidence that mitochondrial ribonucleic acid modification impacts the phenotypic expression of oxidative phosphorylation disorders. (J Child Neurol 2005;20:449—452).

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References

Bridges KR : Sideroblastic anemia: A mitochondrial disorder. J Pediatr Hematol Oncol 1997;19:274—278.

May A. , Fitzsimons E. : Sideroblastic anaemia. Baillieres Clin Haematol 1994;7:851—879.

Pearson HA , Lobel JS , Kocoshis SA , et al: A new syndrome of refractory sideroblastic anemia with vacuolization of marrow precursors and exocrine pancreatic dysfunction. J Pediatr 1979;95:976—984.

Rotig A. , Cormier V. , Blanche S. , et al: Pearson's marrow-pancreas syndrome: A multisystem mitochondrial disorder in infancy. J Clin Invest 1990;86:1601—1608.

Inbal A. , Avissar N. , Shaklai M. , et al: Myopathy, lactic acidosis, and sideroblastic anemia: A new syndrome . Am J Med Genet 1995;55:372—378.

Casas KA , Fischel-Ghodsian N. : Mitochondrial myopathy and sideroblastic anemia. Am J Med Genet 2004;25A:201—204.

Casas K. , Bykhovskaya Y. , Mengesha E. , et al: Gene responsible for mitochondrial myopathy and sideroblastic anemia (MSA) maps to chromosome 12q24.33. Am J Med Genet A 2004;127(1):44—49.

Bykhovskaya Y. , Casas K. , Mengesha E. , et al: Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA) . Am J Hum Genet 2004;74:1303—1308.

Birch-Machin MA , Shepherd IM , Watmough NJ , et al: Fatal lactic acidosis in infancy with a defect of complex III of the respiratory chain. Pediatr Res 1989;25:553—559.

10.

Rustin P. , Chretien D. , Bourgeron T. , et al: Biochemical and molecular investigations in respiratory chain deficiencies. Clin Chim Acta 1994;228:35—51.

11.

Sherrat HS , Watmough MA , Johnson MA , Turnbull DM : Methods for study of normal and abnormal skeletal muscle mitochondria. Methods Biochem Anal 1988;33:243—335.

12.

Lowry OH , Rosenbrough NJ , Farr AL , Randall RJ : Protein measurement with Folin phenol reagent. J Biol Chem 1951;193:265—275.

13.

Zeviani M. , Tiranti V. , Piantadosi C. : Mitochondrial disorders. Medicine 1998;77:59—72.

14.

Zeviani M. , Servidei S. , Gellera C. , et al: An autosomal dominant disorder with multiple deletions of mitochondrial DNA starting at the D-loop region. Nature 1989;339:309—311.

15.

Bottomley SS , May BK , Cox TC , et al: Molecular defects of erythroid 5-aminolevulinate synthase in X-linked sideroblastic anemia. J Bioenerg Biomembr 1995;27:161—168.

16.

Nusbaum NJ : Concise review: Genetic bases for sideroblastic anemia. Am J Hematol 1991;37:41—44.

17.

Rawles JM , Weller RO : Familial association of metabolic myopathy, lactic acidosis and sideroblastic anemia. Am J Med 1974;56:891—897.

18.

Casademont J. , Barrientos A. , Cardellach F. , et al: Multiple deletions of mtDNA in two brothers with sideroblastic anemia and mitochondrial myopathy and in their asymptomatic mother. Hum Mol Genet 1994;3:1945—1949.

19.

Allikmets R. , Raskind WH , Hutchinson A. , et al: Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A) . Hum Mol Genet 1999;8:743—749.

20.

Cormier V. , Rotig A. , Quartino AR , et al: Widespread multi-tissue deletions of the mitochondrial genome in the Pearson marrow-pancreas syndrome. J Pediatr 1990;117:599—602.

21.

Rotig A. , Cormier V. , Chatelain P. : Deletion of mitochondrial DNA in a case of early-onset diabetes mellitus, optic atrophy, and deafness (Wolfram syndrome, MIM 222300). J Clin Invest 1993;91:1095—1098.

22.

Borgna-Pignatti C. , Marradi P. , Pinelli L. , et al: Thiamine-responsive anemia in DIDMOAD syndrome. J Pediatr 1989;114:405—410.

23.

Barrientos A. , Volpini V. , Casademont J. , et al: A nuclear defect in the 4p16 region predisposes to multiple mitochondrial DNA deletions in families with Wolfram syndrome. J Clin Invest 1996;97:1570—1576.

24.

Bykhovskaya Y. , Mengesha E. , Wang D. , et al: Human mitochondrial transcription factor B1 as a modifier gene for hearing loss associated with the mitochondrial A1555G mutation. Mol Genet Metab 2004;82:27—32.