Abstract
This paper reports the third proven human case of deficient S-adenosylhomocysteine (AdoHcy) hydrolase activity. The patient is similar to the only two previously reported cases with this disorder in having severe myopathy, developmental delay, elevated serum creatine kinase (CK) concentrations, and hypermethioninaemia. Although he has been followed from infancy, the basic enzyme deficiency was established only at age 26 years. The diagnosis was based on markedly elevated plasma concentrations of both AdoHcy and S-adenosylmethionine, some 20% of the mean control activity of AdoHcy hydrolase activity in haemolysates of his red-blood cells, and two missense mutations in his gene encoding AdoHcy hydrolase. He had low values of erythrocyte phosphatidylcholine and plasma free choline and marginally elevated excretion of guanidinoacetate, suggesting that the elevated AdoHcy may have been inhibiting methylation of phosphatidylethanolamine and guanidinoacetate. His leukocyte DNA was globally more methylated than the DNA's of his parents or the mean extent of methylation measured in age-matched control subjects.
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References
Allen RH, Stabler SP, Lindenbaum J (1993) Serum betaine, N,N-dimethylglycine and N-methylglycine levels in patients with cobalamin and folate deficiency and related inborn errors of metabolism.Metabolism 42: 1448–1460.
Augoustides-Savvopoulou P, Luka Z, et al (2003) Glycine N-methyltransferase deficiency: a new patient with a novel mutation.J Inherit Metab Dis 26: 745–759.
Barić I, Fumić K, Glenn B, et al (2004) S-Adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism.Proc Natl Acad Sci USA 101: 4234–4239.
Barić I, Fumić K, Vugrek O, et al (2005a) S-Adenosylhomocysteine (AdoHcy) hydrolase deficiency: myopathy seems to be congenital.J Inherit Metab Dis 28(Suppl 1): 76.
Barić I, Ćuk M, Fumić K, et al (2005b) S-Adenosylhomocysteine hydrolase deficiency: a second patient and outcomes of therapy.J Inherit Metab Dis, 28: 885–902.
Capdevila A, Wagner C (1998) Measurement of plasma S-adenosyl- methionine and S-adenosylhomocysteine as their fluorescent isoindoles.Anal Biochem 264: 180–184.
Clarke S, Banfield K (2001) S-Adenosylmethionine-dependent methyltransferases. In: Carmel R, Jacobsen DW, eds.Homocysteine in Health and Disease. Cambridge, UK: Cambridge University Press, 63–78.
Coulter-Karis DE, Hershfield MS (1989) Sequence of full length cDNA for human S-adenosylhomocysteine hydrolase.Ann Hum Genet 53: 169–175.
Devlin AM, Bottiglieri T, Domann FE, Lentz SR (2005) Tissue-specific changes in H19 methylation and expression in mice with hyperhomocysteinemia.J Biol Chem 280: 25506–25511.
Gaull GE, Tallan HH, Vulovic D (1979) Methioninemia, myopathy and mental deficiency: a new disorder.Pediatr Res 13: 419.
Gaull GE, Bender AN, Vulovic D, Tallan HH, Schaffner F (1981) Methioninemia and myopathy: a new disorder.Ann Neurol 9: 423–432.
Gellekink H, den Heijer M, Kluijtmans LAJ, Blom HJ (2004) Effect of genetic variation in the human S-adenosylhomocysteine hydrolase gene on total homocysteine concentrations and risk of recurrent venous thrombosis.Eur J Hum Genet 12: 942–948.
Hershfield MS, Kredich NM, Ownby DR, Ownby H, Buckley, R (1979)In vivo inactivation of erythrocyte S-adenosylhomocysteine hydrolase by 2′-deoxyadenosine in adenosine deaminase-deficient patients.J Clin Invest 63: 807–811.
Hershfield MS, Alyar VN, Premakumar R, Small WC (1985) S-Adenosylhomocysteine hydrolase from human placenta. Affinity purification and characterization.Biochem J 230: 43–52.
Hu Y, Komoto J, Huang Y, et al (1999) Crystal structure of S-adenosylhomocysteine hydrolase from rat liver.Biochemistry 38: 8323–8333.
Kasir J, Aksamit RR, Backlund PS Jr, Cantoni GL (1988) Amino acid sequence of S-adenosyl-l-homocysteine hydrolase fromDictyostelium discoides as deduced from the cDNA sequence.Biochem Biophys Res Commun 153: 359–364.
Koc H, Mar M-H, Ranasinghe A, Swenberg JA, Zeisel SH (2002) Quantitation of choline and its metabolites in tissues and foods by liquid chromatography/electrospray ionization-isotope dilution mass spectrometry.Anal Chem 74: 4734– 4740.
Kucharczyk W, Kelly WM, Chuang SH, Bertram EG (1990) The brain. In: Kucharczyk W, ed.MRI: Central Nervous System. Philadelphia: JB Lippincott, 1.2–1.77.
Marescau B, Deshmukh DR, Kockx M, et al (1992) Guanidino compounds in serum, urine, liver, kidney, and brain of man and urotelic animals.Metabolism 41: 526–532.
Miller MW, Duhl DMJ, Winkes BM, et al (1994) The mouselethal nonagouti (âx) mutation deletes theS-adenosylhomo- cysteine hydrolase (Ahcy) gene.EMBO J 13: 1806–1816.
Morris GS, Simmonds HA (1985) Use of a fundamental elution protocol for the development of reversed phase high performance liquid chromatography enabling rapid simultaneous determinations of purines, pyrimidines and allied compounds commonly found in human biological fluids.J Chromatogr 344: 101– 113.
Mudd SH, Cerone R, Schiaffino MC, et al (2001) Glycine N-methyl- transferase deficiency: a novel inborn error causing persistent isolated hypermethioninaemia.J Inherit Metab Dis 24: 448–464.
Ohura T, Kobayashi K, Abukawa D, et al (2003) A novel inborn error of metabolism detected by elevated methionine and/or galactose in newborn screening; neonatal intrahepatic cholestasis caused by citrin deficiency.Eur J Pediatr 162: 317–322.
Pogribny I, Yi P, James SJ (1999) A sensitive new method for rapid detection of abnormal methylation patterns in global DNA and within CpG islands.Biochem Biophys Res Commun 262: 624–628.
Schulze A, Ebinger F, Rating D, Mayatepek E (2001) Improving treatment of guanidinoacetate methyltransferase deficiency: reduction of guanidinoacetate in body fluids by arginine restriction and ornithine supplementation.Mo. Genet Metab 74: 413–419.
Stabler SP, Marcell PD, Podell ER, Allen RH (1987) Quantitation of total homocysteine, total cysteine, and methionine in normal serum and urine using capillary gas chromatography-mass spectrometry.Anal Biochem 162: 185–196.
Stabler SP, Lindenbaum J, Savage DG, Allen RH (1993) Elevation of serum cystathionine levels in patients with cobalamin and folate deficiency.Blood 81: 3404–3413.
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Communicating author: Mike Gibson
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Buist, N.R.M., Glenn, B., Vugrek, O. et al. S-Adenosylhomocysteine hydrolase deficiency in a 26-year-old man. J Inherit Metab Dis 29, 538–545 (2006). https://doi.org/10.1007/s10545-006-0240-0
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DOI: https://doi.org/10.1007/s10545-006-0240-0