S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism

Abstract

We report studies of a Croatian boy, a proven case of human S-adenosylhomocysteine (AdoHcy) hydrolase deficiency. Psychomotor development was slow until his fifth month; thereafter, virtually absent until treatment was started. He had marked hypotonia with elevated serum creatine kinase and transaminases, prolonged prothrombin time and low albumin. Electron microscopy of muscle showed numerous abnormal myelin figures; liver biopsy showed mild hepatitis with sparse rough endoplasmic reticulum. Brain MRI at 12.7 months revealed white matter atrophy and abnormally slow myelination. Hypermethioninemia was present in the initial metabolic study at age 8 months, and persisted (up to 784 microM) without tyrosine elevation. Plasma total homocysteine was very slightly elevated for an infant to 14.5-15.9 microM. In plasma, S-adenosylmethionine was 30-fold and AdoHcy 150-fold elevated. Activity of AdoHcy hydrolase was approximately equal to 3% of control in liver and was 5-10% of the control values in red blood cells and cultured fibroblasts. We found no evidence of a soluble inhibitor of the enzyme in extracts of the patient's cultured fibroblasts. Additional pretreatment abnormalities in plasma included low concentrations of phosphatidylcholine and choline, with elevations of guanidinoacetate, betaine, dimethylglycine, and cystathionine. Leukocyte DNA was hypermethylated. Gene analysis revealed two mutations in exon 4: a maternally derived stop codon, and a paternally derived missense mutation. We discuss reasons for biochemical abnormalities and pathophysiological aspects of AdoHcy hydrolase deficiency.

Fig. 1.

Methionine, AdoMet, and AdoHcy metabolism. AdoMet, S-adenosylmethionine; AdoHcy, S-adenosylhomocysteine; THF, tetrahydrofolate; 5-MTHF, 5-methyltetrahydrofolate; AMP, adenosine monophosphate; MAT, methionine adenosyltransferase (E.C.2.5.1.6); GNMT, glycine N-methyltransferase (E.C.2.1.1.20); MTs, a variety of AdoMet-dependent methyltransferases; SAHH, AdoHcy hydrolase (E.C.3.3.1.1); CBS, cystathionine β-synthase (E.C.4.2.1.22); MS, methionine synthase (5-MTHF-homocysteine methyltransferase) (E.C.2.1.1.13); BHMT, betaine-homocysteine methyltransferase (E.C.2.1.1.5). The numbers represent the following: 1, sarcosine dehydrogenase (E.C.1.5.99.1); 2, N,N-dimethylglycine dehydrogenase (E.C.1.5.99.2); 3, phospholipase D (E.C.3.1.4.4); 4, choline dehydrogenase (E.C.1.1.99.1); 5, betaine aldehyde dehydrogenase (E.C.1.2.1.8); 6, methylenetetrahydrofolate reductase (MTHFR) (E.C.1.5.1.20); 7, γ-cystathionase (E.C.4.4.1.1); 8, glutamate–cysteine ligase (E.C.6.3.2.2); 9, glutathione synthase (E.C.6.3.2.3); 10, adenosine kinase (E.C.2.7.1.20); 11, adenosine deaminase (E.C.3.5.4.4); 12, AdoMet decarboxylase (E.C.4.1.1.50); 13, spermidine (spermine) synthase (E.C.2.5.1.16 and E.C.2.5.1.22); 14, methionine transamination pathway; and 15, phosphatidylethanolamine methyltransferase (PEMT) (E.C.2.1.1.17).

Fig. 2.

MR studies of the brain at age 12.7 months, before therapy. Myelination is present only in the posterior part of the internal capsule (arrowhead). Note clear delineation of globi pallidi because of unmyelinated lateral and medial lamina (double black arrow). Pattern of myelination corresponds to an age of 2–3 months.

Fig. 3.

Partial nucleotide sequences of directly sequenced PCR products of patient's exon 4. Each allele bears one mutation as indicated by arrows. M, maternally derived allele, the TGG → TGA nonsense mutation in codon 112 causes replacement of a tryptophan by a premature stop codon. F, paternally derived allele, the TAC → TGC missense mutation in codon 143 causes replacement of a tyrosine by a cysteine. WT, related wild-type sequences of each mutated region are presented (Left).