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 M) without tyrosine elevation. Plasma total homocysteine was very slightly elevated for an infant to 14.5-15.9 M. In plasma, S-adenosylmethionine was 30-fold and AdoHcy 150-fold elevated. Activity of AdoHcy hydrolase was Ϸ3% 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.

SummaryS-Adenosylhomocysteine (AdoHcy) hydrolase deficiency has been proven in a human only once, in a recently described Croatian boy. Here we report the clinical course and biochemical abnormalities of the younger brother of this proband. This younger brother has the same two mutations in the gene encoding AdoHcy hydrolase, and has been monitored since birth. We report, as well, outcomes during therapy for both patients. The information obtained suggests that the disease starts in utero and is characterized primarily by neuromuscular symptomatology (hypotonia, sluggishness, psychomotor delay, absent tendon reflexes, delayed myelination). The laboratory abnormalities are markedly increased creatine kinase and elevated aminotransferases, as well as specific amino acid aberrations that pinpoint the aetiology. The latter include, most importantly, markedly elevated plasma AdoHcy. Plasma S-adenosylmethionine (AdoMet) is also elevated, as is methionine (although the hypermethioninaemia may be absent or nonsignificant in the first weeks of life). The disease seems to be at least to some extent treatable, as shown by improved myelination and psychomotor development during dietary methionine restriction and supplementation with creatine and phosphatidylcholine.*Correspondence: Department of Pediatrics, University Hospital Center, Kišpatićeva 12, Rebro, 10000 Zagreb, Croatia. E-mail: ibaric@kbc-zagreb.hr. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptS-Adenosylhomocysteine (AdoHcy) hydrolase (adenosylhomocysteinase, EC 3.3.1.1) is the enzyme that catalyses hydrolysis of AdoHcy to adenosine and homocysteine (De La Haba and Cantoni 1959). Its deficiency (McKusick 180960) had been proven in a human only once, in a Croatian boy we reported recently (Barić et al 2004). The index patient presented with myopathy, characterized by hypotonia and delayed psychomotor development from birth, abnormally slow brain myelination (noted in MRI studies of the brain at 12.7 months) and mild hepatitis-like findings. The main biochemical abnormalities were marked increases of creatine kinase and aminotransferases, prolonged prothrombin time, low albumin, and specific amino acid aberrations indicative of the aetiology: hypermethioninaemia with almost normal total plasma homocysteine and very elevated plasma AdoHcy (up to 150 × normal) and SAdenosylmethionine (AdoMet) (up to 30 times normal). Activity of AdoHcy hydrolase was severely diminished: about 3% of control in liver and 9−15% of the mean controls in fibroblasts and red blood cells. The specific metabolic defect had been identified and the patient started on therapy by age 12.8 months. Here we report a second patient (patient 2), a brother of the proband. Patient 2 has been monitored since birth and was started on therapy at age 3.4 months, by which time the diagnosis of AdoHcy hydrolase deficiency had been clearly established. We report, also, outcomes during therapy in both patients. METHODS Metabolite assaysAmino acids were measured by i...