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 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.

S‐Adenosylhomocysteine hydrolase deficiency in a 26‐year‐old man

“…His behaviour was unchanged. At that time the reports by Barić and colleagues (Barić et al 2004(Barić et al , 2005b) stimulated the collaboration that has proved that this patient is also AdoHcy hydrolase-deficient.…”

“…Assays of red blood cell haemolysates were carried out in the direction of synthesis of AdoHcy by a modification of the method of Hershfield and colleagues (Hershfield et al 1979), as described previously (Barić et al 2004).…”

“…The present work was prompted by reports by Barić and co-workers of two Croatian siblings (Barić et al 2004(Barić et al , 2005b who were the first patients with proven AdoHcy hydrolase deficiency. In the proband, who was investigated because of hypotonia, psychomotor delay and elevated plasma CK, hypermethioninaemia as high as 748 μmol/L (normal 13-45 μmol/L) was first detected at age 8 months.…”

“…In the proband, who was investigated because of hypotonia, psychomotor delay and elevated plasma CK, hypermethioninaemia as high as 748 μmol/L (normal 13-45 μmol/L) was first detected at age 8 months. At age 11 months, the finding of a plasma AdoHcy concentration some 150-fold above normal suggested the correct diagnosis (Barić et al 2004). The second patient, a younger brother of the proband, has been followed since birth and, like his brother, had hypotonia, psychomotor delay, elevated plasma CK and severely elevated plasma AdoHcy (Barić et al 2005a,b).…”

Investigation of inter-individual variability of the one-carbon folate pathway: a bioinformatic and genetic review

“…Deficiency of AHCY protein is another potential cause of hypermethionemia. 62 A case report 62 noted a Croatian boy with hypermethionemia, who possessed two variant alleles encoding non-synonymous changes (p.W112X and p.Y143C) in exon 4 of the AHCY gene. In addition, further coding-region variants in the AHCY gene have been shown to have no significant association with altered plasma homocysteine levels.…”