Hypermethioninemia With S-Adenosylhomocysteine Hydrolase Deficiency

A number sign (#) is used with this entry because hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase can be caused by compound heterozygous mutation in the AHCY gene (180960) on chromosome 20q11.

Clinical Features

In 3 daughters of Tunisian parents who were not known to be related but came from the same village in Tunisia, Labrune et al. (1990) described hypermethioninemia associated with failure to thrive, mental and motor retardation, facial dysmorphism with abnormal hair and teeth, and myocardiopathy. Hepatic S-adenosylhomocysteine hydrolase activity was decreased by 80% in the 3 children. Neonatal cholestasis was also a feature. A fourth daughter, who died of hepatic failure at the age of 9 months, was probably also affected. The disorder was presumably autosomal recessive.

Baric et al. (2004) reported a Croatian boy with hypermethioninemia and deficiency of S-adenosylhomocysteine hydrolase. The patient's psychomotor development was slow until his fifth month when stagnation and regression were noted. The main problems were hypotonia, sluggishness, lack of interest, and very poor head control. Electron microscopy of muscle showed numerous abnormal myelin figures; liver biopsy showed mild hepatitis with sparse rough endoplasmic reticulum. At age 12 months, brain MRI showed white matter atrophy and abnormally slow myelination. Hypermethioninemia was present in the initial metabolic study at age 8 months, and persisted without tyrosine elevation. Plasma total homocysteine was slightly elevated; in plasma, S-adenosylmethionine was 30-fold and S-adenosylhomocysteine 150-fold elevated. Activity of S-adenosylhomocysteine hydrolase was approximately 3% of control values in liver and was 5 to 10% of control values in red blood cells and cultured fibroblasts. Leukocyte DNA was hypermethylated.

Other causes of hypermethioninemia include hereditary tyrosinemia (276700), cystathionine beta-synthase deficiency (236200), and methionine adenosyltransferase deficiency (250850).

Inheritance

Hypermethioninemia with S-adenosylhomocysteine hydrolase deficiency is an autosomal recessive disorder (Baric et al., 2004).

Pathogenesis

In discussing the basis of the pathologic effects of S-adenosylhomocysteine hydrolase deficiency, Baric et al. (2004) pointed to the numerous S-adenosylmethionine-dependent methyltransferases, which are inhibited to a greater or lesser extent by S-adenosylhomocysteine. They pointed out that changes in DNA methylation patterns are heritable and could negatively affect tissue-specific gene expression during embryogenesis and after birth. Because the silencing of genes by inappropriate methylation is the functional equivalent of somatic mutations, the heritability of DNA methylation patterns suggests that restoration of 'normal' genomic methylation patterns may not occur.

Molecular Genetics

In a Croatian boy with S-adenosylhomocysteine hydrolase deficiency, Baric et al. (2004) identified compound heterozygosity for 2 mutations in the AHCY gene (180960.0001 and 180960.0002).