AHCY gene

Also known: S-AdoHcy Deficiency; SAHH deficiency

OMIM#613752 https://omim.org/entry/613752

1. The Disease

A rare, multisystemic inherited metabolic diseases characterized clinically, by a variable spectrum of severity, primarily comprised of psychomotor delay, myopathy and liver dysfunction. Most patients present in infancy, but the onset can be already in utero or in adult age. Hypermethioninemia is frequent, but often absent in infancy. Creatine kinase is elevated in most patients.

2. The Symptoms

Infants are usually initially asymptomatic at birth and in the neonatal period.

Disease onset is typically in infancy but may occur in utero or in adult age.

Lack of early signs or symptoms does not exclude the diagnosis.

  • In infancy, the clinical manifestatios are developmental delay and hypotonia due to myopathy with markedly increased creatine kinase (CK) plasma levels, and more variably with cerebral hypomyelination, coagulation abnormalities and hepatopathy. Microcephaly, strabismus, and behavioral changes are frequent.
  • Severe cases may present in utero with fetal hydrops, congenital brain anomalies (pontine and cerebellar hypoplasia, hypoplastic corpus callosum), liver failure, respiratory insufficiency due to severe muscle weakness and death in early infancy.
  • Specific biochemical findings include markedly increased plasma S-adenosylhomocysteine (AdoHcy) and S-adenosylmethionine (AdoMet) in combination with normal or near normal total homocysteine (tHcy) and hypermethioninemia (increased methionine) which is not always present, particularly not in early infancy.
  • Whilst the disease is typically severe with poor developmental outcomes, the phenotype can vary from mild to asymptomatic (one report). The milder phenotype includes late-onset presentation with milder weakness and developmental delay. Hepatocellular carcinoma was reported in one patient and was possibly present in another.

3. Actions to take in case of early diagnosis

  • Babies with a positive genetic test (having 2 mutations or 2 copies of a single mutations in the AHCY gene) should continue breastfeeding.
  • Biochemical correlation is essential for confirming diagnosis with plasma quantitative amino acids (high methionine), plasma homocysteine (normal in most cases). Biochemical NBS with tandem mass spectrometry can also help. If available, analysis of plasma AdoMet and AdoHcy can confirm the diagnosis.
  • SAHH Deficiency is a lifelong disease that requires lifetime compliance to dietary management and regular follow-up with a metabolic disease specialist and a multidisciplinary approach to care.
  • Early treatment, methionine restriction diet (with methionine-free amino acid mixture supplementation), which can decrease and sometimes even normalize plasma AdoMet and AdoHcy. Liver transplantation has resulted in clinical and biochemical improvement in a single case.
  • Phosphatidylcholine, creatine and cysteine supplementation may be beneficial.
  • Long-term follow-up is missing in most patients and accurate and precise prognosis is not possible.
  • Genetic counseling is highly recommended for family planning and evaluation of at-risk family members such as siblings.

4. For more information

Orphanet: https://www.orpha.net/consor4.01/www/cgi-bin/Disease_Search.php?lng=EN&data_id=11805&Disease_Disease_Search_diseaseGroup=AHCY&Disease_Disease_Search_diseaseType=Gen&Disease(s)/group%20of%20diseases=S-adenosylhomocysteine-hydrolase-deficiency&title=S-adenosylhomocysteine%20hydrolase%20deficiency&search=Disease_Search_Simple


  • Baric I, Fumic K, Glenn B, et al. S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism. Proc Natl Acad Sci U S A. 2004;101(12):4234-4239. PMID: 15024124.
  • Honzík T, Magner M, Krijt J, et al. Clinical picture of S-adenosylhomocysteine hydrolase deficiency resembles phosphomannomutase 2 deficiency. Mol Genet Metab. 2012;107(3):611-613. PMID: 22959829.