Likely inborn error of metabolism

Gene: AHCY

Green List (high evidence)

Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - multiple unrelated families with this neurometabolic disorder caused by variants in AHCY.

Created: 25 Sep 2020, 12:06 p.m. | Last Modified: 25 Sep 2020, 12:06 p.m.

Panel Version: 2.21

Added 'treatable' tag as some patients have shown improvement following dietary management (particularly methionine restriction and supplementation with creatine and phosphatidylcholine)

Created: 25 Sep 2020, 11:54 a.m. | Last Modified: 25 Sep 2020, 11:54 a.m.

Panel Version: 2.18

- PMID: 15024124 (2004), 16435181 (2005) - Two brothers with S-adenosylhomocysteine hydrolase (SAHH) deficiency, and elevated levels of plasma creatine kinase (CK), S-adenosylhomocysteine (AdoHcy), S-adenosylmethionine (AdoMet) and methionine, due to compound het variants (c.336G>A, p.W112X and c.428A>G, p.Y143C) in AHCY. Authors note psychomotor delay, delayed myelination, hypotonia, poor head control, and mild hepatitis-like findings in one sib. [Note: the group also reported on a third brother who resembled the previous cases (https://www.bib.irb.hr/346457) but the article is not in PubMed and full text is unavailable].

- PMID: 16736098 (2006) - 26-year-old male with severe myopathy, hypotonia, DD, and elevated CK, AdoMet and hypermethioninaemia due to SAHH deficiency associated with compound het variants (c.428A>G, p.Y143C and c.266C>T, p.A89V) in AHCY. At 20 years, WAIS testing showed a verbal IQ score of 76, performance IQ 56, and full scale IQ 64.

- PMID: 20852937 (2010) - Two sibling sisters born with fetal hydrops, insufficient liver synthetic function and muscular hypotonia leading to respiratory failure and death in early infancy. Both had anomalies on brain MRI, including hypomyelination, and metabolic abnormalities resembling previously described cases. Deficient SAHH activity due to compound het variants (c.145C>T, p.R49C and c.257A>G; p.D86G) in AHCY was identified. Functional analysis of both variants (PMID: 19177456) showed reduced protein stability and enzymatic inactivation, respectively.

- PMID: 22959829 (2012) - One patient with SAHH deficiency due to compound het variants (c.145C>T, p.R49C and c.211G>A, p.G71S) in AHCY. Clinical characteristics included hypotonia, severe DD (corresponding to a 6-month infant at 4.5-years of age) and progressive hepatopathy, but normal brain MRI. Plasma methionine and homocysteine levels were normal during the neonatal period and increased only after 8 months of age.

- PMID: 26095522 (2015) - One child with SAHH deficiency (AHCY c.428A>G, p.Y143C and c.982T>G, p.Y328Asp) presented at 8 months of age with growth failure, microcephaly, GDD, myopathy, hepatopathy, and factor VII deficiency. Metabolic abnormalities included elevated plasma methionine, AdoHcy and AdoMet.

- PMID: 26527160 (2015) - Homozygous missense variant (c.146G>A, p.R49H) in AHCY identified post-mortem in a 32-year-old woman with elevated aminotransferase and hepatocellular carcinoma. The same variant was detected in her son who had elevated serum levels of aminotransferase, AdoHcy, AdoMet, and methionine (hallmarks of SAHH def), but remained asymptomatic at 7-years-old.

- PMID: 28779239 (2017) - Compound het variants (c.266C>T, p.A89V and c.428A>G, p.Y143C) identified in an infant, who presented following birth with hypotonia, poor sucking reflex, apnea episodes and rhabdomyolysis (no further info available).

- PMID: 30121674 (2018) - Infant with a prenatal diagnosis of non-immune hydrops, hypotonia, poor respiratory effort, chylothorax, encephalopathy, coagulopathy, progressive hepatic failure, and refractory pulmonary hypertension. Life support was withdrawn at 7 days. Novel compound het variants (p.E108K and p.Y328D) in AHCY were found.

- PMID: 31957987 (2020) - One child with compound het variants (c.170C>T, p.T57I and c.649G>A, p.V217M) in AHCY. The patient presented foetal hydrops, diffuse oedema, coagulopathy, CNS abnormalities, and hypotonia. She died in 3 months due to cardiovascular collapse. Metabolic parameters showed normal methionine levels, but AdoMet and AdoHcy could not be measured.

Created: 25 Sep 2020, 11:54 a.m. | Last Modified: 25 Sep 2020, 11:54 a.m.

Panel Version: 2.18

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752

Publications

• 15024124
• 16435181
• 16736098
• 20852937
• 22959829
• 26095522
• 26527160
• 28779239
• 30121674
• 31957987

Red List (low evidence)

The rating of this gene has been updated following NHS Genomic Medicine Service approval

Created: 3 Mar 2022, 12:59 p.m. | Last Modified: 3 Mar 2022, 12:59 p.m.

Panel Version: 2.223

Associated with phenotype in OMIM, not in G2P / DD. At least 4 variants reported in 2 cases. AHCY appears to be imprinted

Created: 23 Feb 2017, 5:11 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
S-adenosylhomocysteine hydrolase deficiency (Disorders of the metabolism of sulphur amino acids)

Publications

• 27604308
• 15024124
• 19177456
• 26974671