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Inborn errors of metabolism

Gene: AHCY

Amber List (moderate evidence)

AHCY (adenosylhomocysteinase)
EnsemblGeneIds (GRCh38): ENSG00000101444
EnsemblGeneIds (GRCh37): ENSG00000101444
OMIM: 180960, Gene2Phenotype
AHCY is in 5 panels

2 reviews

Arina Puzriakova (Genomics England Curator)

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

Sarah Leigh (Genomics England Curator)

Red List (low evidence)

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

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • London North GLH
  • NHS GMS
Phenotypes
  • Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752
  • Disorders of the metabolism of sulphur amino acids
Tags
treatable for-review
OMIM
180960
Clinvar variants
Variants in AHCY
Penetrance
None
Publications
Panels with this gene

History Filter Activity

25 Sep 2020, Gel status: 2

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: AHCY were changed from S-adenosylhomocysteine hydrolase deficiency (Disorders of the metabolism of sulphur amino acids) to Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752; Disorders of the metabolism of sulphur amino acids

25 Sep 2020, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: ahcy has been classified as Amber List (Moderate Evidence).

25 Sep 2020, Gel status: 2

Set mode of inheritance

Arina Puzriakova (Genomics England Curator)

Mode of inheritance for gene: AHCY was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal

25 Sep 2020, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: ahcy has been classified as Amber List (Moderate Evidence).

25 Sep 2020, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: ahcy has been classified as Amber List (Moderate Evidence).

25 Sep 2020, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: ahcy has been classified as Amber List (Moderate Evidence).

25 Sep 2020, Gel status: 1

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: AHCY were set to 15024124; 16435181; 16736098; 20852937; 22959829; 26095522; 26527160; 28779239; 30121674; 31957987

25 Sep 2020, Gel status: 1

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: AHCY were set to 15024124; 16435181; 16736098; 20852937; 22959829; 26095522; 26527160; 28779239; 30121674; 31957987

25 Sep 2020, Gel status: 1

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: AHCY were set to 27604308

25 Sep 2020, Gel status: 1

Added Tag, Added Tag

Arina Puzriakova (Genomics England Curator)

Tag treatable tag was added to gene: AHCY. Tag for-review tag was added to gene: AHCY.

13 Feb 2019, Gel status: 1

Added New Source, Added New Source

Ivone Leong (Genomics England Curator)

Source NHS GMS was added to AHCY. Source London North GLH was added to AHCY.

8 Jan 2019, Gel status: 1

Panel promoted to version 1.0

Ellen McDonagh (Genomics England Curator)

Sarah Leigh: Associated with phenotype in O

16 Dec 2018, Gel status: 1

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Ellen McDonagh (Genomics England Curator)

gene: AHCY was added gene: AHCY was added to Inborn errors of metabolism. Sources: Expert Review Red Mode of inheritance for gene: AHCY was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AHCY were set to 27604308 Phenotypes for gene: AHCY were set to S-adenosylhomocysteine hydrolase deficiency (Disorders of the metabolism of sulphur amino acids)