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Undiagnosed metabolic disorders

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, 12:19 p.m. | Last Modified: 25 Sep 2020, 12:19 p.m.
Panel Version: 1.420
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, 12:18 p.m. | Last Modified: 25 Sep 2020, 12:18 p.m.
Panel Version: 1.419
- 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, 12:17 p.m. | Last Modified: 25 Sep 2020, 12:17 p.m.
Panel Version: 1.419

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
  • Literature
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
Complete
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

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: AHCY were set to 27604308

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

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.

27 Feb 2017, Gel status: 1

panel promoted to version 1

Sarah Leigh (Genomics England Curator)

Construction of “Undiagnosed Metabolic Disorders” (UDM) panel • The 614 genes from the neurometabolic gene panel (PMID: 27604308) added • Green genes downloaded from V1 metabolic panels (Cerebral folate deficiency, Congenital disorders of glycosylation, Hyperammonaemia, Ketotic hypoglycaemia, Mitochondrial disorders, Mucopolysaccharideosis, Gaucher, Fabry, Peroxisomal disorders), sources replaced with "Expert review green", then loaded as a review onto UDM panel, resulting in 367 green genes and 333 red (therefore 86 new green genes included from the additional metabolic panels that weren't previously on the UDM panel) • Downloaded green genes from all panels. Removed genes from none V1 panels. Removed genes from the metabolic panels mentioned above. Compared the remaining genes with the red genes from UDM panel. Loaded as an "Expert review Amber" review to the overlapping genes, (the panel name where the genes came from was used as the phenotype) • Used variant information from PMID 27604308 to review the genes on this panel • Reviewed genes on UDM panel with genes from Emory "Inherited Metabolic Disorders: Sequencing Panel" and UKGTN “Inborn Errors of Metabolism 226 panel”, changing status where appropriate, added 14 UKGTN genes that had not be listed before • Review 10 red genes that had not previously been reviewed, 4/10 were reclassified as green • Review the remaining 145 red genes that had not previously been reviewed (shared between reviewers EM, RF, LD, AT, HB, ON & SL), resulting in 60 green, 11 amber, 70 red, 4 I don’t know reviews) • Reviewed genes from PMID: 24816252 as a publication to genes found in the Inborn error or metabolism Genes metabolomics GWAS paper (figure 5). 2 new genes added

24 Feb 2017, Gel status: 1

Set Mode of Inheritance, Added New Source

Ellen McDonagh (Genomics England Curator)

AHCY was added to Undiagnosed metabolic disorderspanel. Source: Expert Review Red Model of inheritance for gene AHCY was set to BIALLELIC, autosomal or pseudoautosomal

28 Oct 2016, Gel status: 0

Created

Sarah Leigh (Genomics England Curator)

AHCY was created by sleigh

28 Oct 2016, Gel status: 0

Added New Source

Sarah Leigh (Genomics England Curator)

AHCY was added to Undiagnosed metabolic disorderspanel. Sources: Literature