S-Adenosylhomocysteine Hydrolase Deficiency via the AHCY Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
2189 AHCY$940.00 81479 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity

At this time, the sensitivity of this test is difficult to estimate due to the low number of cases reported in the literature. Analytical sensitivity may be high as the only reported causative variants are detectable by sequencing (Baric et al. 2004; Buist et al. 2006; Grubbs et al. 2010; Honzík et al. 2012; Strauss et al. 2015).

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Clinical Features

Defects in the S-Adenosylhomocysteine Hydrolase (AHCY) enzyme have been shown to lead to persistent, isolated hypermethioninemia, which is the elevation of methionine in plasma without accompanying homocystinemia. This hypermethioninemia persists beyond the first months of life (Mudd et al. 2001). A relatively small number of patients have been reported in the literature and thus a cohesive clinical picture has yet to develop, but thus far, all patients have been reported to present with hypotonia and myopathy, along with elevated creatine kinase (CK) levels. Other clinical features observed in affected patients have included severe developmental delays, contractures, poor head control, white matter or other brain abnormalities, microcephaly, behavioral difficulties (including obsessive behavior, severe attention deficit, aggression and self-injurious behavior), poor feeding, respiratory insufficiency, liver abnormalities, and in one family, fetal hydrops. Biochemically, patients present with elevated methionine levels and greatly increased S-adenosylmethionine (AdoMet) and S-adenosylhomocysteine (AdoHcy) levels. In some cases, slight increases in plasma total homocysteine (tHcy), cystathionine and sarcosine were observed. In all patients, low activity of the S-adenosylhomocysteine hydrolase was confirmed (Baric et al. 2004; Buist et al. 2006; Grubbs et al. 2010; Honzík et al. 2012; Strauss et al. 2015).

Plasma methionine levels in reported patients have not always exceeded reference levels in early infancy, although they do increase with time. Therefore, AHCY deficient patients may or may not be detected via newborn screening (Mudd 2011). Treatment via dietary measures has been attempted, although there is no conclusive evidence that such treatment affects the clinical outcome (Baric et al. 2004; Buist et al. 2006). Liver transplantation has been reported to be beneficial in one case (Strauss et al. 2015).


S-adenosylhomocysteine hydrolase deficiency is inherited in an autosomal recessive manner, and is caused by pathogenic variants in the AHCY gene located on chromosome 20 at 20q11.22. Fewer than 10 pathogenic variants have been reported in the AHCY gene. Thus far, all reported variants are missense variants, with the exception of one nonsense variant (Baric et al. 2004; Human Gene Mutation Database). The variants Arg49Cys and Tyr143Cys have both been reported in more than one family; all other variants reported to date have been observed only in a single family (Baric et al. 2004; Buist et al. 2006; Vugrek et al. 2009; Honzík et al. 2012; Strauss et al. 2015).

The S-adenosylhomocysteine hydrolase (AHCY) enzyme is responsible for the hydrolysis of S-adenosylhomocysteine (AdoHcy) to adenosine and homocysteine (Baric et al. 2004; Mudd 2011). This reaction is a part of the transmethylation and transsulfuration pathways, which are necessary for recycling methionine, generating methyl groups for methyltransfer reactions, and the generation of cysteine (Mudd et al. 2014).

Testing Strategy

This test involves bidirectional Sanger sequencing using genomic DNA of all coding exons of the AHCY gene plus ~10 bp of flanking non-coding DNA on each side. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.

Indications for Test

Patients with hypermethioninemia are good candidates for this test, particularly if they have elevated plasma AdoHcy and AdoMet levels and normal or only slightly elevated plasma homocysteine, tyrosine and sarcosine levels. Family members of patients known to have AHCY pathogenic variants are also good candidates, and we will also sequence the AHCY gene to determine carrier status.


Official Gene Symbol OMIM ID
AHCY 180960
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Hypermethioninemia Sequencing Panel


Genetic Counselors
  • Baric I. et al. 2004. Proceedings of the National Academy of Sciences of the United States of America. 101: 4234-9. PubMed ID: 15024124
  • Buist N.R. et al. 2006. Journal of Inherited Metabolic Disease. 29: 538-45. PubMed ID: 16736098
  • Grubbs R. et al. 2010. Journal of Inherited Metabolic Disease. 33: 705-13. PubMed ID: 20852937
  • Honzík T. et al. 2012. Molecular Genetics and Metabolism. 107: 611-3. PubMed ID: 22959829
  • Human Gene Mutation Database (Bio-base).
  • Mudd H.S. et al. 2014. Disorders of Transsulfuration. In: Valle D, Beaudet AL, Vogelstein B, et al., editors.New York, NY: McGraw-Hill. OMMBID. 
  • Mudd S.H. 2011. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics. 157C: 3-32. PubMed ID: 21308989
  • Mudd S.H. et al. 2001. Journal of Inherited Metabolic Disease. 24: 448-64. PubMed ID: 11596649
  • Strauss K.A. et al. 2015. Molecular Genetics and Metabolism. 116: 44-52. PubMed ID: 26095522
  • Vugrek O. et al. 2009. Human Mutation. 30: E555-65. PubMed ID: 19177456
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 10 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of February 2018, we compared 26.8 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 14 years of our lab operation we have Sanger sequenced roughly 14,300 PCR amplicons. Only one error has been identified, and this was an error in analysis of sequence data.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 10 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

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Ordering Options

myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.


(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.


(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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