S-Adenosylhomocysteine Hydrolase Deficiency via the AHCY Gene

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).

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).

This test provides full coverage of all coding exons of the AHCY gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).