Hypermethioninemia Panel

Hypermethioninemia can be caused by defects in any one of at least six proteins, and may be detected by newborn screening programs in early infancy (Mudd et al. 2000. PubMed ID: 11145114; Mudd et al. 2001. PubMed ID: 11596649; Mudd. 2011. PubMed ID: 21308989; Mudd 2014). Defects in the methionine adenosyltransferase I/III (MATI/III), glycine N-methyltransferase (GNMT) and S-adenosylhomocysteine hydrolase (AHCY) enzymes are responsible for persistent, isolated hypermethioninemia.

Individuals with defects in MAT I/III, GNMT or AHCY enzymes all exhibit persistent, isolated hypermethioninemia, which may or may not be apparent in early infancy (Mudd. 2011. PubMed ID: 21308989). Clinical presentations may differ as well, although a complete clinical spectrum is not well defined for these diseases. The majority of MAT I/III deficient patients are asymptomatic, but they may occasionally present with unusual breath odor and neurologic abnormalities, including intellectual impairment, increased tendon reflexes, dystonia, and nystagmus (Mudd et al. 1995. PubMed ID: 7573050; Chamberlin et al. 1996. PubMed ID: 8770875; Hazelwood et al. 1998. PubMed ID: 9482646; Mudd et al. 2001. PubMed ID: 11596649; Mudd et al. 2014; Chien et al. 2015. PubMed ID: 26289392). Individuals diagnosed with GNMT Deficiency have presented with hepatomegaly and chronic elevation of serum transaminases indicative of liver disease, not attributable to typical causes of liver disease (Mudd et al. 2001. PubMed ID: 11596649; Luka et al. 2009. PubMed ID: 19483083; Augoustides-Savvopoulou et al. 2003. PubMed ID: 14739680). Patients with AHCY deficiency are generally more severely affected, and all have presented with hypotonia and myopathy along with increased creatine kinase (CK) levels. Other common clinical features of AHCY deficiency have included lethargy, poor head control, white matter or other brain abnormalities, microcephaly, developmental delay, strabismus, coagulopathy, liver abnormalities, behavioral issues (including severe attention deficit, self-injurious behavior and aggression), poor feeding, and in one family, fetal hydrops (Baric et al. 2004. PubMed ID: 15024124; Buist et al. 2006. PubMed ID: 16736098; Grubbs et al. 2010. PubMed ID: 20852937; Mudd. 2011. PubMed ID: 21308989; Honzík et al. 2012. PubMed ID: 22959829; Strauss et al. 2015. PubMed ID: 26095522). Additional details regarding these disorders can be found on the individual gene test description pages.

Hypermethioninemia with mild homocystinuria has also been reported in patients with defects in the adenosine kinase enzyme, encoded by the ADK gene. These patients can present with mild to severe liver dysfunction beginning in the neonatal period, muscular hypotonia, global developmental delays, dysmorphism, epilepsy, and recurrent hypoglycemia. Biochemically, they exhibit intermittent hypermethioninemia, increased S-adenosylmethionine and S-adenosylhomocysteine in plasma and increased adenosine in urine (Bjursell et al. 2011. PubMed ID: 21963049; Shakiba et al. 2016. PubMed ID: 27500280; Staufner et al. 2016. PubMed ID: 26642971).

Hypermethioninemia may also be caused by defects in the cystathionine β -synthase (encoded by the CBS gene), fumarylacetoacetate hydrolase (encoded by the FAH gene) and citrin (encoded by the SLC25A13 gene) proteins, as well as by liver disease (Mudd et al. 2000; Mudd et al. 2001; Mudd et al. 2011; Mudd 2014). As defects in the genes encoding CBS, FAH and citrin lead to biochemically distinguishable profiles, testing for these genes is not included in this NextGen sequencing panel.

MAT I/III, GNMT, AHCY, and ADK deficiencies are all autosomal recessive disorders, caused by pathogenic variants in the MAT1A, GNMT, AHCY, and ADK genes, respectively. Pathogenic variants in the MAT1A gene are the most common genetic cause of persistent, isolated hypermethioninemia, with nearly 60 reported causative variants in the literature to date. Pathogenic variants in the ADK, AHCY and GNMT genes are more rare, with fewer than ~15 variants reported in each gene (Human Gene Mutation Database). The majority of reported pathogenic variants in these genes are missense variants, although one nonsense variant has been reported in each AHCY and GNMT, nonsense and small deletion variants have been reported in ADK, and small numbers of nonsense, splicing, small deletions and duplications and three large deletions have been reported in the MAT1A gene (Baric et al. 2004. PubMed ID: 15024124; Human Gene Mutation Database).

The enzymes encoded by these genes are responsible for the catabolism of methionine. The MAT I/III enzyme catalyzes the biosynthesis of S-adenosylmethionine (also known as AdoMet or SAM) from methionine and ATP (Catoni 1953). AdoMet is subsequently converted to S-adenosylhomocysteine (AdoHcy) via the action of GNMT, then the AHCY enzyme hydrolyzes AdoHcy to adenosine and homocysteine (Mudd et al. 2001. PubMed ID: 11596649; Baric et al. 2004. PubMed ID: 15024124; Luka et al. 2009. PubMed ID: 19483083: Mudd. 2011. PubMed ID: 21308989). These reactions make up part of the transmethylation and transsulfuration pathways (Mudd et al. 2014). Adenosine kinase converts adenosine to adenosine monophosphate, and a defect in the ADK enzyme leads to disruption of the methionine cycle due to a resulting accumulation of adenosine that reverses the reaction balance of the AHCY enzyme (Staufner et al. 2016. PubMed ID: 26642971).

Although the overall sensitivity of this test panel is not precisely known, most pathogenic variants reported for the genes in this panel are of the type which can be detected by sequencing.

In two recent reports of patients with MAT1A deficiency, clinical sensitivity was >95% for variants detectable via direct sequencing (Couce et al. 2013. PubMed ID: 23993429; Chien et al. 2015. PubMed ID: 26289392).

The clinical sensitivity of this test for ADK, AHCY and GNMT deficiencies is currently difficult to estimate due to the low number of cases reported in the literature. However, sensitivity is expected to be high as all patients with biochemically and/or enzymatically confirmed ADK, AHCY and GNMT deficiency and molecular analysis have been found to carry two pathogenic variants in the appropriate gene (Luka et al. 2002. PubMed ID: 11810299; Augoustides-Savvopoulou et al. 2003. PubMed ID: 14739680; Baric et al. 2004. PubMed ID: 15024124; Buist et al. 2006. PubMed ID: 16736098; Bjursell et al. 2011. PubMed ID: 21963049; Strauss et al. 2015. PubMed ID: 26095522; Staufner et al. 2016. PubMed ID: 26642971).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes listed 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 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).