Creatine Deficiency Syndrome via the GATM Gene

Cerebral creatine deficiency syndromes (CCDSs) are inborn errors of creatine metabolism (Mercimek-Mahmutoglu and Stockler-Ipsiroglu, “Creatine Deficiency Syndromes”, GeneReviews, www.genereviews.org). L-Arginine:glycine amidinotranferase (AGAT) deficiency (OMIM #612718) is an autosomal recessive inborn error of creatine biosynthesis. The AGAT enzyme normally catalyzes the first step in creatine synthesis; it transfers the amidino group from arginine to glycine, thus forming ornithine and guanidinoacetate (an immediate precursor of creatine) (Item et al. Am J Hum Genet 69: 1127-1133, 2001). Characteristic biochemical findings in affected individuals include low levels of guanidinoacetate in plasma and urine (Verma. Neurology 75:186-188, 2010). In vivo proton magnetic resonance spectroscopy will reveal low brain creatine levels (Verma 2010). Clinical manifestations of AGAT deficiency include developmental delay, mental retardation, severe language impairment, autistic-like behavior, and failure to thrive. Myopathy in adults and hypotonia in infancy have also been reported. Oral creatine supplementation has been associated with improvement in development as well as muscle weakness (Bianchi et al. Ann Neurol 47:511-513, 2000; Johnston et al. 2005 Am Soc Hum Genet Meeting Abstract, P. 58, Abstract #205; Edvardson et al. Mol Genet Metab 101:228-232, 2010; Verma 2010).

L-Arginine:glycine amidinotransferase is encoded by exons 1-9 of the GATM gene (OMIM #602360) located on chromosome 15. AGAT deficiency is a rare autosomal recessive disorder, with only four different variants having been published. All four variants are severe and lead to premature protein termination. These four pathogenic variants include two nonsense variants and two frameshifts (including one resulting from a splice donor variant that caused exon 3 skipping) (Johnston et al. 2005).

At least one GATM variant has been identified in all individuals with enzymatically-confirmed GATM deficiency (Item et al. 2001; Johnston et al. 2005). Furthermore, all gene variants reported to date are detectable using standard polymerase chain reaction and automated sequencing methodologies.

This test provides full coverage of all coding exons of the GATM 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).