Creatine Deficiency Syndrome via the GAMT Gene

Guanidinoacetate N-methyltransferase (GAMT) deficiency (OMIM #612736) is an inborn error of creatine biosynthesis causing cerebral creatine deficiency syndrome (CCDS). GAMT enzyme normally catalyzes the transfer of a methyl group from S-adenosylmethionine to guanidinoacetate, thus forming creatine (Stockler et al. Am J Hum Genet 58:914-922, 1996; Schulze. Molecular and Cellular Biochemistry 244:143-150, 2003.). Characteristic biochemical findings include low urinary creatinine (reflecting a low body creatine pool) and accumulation of guanidinoacetate in urine, plasma, and CSF (Mercimek-Mahmutoglu et al. Neurology 67:480-484, 2006). Direct measurement of total creatine levels in the brain is possible by in vivo proton magnetic resonance spectroscopy (Stromberger et al. J Inherit Metab Dis 26: 299-308, 2003). Clinical manifestations of GAMT deficiency include intellectual disability (usually severe), epileptic seizures, and extrapyramidal movement disorder. Dietary treatment, including oral creatine and ornithine supplementation together with arginine restriction, has been shown to result in clinical and biochemical improvement (Gordon. Brain Dev 32:79-81, 2010).

Guanidinoacetate N-methyltransferase is encoded by exons 1-6 of the GAMT gene (OMIM #601240) located on chromosome 19p13.3. GAMT deficiency is an autosomal recessive disorder, with over 25 different variants having been reported. While the majority of variants are missense, several insertions, deletions, and splice site variants are also recognized causes of disease. The two most common variants include c.59G>C in exon 1 (commonly found in patients of Portuguese or Spanish origin) and c.327G>A in exon 2 (Mercimek-Mahmutoglu et al., “Creatine Deficiency Syndromes”, GeneReviews, 2011, http://www.ncbi.nlm.nih.gov/books/NBK3794/).

At least one GAMT variant has been identified in all individuals with enzymatically-confirmed GAMT deficiency (Mercimek-Mahmutoglu et al. Neurology 67:480-484, 2006).

The sensitivity of duplication/deletion testing for this rare disorder is currently unknown.

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