GAMT – Guanidinoacetate Methyltransferase Deficiency

Autosomal recessive guanidinoacetate methyltransferase (GAMT) deficiency is a well‐characterized inborn error of creatine biosynthesis caused by biallelic pathogenic variants in GAMT (HGNC:4136). The condition, recognized by cerebral creatine depletion on proton magnetic resonance spectroscopy and marked elevation of guanidinoacetate in body fluids, presents in early infancy or childhood with global developmental delay, epilepsy, movement disorders, behavioral abnormalities and, in some cases, autistic features (PMID:24165373).

Genetic evidence supports a definitive association: over 58 affected individuals from multiple unrelated families have been reported with homozygous or compound heterozygous loss‐of‐function and missense variants (PMID:24165373). The prototypic variants include c.578A>G (p.Gln193Arg) and c.391G>C (p.Gly131Arg) identified in a Japanese adult patient and validated by biochemical and cDNA splice‐product analyses (PMID:23846910). A diverse variant spectrum spans frameshifts, nonsense, splice‐site and missense changes affecting enzyme activity.

The phenotype is consistent across cohorts: 81% of patients develop seizures—often drug‐resistant—between 10 months and 3 years, with drop attacks, atypical absences and epileptic spasms reported; movement disorders such as dystonia and extrapyramidal signs appear in early childhood; and behavioral disturbances including hyperactivity and autism spectrum features are common (PMID:24165373).

Functional studies demonstrate that pathogenic GAMT variants abolish enzyme activity in patient fibroblasts and lymphocytes, with residual activity <0.1 nmol/mg protein/hour compared to controls; overexpression of wild‐type GAMT restores activity in deficient cells, confirming a loss‐of‐function mechanism (PMID:15108290; PMID:16899382). Enzyme assays and mass spectrometry provide rapid, noninvasive diagnostic confirmation.

Early diagnosis enables effective treatment: creatine supplementation (250–1000 mg/kg/day) with ornithine and/or sodium benzoate and dietary arginine restriction reduces neurotoxic guanidinoacetate levels, leading to seizure control, improvement in movement disorders and, if initiated neonatally, normal neurodevelopmental outcomes (PMID:24071436; PMID:37465909). Newborn screening by tandem mass spectrometry for elevated guanidinoacetate and low creatine is now recommended.

References

• JIMD reports • 2014 • A Japanese adult case of guanidinoacetate methyltransferase deficiency. PMID:23846910
• Epileptic disorders • 2013 • Epileptic and electroencephalographic manifestations of guanidinoacetate-methyltransferase deficiency. PMID:24165373
• Human mutation • 2004 • Characterization of seven novel mutations in seven patients with GAMT deficiency. PMID:15108290
• Molecular genetics and metabolism • 2006 • Overexpression of GAMT restores GAMT activity in primary GAMT-deficient fibroblasts. PMID:16899382
• Molecular genetics and metabolism • 2013 • Evidence-based treatment of guanidinoacetate methyltransferase (GAMT) deficiency. PMID:24071436
• Pediatrics • 2023 • Evidence and Recommendation for Guanidinoacetate Methyltransferase Deficiency Newborn Screening. PMID:37465909

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