GATM – AGAT Deficiency

Arginine:glycine amidinotransferase (AGAT) deficiency, caused by biallelic variants in GATM and defined as AGAT deficiency, is an autosomal recessive disorder of creatine biosynthesis characterized by severe brain creatine depletion, intellectual disability, language impairment, and muscle weakness.

Genetic evidence comprises loss-of-function variants across multiple pedigrees. A homozygous truncating variant c.446G>A (p.Trp149Ter) was identified in three affected children from a single Italian family by sequencing of 26 relatives, with 10 carriers confirmed (PMID:12468279). Two additional siblings harboring a homozygous c.1111dup (p.Met371AsnfsTer6) variant presented with mild intellectual disability and myopathy (PMID:20682460).

Additional case reports include a neonatal diagnosis with early creatine treatment preventing developmental delay (PMID:16769397) and an adult-onset presentation of progressive myopathy responsive to creatine supplementation (PMID:38350728). Long-term follow-up of four Italian patients confirms reversible creatine deficiency and improved adaptive functioning after supplementation (PMID:28148286).

Biochemical confirmation by brain 1H-MRS demonstrates absent creatine peaks that normalize with supplementation. Functional assays of AGAT variants reveal complete loss of enzymatic activity for truncating and key active-site missense mutations, supporting a loss-of-function mechanism (PMID:9266688; PMID:27233232).

Animal or cellular models remain limited; however, site-directed mutagenesis and structural studies have delineated a catalytic triad crucial for enzyme activity. Clinical rescue by oral creatine monohydrate supplementation in patients constitutes in vivo functional validation of pathogenicity.

The concordance of loss-of-function genetics, robust biochemical markers, and effective treatment across multiple studies establishes a definitive gene–disease relationship for AGAT deficiency. Early diagnosis and supplementation yield significant clinical improvement, underscoring its diagnostic and therapeutic utility.

References

• Molecular genetics and metabolism • 2002 • Creatine depletion in a new case with AGAT deficiency: clinical and genetic study in a large pedigree. PMID:12468279
• Molecular genetics and metabolism • 2010 • l-arginine:glycine amidinotransferase (AGAT) deficiency: clinical presentation and response to treatment in two patients with a novel mutation. PMID:20682460
• The Journal of pediatrics • 2006 • Arginine:glycine amidinotransferase (AGAT) deficiency in a newborn: early treatment can prevent phenotypic expression of the disease. PMID:16769397
• Practical neurology • 2024 • Arginine:glycine amidinotransferase (AGAT) deficiency: an easy-to-miss treatable adult-onset myopathy. PMID:38350728
• Orphanet journal of rare diseases • 2017 • Fifteen-year follow-up of Italian families affected by arginine glycine amidinotransferase deficiency. PMID:28148286
• Human mutation • 2016 • Arginine-Glycine Amidinotransferase Deficiency and Functional Characterization of Missense Variants in GATM. PMID:27233232
• European journal of biochemistry • 1997 • Substrate binding and catalysis by L-arginine:glycine amidinotransferase--a mutagenesis and crystallographic study. PMID:9266688

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