BACKGROUND: Arginine:glycine aminotransferase (AGAT) (GATM) deficiency is an autosomal recessive inborn error of creative synthesis. OBJECTIVE: We performed an international survey among physicians known to treat patients with AGAT deficiency, to assess clinical characteristics and long-term outcomes of this ultra-rare condition. RESULTS: 16 patients from 8 families of 8 different ethnic backgrounds were included. 1 patient was asymptomatic when diagnosed at age 3 weeks. 15 patients diagnosed between 16 months and 25 years of life had intellectual disability/developmental delay (IDD). 8 patients also had myopathy/proximal muscle weakness. Common biochemical denominators were low/undetectable guanidinoacetate (GAA) concentrations in urine and plasma, and low/undetectable cerebral creatine levels. 3 families had protein truncation/null mutations. The rest had missense and splice mutations. Treatment with creatine monohydrate (100-800 mg/kg/day) resulted in almost complete restoration of brain creatine levels and significant improvement of myopathy. The 2 patients treated since age 4 and 16 months had normal cognitive and behavioral development at age 10 and 11 years. Late treated patients had limited improvement of cognitive functions. CONCLUSION: AGAT deficiency is a treatable intellectual disability. Early diagnosis may prevent IDD and myopathy. Patients with unexplained IDD with and without myopathy should be assessed for AGAT deficiency by determination of urine/plasma GAA and cerebral creatine levels (via brain MRS), and by GATM gene sequencing.
Amidinotransferases/deficiency , Amino Acid Metabolism, Inborn Errors/drug therapy , Creatine/therapeutic use , Intellectual Disability/drug therapy , Muscular Diseases/drug therapy , Speech Disorders/drug therapy , Adolescent , Amidinotransferases/chemistry , Amidinotransferases/genetics , Amino Acid Metabolism, Inborn Errors/diagnosis , Amino Acid Metabolism, Inborn Errors/genetics , Amino Acid Metabolism, Inborn Errors/physiopathology , Child , Child, Preschool , Creatine/deficiency , Developmental Disabilities/diagnosis , Developmental Disabilities/drug therapy , Developmental Disabilities/genetics , Developmental Disabilities/physiopathology , Female , Gene Expression , Genes, Recessive , Glycine/analogs & derivatives , Glycine/blood , Glycine/deficiency , Glycine/urine , Humans , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Intellectual Disability/physiopathology , Magnetic Resonance Spectroscopy , Male , Models, Molecular , Muscular Diseases/diagnosis , Muscular Diseases/genetics , Muscular Diseases/physiopathology , Mutation , Protein Structure, Secondary , Protein Structure, Tertiary , Sequence Analysis, DNA , Speech Disorders/diagnosis , Speech Disorders/genetics , Speech Disorders/physiopathology , Treatment Outcome , Young Adult
