Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide

• Published in: Molecular genetics and metabolism 2015-12, Vol.116 (4), p.252-259
• Main Authors: Stockler-Ipsiroglu, Sylvia, Apatean, Delia, Battini, Roberta, DeBrosse, Suzanne, Dessoffy, Kimberley, Edvardson, Simon, Eichler, Florian, Johnston, Katherine, Koeller, David M., Nouioua, Sonia, Tazir, Meriem, Verma, Ashok, Dowling, Monica D., Wierenga, Klaas J., Wierenga, Andrea M., Zhang, Victor, Wong, Lee-Jun C.
• Format: Article
• Language: English
• Subjects: Adolescent; Amidinotransferases - chemistry; Amidinotransferases - deficiency; Amidinotransferases - genetics; Amino Acid Metabolism, Inborn Errors - diagnosis; Amino Acid Metabolism, Inborn Errors - drug therapy; Amino Acid Metabolism, Inborn Errors - genetics; Amino Acid Metabolism, Inborn Errors - physiopathology; Cerebral creatine deficiency; Child; Child, Preschool; Creatine - deficiency; Creatine - therapeutic use; Developmental Disabilities - diagnosis; Developmental Disabilities - drug therapy; Developmental Disabilities - genetics; Developmental Disabilities - physiopathology; Female; GATM; Gene Expression; Genes, Recessive; Glycine - analogs & derivatives; Glycine - blood; Glycine - deficiency; Glycine - urine; Humans; Intellectual disability; Intellectual Disability - diagnosis; Intellectual Disability - drug therapy; Intellectual Disability - genetics; Intellectual Disability - physiopathology; Magnetic Resonance Spectroscopy; Male; Models, Molecular; Muscular Diseases - diagnosis; Muscular Diseases - drug therapy; Muscular Diseases - genetics; Muscular Diseases - physiopathology; Mutation; Myopathy; Protein Structure, Secondary; Protein Structure, Tertiary; Sequence Analysis, DNA; Speech Disorders - diagnosis; Speech Disorders - drug therapy; Speech Disorders - genetics; Speech Disorders - physiopathology; Treatment Outcome; Young Adult
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2015.10.003

Arginine:glycine aminotransferase (AGAT) (GATM) deficiency is an autosomal recessive inborn error of creative synthesis. 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. 16 patients from 8 families of 8 different ethnic backgrounds were included. 1 patient was asymptomatic when diagnosed at age 3weeks. 15 patients diagnosed between 16months and 25years 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 (100–800mg/kg/day) resulted in almost complete restoration of brain creatine levels and significant improvement of myopathy. The 2 patients treated since age 4 and 16months had normal cognitive and behavioral development at age 10 and 11years. Late treated patients had limited improvement of cognitive functions. 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. •AGAT deficiency causes cerebral creatine deficiency and low levels of guanidinoacetate in urine and blood•Developmental delay is a characteristic feature in younger children•Patients may delevelop additional myopathy.•Oral creatine supplementation corrects cerebral creatine deficiency, and improves developmental outcomes and myopathy•Early treated patients have normal outcomes.