Sylvia Stockler-Ipsiroglu1, Delia Apatean2, Roberta Battini3, Suzanne DeBrosse4, Kimberley Dessoffy4, Simon Edvardson5, Florian Eichler6, Katherine Johnston7, David M Koeller8, Sonia Nouioua9, Meriem Tazir9, Ashok Verma10, Monica D Dowling11, Klaas J Wierenga12, Andrea M Wierenga12, Victor Zhang13, Lee-Jun C Wong13. 1. Division of Biochemical Diseases, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada; Child & Family Research Institute, BC Children's Hospital, Vancouver, BC, Canada. Electronic address: sstockler@cw.bc.ca. 2. Division of Biochemical Diseases, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada. 3. Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Pisa, Italy. 4. Center for Medical Genetics, University Hospitals Case Medical Center, Cleveland, OH, USA. 5. Pediatric Neurology Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 6. Division of Neurology, Massachusetts General Hospital, Boston, MA, USA. 7. Genetic Department, The Permanent Medical Group, San Francisco, CA, USA. 8. Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA. 9. Service de Neurologie and Laboratoire de Neurosciences, CHU Mustapha Bacha, Université d'Alger, Algeria. 10. Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA. 11. Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, USA. 12. Department of Pediatrics, Oklahoma University Health Sciences Center, OK, USA. 13. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Abstract
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.
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.
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