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


CONCLUSIONS
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.
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.
Sylvia
S
Stockler-Ipsiroglu
Division of Biochemical Diseases, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.
Delia
D
Apatean
Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Pisa, Italy.
Roberta
R
Battini
Center for Medical Genetics, University Hospitals Case Medical Center, Cleveland, OH, USA.
Suzanne
S
DeBrosse
Center for Medical Genetics, University Hospitals Case Medical Center, Cleveland, OH, USA.
Kimberley
K
Dessoffy
Pediatric Neurology Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Simon
S
Edvardson
Division of Neurology, Massachusetts General Hospital, Boston, MA, USA.
Florian
F
Eichler
Genetic Department, The Permanent Medical Group, San Francisco, CA, USA.
Katherine
K
Johnston
Department of Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA.
David M
DM
Koeller
Service de Neurologie and Laboratoire de Neurosciences, CHU Mustapha Bacha, Université d'Alger, Algeria.
Sonia
S
Nouioua
Service de Neurologie and Laboratoire de Neurosciences, CHU Mustapha Bacha, Université d'Alger, Algeria.
Meriem
M
Tazir
Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA.
Ashok
A
Verma
Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, USA.
Monica D
MD
Dowling
Department of Pediatrics, Oklahoma University Health Sciences Center, OK, USA.
Klaas J
KJ
Wierenga
Department of Pediatrics, Oklahoma University Health Sciences Center, OK, USA.
Andrea M
AM
Wierenga
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Victor
V
Zhang
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Lee-Jun C
LJ
Wong
D000293:Adolescent; D000579:Amidinotransferases / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D003401:Creatine / Q000172:deficiency / Q000627:therapeutic use*; D002658:Developmental Disabilities / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D005260:Female; D015870:Gene Expression; D005808:Genes, Recessive; D005998:Glycine / Q000031:analogs & derivatives / Q000097:blood / Q000172:deficiency / Q000652:urine; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D009135:Muscular Diseases / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D009154:Mutation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017422:Sequence Analysis, DNA; D013064:Speech Disorders / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D016896:Treatment Outcome; D055815:Young Adult
D000579:Amidinotransferases; C020681:glycine amidinotransferase; C004946:glycocyamine; D003401:Creatine; D005998:Glycine
Cerebral creatine deficiency; GATM; Intellectual disability; Myopathy