Creatine Deficiency syndrome (CDS). Arginine:Glycine Amidinotransferase Deficiency. AGAT deficiency.
Incidence
AGAT deficiency is one of the 3 Creatine Deficiency syndromes (CDS). No prevalence studies have been performed to date. Seven individuals with AGAT deficiency have been reported worldwide: four from one Italian family; one from the US; and two sibs of Yemenite Jewish descent. AGAT deficiency is inherited in an autosomal recessive manner. Mutations in the GATM gene cause arginine:glycine amidinotransferase deficiency.
Clinical Characteristics
Arginine:glycine amidinotransferase (AGAT) deficiency is an inherited disorder that primarily affects the brain. Onset is between ages three months and three years. Children with this disorder have mild to moderate intellectual disability and delayed speech development. Some affected children develop autistic behaviors that affect communication and social interaction. They may experience seizures, especially when they have a fever. Children with AGAT deficiency may not gain weight and grow at the expected rate (failure to thrive), and have delayed development of motor skills such as sitting and walking. Affected individuals may also have weak muscle tone and tend to tire easily. A CDS is suspected in a young child with global developmental delay and an older child with intellectual disability, epilepsy, pyramidal / extrapyramidal neurologic findings, and behavior problems. Behavior disorder can include autistic behaviors and self-mutilation; a significant proportion have pyramidal/extrapyramidal findings. Intellectual disability and seizures are common to all three CDS. No genotype-phenotype correlations are known for any of the CDS. Arginine:glycine amidinotransferase (AGAT) deficiency is one of the CDS, and is characterized by psychomotor retardation and very low plasma and urine guanidinoacetate and creatine concentrations. Cerebral creatine concentrations are also strongly reduced. Mutations in the GATM gene cause arginine:glycine amidinotransferase deficiency. AGAT is involved in energetic metabolism at the level of creatine synthesis. GATM gene mutations impair the ability of the arginine:glycine amidinotransferase enzyme to participate in creatine synthesis, resulting in a shortage of creatine. The effects of AGAT deficiency are most severe in organs and tissues that require large amounts of energy, especially the brain. The mode of transmission is autosomal recessive. Early diagnosis and administration of creatine prevents onset of the manifestations of this disorder.
Precipitants
None
Provocation Tests
None
Diagnostic Procedures
Cerebral creatine deficiency in cranial MR spectroscopy (MRS) is the characteristic hallmark of all CDS. Diagnosis of CDS relies on: measurement of guanidinoacetate (GAA), creatine, and creatinine in urine and plasma; and molecular genetic testing of the three genes involved, GAMT, GATM, or SLC6A8. If molecular genetic test results are inconclusive, GAMT enzyme activity (in cultured fibroblast or lymphoblasts), GATM enzyme activity (in lymphoblasts), or creatine uptake in cultured fibroblasts can be assessed.