L-arginine:glycine amidinotransferase deficiency

Alternate names

AGAT deficiency; Arginine:glycine amidinotransferase deficiency; Creatine deficiency syndrome due to AGAT deficiency; GATM deficiency

Definition

L-arginine:glycine amidinotransferase (AGAT) deficiency is a rare condition that primarily affects the brain.

Epidemiology

The prevalence of arginine:glycine amidinotransferase deficiency is unknown. The disorder has been identified in only a few families.

Cause

• Mutations in the GATM gene cause arginine:glycine amidinotransferase deficiency.
• The GATM gene provides instructions for making the enzyme arginine:glycine amidinotransferase.
• This enzyme participates in the two-step production (synthesis) of the compound creatine from the protein building blocks (amino acids) glycine, arginine, and methionine.
• Specifically, arginine:glycine amidinotransferase controls the first step of the process.
• In this step, a compound called guanidinoacetic acid is produced by transferring a cluster of nitrogen and hydrogen atoms called a guanidino group from arginine to glycine.
• Guanidinoacetic acid is converted to creatine in the second step of the process.
• Creatine is needed for the body to store and use energy properly.

Gene mutations

• 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 arginine:glycine amidinotransferase deficiency are most severe in organs and tissues that require large amounts of energy, especially the brain.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

• People with this disorder have mild to moderate intellectual disability and delayed speech development.
• Some affected individuals develop autistic behaviors that affect communication and social interaction.
• They may experience seizures, especially when they have a fever.
• Children with arginine:glycine amidinotransferase 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.

Diagnosis

• Cerebral creatine deficiency in brain MR spectroscopy (1H-MRS) is the characteristic hallmark of all CCDS.
• Diagnosis of CCDS relies on: measurement of guanidinoacetate (GAA), creatine, and creatinine in urine and plasma; and molecular genetic testing of GAMT gene.
• 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.[1].

Treatment

• Treatment of AGAT deficiency is focused on increasing cerebral creatine levels and generally consists of supplementation with creatine monohydrate.
• Treatment of AGAT deficiency aims to replenish cerebral creatine levels by supplementation with creatine monohydrate in oral doses ranging from 400 to 800 mg/kg BW/day in three to six divided doses.
• If initiation of treatment was after age ten years, no improvement in cognitive function or intellectual disability was seen. Normal cognitive function was reported in a female whose treatment was initiated before age two years . Muscle weakness was improved in all individuals treated with creatine monohydrate.

NIH genetic and rare disease info

• NIH info on L-arginine:glycine amidinotransferase deficiency

L-arginine:glycine amidinotransferase deficiency is a rare disease.

L-arginine:glycine amidinotransferase deficiency Resources
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