Guanidinoacetate methyltransferase deficiency

Guanidinoacetate methyltransferase (GAMT) deficiency is a rare inherited disorder of creatine biosynthesis caused by mutations in the GAMT gene located on chromosome 19p13.3. Creatine is essential for energy storage and transmission in tissues with high energy demands, particularly the brain and muscles. In GAMT deficiency, the enzyme responsible for converting guanidinoacetate (GAA) to creatine is impaired, leading to accumulation of GAA (which is neurotoxic) and depletion of creatine and phosphocreatine in the brain. The condition primarily affects the central nervous system, resulting in intellectual disability, speech and language delay, seizures (often refractory to standard anticonvulsant therapy), and movement disorders including dystonia and athetosis. Behavioral abnormalities, including autistic features, may also be present. Symptoms typically manifest in infancy or early childhood. Diagnosis is established through elevated GAA levels in urine and plasma, reduced creatine levels in body fluids, absence of the creatine peak on brain magnetic resonance spectroscopy (MRS), and confirmed by molecular genetic testing of the GAMT gene. Newborn screening programs in some regions can identify affected individuals before symptom onset. Treatment involves oral creatine monohydrate supplementation to replenish cerebral creatine stores, combined with dietary restriction of arginine (the precursor of GAA) and supplementation with ornithine to reduce the toxic accumulation of GAA. Early treatment, ideally in the presymptomatic period, can significantly improve outcomes and may prevent intellectual disability and seizures. However, patients diagnosed and treated later in life may have only partial improvement, particularly in cognitive function. GAMT deficiency is also known as creatine deficiency syndrome due to GAMT deficiency or cerebral creatine deficiency syndrome type 2 (CCDS2).

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