Guanidinoacetate methyltransferase (
GAMT) deficiency (McKusick 601240), an inborn error of
creatine biosynthesis, is characterized by
creatine depletion and accumulation of
guanidinoacetate (GAA) in the brain. Treatment by oral
creatine supplementation had no effect on the intractable
seizures. Based on the possible role of GAA as an epileptogenic agent, we evaluated a dietary treatment with
arginine restriction and
ornithine supplementation in order to achieve reduction of GAA. In an 8-year-old Kurdish girl with
GAMT deficiency arginine intake was restricted to 15 mg/kg/day (0.4 g natural
protein/kg/day) and
ornithine was supplemented with 100 mg/kg/day over a period of 14 months. The diet was enriched with 0.4 g/kg/day of
arginine-free
essential amino acid mixture and
creatine treatment remained unchanged (1.1 g/kg/day). Guanidino compounds in blood, urine, and CSF were measured by means of
cation-exchange chromatography. The combination of
arginine restriction and
ornithine supplementation led to a substantial and permanent decrease of
arginine without disturbance of
nitrogen detoxification. Formation of GAA was effectively reduced after 4 weeks of treatment and sustained thereafter. Biochemical effects were accompanied by a marked clinical improvement. Distinctly reduced epileptogenic activities in electroencephalography accompanied by almost complete disappearance of
seizures demonstrates the positive effect of GAA reduction. This indicates for the first time that GAA may exert an important epileptogenic potential in man.
Arginine restriction in combination with
ornithine supplementation represents a new and rationale therapeutic approach in
GAMT deficiency.