Expanded clinical and molecular spectrum of guanidinoacetate methyltransferase (GAMT) deficiency

Guanidinoacetate methyltransferase (GAMT) deficiency is a disorder of creatine biosynthesis, characterized by excessive amounts of guanidinoacetate in body fluids, deficiency of creatine in the brain, and presence of mutations in the GAMT gene. We present here 8 new patients with GAMT deficiency along with their clinical, biochemical and molecular data. The age at diagnosis of our patients ranges from 0 to 14 years. The age of onset of seizures usually ranges from infancy to 3 years. However, one of our patients developed seizures at age 5; progressing to myoclonic epilepsy at age 8 years and another patient has not developed seizures at age 17 years. Five novel mutations were identified: c.37ins26 (p.G13PfsX38), c.403G > T (p.D135Y), c.507_521dup15 (p.C169_S173dup), c.402C > G (p.Y134X) and c.610_611delAGinsGAA (p.R204EfsX63). Six patients had the c.327G > A (last nucleotide of exon 2) splice-site mutation which suggests that this is one of the most common mutations in the GAMT gene, second only to the known Portuguese founder mutation, c.59G > C (p.W20S). Our data suggests that the clinical presentation can be variable and the diagnosis may be overlooked due to unawareness of this disorder. Therefore, GAMT deficiency should be considered in the differential diagnosis of progressive myoclonic epilepsy as well as in unexplained developmental delay or regression with dystonia, even if the patient has no history of seizures. As more patients are reported, the prevalence of GAMT deficiency will become known and guidelines for prenatal diagnosis, newborn screening, presymptomatic testing and treatment, will need to be formulated.