Severe Intellectual Disability with Speech Delay, Clumsiness, and Drug Responsive Epilepsy in a Boy with GAMT Deficiency

Background/Purpose: Guanidinoacetate methyltransferase (GAMT) deficiency is one of 3 metabolic defects causing cerebral creatine deficiency. The clinical spectrum ranges from mild to severe intellectual disability (ID), delayed or absent speech, autism, seizures and an extrapyramidal movement disorder. Guanidinoacetate (GAA) and the GAA/creatine ratio serve as specific biomarkers. Treatment aims at restoring cerebral creatine and reducing neurotoxic GAA.

Methods: A now 14-year-old boy showed primary developmental delay, walked at the age of 2 years, spoke first words at the age of 5 years. He had 3 generalized seizures at the age of 9 years with prompt response to valproate. MRI was normal. When first seen in our hospital at the age of 11 years he appeared clumsy, had a poor vocabulary of 5 words, and was able to follow one-line commands. Because of seizure relapse after discontinuation of therapy, valproate was reintroduced, leading to electroclinic absence status and hyperammonemic encephalopathy. He rapidly turned seizure free on ethosuximide.

Results: Metabolic workup revealed GAA elevation in plasma and urine and low creatine in basal ganglia and white matter on MR spectroscopy. Molecular analysis of the GAMT gene confirmed a known homozygous truncating mutation (c.64dupG/64dupG).

Conclusion: Our patient presented with unspecific symptoms, that is, severe ID with almost absent expressive speech and late onset epilepsy with good treatment response. Despite the rarity of GAMT deficiency, GAA should be measured in every child with unclear ID, as specific treatment with creatine, ornithine and a low protein diet may be of clear benefit.