SituationPatient A and B are 9 and 4 year old siblings with developmental delay and in particular; speech delay, seizures and behavioural difficulties. They were found to have GAMT deficiency due to a heterozygous pathogenic GAMT splicing mutation c.327G>A and pathogenic GAMT nonsense mutation c.522G>A (Trp174Ter). Patient A and B were referred to the regional metabolic team for further input. Management of this rare disorder involves combination treatment with specialist medications and a protein restricted diet.1,2BackgroundGAMT deficiency is an inherited disorder of creatine synthesis.1,2 Approximately 110 patients have been diagnosed world wide.1 Main clinical features are intellectual disability with speech and language delay, behavioural problems and epilepsy.1,2 Creatine is an important energy source formuscle and brain. The enzyme arginine: amidinotransferase (AGAT) synthesises guanidinoacetate (GAA) using arginine and glycineas substrates.1,2 The enzyme GAMT in the liver then catalyses the last step of creatine synthesis converting GAA into creatine.1,2 Creatine is transported via the bloodstream to other organs where it is utilised.1 In GAMT deficiency there is a deficiency of creatine and an excess of GAA causing neurotoxicity. The sibling’s history and presentation were consistent with GAMT deficiency and plasma GAA levels done before starting ornithine were very elevated confirming the genetic finding.TreatmentCreatine supplementation restores deficient levels. L-Ornithine competitively inhibits the enzyme AGAT reducing GAA synthesis. An arginine restricted diet and sodium benzoate deprives the pathway of arginine and glycine respectively reducing GAA synthesis.1,2Outcome6 months after starting treatment with creatine (400 mg/kg/day) and l-ornithine (400 mg/kg/day), a significant clinical improvement has been observed. Patient A has had improvement in memory recall, speech and sleeping, and her seizures have reduced from daily to occasionally. Her plasma GAA levels have decreased from 13.3 to 6.5 micromoles/L (0.8–3.1 micromole/L).A bigger improvement has been seen for patient B, probably explained by an earlier age of intervention. Seizures have stopped, with normalisation of his electroencephalogram. His behaviour, attention span and speech have improved, with an ability to form sentences and a widening vocabulary. He is able to walk up the stairs rather than crawl or bottom-shuffle. His plasma GAA has decreased from 14.7 to 8.0 micromoles/L.Doses of l-ornithine and creatine have been increased further to 600 mg/kg/day.Both have had brain magnetic resonance spectroscopy on treatment showing there is no creatine deficiency.Lessons learntManagement of GAMT deficiency requires multidisciplinary input with pharmacy playing an important role advising on treatment, dosing and formulation, and sourcing ornithine and creatine of pharmaceutical grade that is palatable for children. As with very rare disorders, recommendations for treatment are based on case reports and expert opinion. However, there is an emerging pattern that combined treatment started early has the best outcome with normal development sometimes being reported. The siblings struggled with the diet so pharmaceutical intervention is the mainstay of management. If GAA levels fail to fall and/or remain low then sodium benzoate may be introduced.1ReferencesSaudubray JM, Baumgartner MR, Walter J. Inborn metabolic diseases: Diagnosis and treatment 2016;6th ed. Berlin: Springer.Stockler-Ipsiroglu S, Van Karnebeek C, Longo N, et al. Guanidinoacetate methyltransferase (GAMT) deficiency: Outcomes in 48 individuals and recommendations for diagnosis, treatment and monitoring. Molecular Genetics and Metabolism2014;111:16–25.
Guanidinoacetate methyltransferase (GAMT) deficiency: a rare but treatable epilepsy
