Dynamic electro-clinical features in Guanidinoacetate N-methyltransferase deficiency: A familial case series

Abstract: Guanidinoacetate N-methyltransferase deficiency is an inborn error of creatine metabolism, responsible for the absent conversion of guanidinoacetic acid into creatine, resulting in cerebral creatine deficit. It could present a variety of symptoms such as neurodevelopmental delay, epilepsy, movement disorder (ataxia, dystonia, and chorea), and behavioral disturbances. After intellectual disability, epilepsy is the second most frequent expression of the disorder, usually arising during infancy with febrile seizures that are typically followed by generalized seizures and electroencephalographic anomalies. Herein, we describe three siblings with the same homozygous truncating variant in GAMT, all of whom showed significant global developmental delay during early infancy. The eldest two developed initially neglected atypical absences, preceded by focal motor seizures in the older brother, with complete remission with antiseizure medications and dietary treatment. Despite seizure freedom, during follow-up, both developed overt focal epileptiform discharges that have persisted after 2 years of creatine supplementation. Neither seizures nor electroencephalographic abnormalities were noted in the youngest brother who took advantage of an earlier diagnosis and treatment. The dynamic electroclinical pattern we observed has never been reported beforehand. Further studies are needed to assess the long-term prognosis of epilepsy in patients who have introduced dietary treatment after the seizure onset. PLAIN LANGUAGE SUMMARY: GAMT deficiency is a rare genetic disorder that prevents the brain from getting enough creatine, leading to developmental delay, seizures, movement disorders, and behavior problems. This condition often starts in infancy with seizures in fever and can be partially limited by creatine supplementation. In this paper, we present three siblings with the same mutation. The older two had seizures that improved with treatment, but their brain activity remained abnormal. The youngest, diagnosed and treated earlier with supplementation, did not develop epilepsy. More research is needed to understand electro-clinical features of this condition and the long-term effects of early or late dietary treatment.

Parent Summary: This study describes three siblings with GAMT deficiency caused by the same mutation. All three showed signs of delayed development early in life. The two older siblings developed epilepsy, starting with seizures during fevers or brief uncontrolled movements, followed by atypical absence seizures characterized by brief episodes of impaired awareness. These seizures stopped with a combination of anti-seizure medication and creatine, ornithine, and sodium benzoate supplements, but both continued to show abnormal brain activity on EEG scans. The youngest sibling was diagnosed and treated at 16 monthsof age before showing any symptoms and did not develop seizures or abnormal brain activity. This is the first report to describe this changing pattern of brain activity in GAMT deficiency and shows that early diagnosis and treatment may help prevent epilepsy and lead to better brain development.

Link to article: https://pubmed.ncbi.nlm.nih.gov/40543028/

PubMed:  https://pubmed.ncbi.nlm.nih.gov/40543028/

Authors: Mariapaola Schifino, Emanuele Bartolini, Stefano Pagano, Camilla Meossi, Rosa Pasquariello, Roberta Battini

Key Terms: GAMT, Clinical Study, Mutation Study, MRS, Pediatric Patient, Male + Female Patients