Hyperinsulinism-hyperammonemia syndrome in two Peruvian children with refractory epilepsy

Objectives: Congenital hyperinsulinism (HI) is a heterogeneous clinical disorder with great variability in its clinical phenotype, and to date, pathogenic variants in 23 genes have been recognized. Hyperinsulinism-hyperammonemia syndrome (HI/HA) is the second most frequent cause of this disease that shows an autosomal dominant pattern and is caused by an activating mutation of the GLUD1 gene, which responds favorably to the use of diazoxide. HI/HA syndrome presents with fasting hypoglycemia; postprandial hypoglycemia, especially in those with a high protein content (leucine); and persistent mild hyperammonemia. Neurological abnormalities, in the form of epilepsy or neurodevelopmental delay, are observed in a high percentage of patients; therefore, timely diagnosis is crucial for proper management. Case presentation: We report the clinical presentation of two Peruvian children that presented with epilepsy whose genetic analysis revealed a missense mutation in the GLUD1 gene, one within exon 11, at 22% mosaicism; and another within exon 7, as well as their response to diazoxide therapy. To the best of our knowledge, these are the first two cases of HI/HA syndrome reported in Peru. Conclusion: HI/HA syndrome went unnoticed, because hypoglycemia was missed and were considered partially controlled epilepsies. A failure to recognize hypoglycemic seizures will delay diagnosis and adequate treatment, so a proper investigation could avoid irreversible neurological damage.

Automated summary

Congenital hyperinsulinism is a heterogeneous disorder with variable clinical phenotypes caused by pathogenic variants in multiple genes. Hyperinsulinism-hyperammonemia syndrome, characterized by fasting and postprandial hypoglycemia and mild hyperammonemia with associated neurological abnormalities, is the second most common cause of the disease. We present two Peruvian children with epilepsy who were found to have missense mutations in the GLUD1 gene, which responded well to diazoxide therapy, and highlight the importance of timely diagnosis for proper management.