Hyperinsulinism-hyperammonemia syndrome associated with GLUD1 gene mutation: a case series.

Background: Congenital hyperinsulinism is a rare disorder characterized by inappropriate insulin secretion, leading to persistent hypoglycemia. One genetic subtype, hyperinsulinism-hyperammonemia syndrome, results from activating mutations in the GLUD1 gene. This study aimed to describe the clinical spectrum, genetic variants, and outcomes of patients with GLUD1-related hyperinsulinism-hyperammonemia syndrome treated at a tertiary care center in Saudi Arabia.

Methods: This retrospective case series included five patients of Saudi ethnicity diagnosed with GLUD1-associated hyperinsulinism-hyperammonemia syndrome between September and November 2023 at King Faisal Specialist Hospital and Research Centre. Clinical, biochemical, imaging, and genetic data were collected from medical records. Descriptive statistics were used to summarize the findings.

Results: All five patients (four pediatric, one adult) presented with hypoglycemia, elevated insulin levels, and persistent hyperammonemia. Genetic testing confirmed GLUD1 mutations in all cases, with two patients sharing the c.1493C > T (p.Ser498Leu) variant. Diazoxide therapy effectively controlled hypoglycemia in most patients. Two patients experienced significant neurological complications, including seizures and developmental delay. One adult patient underwent pancreatectomy with improvement in hypoglycemia control but retained chronic neurological sequelae. Brain magnetic resonance imaging abnormalities and secondary genetic variants were identified in two cases.

Conclusion: GLUD1-related hyperinsulinism-hyperammonemia syndrome presents with a wide clinical spectrum, often with early onset and risk of neurological impairment if not promptly treated. Early diagnosis and individualized management-including genetic testing and diazoxide therapy-are essential to prevent irreversible complications. Further multicenter studies are warranted to better understand long-term outcomes in affected populations.