Introduction: The hyperinsulinism/hyperammonemia (HI/HA) syndrome is the second most common cause of hyperinsulinemic hypoglycaemia (HH), caused by activating mutations in GLUD1 [which encodes the mitochondrial enzyme glutamate dehydrogenase (GDH)].
Methods: We describe phenotypic variations in three patients from 3 non-related families with HI/HA syndrome due to GLUD1 mutation.
Results: Patient 1, a 10-year-old Caucasian female born to non-consanguineous parents, presented with persistent hypoglycaemia and seizures at 7 months of age. Subsequent investigations during hypoglycaemia showed an inappropriately raised plasma insulin concentration (80 pmol/l) with supressed ketones and fatty acids confirming the diagnosis of HH. She had persistently high serum ammonia concentration [90100 μmol/l (normal <70 μmol/l)]. A protein load test demonstrated protein-sensitive HH. Diazoxide was commenced (5 mg/kg per day) with good response and anticonvulsants were weaned and discontinued. At 8 years of age, diazoxide was gradually weaned and stopped as some high blood glucose values were noted. A 20-hour controlled fast [off diazoxide] and an oral protein load test did not show any hypoglycaemia. She continues to remain free from seizures and hypoglycaemia. Patient 2, a 4-year-old Caucasian boy born to non-consanguineous parents, presented with seizures at 8 months of age requiring anticonvulsant medications. Initial investigations at local hospital did not suggest HH but further investigations during seizures at 4 years of age confirmed HH. Diazoxide (6 mg/kg per day) was commenced with a good response and he continues on anticonvulsants. Patient 3, an 11-year-old Caucasian girl born to Polish non-consanguineous parents with a history of transient neonatal hypoglycaemia, presented with absence seizures at 12 months of age. Further investigations confirmed HH with hyperammoninaemia and good response to diazoxide (10 mg/kg per day) was noted and she did not require anticonvulsants. The genetic analysis in all three patients confirmed GLUD1 mutation.
Conclusions: The cases highlight the highly variable presentation of HI/HA syndrome leading to diagnostic challenges. Mild persistent hyperammonemia and hypoglycaemia in patients presenting with seizures should suggest HI/HA syndrome. Diazoxide may help weaning anticonvulsants in some patients. We noted complete spontaneous resolution of HI/HA in one patient at the age of 8 years, which has not been previously reported in the literature.