Spectrum of neuro-developmental disorders in children with congenital hyperinsulinism due to activating mutations in GLUD1

Abstract

Background: Hyperinsulinism/hyperammonemia (HI/HA) syndrome is the second most common type of congenital hyperinsulinism caused by an activating GLUD1 mutation. Objective: The aim of this study was to determine the clinical profile and long-term neurological outcomes in children with HI/HA syndrome. Method: Retrospective review of patients with GLUD1 mutation, treated at two centers in the UK and Russia, over a 15-year period. Different risk factors for neuro-developmental disorders were analyzed by Mann-Whitney U test and Fisher exact p. Results: We identified 25 cases with GLUD1 mutations (12 males). Median age of presentation was 7 months (12 hours-18 months). Hypoglycaemic seizures were the presenting feature in 24 (96%) cases. 24 cases responded to diazoxide and protein restriction whilst one patient underwent partial pancreatectomy. In total, 13 cases (52%) developed neurodevelopmental manifestations. Epilepsy (n=9/25, 36%), learning difficulties (n=8/25, 32%) and speech delay (n=8/25, 32%) were the most common neurological manifestation. Median age of presentation for epilepsy was 12 months with generalized tonic-clonic seizures being the most common (n=4/9, 44.4%) followed by absence seizures (n=3/9, 33.3%). Early age of presentation (p=0.02), diazoxide dose (p=0.04), and a mutation in exon 11 or 12 (p=0.01) was associated with neurological disorder. Conclusion: HI/HA syndrome is associated with wide spectrum of neurological disorders. These neurological manifestations were more frequent in cases with mutations affecting the GTP-binding site of GLUD1 in our cohort.

Standardised practices in the networked management of congenital hyperinsulinism: a UK national collaborative consensus

“…Although an exhaustive list of the genetic causes of congenital hyperinsulinism has not been provided in this consensus, a few relatively common causes have been noted. Pathogenic variants in the gene encoding glutamate dehydrogenase (GLUD1), are associated with hyperinsulinaemia/hyperammonaemia syndrome where patients develop relatively mild hyperammonaemia (2-3 times the upper limit for serum ammonia) and a post-prandial hypoglycaemia aggravated by protein intake (11,77,78). GLUD1 variants are dominantly acting but are most commonly sporadic in origin.…”