Background & Objective: Hyperinsulinism-Hyperammonaemia (HI/HA) syndrome is the second most common type of congenital hyperinsulinism (CHI) in outbred populations. HI/HA is caused by an activating mutation in the GLUD1 gene which encodes the intra-mitochondrial enzyme glutamate dehydrogenase (GDH).
The aim of this study was to determine the clinical presentation, treatment and risk factors of neuro-developmental disorders in children with HI/HA syndrome due to activating GLUD1 mutations.
Method: Retrospective review of patients GLUD1 CHI mutation treated at two specialist centers in the UK and Russia over a 15-year period. Statistical analyses included Mann-Whitney U test and Fisher exact p to assess the significance of different risk factors for neuro-developmental disorders.
Results: We identified 24 cases with GLUD1 mutations (11 males). Median age of presentation was 23 weeks (12 hours-72 weeks). De novo mutation was confirmed in 12 (50%) cases. In 8 (30%) of them, the inheritance could not be established due to unavailability of parental samples. Hypoglycaemic seizures were the presenting feature in 23 (95.8%) cases. However, one patient presented with screaming at the age of 8 months. 23 cases responded to diazoxide and protein restriction whilst one underwent partial pancreatectomy due to uncontrolled hypoglycaemia on octreotide (as diazoxide unavailable).
In total, 16 cases (66.7%) developed a neuro-developmental manifestation. Epilepsy (n=9/24, 37.5%), learning difficulties (n=8/24, 33.3%) and speech delay (n=8/24, 33.3%) were the most common neurological manifestation followed by motor delay (n=7/24, 29.1%), abnormal movement (n=6/24, 25%) and vision problems (n=4/24, 16.7%). Median age of presentation for epilepsy was 42 weeks. In terms of seizures, generalized tonic-clonic seizures were the most common (n=4/9, 44.4%) followed by absence seizures (n=3/9, 33.3%). Abnormal electroencephalogram (EEG) and brain magnetic resonance imaging (MRI) was found in 5/9 (55.6%) and 4/9 (44.4%) respectively.
Mutations in exons 11 and 12 of GLUD1 gene (in charge of communication between adjacent GDH subunits) seems to be significant risk factor for epilepsy (P=0.045). Early age of presentation for CHI (P=0.027) was more likely to cause neurological disorder, while gestational age (P=0.79), birth weight (P=0.85), asphyxia (P=0.10) and ammonia level (P=0.63) do not seem to be associated with long-term neurodevelopmental disorders.
Conclusion: HI/HA syndrome is associated with wide spectrum of neurological disorders. Epilepsy, learning difficulties and speech delay are the most common neurological manifestation. These neurological manifestations seem to be more frequent in cases with mutations of GTP-binding site in GLUD1 gene in our cohort.
19 Sep 2019 - 21 Sep 2019