Wide range of neurological issues in paediatric hyperinsulinism/hyperammonaemia syndrome

medwireNews: Neurodevelopmental disorders are frequent and diverse in children with hyperinsulinism/hyperammonaemia (HI/HA) syndrome caused by a GLUD1 mutation, a study shows.

Researchers led by Pratik Shah (The Royal London Children’s Hospital, UK) and Maria Melikyan (Endocrinology Research Centre, Moscow, Russia) examined the records of 25 children with HI/HA syndrome and an underlying
GLUD1 mutation who presented to one of two centres in London and Moscow between 2003 and 2018.

They explain that HI/HA syndrome “is a distinctive form of diazoxide responsive congenital hyperinsulinism, which is characterized by fasting/postprandial recurrent hypoglycaemia, asymptomatic hyperammonemia and association with neurological manifestations including epilepsy.”

As reported in Endocrine Connections, epilepsy was the most common neurodevelopmental disorder in the team’s cohort, occurring in nine (36%) of the 25 children.

Three of the children with epilepsy had generalized tonic-clonic seizures, two had absence seizures, one had a mixture and in the other three cases the type of seizure was not specified. The median age at epilepsy onset was 12 months.

The next-most frequent neurodevelopmental disorders were learning difficulties and speech delay, both in eight children, followed by motor delay in seven, abnormal movement in six and vision problems in four. Abnormal movement included ataxia, tics, spasticity and dystonia; and vision problems included impaired central vision, bilateral cataract, optic nerve atrophy, myopia and amblyopia.

In total, 56% of the children had at least one disorder. In addition, electroencephalography revealed abnormal findings in six of the 14 children who underwent one, and brain magnetic resonance imaging was abnormal in six of 12 patients.

The “vast majority” of the children presented during the first year of life with hypoglycaemic seizures, with just three presenting when older, between 13 and 18 months. Seven children presented within the first month after birth, and the researchers note that all of these patients had a mutation in exon 11 or 12.

They say this is consistent with a previous report and “suggests that an activating GLUD1 mutation within these two exons may result in more severe phenotype leading to an earlier presentation.”

Of note, having a mutation in exon 11 or 12 was also significantly associated with an increased likelihood of having a neurodevelopmental disorder.

GLUD1 encodes the intra-mitochondrial matrix enzyme glutamate dehydrogenase (GDH), and the researchers speculate that children with mutations in exon 11 or 12 might have “increased GDH activity in different body tissues including brain and pancreas.”

But they stress that the pathophysiology of the neurodevelopmental disorders arising from GLUD1 mutations “is not well understood and is likely to be complex”.

A younger age at presentation and a higher diazoxide requirement were also associated with an increased likelihood for neurodevelopmental disorders.

The median diazoxide dose given was 7 mg/kg per day, and the researchers note that almost all patients responded well to the medication, given alongside dietary advice.

By Eleanor McDermid

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group

Endocr Connect 2022; doi:10.1530/EC-22-0008
Martin Savage
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