Hyperinsulinism hyperammonaemia (HI/HA) syndrome due to GLUD1 mutation: phenotypic variations ranging from late presentation to spontaneous resolution

Agnieszka Brandt; Neha Agarwal; Dinesh Giri; Zoe Yung; Mohammad Didi; Senthil Senniappan

doi:10.1515/jpem-2019-0416

Article

Hyperinsulinism hyperammonaemia (HI/HA) syndrome due to GLUD1 mutation: phenotypic variations ranging from late presentation to spontaneous resolution

Agnieszka Brandt , Neha Agarwal , Dinesh Giri , Zoe Yung , Mohammad Didi and Senthil Senniappan

Published/Copyright: March 25, 2020

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From the journal Journal of Pediatric Endocrinology and Metabolism Volume 33 Issue 5

Abstract

Background

The hyperinsulinism/hyperammonaemia (HI/HA) syndrome is the second most common cause of hyperinsulinaemic hypoglycaemia, caused by activating mutations in GLUD1. In this article, we report a series of three unrelated patients with HI/HA syndrome who demonstrated variable phenotypes, ranging from delayed presentation to spontaneous resolution of hypoglycaemia, thereby expanding the current knowledge and understanding of GLUD1 mutations.

Case presentation

This paper is a retrospective analysis of patients with HI/HA syndrome who demonstrated a variable disease course. Patient 1 presented with hypoglycaemic seizures at the age of 7 months and was diagnosed with HI/HA syndrome. Patient 2, a 5-year-old boy, on anti-convulsants since 8 months of age, was diagnosed with HI/HA at the age of 4 years. Patient 3, an 11-year-old girl with a history of transient neonatal hypoglycaemia, was diagnosed with HI/HA at the age of 12 months following evaluation for absence seizures. Patients 1 and 2 had raised ammonia levels, whilst patient 3 had normal ammonia level. The genetic analysis in all three patients confirmed GLUD1 mutation. Good glycaemic control was observed in all following diazoxide treatment. All patients have learning difficulties. Patient 1 demonstrated spontaneous resolution of hypoglycaemia at the age of 8 years, enabling discontinuation of diazoxide.

Conclusions

The cases highlight the diagnostic challenges in HI/HA syndrome due to a highly variable presentation. Knowledge of variable phenotypes would enable early diagnosis, thereby decreasing the risk of long-term neurological damage. Spontaneous resolution of hyperinsulinism could occur, and it is important to consider a trial off diazoxide therapy especially if the patients are on a small dose of diazoxide.

Keywords: hyperammonaemia; hyperinsulinaemia; hypoglycaemia

Corresponding author: Dr. Senthil Senniappan, MD FRCPCH MSc PhD, Consultant Paediatric Endocrinologist and Honorary Senior Lecturer, Alder Hey Children’s NHS Foundation Trust, LiverpoolL12 2AP, UK; and Department of Paediatric Endocrinology, Alder Hey Children’s Hospital, Liverpool, UK, Phone: +441512525281, Fax: +441512824606

aAgnieszka Brandt and Neha Agarwal contributed equally to this work.

Author contributions: AB, MD, ZY and SS were involved in the patient management and data collection. AB, DG and NA did literature review and drafted the initial manuscript. SS conceptualised and planned the study, critically reviewed the manuscript and would act as guarantor of the paper. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
Conflict of interest: None.

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Received: 2019-09-09

Accepted: 2020-02-06

Published Online: 2020-03-25

Published in Print: 2020-05-26

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Articles in the same Issue

https://doi.org/10.1515/jpem-2019-0416

Keywords for this article

hyperammonaemia; hyperinsulinaemia; hypoglycaemia