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

Abstract

BackgroundThe 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 presentationThis 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.ConclusionsThe 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.

Primary Dysmenorrhea: Pathophysiology, Diagnosis, and Treatment Updates

“…Therefore, to provide patient-centered care, dysmenorrheic females should be educated about dysmenorrhea, its treatment options, and potential adverse effects, for enabling them to decide. Clinicians should consider the patient’s choice, preferences, desire for contraception, potential adverse effects, and contraindications to hormonal therapy [ 10 , 12 , 13 , 29 - 31 ].…”

Congenital Hyperinsulinism: Current Laboratory-Based Approaches to the Genetic Diagnosis of a Heterogeneous Disease

“…Whilst this phenotype-driven approach works well in many scenarios [for example in the rapid screening of KATP channel genes in individuals with diazoxide-unresponsive disease ( 68 , 69 )], the reliance of clinical features to guide testing can delay a genetic diagnosis for individuals with an atypical presentation. This is an important consideration for HI, as phenotypic variability is described within most genetic subgroups, for example the presence of normal ammonia levels in some children with GLUD1 -HI ( 70 , 71 ). Using the clinical characteristics to guide genetic testing in syndromic HI should also be applied with caution as additional features may develop after the diagnosis of HI ( 72 ).…”

Hyperinsulinism/hyperammonemia syndrome caused by biallelic SLC25A36 mutation

“…HI/HA syndrome has been shown to be caused by dominant activating mutations in GLUD1 , encoding the intra‐mitochondrial enzyme glutamate dehydrogenase (GDH1) 4 . The vast majority of cases are caused by de novo mutations, although some cases demonstrate autosomal dominant inheritance 4 . GDH1 is highly expressed in pancreatic β‐cells, as well as in the liver, the kidney, and the brain 3 .…”

“…4 The vast majority of cases are caused by de novo mutations, although some cases demonstrate autosomal dominant inheritance. 4 GDH1 is highly expressed in pancreatic β-cells, as well as in the liver, the kidney, and the brain. 3 GDH1 catalyzes reversible conversion of glutamate to α-ketoglutarate and ammonia with the reduction of NAD(P) + to NAD(P)H. In β-cells, α-ketoglutarate enters the citric acid cycle, increasing adenosine triphosphate (ATP) to adenosine diphosphate (ADP) ratio, which in turn inhibits the ATP-sensitive potassium (KATP) channel, resulting in its closure.…”