Late presentation of a GLUD-1 activating mutation: consider this rare genetic cause in adults with fasting and protein-sensitive hyperinsulinaemic hypoglycaemia

Samuel Conway1, Bhavika Sethi1, Clare Gilbert2, Kate Green2, Carol Jairam1, Nick Oliver1, Pratik Shah2 & Shivani Misra1

1St. Mary’s Hospital, Imperial College Healthcare NHS Trust.

2Great Ormond Street Hospital.

We present the case of a 35-year-old man with a history of childhood epilepsy and symptoms consistent with hypoglycaemia. The episodes of hypoglycaemia were mild and had never been formally investigated. He had identified that protein rich meals precipitated the symptoms and so avoided high protein content foods.

At the age of 9 months, his daughter presented with hypoglycaemic seizures and hyperammonaemia was noted on her metabolic screen. The hypoglycaemia was found to be protein-sensitive, commencing shortly after she had started weaning and was associated with hyperinsulinism. Genetic testing confirmed a GLUD-1 heterozygous missense mutation causing hyperinsulinaemia and hyperammonaemia syndrome (HIHA). Her hypoglycaemia was managed with diazoxide and a protein-restricted diet. Mutations in GLUD-1 causing HIHA usually occur de novo but can be autosomal dominant therefore parental testing was requested. This confirmed the same pathogenic mutation in her Father.

HIHA is characterised by fasting and protein-sensitive hypoglycaemia along with asymptomatic hyperammonaemia. It is caused by an activating mutation in the gene encoding the mitochondrial enzyme, glutamate dehydrogenase (GLUD-1), responsible for oxidative deamination of glutamate to alpha-ketoglutarate and ammonia. The most common additional features are epilepsy and learning difficulties presenting in late-infancy. These neurological defects may be independent of hypoglycaemia, which is usually managed effectively with diazoxide.

Our case had a milder phenotype than his daughter and in retrospect, his childhood seizures may have been hypoglycaemia-induced. He still reports symptoms of hypoglycaemia but has managed these with dietary changes. In addition to epilepsy, he was noted to have hyperammonaemia (random plasma ammonia 116 umol/L, normal range <50) but has no documented history of learning difficulties.

Our case highlights the variable phenotype and incomplete penetrance observed in GLUD-1 mutations. Though classically presenting in infants, this phenotype warrants consideration in adults with hyperinsulinaemic hypoglycaemia for which other causes have been excluded, even in the absence of a family history and especially in the presence of hyperammonaemia.