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eP007: Delayed onset hyperammonemic encephalopathy in an adult with GLUD1 deficiency

      Background

      Hyperammonemic encephalopathy is characterized by altered mental status due to toxic accumulation of ammonia in the circulation. Prolonged hyperammonemia can result in persistent seizures, cerebral edema, coma, and death. Therefore, prompt evaluation for underlying cause and initiating appropriate therapy is crucial in the management of this condition. In adults, common causes of hyperammonemia include hepatic dysfunction, infections, portosystemic shunting, and medications like valproic acid. Rarely, urea cycle defects and organic acidemias may present in the adulthood. GLUD1 deficiency is an autosomal dominant condition that is associated with infantile onset hyperinsulinemic hypoglycemia and hyperammonemia. GLUD1 encodes for glutamate dehydrogenase (GDH), which plays an important role in the mitochondria in glutamate metabolism by converting it to α-ketoglutarate and ammonia. Pathogenic variants in GLUD1 result in decreased sensitivity to guanosine-5’-triphosphate (GTP), which is a direct inhibitor of this enzyme. Consequently, this results in fasting-induced and protein meal-induced hyperinsulinemic hypoglycemia and hyperammonemia. We describe a unique case of hyperammonemic encephalopathy due to GLUD1 deficiency presenting in an older adult.

      Case presentation

      A 60-year-old female presented to our hospital with altered mental status and status epilepticus. Her initial laboratory evaluation revealed a high anion gap metabolic acidosis and an elevated lactate, both of which normalized after controlling her seizures. She had a normal blood sugar level and liver function tests. Interestingly, she had persistently elevated ammonia levels in the range of 70-130 μM /L. Her past medical history was significant for childhood-onset epilepsy, intellectual disability, hypothyroidism, hyperlipidemia, and type 2 diabetes mellitus. Her pediatric history was significant for multiple evaluations for recurrent hypoglycemic attacks associated with inappropriately elevated insulin levels. Her family history was unremarkable. One of the initial considerations during the admission was valproate-induced hyperammonemia. However, her ammonia remained mildly elevated despite switching valproic acid to levetiracetam. Her metabolic workup revealed a low plasma citrulline, low free and total carnitine and mildly elevated urine orotic acid. Her molecular panel testing for urea cycle disorders was negative. Based on her pediatric history of hyperinsulinism, we performed molecular testing to exclude GLUD1 deficiency. GLUD1 gene sequencing revealed a pathogenic variant (NM_005271.5: c.820C>T, p.Arg274Cys), confirming the diagnosis of autosomal dominant hyperinsulinism-hyperammonemia syndrome.

      Conclusion

      We report an unusual presentation of GLUD1 deficiency in an adult patient with hyperammonemic encephalopathy. Although inborn errors of metabolism primarily manifest in the pediatric age group, they may present with a highly variable clinical phenotype in adults. Therefore, it is crucial to consider these disorders in adults presenting with unexplained metabolic derangements such as persistent hyperammonemia. Rapid access to molecular testing using next generation sequencing technologies is slowly becoming instrumental in establishing diagnoses in rare metabolic disorders.