Hyperinsulinism Secondary to Congenital Disorder of Glycosylation Type 1a




Thornton, Paul
Choi, Woongsoon
Basinger, Alice
Caldwell, James
Hamilton, Luke
Wilson, Don


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Purpose Congenital disorders of glycosylation (CDG) are a group of rare genetic disorders caused by defects in enzymes responsible for a series of post-transcriptional glycosylation reactions. The most well known subtype of these disorders is CDG type 1a. More than 700 cases have been reported worldwide. Its clinical spectrum and severity are widely variable; common symptoms include seizure, ataxia, hypotonia, developmental delay, liver dysfunction, and cardiomegaly, but hypoglycemia secondary to hyperinsulinism has rarely been reported. A closely related subtype of CDG is CDG type 1b. CDG type 1b is characterized by protein-losing enteropathy and diarrhea, as well as endocrine-related symptoms, such as hypoglycemia. Methods A 2-month-old male was admitted for severe hypoglycemia and liver dysfunction. Because of his concomitant liver disease, enzymatic testing and gene sequencing for a disorder of glycosylation were requested. He was found to have a mutation of the gene for CDG type 1a. Over the subsequent 2 years, the child was noted to have ataxia and hypotonia. An MRI scan of the brain demonstrated a hypoplastic cerebellum and vermis. He experienced multiple seizures. Hypoglycemia, secondarily to hyperinsulinism, was controlled with diazoxide. The hypoglycemia resolved by 2 yrs of age when he was able to fast for >24 hours while maintaining a glucose >50mg/dL and beta-hydroxybutyrate>3mmol/L. Therefore, the diazoxide was discontinued. Results The most common presenting symptoms of CDG type 1a are neurological. In addition to hypotonia and seizures, our patient has persistent hypoglycemia associated with hyperinsulinemia, an unusual presentation of CDG type 1a as opposed to CDG type 1b. The proposed mechanism hyperinsulinemia is secondary to constitutively closed ATP-sensitive K+ channel, producing unregulated release of insulin. Given its ability to open the ATP-sensitive K+ channel, diazoxide is a reasonable treatment option. Our patient’s hypoglycemia responded well to diazoxide. Conclusion Currently, there is no cure for disorders of glycosylation. Mortality within the first year of life is as high as 20%. Treatment options are being explored to facilitate glycosylation with either a membrane-permeable mannose-1-phosphate treatment or enzyme replacement therapy. Additional research is needed to find more effective treatments to improve morbidity and reduce mortality in affected patients.