Continuous Glucose Monitoring Facilitates Diazoxide Use in the Management of Glut1 Deficiency Syndrome

Background: Glut1 deficiency syndrome (Glut1DS) is caused by mutations in SLC2A1 on chromosome 1p34.2, which impairs transmembrane glucose transport across the blood brain barrier resulting in hypoglycorrhachia and decreased glucose availability for brain metabolism. This causes a drug-resistant, metabolic epilepsy due to energy deficiency. Standard treatment for Glut1DS is the ketogenic diet (KD) but treatment options are limited if patients fail the KD. Diazoxide, which inhibits insulin release, was used sparingly in the past for a few Glut1DS patients to increase blood glucose levels and thus intracerebral glucose levels. Unfortunately, their treatment was complicated by unacceptable persistent hyperglycemia with blood glucoses in the 300s to 500s. We investigated the use of a continuous glucose monitor (CGM) to enable titration of diazoxide therapy in a patient with KD-resistant Glut1DS. Clinical Case: A 14-year-old girl with Glut1DS (c.398_399delGCinsTT:p.Lys133Phe) failed the KD due to severe nausea, vomiting, abdominal pain, and hypertriglyceridemia. Laboratory tests revealed CSF glucose of 36 mg/dL when blood glucose was 93 mg/dL. Over the course of 3 hospitalizations targeting blood glucose levels in the range of 120-180 mg/dL with diazoxide, EEG seizure activity decreased from 3 to 0 absence seizures per hour. CGM placement during the third hospitalization showed an average interstitial glucose of 157 mg/dL with glucose variability of 20.8% on diazoxide dose of 7.3 mg/kg/day. After discharge, CGM has been used to adjust diazoxide doses 2-4 times a week to achieve target interstitial glucoses of 140-180 mg/dL. Repeat laboratory tests revealed CSF glucose of 55 mg/dL when interstitial glucose was 158 mg/dL. Current diazoxide dose is 7.9 mg/kg/day and most recent hemoglobin A1c was 5.4%. Conclusions: This is the first report demonstrating CGM as a tool facilitating the safe initiation and real-time titration of diazoxide in Glut1DS patients who have failed the KD. Diazoxide addresses neuroglycopenia more physiologically by raising blood glucose levels and subsequently intracerebral glucose levels. CGM allows for more accurate titration of blood glucose with diazoxide while avoiding complications of hyperglycemia and thus introduces the possibility of diazoxide becoming a standard of care for Glut1DS. More broadly, CGM provides a valuable tool for the management of other disorders of glucose transport and carbohydrate metabolism.