AMINOGLYCOSIDE ENHANCEMENT OF GLUCOSE TRANSPORT IN GLUT1 DEFICIENCY SYNDROME

Abstract 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.

Download Full-text

GLUT1 deficiency syndrome in a consanguineous Arab family carrying a novel homozygous missense mutation

Neuropediatrics ◽

10.1055/s-0029-1215773 ◽

2008 ◽

Vol 39 (05) ◽

Author(s):

J Klepper ◽

T Ben-Omran ◽

H Scheffer

Keyword(s):

Missense Mutation ◽

Deficiency Syndrome ◽

Homozygous Missense Mutation ◽

Glut1 Deficiency ◽

Glut1 Deficiency Syndrome

Download Full-text

Faculty Opinions recommendation of Stomatin-deficient cryohydrocytosis results from mutations in SLC2A1: a novel form of GLUT1 deficiency syndrome.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.12287956.13463054 ◽

2011 ◽

Author(s):

Richard J Naftalin

Keyword(s):

Deficiency Syndrome ◽

Glut1 Deficiency ◽

Glut1 Deficiency Syndrome

Download Full-text

Classic Ketogenic Diet and Modified Atkins Diet in SLC2A1 Positive and Negative Patients with Suspected GLUT1 Deficiency Syndrome: A Single Center Analysis of 18 Cases

Nutrients ◽

10.3390/nu13030840 ◽

2021 ◽

Vol 13 (3) ◽

pp. 840

Author(s):

Jana Ruiz Herrero ◽

Elvira Cañedo Villarroya ◽

Luis González Gutiérrez-Solana ◽

Beatriz García Alcolea ◽

Begoña Gómez Fernández ◽

...

Keyword(s):

Movement Disorder ◽

Glucose Transporter ◽

Deficiency Syndrome ◽

Laboratory Assessment ◽

Modified Atkins Diet ◽

Atkins Diet ◽

Glut1 Deficiency ◽

Glut1 Deficiency Syndrome ◽

The Impact

Background: Glucose transporter type 1 deficiency syndrome (GLUT1DS) is caused by mutations in the SLC2A1 gene and produces seizures, neurodevelopmental impairment, and movement disorders. Ketogenic dietary therapies (KDT) are the gold standard treatment. Similar symptoms may appear in SLC2A1 negative patients. The purpose is to evaluate the effectiveness of KDT in children with GLUT1DS suspected SLC2A1 (+) and (-), side effects (SE), and the impact on patients nutritional status. Methods: An observational descriptive study was conducted to describe 18 children (January 2009–August 2020). SLC2A1 analysis, seizures, movement disorder, anti-epileptic drugs (AEDS), anthropometry, SE, and laboratory assessment were monitored baseline and at 3, 6, 12, and 24 months after the onset of KDT. Results: 6/18 were SLC2A1(+) and 13/18 had seizures. In these groups, the age for debut of symptoms was higher. The mean time from debut to KDT onset was higher in SLC2A1(+). The modified Atkins diet (MAD) was used in 12 (5 SLC2A1(+)). Movement disorder improved (4/5), and a reduction in seizures >50% compared to baseline was achieved in more than half of the epileptic children throughout the follow-up. No differences in effectiveness were found according to the type of KDT. Early SE occurred in 33%. Long-term SE occurred in 10, 5, 7, and 5 children throughout the follow-up. The most frequent SE were constipation, hypercalciuria, and hyperlipidaemia. No differences in growth were found according to the SLC2A1 mutation or type of KDT. Conclusions: CKD and MAD were effective for SLC2A1 positive and negative patients in our cohort. SE were frequent, but mild. Permanent monitoring should be made to identify SE and nutritional deficits.

Download Full-text