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  • Updated 05.14.2024
  • Released 02.18.2014
  • Expires For CME 05.14.2027

GLUT1DS-related developmental and epileptic encephalopathy

Introduction

Overview

GLUT1 deficiency syndrome is a metabolic disorder due to defective transport of glucose across the blood-brain barrier. First described by De Vivo in 1991, GLUT1 deficiency in its classic form presents in infancy with drug-resistant seizures and developmental delay. Dietary treatment can provide dramatic improvement in seizure control and may improve developmental outcome. Milder phenotypes have been described, including patients presenting with only paroxysmal dystonia.

Key points

• GLUT1 deficiency syndrome is a metabolic disorder due to defective transport of glucose across the blood-brain barrier.

• The classic picture is that of a child with refractory seizures starting in infancy, developmental delay, acquired microcephaly, hypotonia, and a movement disorder typically consisting of ataxia, spasticity, and dystonia.

• Increasingly, milder phenotypes are being recognized, including patients with normal cognition, early-onset absence or other generalized epilepsy, paroxysmal dystonia, or other movement disorders with and without epilepsy.

• Treatment with a ketogenic diet or a modified Atkins diet can lead to rapid seizure control and should be initiated as early as possible to provide the best possible outcome.

Historical note and terminology

GLUT1 deficiency syndrome (GLUT1-DS) is a metabolic disorder first described by De Vivo and colleagues in 1991 and is, therefore, sometimes called De Vivo disease (18). They noted two children with seizures and developmental delay whose spinal fluid demonstrated persistent low glucose concentrations (hypoglycorrhachia) in the face of a normal peripheral glucose concentration. A defect in the transport of glucose across the blood-brain barrier was suspected, and the authors hypothesized that these children needed an alternative energy source for brain metabolism. Both children were started on a ketogenic diet, which provides energy in the form of ketones in place of glucose. The children stopped having seizures within a few days of starting the diet.

Seven years later, the same group described heterogeneous mutations leading to functional defects of the type 1 glucose transporter protein (GLUT1), which is the glucose transporter most widely distributed in human brain and erythrocytes (85). The gene coding for this protein (known as SLC2A1 for solute carrier 2 A, type 1) had previously been mapped to the short arm of chromosome 1 (60). More than 100 different mutations in SCL2A1 have since been described (38).

There is a wide range of phenotypes for this treatable disease (03; 70; 14). By 2005, the classic phenotype, including infantile seizures, acquired microcephaly, hypotonia, ataxia, and developmental delay, was well established, and treatment with the ketogenic diet had emerged as the gold standard therapy for these children. Since 2008, many reports of patients with GLUT1 deficiency syndrome who presented with “atypical” features, namely idiopathic generalized epilepsy and early-onset absence epilepsy (before 4 years of age) have appeared, often in individuals with normal or only mildly impaired cognition (78; 11). Patients with a broad spectrum of movement disorders have also been reported, with and without epilepsy, ranging from mild tremor to dystonia and chorea (72).

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