GLUT1 deficiency syndrome (GLUT1 DS)

SLC2A1 gene

Also known as: De Vivo disease; Glucose transport defect, blood-brain barrier; Severe infantile-onset GLUT1 deficiency syndrome 1; GLUT1 deficiency syndrome 2; Paroxysmal exercise-induced dyskinesia with or without epilepsy and/or haemolytic anaemia; PED with or without epilepsy and/or haemolytic anaemia; Paroxysmal exertion-induced dystonia with or without epilepsy and/or haemolytic anaemia
Dystonia 18 (DYT18)

– Includes:

– OMIM#606777 https://omim.org/entry/606777

– OMIM#2612126 https://omim.org/entry/612126

1. The Disease:

The phenotypic spectrum of glucose transporter type 1 deficiency syndrome (GLUT1 DS) is now known to be a continuum that includes the classic phenotype as well as paroxysmal exercise-induced dyskinesia and epilepsy (PED), atypical childhood absence epilepsy, myoclonic astatic epilepsy, and paroxysmal non-epileptic findings including intermittent ataxia, choreoathetosis, dystonia, and alternating hemiplegia.

2. The symptoms:

The classic phenotype is characterized by infantile-onset seizures, delayed neurologic development, acquired microcephaly, and complex movement disorders. Lack of early signs or symptoms does not exclude the diagnosis.

Seizures in classic early-onset GLUT1 DS begin before age six months. Several seizure types occur: generalized tonic or clonic, focal, myoclonic, atypical absence, atonic, and unclassified.

In some infants, apnoeic episodes, and abnormal episodic eye-head movements like opsoclonus may precede the onset of seizures. The frequency, severity, and type of seizures vary among affected individuals and are not related to disease severity.

Cognitive impairment, ranging from learning disabilities to severe intellectual disability, is typical.

The complex movement disorder, characterized by ataxia, dystonia, and chorea, may occur in any combination and may be continuous, paroxysmal, or continual with fluctuations in severity influenced by environmental factors such as fasting or with infectious stress.

Symptoms often improve substantially when a ketogenic diet is started.

3. Actions to take in case of early diagnosis:

Clinical and biochemical correlation with a baby presenting suggestive clinical findings, normal blood glucose concentration, CSF glucose concentration <60 mg/dL. 3-O-methyl-D-glucose uptake in erythrocytes can be performed; results between 35% and 74% of controls are diagnostic.

GLUT1 DS is a lifelong disease requiring lifetime management and regular follow-up with a Paediatric Neurology Center Management is provided by multidisciplinary team.

The ketogenic diet is highly effective in controlling the seizures and improving gait disturbance and is generally well tolerated. Affected individuals treated effectively at a younger age have a better outcome. The ketogenic diet is deficient in L-carnitine necessitating its supplementation.

Therapies under investigation: Triheptanoin is a specially designed synthetic triglyceride compound of three seven-carbon (C7) fatty acids intended to provide other sources of energy as ketone bodies that can cross the blood-brain barrier. Trials are under investigation. Good landscape for future gene therapy possibility.

Agents to avoid: Barbiturates (e.g., phenobarbital, the antiepileptic drug most used in treating infants), methylxanthines (e.g., caffeine), valproic acid.

Genetic counselling should be offered to at-risk family members.

4. For more information:

Orphanet:

Biblio: https://www.ncbi.nlm.nih.gov/books/NBK1430/