Classic glucose transporter type 1 deficiency syndrome (ORPHA:71277)
A rare inborn error of metabolism characterized by encephalopathy due to impaired glucose transport into neural cells. The most frequent clinical manifestations are epilepsy, intellectual disability and movement disorder.
Epidemiology
In retrospective cohorts, the prevalence of GLUT1-DS is estimated between 1/25.000 and 1/80.000. However, it might be underestimated since many patients present a minimal symptom phenotype.
Clinical description
New-borns usually have normal head size at birth, but acquired microcephaly may become evident in childhood. A frequent initial sign is paroxysmal eye-head movement, characterized by episodes of multidirectional saccadic movements of the eyes and head, without loss of consciousness. Psychomotor developmental delay is usually observed, evolving into intellectual disability, ranging from mild to severe. Most patients have some degree of speech impairment with dysarthria. The most common symptom in infancy/childhood is epilepsy, frequently early onset absences and/or myoclonic-atonic seizures. Movement disorder usually become more evident later in life. They may be persistent, including gait disorders with variable combinations of ataxia and spasticity, or they may also be paroxysmal. Paroxysmal exercise-induced dyskinesia often triggered by physical and emotional stressors is characteristic. Alternating hemiplegia, migraine, cyclic vomiting, stroke-like episodes, writers' cramp, intermittent ataxia, may be possible combined features.
Etiology
Glut1 protein, encoded by SLC2A1 gene, is primarily expressed in blood-brain barrier and astrocytes and facilitates glucose transport into the brain; its defect impairs glucose transport into neural cells resulting in cerebral energy deficiency causing encephalopathy.
Diagnostic methods
Diagnosis is suggested by clinical features and confirmed by lumbar puncture showing hypoglycorrhachia in a setting of normoglycemia. Mutations or deletions/duplications in SLC2A1 gene are identified in almost 90% of patients. Molecular diagnosis remains elusive in 10% of patients with typical clinical features and CSF profile.
Differential diagnosis
Neurological disorders with similar symptoms and age of onset are familial epilepsies with autosomal dominant transmission, developmental epileptic encephalopathies, paroxysmal movement disorders, opsoclonus-myoclonus syndrome or other paroxysmal neurologic dysfunctions.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
Mutations are mainly de novo autosomal dominant. Familial cases and autosomal recessive inheritance have been reported. Once a parent is diagnosed with a SLC2A1 pathogenic variant, prenatal genetic testing is possible.
Management and treatment
To establish the extent of disease and needs of a GLUT1-DS patient, the following evaluations are recommended: neurological examination, EEG monitoring, consultation with a clinical geneticist, neuropsychological assessment in order to implement a personalized motor, occupational and speech therapy. Ketogenic dietary therapies (KDTs) are, to date, the gold standard treatment for the syndrome: ketone bodies can cross the blood brain barrier and act as alternative fuel for brain metabolism. KDTs are usually effective in controlling seizures; furthermore, neuropsychological impairment and movement disorders may improve. Patients should start KDT as early as possible and continue in adulthood, as symptoms may return upon discontinuation. Some patients may also receive treatment with anti-seizure medications. Certain molecules, such as methylxanthines, phenobarbital, and valproic acid, should be avoided as they have the potential to inhibit Glut1 transport. Therapies currently under investigation are alpha-lipoic acid, ketone esters, triheptanoin and gene therapy.
Prognosis
Epileptic manifestations tend to improve or disappear later in life; however, the movement disorder becomes more prominent. Neuropsychological impairment and language disorder do not worsen, but they could be more evident affecting social functioning in adulthood.

                            Last update: 
                            September 2023


                            - Expert reviewer(s): 
                            Dr Alessandra CAMERINI  - Dr Valentina DE GIORGIS | EpiCARE* - Pr Roser PONS 


                                * European Reference Network