Glucose Transporter Type 1 Deficiency Syndrome (GLUT1-DS), also known as De Vivo disease, is a rare metabolic disorder that impairs the brain’s ability to receive glucose, its primary energy source. This deficiency leads to a range of neurological symptoms, most notably epilepsy, intellectual disability, and movement disorders. Understanding GLUT1-DS is crucial for timely diagnosis and effective management, which can significantly improve the quality of life for affected individuals.
What is Classic Glucose Transporter Type 1 Deficiency Syndrome?
Classified as a rare inborn error of metabolism, Classic GLUT1-DS is characterized by encephalopathy resulting from insufficient glucose transport into neural cells. This condition is also referred to as Classic GLUT1 deficiency syndrome or Classic GLUT1-DS, and historically known as De Vivo disease.
- ORPHA: 71277
- Classification level: Disorder
- Synonyms:
- Classic GLUT1 deficiency syndrome
- Classic GLUT1-DS
- De Vivo disease
- Encephalopathy due to GLUT1 deficiency
- Source: PubMed ID 20301603
- ICD-10: G40.4
- ICD-11: 5C61.5
- OMIM: 606777
- UMLS: C4551966
- GARD: 9265
Prevalence and Inheritance of GLUT1-DS
The prevalence of GLUT1-DS is estimated to be between 1 in 25,000 and 1 in 80,000 individuals based on retrospective studies. However, experts believe the actual number might be higher because some patients exhibit milder symptoms, leading to underdiagnosis.
GLUT1-DS is primarily caused by genetic mutations in the SLC2A1 gene. Inheritance patterns can vary:
- Autosomal Dominant: Most cases arise from new (de novo) mutations, meaning they occur spontaneously and are not inherited from parents. In these dominant cases, only one copy of the mutated gene is necessary to cause the disorder.
- Autosomal Recessive: Familial cases and autosomal recessive inheritance are less common but have been reported, requiring two copies of the mutated gene (one from each parent) for the condition to manifest.
The onset of GLUT1-DS is typically in infancy or the neonatal period.
Clinical Manifestations and Symptoms
Individuals with GLUT1-DS present with a spectrum of symptoms that vary in severity.
Early Signs:
- Microcephaly: While newborns often have a normal head size at birth, acquired microcephaly (smaller head circumference than normal for age) may become noticeable during childhood.
- Paroxysmal Eye-Head Movement: A frequent initial sign involves episodes of involuntary, rapid, multidirectional eye and head movements without loss of consciousness.
Neurological and Developmental Issues:
- Psychomotor Developmental Delay: Delayed achievement of developmental milestones is commonly observed, progressing into intellectual disability that can range from mild to severe.
- Speech Impairment: Most individuals experience some degree of speech difficulties, including dysarthria (unclear speech).
- Epilepsy: Seizures are a prevalent symptom, particularly in infancy and childhood. Common seizure types include early-onset absence seizures and myoclonic-atonic seizures.
Movement Disorders:
- Persistent Movement Disorders: These often become more apparent later in life and can include gait abnormalities with varying combinations of ataxia (lack of coordination) and spasticity (muscle stiffness).
- Paroxysmal Exercise-Induced Dyskinesia: Characteristic episodes of involuntary movements triggered by physical exertion or emotional stress.
- Other Paroxysmal Features: Some patients may experience alternating hemiplegia (temporary paralysis on one side of the body), migraine, cyclic vomiting, stroke-like episodes, writer’s cramp, and intermittent ataxia.
Etiology and Pathophysiology of GLUT1-DS
GLUT1 protein, encoded by the SLC2A1 gene, plays a vital role in transporting glucose across the blood-brain barrier and into astrocytes. These are critical areas for ensuring the brain receives adequate glucose. In GLUT1-DS, defects in this protein impair glucose transport into neural cells, leading to cerebral energy deficiency and subsequent encephalopathy. Essentially, the brain is starved of its primary fuel source.
Diagnostic Approaches for GLUT1-DS
Diagnosis of GLUT1-DS is typically initiated based on clinical observation of characteristic symptoms. Confirmation involves:
- Lumbar Puncture: Analyzing cerebrospinal fluid (CSF) obtained via lumbar puncture (spinal tap) often reveals hypoglycorrhachia – abnormally low glucose levels in the CSF despite normal blood glucose levels. This is a key indicator of impaired glucose transport into the brain.
- Genetic Testing: Molecular genetic testing to identify mutations or deletions/duplications in the SLC2A1 gene confirms the diagnosis in approximately 90% of clinically diagnosed patients. However, about 10% of patients with typical clinical and CSF findings may not have identifiable mutations through standard genetic testing, suggesting other genetic or possibly non-genetic factors might be involved in these cases.
Differential Diagnosis
When diagnosing GLUT1-DS, it is essential to differentiate it from other neurological conditions that present with similar symptoms, especially in infancy and early childhood. These include:
- Familial epilepsies with autosomal dominant transmission
- Developmental epileptic encephalopathies
- Paroxysmal movement disorders
- Opsoclonus-myoclonus syndrome
- Other paroxysmal neurologic dysfunctions
Prenatal Diagnosis and Genetic Counseling
Prenatal diagnosis is feasible if a pathogenic variant in the SLC2A1 gene has been previously identified in a family member. Genetic counseling is recommended for families with a history of GLUT1-DS to understand the inheritance patterns, recurrence risks, and available options for prenatal or preimplantation genetic testing.
Management and Treatment Strategies
The management of GLUT1-DS is multifaceted and aims to alleviate symptoms and improve neurological function.
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Comprehensive Evaluations: To fully understand the extent of the disease and the individual needs of a GLUT1-DS patient, several evaluations are recommended:
- Neurological examination
- Electroencephalogram (EEG) monitoring to assess seizure activity
- Consultation with a clinical geneticist
- Neuropsychological assessment to guide personalized motor, occupational, and speech therapy interventions.
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Ketogenic Dietary Therapies (KDTs): Currently, ketogenic diet therapy is the cornerstone of GLUT1-DS treatment. This high-fat, very low-carbohydrate diet induces a metabolic state where the body produces ketone bodies. Ketones can cross the blood-brain barrier and serve as an alternative energy source for the brain, bypassing the impaired glucose transport. KDTs are often highly effective in controlling seizures and can also lead to improvements in neuropsychological function and movement disorders. Early initiation of KDT and continuation into adulthood is generally recommended, as symptoms may recur if the diet is discontinued.
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Anti-Seizure Medications: While KDT is primary, some patients may require adjunctive treatment with anti-seizure medications to manage epilepsy effectively. However, it’s important to note that certain anti-seizure medications, such as methylxanthines, phenobarbital, and valproic acid, should be avoided as they can inhibit Glut1 transport, potentially worsening the condition.
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Emerging Therapies: Research is ongoing to explore new therapeutic avenues for GLUT1-DS, including:
- Alpha-lipoic acid
- Ketone esters
- Triheptanoin
- Gene therapy
Prognosis and Long-Term Outlook
The prognosis for individuals with GLUT1-DS varies. While epileptic manifestations often improve or may even resolve later in life, movement disorders tend to become more prominent with age. Neuropsychological impairment and language difficulties typically do not worsen over time but can significantly impact social functioning and independence in adulthood. With early diagnosis and consistent ketogenic diet therapy, many individuals with GLUT1-DS can lead more fulfilling and active lives.
Further Information and Resources:
For more detailed information and resources about Glucose Transporter Type 1 Deficiency Syndrome, please refer to the following links:
General public:
- Svenska (2016) – Socialstyrelsen
Guidelines:
- Français (2023) – G2M – Emergency guidelines
- English (2012.pdf) – Brit Inher Metab Dis Group – Emergency guidelines
- Français (2024) – PNDS – Clinical practice guidelines
Disease review articles:
- English (2018) – GeneReviews – Clinical genetics review
Patient-Centered Outcome Measures (PCOMs):
- English (2023) – PROQOLIDTM – Patient-Centered Outcome Measures (PCOMs)
Additional resources:
- Patient-centred resources for this disease
- Research activities on this disease
- Newborn screening information
This information is intended for educational purposes and should not be considered medical advice. Always consult with a qualified healthcare professional for diagnosis and treatment of medical conditions.
