GLUT1 Deficiency Syndrome 1

Alternative Names

  • GLUT1DS1
  • Glucose Transport Defect, Blood-Brain Barrier
  • GLUT1 Deficiency Syndrome 1, Autosomal Recessive
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WHO-ICD-10 version:2010

Diseases of the nervous system

Other disorders of the nervous system

OMIM Number

606777

Mode of Inheritance

Autosomal dominant; autosomal recessive

Gene Map Locus

1p35-p31.3

Description

GLUT1 deficiency syndrome-1 is a neurologic disorder showing wide phenotypic variability. The most severe 'classic' phenotype is characterized by an encephalopathy marked by infantile seizures that is refractory to treatment (anticonvulsants), deceleration of cranial growth leading to microcephaly, psychomotor retardation, spasticity, ataxia, dysarthria, dystonia, opsoclonus and other paroxysmal neurological phenomena (confusion, lethargy, sleep disturbance, and headache), often worse prior to meals. Affected infants appear normal at birth following an uneventful pregnancy and delivery. Birth weight and Apgar scores are normal. Seizures begin between age one and four months in 90% of cases. Apneic episodes and abnormal episodic eye movements simulating opsoclonus may precede the onset of seizures by several months. Five seizure types occur: generalized tonic or clonic, myoclonic, atypical absence, atonic, and unclassified. The frequency and severity of seizures varies among affected individuals. Varying degrees of cognitive impairment can occur, ranging from learning disabilities to severe mental retardation.

The diagnosis of GLUT1 deficiency is based on the clinical picture and biochemical analysis of the cerebrospinal fluid (CSF). It is established in neurologically impaired individuals with hypoglycorrhachia (reduced CSF glucose concentration, less than 40 mg/dl) and low CSF lactate. The ketogenic diet is highly effective in controlling the seizures and is generally well tolerated because ketone bodies are easily transported across tissue membranes, and they are readily available for uptake and metabolism by brain cells. However, neurobehavioral and motor deficits persist in most cases. Despite that, correct diagnosis of GLUT1 deficiency is still important because early initiation of the ketogenic diet may result in better seizure control and improved neurobehavioral development.

Molecular Genetics

More than 50 mutations in the SLC2A1 gene are found to be responsible for GLUT1 deficiency syndrome 1. This gene encodes a major glucose transporter in the mammalian blood-brain barrier. In the majority of GLUT1 deficiency cases, the disease is associated with de novo mutations in the SLC2A1 gene. GLUT1 deficiency syndrome is transmitted as an autosomal dominant trait and in these cases the affected parent presents with a mild form of the disease.

Epidemiology in the Arab World

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Subject IDCountrySexFamily HistoryParental ConsanguinityHPO TermsVariantZygosityMode of InheritanceReferenceRemarks
606777.1LebanonUnknownNo Global developmental delay; Ataxia; Hypo...NM_006516.4:c.1279-2A>CHeterozygousJalkh et al. 2019

Other Reports

Qatar

Klepper et al. (2009) described a 6-year-old girl with GLUT1 deficiency syndrome-1, born to consanguineous Arab parents from a Bedouin kindred from Qatar. The patient has an unsteady ataxic gait at age 18 months, as well as paroxysmal choreoathetosis. She also had developmental delay and hypotonia. EEG showed a polymorphic baseline alpha-theta activity with an isolated monomorphic sharp wave focus. Lumbar puncture showed hypoglycorrhachia and decreased CSF lactate. Genetic analysis identified a homozygous mutation in the GLUT1 gene (c.1402C>T, p.Arg468Trp). Her asymptomatic 2-year-old sister was also homozygous for the mutation; she was found to have hypoglycorrhachia and decreased CSF lactate. The parents, who were unaffected, were heterozygous for the mutation. Klepper et al. (2009) concluded that the mutation was pathogenic, and suggested that the sister who was homozygous for the mutation was too young for symptom onset. The findings suggested that GLUT1 deficiency can also be inherited in an autosomal recessive pattern.

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