GLUT1 deficiency is a rare disorder. Fewer than 200 cases have been reported since the disorder was first identified in 1991.
Glucose transporter type 1 deficiency syndrome (Glut1-DS) is characterized by infantile seizures refractory to anticonvulsants, followed by deceleration of head growth, delays in mental and motor development, spasticity, ataxia, dysarthria, opsoclonus, and other paroxysmal neurologic phenomena, often occurring prior to meals.
Affected infants appear normal at birth following an uneventful pregnancy and delivery. Birth weight and Apgar scores are normal. Affected children then experience infantile-onset epileptic encephalopathy associated with delayed neurologic development, deceleration of head growth and resulting microcephaly,ataxia, and spasticity [De Vivo et al 2002a, De Vivo et al 2002b].
Seizures usually begin between age one and four months, are the first clinical indication of brain dysfunction.
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 of seizures varies among affected individuals some experience daily events; others have only occasional seizures separated by days, weeks, or months; two individuals never had a clinical seizure [von Moers et al 2002, Leary et al 2003].
Other paroxysmal events including intermittent ataxia, mental confusion, lethargy or somnolence, hemiparesis, abnormalities of movement or posture such as dystonia, total body paralysis, sleep disturbances, and recurrent headaches have also been described [Overweg-Plandsoen et al 2003]. It is unclear whether these events represent epileptic or non-epileptic phenomena. These neurologic symptoms generally fluctuate and may be influenced by factors such as fasting or fatigue.
Varying degrees of cognitive impairment, ranging from learning disabilities to severe mental retardation, are characteristic.
Varying degrees of speech and language impairment are observed in all affected individuals. Dysarthria is common and associates with dysfluency (i.e., excessively interrupted speech). Both receptive and expressive language abilities are affected, with expressive language skills disproportionately affected.
Social adaptive behavior is an exceptional strength. Individuals with Glut1-DS tend to be comfortable in group and school settings and interact well with others.
Paroxysmal exercise-induced dyskinesias (PED) are involuntary intermittent movements triggered by prolonged physical exertion. Autosomal dominant inheritance may occur. Recently, mutations in the glucose transporter 1 (GLUT1) gene (chr. 1p35-p31.3) have been identified as a cause in some patients with autosomal dominant PED.
The diagnosis of Glut1-DS is established in neurologically impaired individuals with 1) reduced cerebrospinal fluid (CSF) glucose concentration (hypoglychorrhachia) that seldom, if ever, exceeds 40 mg/dL and 2) low ratio of CSF glucose concentration to blood glucose concentration (consistently -0.33-0.01; normal ratio: 0.65 -0.01). SLC2A1 is the only gene known to be associated with Glut1-DS.
Pathogenesis. The disease manifestations can be explained in terms of current understanding of glucose transport in the brain. Glucose is the principal fuel source for brain metabolism; the glucose transporter Glut1 (solute carrier family 2, facilitated glucose transporter member 1), the protein product of SLC2A1, is the fundamental vehicle by which glucose enters the brain.
The cerebral metabolic rate for glucose is low during fetal development and at birth. The rate increases linearly after birth, peaks around age three years, remains high for the remainder of the first decade of life, and gradually declines during the second decade of life to the rate of glucose utilization seen in early adulthood. It thus appears that the risk for clinical manifestations during fetal development and the newborn period is low, whereas the risk is increased later in infancy and early childhood.
GeneReviews: Glucose Transporter Type 1 Deficiency Syndrome
Pathogenesis. The disease manifestations can be explained in terms of current understanding of glucose transport in the brain. Glucose is the principal fuel source for brain metabolism; the glucose transporter Glut1 (solute carrier family 2, facilitated glucose transporter member 1), the protein product of SLC2A1, is the fundamental vehicle by which glucose enters the brain.
The cerebral metabolic rate for glucose is low during fetal development and at birth. The rate increases linearly after birth, peaks around age three years, remains high for the remainder of the first decade of life, and gradually declines during the second decade of life to the rate ofglucose utilization seen in early adulthood. It thus appears that the risk for clinical manifestations during fetal development and the newborn period is low, whereas the risk is increased later in infancy and early childhood.
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