GLUT1 deficiency syndrome, also known as GLUT1-DS, De Vivo disease or Glucose transporter type 1 deficiency syndrome, is an autosomal dominant genetic metabolic disorder associated with a deficiency of GLUT1, the protein that transports glucose across the blood brain barrier. Glucose Transporter Type 1 Deficiency Syndrome has an estimated birth incidence of 1 in 90,000 to 1 in 24,300. This birth incidence translates to an estimated prevalence of 3,000 to 7,000 in the U.S.
Presentation GLUT1 deficiency is characterized by an array of signs and symptoms including mental and motor developmental delays, infantile seizures refractory to anticonvulsants, ataxia, dystonia, dysarthria, opsoclonus, spasticity, other paroxysmal neurologic phenomena and sometimes deceleration of head growth also known as microcephaly. The presence and severity of symptoms vary considerably between affected individuals. Individuals with the disorder generally have frequent seizures (epilepsy), often beginning in the first months of life. In newborns, the first sign may be involuntary eye movements that are rapid and irregular. Patients typically begin to experience seizures between three and six months of age, but some occur much later. Other seizure types may occur, including generalized tonic clonic, focal, myoclonic, atypical absence, atonic or unclassified. Mothers of infants with this disorder usually have uneventful pregnancies and deliveries, with the child appearing normal and within typical birth weight and length ranges. Infants with GLUT1 deficiency syndrome have a normal head size at birth, but the growth of the brain and skull is slow, in severe cases resulting in an abnormally small head size (microcephaly). Typically, seizures start between one and four months in 90% of cases with abnormal eye movements and apneic episodes preceding the onset of seizures in some cases. Seizures usually are complex to begin with and later become more generalized. Seizure frequency is variable and a history of decreasing frequency during times of ketosis may prompt a diagnosis. It is estimated that 10% of individuals with Glut 1 Deficiency do not have seizures and symptoms are typically less severe in these cases. Most of these non-epileptic cases will still have developmental delay, intellectual delays and movement disorders such as ataxia, alternating hemiplegia or dystonia. Some symptoms may be present all the time (like walking difficulties), while other signs may come and go (like seizures or poor balance). These findings can be clustered under three major domains: cognition, behavior and movement.
Effects The syndrome can cause infantile seizures refractory to anticonvulsive drugs, developmental delay, acquired microcephaly and neurologic manifestations including spasticity, hypotonia and ataxia. The frequency, severity and types of seizures may vary considerably among GLUT1 deficiency patients and do not necessarily correspond to the severity of other symptoms. Most seizures in GLUT1 deficiency patients are not easily treated with anti-seizure medications. A minority of GLUT1 deficiency patients (approximately 10%) do not experience seizures. Cognitive symptoms often become apparent as developmental milestones are delayed. Cognitive deficits range from subtle learning difficulties to severe intellectual disabilities. Often speech and language are impaired. Behavioral symptoms affect relations with other people and may include short attention span, intractability, and delays in achieving age-appropriate behaviors. Sociability with peers, however, is a strength in GLUT1 deficiency patients. Movement symptoms relate to the quality of motor functions. Walking may be delayed or difficult because legs are stiff (spasticity), balance is poor (ataxia) or posture is twisted (dystonia). Fine motor deficits may affect speech quality and manipulative skills, such as writing. These abnormalities may be constant or intermittent (paroxysmal). Paroxysmal exercise-induced dyskinesia (PED) may also be present. Other intermittent symptoms may include headaches, confusion, and loss of energy. Episodes of confusion, lack of energy/stamina, and/or muscle twitches may occur; particularly during periods without food. Some young patients experience occasional abnormal eye movements that may resemble opsoclonus or nystagmus. The rapid eye movements that some Glut 1 patients exhibit are rapid, multidirectional, and there is often a head movement in the same direction as the eye movement. These abnormal eye movements were recently named aberrant gaze saccades. Hemiplegia or alternating intermittent hemiplegia may occur in some patients and mimic stroke-like symptoms. Another characteristic of GLUT1 deficiency is that symptoms are sensitive to food (e.g. symptoms that can be temporarily improved by intake of carbohydrates), and symptoms may be worse in the morning upon and just after waking. All symptoms may be aggravated or triggered by factors such as hunger, fatigue, heat, anxiety, and sickness. The symptom picture for each patient may evolve and change over time as children with GLUT1 deficiency grow and develop through adolescence and into adulthood. Data on adult Glut1DS are just emerging. Changes in symptomatology over time include a shift from infantile-childhood onset epilepsy to adolescent-adult onset movement disorders including PED.
Genetics The GLUT1 protein that transports glucose across the blood brain barrier is encoded by the SLC2A1 gene, located on chromosome 1. In GLUT1 deficiency syndrome, one of the two genes is damaged by a mutation and an insufficient amount protein is made. As a result, insufficient glucose is passing the blood brain barrier. Having less functional GLUT1 protein reduces the amount of glucose available to brain cells, which affects brain development and function. Because glucose is the primary source of fuel for the brain, patients with GLUT1 deficiency have insufficient cellular energy to permit normal brain growth and function. Around 90% of cases of GLUT1 deficiency syndrome are de novo mutations of the SLC2A1 gene (a mutation not present in the parents, but present in one of the two copies of the gene in the baby), although it can be inherited. Glut 1 Deficiency can be inherited in an autosomal dominant manner. A person with GLUT1 deficiency syndrome has a 50% chance of passing along the altered SLC2A1 gene to his or her offspring.
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