NORD gratefully acknowledges Darryl De Vivo, MD, Department of Pediatric Neurology Columbia University, Neurological Institute of New York, for assistance in the preparation of this report.
SummaryGlucose transporter type 1 (Glut1) deficiency syndrome is a rare genetic metabolic disorder characterized by deficiency of a protein that is required for glucose (a simple sugar) to cross the blood-brain barrier. The most common symptom is seizures (epilepsy), which usually begin within the first few months of life. However, the symptoms and severity of Glut1 deficiency syndrome can vary substantially from one person to another. For example, some affected individuals may not develop epilepsy. Additional symptoms that can occur include movement disorders, developmental delays, and varying degrees of cognitive impairment and speech and language abnormalities. Glut1 deficiency syndrome is caused by mutations in the SLC2A1 gene and is inherited as an autosomal dominant trait. Rarely, the condition also may be inherited as an autosomal recessive trait. Glut1 deficiency syndrome does not respond to traditional epilepsy treatments (e.g., anti-seizure medications), but has been successfully treated with the ketogenic diet.
IntroductionGlut1 deficiency syndrome was first described in the medical literature in 1991 by Dr. De Vivo, et al. The disorder is sometimes known as De Vivo disease. Glut1 deficiency syndrome is classified as an epileptic encephalopathy. Epileptic encephalopathies are a group of disorders in which seizure activity is associated with progressive psychomotor dysfunction. Paroxysmal exercised-induced dyskinesias (PED), also known previously as dystonia 18 and dystonia 9, are now considered part of the Glut1 deficiency syndrome spectrum. Epilepsy commonly presents in infancy whereas PED commonly emerges in late childhood and adolescence.
Glut1 deficiency syndrome represents a spectrum of disease. The symptoms and severity can vary dramatically from one individual to another. Mild cases can go undiagnosed, while other cases can potentially lead to severe, debilitating complications. It is important to note that affected individuals may not have all of the symptoms discussed below or may have less severe symptoms. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.
The classic expression of Glut1 deficiency syndrome is the development of seizures during infancy usually during the first four months of life. The type, frequency and severity of seizures vary from one individual to another. In some individuals, seizures may be a daily occurrence; in other individuals, seizures may be separated by days, weeks or months. Five different seizure types can occur including generalized tonic or clonic, myoclonic, atypical absence, atonic and unclassified.
Generalized tonic-clonic seizures (once known as grand mal seizures), usually last a minute or more and are characterized by stiffening of the limbs (tonic phase) and then repeated jerking of the limbs and face (clonic phase). Generalized tonic-clonic seizures can cause people to momentarily lose consciousness, bite their lips, or drool.
Myoclonic seizures are characterized by brief muscle contractions that cause abnormal, jerky movements.
Atypical absence seizures are associated with a period of unconsciousness usually marked by unresponsive staring. Absence seizures usually begin and end abruptly and the affected individual usually resumes activity with no memory of the episode. Absence seizures do not cause convulsions and may be so mild that they go unnoticed.
Atonic seizures cause a sudden loss of muscle tone and limpness. They can cause the head to drop or nod, problems with posture or sudden falls. Atonic seizures are also known as drop attacks. Atonic seizures can lead to injuries of the head and face because of sudden, unexpected falls. When sitting, affected individuals may collapse forward or backward at the waist. Atonic seizures may only partially affect consciousness and usually last only a few seconds.
Unclassified seizures do not clearly fit into any of the standard seizure categories.
Additional symptoms are associated with Glut1 deficiency syndrome including deceleration of head growth. Affected individuals can develop mild to moderate delays in attaining developmental milestones. Many individuals eventually develop microcephaly, a condition marked by head circumference that is smaller than would be expected for age and gender.
Individuals with Glut1 deficiency syndrome may also develop symptoms associated with movement disorders including diminished muscle tone (hypotonia), an inability to coordinate voluntary movements (ataxia), involuntary muscle spasms that result in slow, stiff, rigid movements (spasticity) and dystonia. Dystonia is a general term for a group of muscle disorders generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). Movement disorders associated with Glut1 deficiency syndrome can cause difficulty walking. Such difficulties can be a constant issue or may come and go.
Individuals with Glut1 deficiency syndrome also develop varying degrees of cognitive impairment, which can range from mild learning disabilities to severe intellectual disability. Some degree of speech and language impairment is usually seen as well. Affected individuals may experience difficulty speaking due to abnormalities affecting the muscles that enable speech (dysarthria) and disruption in the smooth flow or expression of speech (dysfluency), marked by frequent pauses or interruptions when speaking.
Individuals with Glut1 deficiency syndrome usually do not have problems with social adaptive behavior and, generally, affected individuals tend to be comfortable in group situations.
Additional symptoms have been reported in individuals with Glut1 deficiency syndrome including mental confusion, lethargy, drowsiness (somnolence), repeated, abnormal, rapid eye movements in both horizontal and vertical directions (opsoclonus), paralysis of one side of the body (hemiparesis), total body paralysis, and recurrent headaches. Sleep disturbances such as sleep apnea have also been reported in individuals. These various symptoms can fluctuate in severity and may be influenced by additional factors such as fatigue or when individuals go an extended period of time without eating (fasting). Sleep apnea and opsoclonus can precede the development of seizures in some cases.
Although most affected individuals develop so-called classic Glut1 deficiency syndrome, some individuals develop different expressions (phenotypes) of the disorder. Some affected individuals develop movement disorders and cognitive impairment without epilepsy. In addition, at least one adult case of Glut1 deficiency syndrome was identified in which the affected person had only mild symptoms of the disorder.
A group of individuals with mutations in the SLC2A1 gene have also been identified who have paroxysmal exercise-induced dyskinesia (PED), a condition in which episodes of abnormal, involuntary movements occur, brought on by prolonged exercise such as walking or running long distances. These individuals may or may not have epilepsy as well.
Glut1 deficiency syndrome is caused by mutations of the SLC2A1 gene. This gene mutation is inherited as an autosomal dominant (or rarely recessive) trait or occurs as a spontaneous genetic change (i.e., new mutation) that occurs sporadically for no apparent reason.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. Recessive genetic disorders occur when the same abnormal gene is inherited from both parents. The risk for two carrier parents to both pass on the defective gene and have an affected child is 25 percent for each pregnancy.
Investigators have determined that the SLC2A1 gene is located on the short arm (p) of chromosome 1 (1p34.2). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 1q34.2” refers to band 34.2 on the long arm of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The symptoms of Glut1 deficiency syndrome result from abnormalities of glucose transport to the brain. Glucose is a simple sugar and is the main source of fuel for brain metabolism. The SLC2A1 gene contains instructions for creating (encoding) a protein known as glucose transporter type 1 (Glut1). Mutations of the SLC2A1 gene result in low levels of functional Glut1. Without proper levels of Glut1, the body cannot transport sufficient amounts of glucose across the blood-brain barrier. The blood-brain barrier basically determines what materials from the blood can enter the brain. Without proper levels of glucose, the brain cannot grow and function properly. The exact effects that reduced glucose levels have in the brain or how it specifically leads to the symptoms of Glut1 deficiency syndrome are not fully understood.
Glut1 deficiency syndrome affects males and females in equal numbers. The incidence and prevalence of Glut1 deficiency syndrome in the general population is unknown. Because the disorder may go unrecognized or misdiagnosed, determining its true frequency in the general population is difficult. More than 200 cases have been identified.
A diagnosis of Glut1 deficiency syndrome is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.
Clinical Testing and Work-Up
Individuals suspected of Glut1 deficiency syndrome are recommended to undergo a spinal tap (lumbar puncture). During this procedure, a needle is inserted into the spinal canal in the lower back allowing a physician to withdraw spinal fluid. Spinal fluid is evaluated to measure the level of glucose. The test is performed after fasting. Low fluid concentration of glucose (hypoglycorrhachia) in the absence of low blood sugar (hypoglycemia) is indicative of Glut1 deficiency syndrome. Physicians will also measure levels of lactate in the CSF. Lactate may be low in some individuals with Glut1 deficiency syndrome.
The Glut1 protein is also found in red blood cells (erythrocytes). Testing is available on a clinical basis to assess erythrocyte glucose transporter activity, which is reduced by approximately 50 percent in individuals with Glut1 deficiency syndrome.
A positron emission tomography (PET) scan may sometimes be used to help support a diagnosis of Glut1 deficiency syndrome. During a PET scan, three dimensional images are produced that reflect the brain’s chemical activity. However, the accuracy and reliability of PET scans in identifying reduced chemical activity (hypometabolism) in individuals with Glut1 deficiency syndrome is unknown.
A diagnosis of Glut1 deficiency syndrome can be confirmed by molecular genetic testing that identifies the characteristic SLC2A1 gene mutation associated with the disorder. Molecular genetic testing is available through commercial and academic research laboratories.
There is no cure for Glut1 deficiency syndrome. The disorder is treated with the ketogenic diet, which may prevent seizure activity in many individuals with Glut1 deficiency syndrome. The response of seizure activity to the ketogenic diet is often prompt and dramatic. It is recommended that the ketogenic diet be started as early as possible and be continued to at least adolescence.
The ketogenic diet is a high-fat, low-carbohydrate diet that causes the body to burn fat for energy instead of sugar (glucose). The ketogenic diet requires strict adherence to relatively rigid principles. Individuals who are on the ketogenic diet should be regularly monitored by their physicians, a dietician and a nutritionist because of the need to strictly adhere to the diet’s guidelines and the potential risk of side effects. Affected individuals on the diet will require supplemental treatment with vitamins, minerals and trace elements. Although the ketogenic diet is effective in treating seizures, it is less effective in treating cognitive impairment or behavioral issues. However, there are anecdotal reports that the ketogenic diet frequently leads to subjective improvement of cognition, mental alertness and endurance. But, clinical studies with standard neurocognitive tests have not been performed on the effect of the ketogenic diet on cognition in individuals with Glut1 deficiency syndrome.
The ketogenic diet is also effective in reducing the severity of movement disorders associated with the classical form of Glut1 deficiency syndrome in approximately half of cases. It is even more effective in treating movement disorders in individuals with non-classical forms of Glut1 deficiency syndrome.
Thioctic acid, also known as alpha-lipoic acid, is a naturally occurring compound that is made is small amounts by the human body. Thioctic acid is believed to help glucose transport in the body and has been used as an adjunct therapy for some individuals with Glut1 deficiency syndrome.
Drugs that are used to treat seizures (anti-convulsants) are generally ineffective in treating individuals with Glut1 deficiency syndrome. Other drugs including phenobarbital, narcotics and caffeine inhibit the function of Glut1 and can worsen Glut1 deficiency syndrome in some affected individuals. Other drugs such as valproate, topiramate, zonisamide and acetazolamide interact or interfere with a ketogenic diet. All such drugs should be avoided by individuals with Glut1 deficiency syndrome.
Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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