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.
Glucose transporter type 1 deficiency syndrome (Glut1DS) 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 and other tissue barriers. The most common symptom is seizures (epilepsy), which usually begin within the first few months of life. However, the symptoms and severity of Glut1DS can vary substantially from one person to another. For example, some affected individuals may not develop epilepsy. Additional symptoms that can occur include abnormal eye-head movements, body movement disorders, developmental delays, and varying degrees of cognitive impairment, slurred speech and language abnormalities. Glut1DS is caused by changes (mutations) in the SLC2A1 gene and is inherited in an autosomal dominant pattern. Rarely, the condition also may be inherited in an autosomal recessive pattern. Glut1DS does not respond to traditional epilepsy treatments (e.g., anti-seizure medications), but is successfully treated with the ketogenic diet.
Glut1DS was first described in the medical literature in 1991 by Dr. De Vivo, et al. The disorder is also known as De Vivo disease. Glut1DS is classified as an epileptic encephalopathy. Epileptic encephalopathies are a group of disorders in which seizure activity is associated with progressive psychomotor dysfunction. Paroxysmal exercise-induced dyskinesias (PED), also known previously as dystonia 18 and dystonia 9, are now considered part of the Glut1DS spectrum. Epilepsy commonly presents in infancy whereas PED commonly emerges in late childhood and adolescence.
Glut1DS represents a clinical spectrum disease. The symptoms and severity can vary dramatically from one individual to another. Mild cases often go undiagnosed, while other cases can potentially lead to severe, debilitating complications. It is important to note that affected individuals may not have all the classic symptoms discussed below or may have less severe symptoms. Affected individuals should talk to their physician and medical team about their specific clinical features, standard management and prognosis.
The classic presentation of Glut1DS is the development of seizures during infancy usually during the first six 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 brief 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. Often these spells may be misinterpreted as “day-dreaming”.
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 associated with Glut1DS include deceleration of head growth during infancy. Affected individuals can develop mild to moderate delays in attaining developmental milestones. Deceleration of head growth may lead to acquired microcephaly in some individuals, a condition marked by head circumference that falls below the 3rd percentile for age and gender.
Individuals with Glut1DS may also develop disorders of movement including diminished muscle tone (hypotonia), poor balance or difficulty coordinating voluntary movements (ataxia), slow, stiff limb movements (spasticity) and awkward postures (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 Glut1DS can cause difficulty walking. Such difficulties can be a constant problem or may come and go (episodic or paroxysmal) often triggered by exercise.
Individuals with Glut1DS 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 present as well. Individuals may experience difficulty speaking due to abnormalities affecting the muscles that enable speech (dysarthria) and control the smooth flow or expression of speech (dysfluency). Speaking may be marked by frequent pauses or interruptions.
Individuals with Glut1DS generally are friendly and enjoy socializing with others. Social adaptive behavior is viewed as a relative strength and affected individuals are 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 and head movements in both horizontal and vertical directions, 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 extended periods of time without eating (fasting). Sleep apnea and abnormal eye-head movements, like seizures, usually present in infancy as one of the first clinical signs and should immediately alert the physician to Glut1DS as a diagnostic possibility. Early diagnosis and treatment is associated with a better long term prognosis.
Although most affected individuals develop so-called classic Glut1DS, some individuals develop different (non-classic) presentations (phenotypes). Some affected individuals develop movement disorders and cognitive impairment without epilepsy. In addition, a few individuals have been asymptomatic or had only mild symptoms of the disorder. These individuals might have a mixture of normal and mutated SLC2A1 genes, a condition known as mosaicism
Some 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.
Glut1DS is caused by mutations in the SLC2A1 gene. These mutations are inherited in an autosomal dominant (or rarely recessive) pattern. Most individuals with Glut1DS have a spontaneous genetic change (i.e., new mutation) in the SLC2A1 gene. In essence, the mutation started with the individual, was not inherited from the parents, but can be passed on to future generations.
Dominant genetic disorders occur when only one copy of the abnormal gene causes the disease. Recessive genetic disorders require both copies to be abnormal. An abnormal gene can be inherited from either parent or can be the result of a new (de novo) mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
The symptoms of Glut1DS result from decreased glucose transport into 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 lower levels of functional Glut1. Without proper levels of Glut1, the body cannot transport sufficient amounts of glucose across the blood-brain barrier and other cell membranes. 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 consequences of reduced brain glucose levels and the links to the symptoms of Glut1DS are not fully understood.
Glut1DS affects males and females in equal numbers. The incidence and prevalence of Glut1DS in the general population is unknown. Because the disorder may go unrecognized or misdiagnosed, determining its true frequency in the general population is difficult. Several hundred cases have been identified and described in the medical literature since 1991. The prevalence estimates have ranged from 1:90,000 to 1:24,000 suggesting that there are several thousand cases of Glut1DS in the USA.
A diagnosis of Glut1DS is confirmed by the presence of characteristic clinical features, hypoglycorrhachia and a disease-causing mutation in the SLC2A1 gene.
Clinical Testing and Work-Up
Individuals suspected of Glut1DS should 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 cerebrospinal fluid (CSF). The test should be performed in the post-absorptive state 4-6 hours after eating. Low CSF concentration of glucose (hypoglycorrhachia) in the absence of low blood sugar (hypoglycemia) is indicative of Glut1DS. Physicians should also measure lactate levels in the CSF. Lactate is low-normal or low in individuals with Glut1DS. These CSF findings are necessary but not sufficient to make the diagnosis of Glut1DS.
The Glut1 protein is also found in red blood cell (erythrocyte) membrane. Testing is available on a research basis to assess erythrocyte glucose transporter activity, which is reduced by approximately 50 percent (35-73%) in individuals with Glut1DS. Decreased erythrocyte transport of glucose is a surrogate for decreased gene dosage (haploinsufficiency) and consistent with the diagnosis of Glut1DS.
A positron emission tomography (PET) scan may be used to help support a diagnosis of Glut1DS. 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 Glut1DS has not been established.
A diagnosis of Glut1DS can be confirmed by molecular genetic testing that identifies a disease causing SLC2A1 gene mutation associated with the disorder. Hundreds of pathogenic SLC2A1 mutations have been identified. Molecular genetic testing is available through commercial and academic research laboratories
There is no cure for Glut1DS. The disorder is treated with the ketogenic diet, which may prevent seizure activity in many individuals with Glut1DS. 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 at least until adolescence. Compliance becomes a bigger problem as children grow and become more independent. However, the ketogenic diet seems to help individuals of all ages.
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 regarding the effect of the ketogenic diet on cognition in individuals with Glut1DS.
The ketogenic diet is also effective in reducing the severity of movement disorders associated with the classical form of Glut1DS in approximately half of cases. It is even more effective in treating movement disorders in individuals with non-classical forms of Glut1DS.
Thioctic acid, also known as alpha-lipoic acid, is a naturally occurring compound that is made in small amounts by the human body. Thioctic acid is believed to help glucose transport in the body and has been used as a supplement for some individuals with Glut1DS.
Drugs that are used to treat seizures (anti-convulsants) are generally ineffective in treating individuals with Glut1DS. Other drugs including phenobarbital, narcotics and caffeine inhibit the function of Glut1 and can worsen Glut1DS in some affected individuals. Other drugs such as valproate, topiramate, zonisamide and acetazolamide may interfere with a ketogenic diet. All such drugs should be avoided by individuals with Glut1DS.
Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
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