Paroxysmal Nonepileptic Events in Glut1 Deficiency
Movement disorders are a major feature of Glut1 deficiency. As recently identified in adults with paroxysmal exercise-induced dystonia, similar events were reported in paediatric Glut1 deficiency. In a case series, parent videos of regular motor state and paroxysmal events were requested from children with Glut1 deficiency on clinical follow-up. A questionnaire was sent out to 60 families. Videos of nonparoxysmal/paroxysmal states in 3 children illustrated the ataxic-dystonic, choreatiform, and dyskinetic-dystonic nature of paroxysmal events. Fifty-six evaluated questionnaires confirmed this observation in 73% of patients. Events appeared to increase with age, were triggered by low ketosis, sleep deprivation, and physical exercise, and unrelated to sex, hypoglycorrhachia, SLC2A1 mutations, or type of ketogenic diet. We conclude that paroxysmal events are a major clinical feature in Glut1 deficiency, linking the paediatric disease to adult Glut1D-associated exercise-induced paroxysmal dyskinesias.
Glut1 deficiency (Glut1D) represents a rare metabolic encephalopathy with many faces. A defect in the facilitated glucose transporter, GLUT1, at the blood–brain barrier and in brain cells impairs glucose transport into the brain. This is reflected by hypoglycorrhachia, the diagnostic hallmark of this entity. Approximately 80% of patients carry mutations in the SLC2A1 gene. The resulting cerebral energy deficit is treatable and potentially curable by means of ketogenic diets (KDs) providing ketones as an alternative fuel. Patients present with epilepsy, a range of developmental disorders, and movement abnormalities or a complex combination of these features. Recently, paroxysmal events (PEs) were recognised in Glut1D children and SLC2A1 mutations detected in adults with paroxysmal exercise-induced dystonia (PED), linking this entity to the Glut1D spectrum.[3-7] Here, we provide video examples of normal and paroxysmal state in 3 children with Glut1D and investigated the incidence, type, and potential associations of PEs in 56 children with Glut1D with and without SLC2A1 mutations by questionnaire.
Patients and Methods
Three children from outpatient clinics (authors J.K. and C.E.) with confirmed Glut1D (for details, see the Video Case Reports section below) described PEs on regular follow-up. Families were asked to provide representative videos of the normal motor state (video part A), and of PEs (video part B). Consent for video publication was obtained in all cases
Sixty patients with a diagnosis of Glut1D confirmed by hypoglycorrhachia and/or molecular testing were contacted by phone, e-mail, parent support groups, and in follow-up clinics and were asked to complete a questionnaire (see Supplemental Questionnaire 1). Parents were asked to provide information and videos on paroxysmal events that were clearly different from seizures. Response to KD was defined as (1) adequate seizure control (>50% seizure reduction) on the introduction of a KD and/or (2) significant clinical improvement of motor disorders as observed by parents/caretakers and stated on clinical follow-up by the treating physician. A total of 56 of 60 families answered; 27 of 56 patients, including the 3 index cases, were on regular clinical follow-up by two of the authors (J.K. and C.E.).
A total of 56 of 60 questionnaires were completed (Table 1). Glut1D was diagnosed by hypoglycorrhachia (15 of 56; 27%), SLC2A1 mutations (12 of 56; 21%), or a combination (29 of 56; 52%). Twenty-seven patients were followed clinically by two of the authors (J.K. and C.E.)—the genetic diagnosis was backed by multiplex ligation-dependent probe assay (MLPA) analysis in all patients of this subgroup. A total of 13 of 56 (23%) patients presented with isolated movement disorders, 4 of 56 (7%) exclusively with epilepsy, and 2 of 56 (4%) with cognitive/behavioural disturbances only. A total of 37 of 56 (66%) patients combined all three features.
Corresponding author: E-mail address: email@example.com
Department of Pediatrics and Neuropediatrics, Children’s Hospital Aschaffenburg–Alzenau, Aschaffenburg, Germany
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What is Glut1 Deficiency?
Glucose Transporter Type 1 Deficiency Syndrome (Glut1 Deficiency, G1D, Glut1 DS, or De Vivo Disease) is a genetic disorder that impairs brain metabolism. Glucose isn’t transported properly into the brain, leaving it starving for the energy it needs to grow and function.
Glut1 Deficiency causes an array of symptoms which may vary considerably from one patient to another. Some signs and symptoms may include seizures, movement disorders, speech and language disorders, and developmental delays. There are currently around 500 cases diagnosed worldwide, but experts believe there are many more patients yet to be discovered.
There is no cure for Glut1 Deficiency. The standard of care treatment is a ketogenic diet, which helps improve most symptoms for most patients by giving the brain an alternate source of energy.
Learning About Glut1 Deficiency Syndrome
Seizures may be just one symptom of a rare genetic disorder called glucose transporter type 1 deficiency syndrome (Glut1 DS). Follow links below to learn more.
Glucose transporter type 1 (Glut1) deficiency syndrome is a rare genetic metabolic disorder characterised by a 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.
Glut1 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.
Signs & Symptoms
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 generalised tonic or clonic, myoclonic, atypical absence, atonic and unclassified.
Generalised tonic-clonic seizures (once known as grand mal seizures), usually last a minute or more and are characterised by stiffening of the limbs (tonic phase) and then repeated jerking of the limbs and face (clonic phase). Generalised tonic-clonic seizures can cause people to momentarily lose consciousness, bite their lips, or drool.
Myoclonic seizures are characterised 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 backwards 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 characterised 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 behaviour 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.