GLUT1 deficiency

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De Vivo disease
Other namesDe Vivo disease
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De Vivo disease has an autosomal dominant pattern of inheritance
Specialty Medical genetics   OOjs UI icon edit-ltr-progressive.svg


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. [1] Glucose Transporter Type 1 Deficiency Syndrome has an estimated birth incidence of 1 in 90,000 [2] to 1 in 24,300. [3] This birth incidence translates to an estimated prevalence of 3,000 to 7,000 in the U.S. [2]

Contents

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 of the disorder may be involuntary eye movements that are rapid and irregular. [4] Patients typically begin to experience seizures between three and six months of age, but some occur much later. [5] Other seizure types may occur, including generalized tonic clonic, focal, myoclonic, atypical absence, atonic or unclassified. [5]

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). [4] 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. [6] 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. [7] Most of these non-epileptic cases will still have developmental delay, intellectual delays and movement disorders such as ataxia, alternating hemiplegia or dystonia. [7]

Some symptoms may be present all the time (like walking difficulties), while other signs may come and go (like seizures or poor balance). [8] These findings can be clustered under three major domains: cognition, behavior and movement. [8]

Effects

The syndrome can cause infantile seizures refractory to anticonvulsive drugs, developmental delay, acquired microcephaly and neurologic manifestations including spasticity, hypotonia and ataxia. [9] 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. [5] 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. [5] 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. [5] 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). [5] Paroxysmal exercise-induced dyskinesia (PED) may also be present. [10] 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. [7] Some young patients experience occasional abnormal eye movements that may resemble opsoclonus or nystagmus. [5] 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. [11] These abnormal eye movements were recently named aberrant gaze saccades. [11] Hemiplegia or alternating intermittent hemiplegia may occur in some patients and mimic stroke-like symptoms. [12] 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. [5] 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. [5] Data on adult Glut1DS are just emerging. [13] 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. [8]

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. [14] 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. [8]

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. [15]

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. [16]


In a study focusing on GLUT1 mice model brain slides, physiological glucose concentration was found to be a modulator of frequency oscillations and less frequent 30–50 Hz or gamma oscillations. [17]

Diagnosis

Early diagnosis is crucial in order to initiate treatment during the important early stages of brain development. To make a proper diagnosis, it is important to know the various symptoms of GLUT1 deficiency and how those symptoms evolve with age. [18]

GLUT1 deficiency is diagnosed based on the clinical features in combination with determining the glucose concentration in the CSF and/or a genetic analysis through a lumbar puncture (spinal tap). [13] A low glucose value in CSF (<2.2 mmol/L) or lowered CSF/plasma glucose ratio (<0.4)are indicatieve of GLUT1 deficiency. A genetic mutation in the SLC2A1 gene also confirms the diagnosis, although mutations have not been identified in approximately 15% of GLUT1 deficiency patients. [19] A highly specialized lab test called the red blood cell uptake assay may confirm GLUT1 deficiency but is not commercially available. [20]

Management

Anti-seizure medications are generally not effective, since they do not provide nourishment to the starved brain. [8]

Once diagnosed, a medically supervised ketogenic diet is usually recommended as it can help to control seizures. [21] The ketogentic diet is the current standard of care treatment, with 80% of patients having >90% seizure reduction [13] and improving some movement disorders in approximately two thirds of GLUT1 deficiency patients. [18] There is also some evidence of some cognitive benefits for GLUT1 deficiency patients on a ketogenic diet, and most parents report improved energy, alertness, balance, coordination, and concentration, [18] especially when the diet is started early in childhood.

The ketogenic diet is a diet high in fat and low in protein and carbohydrates, with up to 90% of calories obtained from fat. Since the diet is low in carbohydrates, the body gets little glucose, normally the main energy source. The fat in the diet is converted by the liver in ketone bodies, which causes a build up of ketones in the blood stream, called ketosis. Ketone bodies are transported across the blood-brain barrier by other means than the GLUT1 protein and thus serve as an alternative fuel for the brain when glucose is not available. [22]

While ketogenic diets have been proven effective to control seizures and relieve some movement disorders in many GLUT1 deficiency patients, some patients do not respond as well as others. In addition, some critical symptoms, including cognitive deficits and certain movement difficulties, tend to persist in GLUT1 deficiency patients treated by a ketogenic diet, raising the question whether GLUT1 deficiency is caused simply by a lack of proper brain energy or if there are more complicated and widespread systems and processes affected. [18]

The ketogenic diet must be carefully crafted and tailored to meet the needs of each patient and reduce the risk of side effects. It should only be used under the care of medical professionals and dietitians, and it may take some time to establish the ideal ratio of fat versus proteins and carbohydrates and other diet variables for each individual patient to experience optimal tolerance and benefits. Variations on the ketogenic diet, including the Modified Atkins Diet, and diets based on MCT oil have also been shown to be beneficial for some GLUT1 deficiency patients. [18]

While the classic ketogenic diet is commonly used for younger children, compliance with the ketogenic diet can be difficult for older children and adults. In recent years, the Modified Atkins Diet, and MCT oil based diets, have gained increasing acceptance among doctors treating these groups and may be more feasible for quality of life and compliance. [13] There is growing empirical evidence that these diets can provide at least some of the benefits of the classical ketogenic diet for some GLUT1 deficiency patients. [18]

Ketone esters are an area of dietary therapy currently under investigation for potential treatment of GLUT1 deficiency and other medical conditions. Ketone esters are synthetic ketones that break down into natural ketones when metabolized. Ketone esters have been shown in recent research to improve seizures and movement disorders in GLUT1 deficient mice, but human studies have not yet been conducted. [18]

Triheptanoin (C7 oil), a triglyceride oil synthesized from castor beans. [18] is an investigational pharmaceutical-grade medical food that has shown potential as a treatment for a number of inherited metabolic diseases. When metabolized by the body, C7 oil produces ketones similar to those produced on a ketogenic diet in addition to other types of ketones that are thought to fulfill further metabolic requirements in the absence of sufficient glucose. [18] A phase 3 clinical trial however failed to find an improvement in patients with GLUT1 DS with disabling movement disorders.

The inhibition of insulin production to increase glucose in the blood with the medicine diazoxide, in combination with continuous glucose monitoring, has been successful in one adolescent. The increased blood glucose also increases the availability of glucose in the brain, through the increased transfer of more glucose through the GLUT1-protein. She became seizure-free, became more physically active and had improved cognition. [23]

Researchers are studying gene therapy as a possible effective treatment for Glut 1 Deficiency. [24] [25]

Therapies and rehabilitative services are beneficial since most GLUT1 deficiency patients experience movement disturbances as well as speech and language disorders. Occupational, physical, and speech/language therapies are standard for most patients, especially in childhood. [18] Many families greatly benefit from other therapies such as aquatic therapy, hippotherapy, specific learning strategies, and behavioral therapy. [18]

Glut 1 patients Weak Areas are lowered IQ and adaptive behavior scores, expressive-language deficits, weakness in fine motor skills, limited visual attention to details, weakness in abstract analytical skills, and weakness in transfer of learning to new contexts.[ citation needed ]

Related Research Articles

<span class="mw-page-title-main">Ketogenesis</span> Chemical synthesis of ketone bodies

Ketogenesis is the biochemical process through which organisms produce ketone bodies by breaking down fatty acids and ketogenic amino acids. The process supplies energy to certain organs, particularly the brain, heart and skeletal muscle, under specific scenarios including fasting, caloric restriction, sleep, or others.

<span class="mw-page-title-main">Ketogenic diet</span> High-fat dietary therapy for epilepsy

The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate dietary therapy that in conventional medicine is used mainly to treat hard-to-control (refractory) epilepsy in children. The diet forces the body to burn fats rather than carbohydrates.

<span class="mw-page-title-main">Uniporter</span>

Uniporters, also known as solute carriers or facilitated transporters, are a type of membrane transport protein that passively transports solutes across a cell membrane. It uses facilitated diffusion for the movement of solutes down their concentration gradient from an area of high concentration to an area of low concentration. Unlike active transport, it does not require energy in the form of ATP to function. Uniporters are specialized to carry one specific ion or molecule and can be categorized as either channels or carriers. Facilitated diffusion may occur through three mechanisms: uniport, symport, or antiport. The difference between each mechanism depends on the direction of transport, in which uniport is the only transport not coupled to the transport of another solute.

Neuroglycopenia is a shortage of glucose (glycopenia) in the brain, usually due to hypoglycemia. Glycopenia affects the function of neurons, and alters brain function and behavior. Prolonged or recurrent neuroglycopenia can result in loss of consciousness, damage to the brain, and eventual death.

<span class="mw-page-title-main">Beta-ketothiolase deficiency</span> Medical condition

Beta-ketothiolase deficiency is a rare, autosomal recessive metabolic disorder in which the body cannot properly process the amino acid isoleucine or the products of lipid breakdown. Along with SCOT deficiency, it belongs to a group of disorders called ketone utilisation disorders.

<span class="mw-page-title-main">Lennox–Gastaut syndrome</span> Rare form of childhood-onset epilepsy

Lennox–Gastaut syndrome (LGS) is a complex, rare, and severe childhood-onset epilepsy syndrome. It is characterized by multiple and concurrent seizure types including tonic seizure, cognitive dysfunction, and slow spike waves on electroencephalogram (EEG), which are very abnormal. Typically, it presents in children aged 3–5 years and most of the time persists into adulthood with slight changes in the electroclinical phenotype. It has been associated with perinatal injuries, congenital infections, brain malformations, brain tumors, genetic disorders such as tuberous sclerosis and numerous gene mutations. Sometimes LGS is observed after infantile epileptic spasm syndrome. The prognosis for LGS is marked by a 5% mortality in childhood and persistent seizures into adulthood.

<span class="mw-page-title-main">GLUT2</span> Transmembrane carrier protein

Glucose transporter 2 (GLUT2) also known as solute carrier family 2, member 2 (SLC2A2) is a transmembrane carrier protein that enables protein facilitated glucose movement across cell membranes. It is the principal transporter for transfer of glucose between liver and blood Unlike GLUT4, it does not rely on insulin for facilitated diffusion.

Neuroacanthocytosis is a label applied to several genetic neurological conditions in which the blood contains misshapen, spiculated red blood cells called acanthocytes.

Pyruvate dehydrogenase deficiency is a rare neurodegenerative disorder associated with abnormal mitochondrial metabolism. PDCD is a genetic disease resulting from mutations in one of the components of the pyruvate dehydrogenase complex (PDC). The PDC is a multi-enzyme complex that plays a vital role as a key regulatory step in the central pathways of energy metabolism in the mitochondria. The disorder shows heterogeneous characteristics in both clinical presentation and biochemical abnormality.

<span class="mw-page-title-main">GLUT1</span> Uniporter protein

Glucose transporter 1, also known as solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1), is a uniporter protein that in humans is encoded by the SLC2A1 gene. GLUT1 facilitates the transport of glucose across the plasma membranes of mammalian cells. This gene encodes a facilitative glucose transporter that is highly expressed in erythrocytes and endothelial cells, including cells of the blood–brain barrier. The encoded protein is found primarily in the cell membrane and on the cell surface, where it can also function as a receptor for human T-cell leukemia virus (HTLV) I and II. GLUT1 accounts for 2 percent of the protein in the plasma membrane of erythrocytes.

Pyruvate carboxylase deficiency is an inherited disorder that causes lactic acid to accumulate in the blood. High levels of these substances can damage the body's organs and tissues, particularly in the nervous system. Pyruvate carboxylase deficiency is a rare condition, with an estimated incidence of 1 in 250,000 births worldwide. Type A of the disease appears to be much more common in some Algonkian Indian tribes in eastern Canada, while the type B disease is more present in European populations.

Glucose transporter 3, also known as solute carrier family 2, facilitated glucose transporter member 3 (SLC2A3) is a protein that in humans is encoded by the SLC2A3 gene. GLUT3 facilitates the transport of glucose across the plasma membranes of mammalian cells. GLUT3 is most known for its specific expression in neurons and has originally been designated as the neuronal GLUT. GLUT3 has been studied in other cell types with specific glucose requirements, including sperm, preimplantation embryos, circulating white blood cells and carcinoma cell lines.

<span class="mw-page-title-main">Inborn errors of carbohydrate metabolism</span> Medical condition

Inborn errors of carbohydrate metabolism are inborn error of metabolism that affect the catabolism and anabolism of carbohydrates.

The paroxysmal dyskinesias (PD) are a group of movement disorders characterized by attacks (paroxysms) of hyperkinesia with intact consciousness. Paroxysmal dyskinesia is a rare disorder, however the number of individuals it affects remains unclear. There are three different subtypes of PD that include paroxysmal kinesigenic dyskinesia (PKD), paroxysmal nonkinesigenic dyskinesia (PNKD), and paroxysmal exercise-induced dystonia (PED). Other neurological diseases have similar symptoms to PD, such as epilepsy and Parkinson's. The different subtypes make accurate and quick diagnosis of PD challenging. Thus, PD is often under reported and misdiagnosed, making it difficult to accurately study its prevalence in human populations. Onset of PD is usually in late childhood to early adolescence. New drug regimens help treat symptoms of PD, but no cure for the disorder is known.

<span class="mw-page-title-main">Paroxysmal exercise-induced dystonia</span> Episodes of involuntary movement triggered by exercise

Paroxysmal exercise-induced dystonia (PED) is a rare neurological disorder that belongs to the paroxysmal dyskinesias, a group of rare movement disorders that involve attacks of hyperkinesia with intact consciousness. It is characterized by sudden, transient, involuntary movements, often including repetitive twisting motions and painful posturing triggered by exercise or other physical exertion. The term paroxysmal indicates that the episodes are sudden and short lived and usually unpredicted, and return to normal is rapid. The number of reported cases of people with PED is very small leading to difficulty in studying and classifying this disease and most studies are limited to a very small number of test subjects.

EAST syndrome is a syndrome consisting of epilepsy, ataxia, sensorineural deafness and salt-wasting renal tubulopathy. The tubulopathy in this condition predispose to hypokalemic metabolic alkalosis with normal blood pressure. Hypomagnesemia may also be present.

Myoclonic astatic epilepsy (MAE), also known as myoclonic atonic epilepsy or Doose syndrome, and renamed "Epilepsy with myoclonic-atonic seizures" in the ILAE 2017 classification, is a generalized idiopathic epilepsy. It is characterized by the development of myoclonic seizures and/or myoclonic astatic seizures. Some of the common monogenic causes include mutations in the genes SLC6A1 (3p25.3),CHD2 (15q26.1), AP2M1 (10q23.2).

<span class="mw-page-title-main">Creatine transporter defect</span> Medical condition

Creatine transporter deficiency (CTD) is an inborn error of creatine metabolism in which creatine is not properly transported to the brain and muscles due to defective creatine transporters. CTD is an X-linked disorder caused by mutation in SLC6A8. SLC6A8 is located at Xq28. Hemizygous males with CTD express speech and behavior abnormalities, intellectual disabilities, development delay, seizures, and autistic behavior. Heterozygous females with CTD generally express fewer, less severe symptoms. CTD is one of three different types of cerebral creatine deficiency (CCD). The other two types of CCD are guanidinoacetate methyltransferase (GAMT) deficiency and L-arginine:glycine amidinotransferase (AGAT) deficiency. Clinical presentation of CTD is similar to that of GAMT and AGAT deficiency. CTD was first identified in 2001 with the presence of a hemizygous nonsense change in SLC6A8 in a male patient.

CDKL5 deficiency disorder (CDD) is a rare genetic disorder caused by pathogenic variants in the gene CDKL5.

SLC13A5 citrate transporter disorder, or SLC13A5 Epilepsy, is a rare genetic spectrum disorder that presents with neurological symptoms. Symptoms include severe seizures, ataxia, dystonia, teeth hypoplasia, poor communication skills, difficulty standing or walking, as well as developmental delay. Other names associated with SLC13A5 Epilepsy include SLC13A5 Citrate Transporter Disorder, Citrate Transporter Disorder, SLC13A5 Deficiency, Early Infantile Epilepsy Encephalopathy 25 (EIEE25), Developmental Epilepsy Encephalopathy 25 (DEE25), and Kohlschutter-Tonz Syndrome (non-ROGDI).

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