First published: 

Paroxysmal Nonepileptic Events in Glut1 Deficiency

Abstract

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.[1] The resulting cerebral energy deficit is treatable and potentially curable by means of ketogenic diets (KDs) providing ketones as an alternative fuel.[2] 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

Video

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

Questionnaire

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.).

Results

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: joerg.klepper@klinikum-ab-alz.de

Department of Pediatrics and Neuropediatrics, Children’s Hospital Aschaffenburg–Alzenau, Aschaffenburg, Germany

http://onlinelibrary.wiley.com/doi/10.1002/mdc3.12387/full

Support Group

http://www.g1dfoundation.org/

Medical Advisory Board

http://www.g1dfoundation.org/about/medical-advisory-board/

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.

http://www.epilepsy.com/learn/types-epilepsy-syndromes/glut1-deficiency-syndrome

http://www.g1dfoundation.org/

http://www.matthewsfriends.org/

http://www.epilepsy.com/article/2013/11/glut1-deficiency-syndrome-and-ketogenic-diet

General Discussion

Summary

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.

Introduction

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.

Causes

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.

Related Disorders

Ketogenic Diet and Cancer

Click on the RED underlined wording for other links

There is currently no cure for Glut1 Deficiency.  Treatment is aimed at controlling symptoms, and the current standard of care is the ketogenic diet.  It is a high fat, moderate protein, and low carbohydrate diet that causes the body to produce and burn ketones for fuel in the absence of glucose.   These ketones can act as an alternative fuel source, and the energy they provide can help alleviate some of the symptoms of Glut1 Deficiency.

The ketogenic diet is also used as an effective treatment for seizures in the general epilepsy population, typically in children but recently also in adults.  In its general application, it is often used after 2-3 anticonvulsant medications have failed.  It is showing promise in helping other neurological conditions as well.

The ketogenic diet is carefully tailored to individual patients, has potential side effects, and should only be used under the care of medical professionals.  The diet can help improve most symptoms associated with Glut1 Deficiency, but often does not completely control them.  Other forms of treatment are currently under investigation by Glut1 Deficiency researchers, but as of now, there are no other available treatments.

It can take some time for the full potential of the diet to take effect, and adjustments and modifications are sometimes required.  Anticonvulsant medications can usually be reduced or discontinued, as they are generally not very effective in treating the seizures caused by Glut1 Deficiency because they do not help nourish the starving brain.  However, it is not unusual for children with Glut1 Deficiency to remain on and benefit from a single anticonvulsant along with the diet.

Ketogenic diet does not “beat chemo for almost all cancers”

One of the difficult things about science-based medicine is determining what is and isn’t quackery. While it is quite obvious that modalities such as homeopathy, acupuncture, reflexology, craniosacral therapy, Hulda Clark’s “zapper,” the Gerson therapy and Gonzalez protocol for cancer, and reiki (not to mention every other “energy healing” therapy) are the rankest quackery, there are lots of treatments that are harder to classify. Much of the time, these treatments that seemingly fall into a “grey area” are treatments that have shown promise in animals but have never been tested rigorously in humans or are based on scientific principles that sound reasonable but, again, have never been tested rigorously in humans. (Are you sensing a pattern here yet?) Often these therapies are promoted by true believers whose enthusiasm greatly outstrips the evidence base for their preferred treatment. Lately, I’ve been seeing just such a therapy being promoted around the usual social media sources, such as Facebook, Twitter, and the like. I’ve been meaning to write about it for a bit, but, as is so often the case with my Dug the Dog nature—squirrel!—other topics caught my attention.

https://www.sciencebasedmedicine.org/ketogenic-diets-for-cancer-hype-versus-science/

Ketogenic diet beats chemotherapy for almost all cancers says, Thomas Seyfried

The low-carb, high-fat ketogenic diet can replace chemotherapy and radiation for even the deadliest of cancers, said Dr Thomas Seyfried, a leading cancer researcher and professor at Boston College.

DR

 In an exclusive Examiner interview, Dr Seyfried discussed why the ketogenic diet has not been embraced by the medical community to treat cancer despite its proven track record both clinically and anecdotally.

 “The reason why the ketogenic diet is not being prescribed to treat cancer is purely economical,” Dr Seyfried told Examiner. “Cancer is big business. There are more people making a living off cancer than there are dying of it.” According to Seyfried, the medical community is reluctant to publicly acknowledge the efficacy of the ketogenic diet for preventing and treating cancer because doing so would cut off the massive streams of revenue hospitals generate from chemotherapy and radiation treatments.

(It’s a simple economic issue. There’s no money in it for the hospitals, doctors, and drug companies to prescribe a ketogenic diet when they can make hundreds of millions of dollars from the standard of care. Radiation therapy is a huge revenue generator for hospitals.”)

Read More

http://homehealthcareinc.info/ketogenic-diet-beats-chemotherapy-for-almost-all-cancers-says-thomas-seyfried/

http://www.bc.edu/schools/cas/biology/facadmin/seyfried.html

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New idea for fighting Cancer

Immunotherapy Method

NIH study demonstrates that a new cancer immunotherapy method could be effective against a wide range of cancers.

A new method for using immunotherapy to specifically attack tumour cells that have mutations unique to a patient’s cancer has been developed by scientists at the National Cancer Institute (NCI), part of the National Institutes of Health. The researchers demonstrated that the human immune system can mount a response against mutant proteins expressed by cancers that arise in epithelial cells which can line the internal and external surfaces (such as the skin) of the body. These cells give rise to many types of common cancers, such as those that develop in the digestive tract, lung, pancreas, bladder and other areas of the body.

The research provides evidence that this immune response can be harnessed for therapeutic benefit in patients, according to the scientists. The study appeared May 9, 2014, in the journal Science.

“Our study deals with the central problem in human cancer immunotherapy, which is how to effectively attack common epithelial cancers,” said Steven A. Rosenberg, M.D., Ph.D., chief of the Surgery Branch in NCI’s Center for Cancer Research. “The method we have developed provides a blueprint for using immunotherapy to specifically attack sporadic or driver mutations, unique to a patient’s individual cancer.”

-immunotherapy cancer

 

Six months after ACT with mutation-specific T-cells, tumours that metastasized to the lung have shrunk.Rosenberg Lab

All malignant tumours harbour genetic alterations, some of which may lead to the production of mutant proteins that are capable of triggering an antitumor immune response. Research led by Rosenberg and his colleagues had shown that human melanoma tumours often contain mutation-reactive immune cells called tumor-infiltrating lymphocytes, or TILs. The presence of these cells may help explain the effectiveness of adoptive cell therapy (ACT) and other forms of immunotherapy in the treatment of melanoma.

In ACT, a patient’s own TILs are collected, and those with the best antitumor activity are grown in the laboratory to produce large populations that are infused into the patient. However, prior to this work, it had not been clear whether the human immune system could mount an effective response against mutant proteins produced by epithelial cell cancers. These cells comprise more than 80 percent of all cancers. It was also not known whether such a response could be used to develop personalised immunotherapies for these cancers.

In this study, Rosenberg and his team set out to determine whether TILs from patients with metastatic gastrointestinal cancers could recognise patient-specific mutations. They analysed TILs from a patient with bile duct cancer that had metastasized to the lung and liver and had not been responsive to standard chemotherapy. The patient, a 43-year-old woman, was enrolled in an NIH trial of ACT for patients with gastrointestinal cancers (Clinical trial number NCT01174121).

The researchers first did whole-exome sequencing, in which the protein-coding regions of DNA are analysed to identify mutations that the patient’s immune cells might recognise. Further testing showed that some of the patient’s TILs recognised a mutation in a protein called ERBB2-interacting protein (ERBB2IP). The patient then underwent adoptive cell transfer of 42.4 billion TILs, approximately 25 percent of which were ERBB2IP mutation-reactive T lymphocytes, which are primarily responsible for activating other cells to aid cellular immunity, followed by treatment with four doses of the anticancer drug interleukin-2 to enhance T-cell proliferation and function.

Read More

https://www.nih.gov/news-events/news-releases/nih-study-demonstrates-new-cancer-immunotherapy-method-could-be-effective-against-wide-range-cancers

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Ground-breaking research

2016

Ground-breaking research in the fight against cancer

Watch Video of this

http://www.cbc.ca/news/thenational/ground-breaking-research-in-the-fight-against-cancer-1.3449351

Researchers at The Ottawa Hospital have launched a clinical trial in the fight against cancer, using an unlikely duo: the common cold and a Brazilian sand fly.

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