1. Overview of GLUT1 DS

Transcription

1 1. Overview of GLUT1 DS 1.1 History and General Description In 1991, De Vivo et al. published a case report describing two patients presenting with developmental delay, seizures, and persistent hypoglycorrhia (reduced amounts of glucose in the cerebrospinal fluid). This clinical presentation was thought to be related to a lack of glucose entering the brain, caused by a genetic defect affecting the patients GLUT1 transporters. Both patients were treated with a ketogenic diet, resulting in a prompt end to the seizures. 1 This case report constituted the first description of GLUT1 Deficiency Syndrome (GLUT1 DS). 2 In 1998, mutations in genetic coding for the GLUT1 transporter were reported to be the molecular basis for disrupted glucose transport. 3-4 Since 1991, more than 400 patients worldwide have been diagnosed with GLUT1 DS Pathophysiology: Functional Changes Associated with Disorder GLUT1 DS is a rare but treatable neurologic disorder 5 that results from a reduction or elimination of the function of a number of a person s GLUT1 facilitated glucose transporters. 6 The GLUT1 transporter is one of fourteen GLUT transporters in the body. All are involved in transporting glucose to maintain glucose homeostasis. GLUT1 is the most ubiquitously expressed GLUT transporter, as well as the only GLUT transporter supplying glucose to the brain across the blood-brain barrier. 3 Because the GLUT1 transporter is the only carrier of glucose across the blood-brain barrier, damage to or a deficiency of this transporter causes a lack of fuel to brain tissue. This becomes a critical issue, as the sole source of energy metabolism in the brain under normal conditions is glucose. 6-7 The symptoms and clinical signs of GLUT1 DS are likely caused by the lack of available glucose for the brain. 6-8 Many GLUT1 DS patients may experience episodic or increased symptoms before meals, 6 or in the setting of environmental stressors such as anxiety, fasting, or prolonged exercise. 8 Short-term improvement in symptoms may be seen with carbohydrate intake, reflecting the energy deficit in the brain Phenotypes The classic phenotype (clinical signs and symptoms) presentation of GLUT1 DS is intractable epilepsy within six months after birth, followed by a complex movement disorder and global development delay. 9 However, the phenotype of the disease continues to expand, and includes a broad mix of clinical presentations and presenting ages. One phenotype is GLUT1 DS2, called paroxysmal exercise-induced dyskinesia (PED). PED is caused by a mutation in the gene encoding for the GLUT1 transporter, and is a less severe phenotype than the classical GLUT1 DS1 phenotype. 10 A spectrum of other phenotypes also exist. To add to the confusion, phenotypes seen in GLUT1 DS have also been seen in diseases. 8 It has been suggested that in clinical practice, GLUT1 DS should be suspected in any age child who presents with one or a combination of the following features: 1) Any form of intractable epilepsy, in particular early onset absence epilepsy; 2) Global developmental delay, particularly in speech; 3) Complex movement disorders; or 4) Paroxysmal events triggered by exercise, exertion, or fasting. 9 These are also listed in Table 1 9 below. 2

2 Table 1. Phenotype Presentation in Suspect GLUT1 DS One or a combination of Any form of intractable epilepsy, in particular early onset absence epilepsy Global developmental delay, particularly in speech Complex movement disorders Paroxysmal events triggered by exercise, exertion, or fasting 1.4 Etiology The majority of GLUT1 DS patients (approximately 70-80%) show various mutations in the SLC2A1 gene, the gene encoding the GLUT1 transporter. 9 Almost all mutations to date are heterozygous, meaning only 1 of the 2 alleles encoding the GLUT1 transporter that are present in each cell is affected. Most of these mutations are also de novo (new mutations). However, autosomal dominant (meaning only one of the two copies of the gene, either the paternal or maternal copy, is mutated, causing the disorder) and autosomal recessive patterns of inheritance (both copies of the gene, paternal and maternal, are mutated, causing the disorder) have been documented. 11 Homozygous GLUT1 mutations where both alleles encoding for the GLUT1 transporter are mutated in such a way that the result is a complete loss of the GLUT1 transporter is presumed to be lethal, as demonstrated in animal studies. 12 In one recent case study, however, two patients homozygous for the same mutation (meaning the same mutation on both the paternal and maternal copies of the gene encoding for the GLUT1 transporter) had mild to minimal phenotypes and only mild haploinsufficiency of the GLUT1 transporter. 4 It has been hypothesized that GLUT1 DS phenotypes result from the amount of the GLUT1 transporter protein expressed, the activity of the GLUT1 transporter protein, as well as whether the expressed protein is misfolded. 12 Therefore, for 70-80% of GLUT1 DS patients, genetic mutations are responsible for the pathophysilogical disruption of the GLUT1 transporter and resulting lack of glucose to the brain. Some mutations lead to a percentage loss of the GLUT1 transporter protein; other mutations in SLC2A1 gene may simply lead to a decrease in the rate of glucose transport. 12 With reduced numbers of GLUT1 transporters to carry glucose to the brain, and/or reduced function of a number of GLUT1 transporters, the amount of glucose available to the brain is negatively impacted. Patients who are clinically symptomatic of GLUT1 DS, but who do not have a SLC2A1 mutation may have post-transcriptional modifications to the GLUT1 transporter that impact its function. Or, these patients may have a GLUT1 transporter deficiency due to secondary causes such as a metabolic or traumatic insult to the body Epidemiology of GLUT1 DS 2.1 Incidence and Prevalence Presently, the incidence and prevalence of GLUT1 DS remain unknown; no firm estimates exist Additionally, physician awareness of the disorder may bias such estimates, 14 as there is need for more communication and awareness regarding the disorder. 13 As noted earlier, more than 400 GLUT1 DS patients world-wide have been diagnosed since Mild phenotypes continue to be seen, and the expectation is that more will be seen in the future. 2 More 3

3 research is also needed to ascertain which additional genetic, epigenetic, or environmental factors play a role in modifying phenotypes. 8 Currently, correlation between specific mutations and phenotypes has not been established, 3 but data confirm a relationship does exist. 15 Additionally, mutation hot spots (areas highly susceptible to mutation) on the SLC2A1 gene have been identified Standard of Care To date, no Standard of Care document exits for the management of GLUT1 DS patients; management of the disorder varies. 2 The literature agrees that the ketogenic diet is the current treatment of choice, 11 and along with alternative ketogenic diets is the only treatment. 17 The spectrum of the ketogenic diet has expanded over time beyond the classical 4:1 and 3:1 (ratios of fat: carbohydrate and protein combined) diets to include alternative ketogenic diets such as the modified Atkins diet, the medium-chain triglyceride diet, and the low glycemic index treatment. 17 However, most GLUT1 DS patients have been treated with the classical 4:1 and 3:1 ketogenic diet. 9 For most GLUT1 DS patients treated therapeutically with the 4:1 or 3:1 ketogenic diet, control of seizures is immediate. 9 The severity of the movement disorder shows a marked reduction, and frequently behavior and alertness improve. 15 For some GLUT1 DS patients on the ketogenic diet, however, anticonvulsant drugs are still needed as part of the treatment plan. 9 Substances that impair the function of the GLUT1 transporter include caffeine; androgens; dioxine; tricyclic antidepressants; and anticonvulsants such as diazepam, valproate, and Phenobarbital. The literature recommends that GLUT1 DS patients avoid these substances. 11 Also, because of the need for possible longer-term use of the ketogenic diet in treating GLUT1 DS, it has been suggested that long-term effects of the diet such as atherosclerosis and growth impairment should be monitored with care Other Possible Therapies There are reports of successful use of the modified Atkins diet in a handful of GLUT1 DS patients, and there is a report of successful introduction of a medium-chain triglyceride diet in one patient However, no reports exist documenting the use of the low glycemic index treatment in treating GLUT1 DS. 9 The modified Atkins diet is less ketone-inducing than the ketogenic diet, but more ketone-inducing than the low glycemic index diet. It is not yet clear whether a higher ketogenic ratio is more effective in GLUT1 DS treatment. 9 Other potential strategies for treatment include increasing the expression / mobilization of the GLUT1 transporter proteins or stimulating the insulin cascade; use of acetezolamide (for treating seizures); chaperone gene therapy; blocking degradation of the GLUT1 transporter protein; reading through a GLUT1 gene mutation to prevent the mutation from prematurely stopping the process of making proteins; and inserting a new GLUT1 gene through gene therapy. Some of these strategies are undergoing study in other disorders, and if found useful, might possibly be of use in the treatment of GLUT1 DS Long-Term Studies Due to the small number of patients currently diagnosed with GLUT1 DS and the relative short amount of time since the discovery of this disorder, there is a dirth of long-term studies of GLUT1 DS patients treated by dietary therapies. One 2-to 5-year follow up study of 15 children diagnosed with the disorder and treated with the ketogenic diet found effective seizure control and limited adverse affects for most patients. Also, parental ratings of the effects of the diet were higher than for refractory childhood epilepsy. 7 4

4 3. Diagnostic tests Diagnostic tools for GLUT1 DS include those summarized in Table 2 9 below. Table 2. Diagnostic Tools for GLUT1 DS Absolute concentration of cerebral spinal fluid (CSF) glucose Ratio of absolute CSF glucose to blood glucose Molecular analysis of the SLC2A1 gene Red blood cell (RBC) assay Electroencephalogram (EEG) recordings in both the fasted and postprandial states Position emission tomography (PET) scans 3.1. CSF Glucose CSF glucose levels are obtained through performing a lumbar puncture. The CSF glucose concentration can then be determined, or the ratio of CSF glucose to blood glucose may be evaluated. According to a recent publication targeted toward clinical practice, low glucose concentration in the cerebrospinal fluid (hypoglycorrhachia), defined by Rotstein and De Vivo in 2010 as < 2.2 mmol/l (< 40 mg/dl) represents the diagnostic gold standard for GLUT1 DS. 9 However, it has been reported that 9% of GLUT1 DS patients have a CSF absolute glucose level between mg/dl. 2 A few others have debatable hypoglycorrhachia. 2 Furthermore, controversy exists around evaluating CSF levels Ratio of absolute CSF glucose to blood glucose In the first report by De Vivo et al. describing GLUT1 DS, the normal ratio of CSF glucose to blood glucose was given as According to a recent article, the ratio should be <0.45 for patients with GLUT1 DS. 9 Whether the ratio of CSF glucose to blood glucose is a superior diagnostic tool to evaluation of absolute levels of glucose in CSF is controversial. Some consider the CSF glucose:blood glucose ratio a biomarker that is less reliable, 22 while others maintain it is superior to evaluating absolute CSF glucose concentration Molecular Analysis of the SLC2A1 Gene Molecular analysis of the SLC2A1 gene for pathogenic mutations has been suggested as another gold standard diagnostic test. If the outcome of the testing is negative, multiplex ligationdependent probe and SNP oligonucleotide microray analysis are additional techniques that can be used to find deletions and duplications in the SLC2A1 gene. 9 Searching the SLC2A1 gene for mutations may help diagnose GLUT1 DS patients, especially for patients without clear hypoglycorrhachia. However, it should be repeated that 20-30% of patients do not have genetic mutations in the SLC2A1 gene Red Blood Cell (RBC) assay The RBC assay test consists of glucose uptake studies in red blood cells (erythrocytes). The GLUT1 transporter is highly expressed in erythrocytes, constituting 3-5% of all erythrocyte proteins. 3 It is reported to be a more sensitive test than genetic analysis, and has been suggested as another gold standard diagnostic test. 2 However, the RBC assay has given false-negative reports in some patients who do have pathogenic mutations in the SLC2A1 gene. It is also not commercially available Electroencephalogram (EEG) An EEG, which measures and records electrical activity in the brain, may show abnormal activity for fasted GLUT1 DS patients with improvements after the patients eat. This pre- and postprandial effect may indicate a GLUT1 transporter defect. 9 5

5 3.6 Position emission tomography (PET) scans PET scans are useful in that they may show a metabolic footprint that is characteristic of GLUT1 DS. However, limitations include availability; limited reference values in young children; sedation; and radiation exposure Summary of Tools In summary, benefits and drawbacks exist for each tool, and for some tools, controversy exists over evaluating outcomes. 9 Additionally, there is a lack of universal agreement on ranking the tools for diagnosis in terms of superiority, and in terms of gold standard status. The lumbar puncture, SLC2A1 analysis, and the RBC assay have been suggested as gold standards. 9 It has also been suggested, however, that relying on only one method or tool runs the risk of false negative results, especially in certain phenotypes. 9 For patients who do not show a pathogenic SLC2A1 mutation and do not have clear hypoglycorhachia, it has been recommended that suspecting GLUT1 DS and initiating a ketogenic diet appears adequate. A positive or negative response to the diet may support or undermine the diagnosis, respectively Nutritional relevancy The nutritional relevancy of GLUT1 DS is vast. As stated earlier, the literature agrees that the ketogenic diet is the current treatment of choice. 11 The mechanisms behind how the ketogenic diet and the alternative ketogenic diets work in treating refractory childhood epilepsy is not yet understood. In both the ketogenic and alternative ketogenic diets, as well as in times of fasting, the metabolism of the body shifts from using glucose as a primary fuel source to using ketones for fuel. Ketones, namely acetoacetate, β-hydroxybutyrate, and acetone, are produced in the liver predominantly from fatty acids through fatty acid metabolism. 23 From the liver, the ketones travel to the brain, where they are metabolized for energy. Interestingly, the brain cannot metabolize fatty acids, the precursor of ketones. Therefore, it is only through ketones that the brain is able to tap the body s fat stores in times of fasting, 23 or use fats for fuel when a high-fat diet is consumed as is the case for GLUT1 DS patients. In the treatment of GLUT1 DS, the ketones produced serve to provide an alternative fuel source to the glucose-starved brain. The anticonvulsant actions of the diets may also support the effectiveness of the treatment. 17 Additionally, the need to rely solely on GLUT1 transporters to supply fuel for the brain is negated for patients on ketone-inducing diets. Ketones enter the brain through another route, a monocarboxylic acid transporter (MCT1) Diet Therapy 5.1 The Ketogenic Diet Used as a medical nutritional therapy for over 90 years, the ketogenic diet was introduced as a treatment for epilepsy in the 1920 s, although the diet fell out of favor for a number of years due to discovery of antiepileptic drugs. 24 The diet has seen a resurgence of use and scientific interest in the last approximately 18 years due to increased media attention from the film First Do No Harm (1997), as well as publicity and funding for research and education from the Charlie Foundation. 24 Over time, hundreds of studies, including evidence from randomized, controlled trials and meta-analyses have shown that approximately 50% of children treated with the ketogenic diet will see at least a 50% reduction in seizures. 25 6

6 5.1.a The Basics of the Ketogenic Diet As mentioned earlier, the ketogenic diet is a high fat, low carbohydrate diet in a 4:1 (most common, with 90% of calories from fat) or 3:1 ratio. It should be noted that a 4:1 ratio is contraindicated in infants altogether due to protein requirements for growth. 9 Used primarily in children, the diet is usually initiated over several days through an inpatient hospital admission with foods weighed on gram scales. During the hospital stay, the diet is advanced to the appropriate ratio Calorie restriction is no longer considered an essential component of the ketogenic diet, 25 and many centers no longer restrict fluids on the diet, due to concerns surrounding possible nephrolithiasis. 28 Ketogenic diet patients do need micronutrient supplementation in the form of vitamins and minerals. Although outpatient initiation of the ketogenic diet has been reported to be safe, the majority of institutions employ the hospital stay as the means to implement the diet. This is due to the need to closely monitor patients and offer intense education to parents. 25 Furthermore, all medications for patients must be compounded to be carbohydrate-free. 25 Initial fasting to produce the ketosis state prior to diet initiation may or may not be used as part of the protocol, as some data indicate it is not necessary to achieve ketosis. 27 The timing for when the ketogenic diet is discontinued is often determined on an individualized basis. Most families are encouraged to try the ketogenic diet for at least 3 months. In children with >50% seizure response, the diet is often discontinued after 2 years. For children with near-complete seizure control (>90%), and who do not experience many side effects, a ketogenic diet duration for as long as 6-12 years has been reported to be helpful. GLUT1 DS patients may also need a longer diet duration. 27 For pediatric GLUT1 DS patients, it is recommended that the ketogenic diet be continued until adolescence b Additional Guidelines for the Ketogenic Diet In practical terms for therapy, the American Dietetic Association does not currently have position papers, nor has published evidence-based guidelines for the use of the ketogenic diet. However, the diet as developed for medical use follows a protocol including the features outlined above. The pre-initiation steps of counseling; nutritional evaluation; laboratory evaluation; and ancillary testing (optional) should be initiated for all patients prior to beginning the diet, according to a list from the 2009 International Consensus Statement from the International Ketogenic Diet Study Group, updated and modified in a recent 2011 review. 25 Practitioners must also be aware of possible short- and long-term effects of the diet. These are listed in Table 3 25 below. Table 3. Possible Short- and Long-Term Adverse Effects of the Ketogenic Diet Possible Immediate, Short-Term Adverse Effects Possible Long-term Adverse Effects Acidosis Bone fractures Constipation Decreased bone mineral density Exacerbation of gastroesophageal reflux disease Dyslipidemia Excessive ketosis Kidney stones Fatigue Poor linear growth Food refusal Secondary carnitine deficiency Hypoglycemia Vitamin D deficiency Increased seizure frequency Weight loss (or insufficient weight gain) Vomiting ~ 7

7 Despite possibilities of adverse effects, many complications of the diet are preventable and can be dealt with through outpatient care. Dietary support throughout the therapy is essential, and if the therapy is discontinued, the diet should be gradually tapered through reducing the fat:carbohydrate and protein ratio over a number of weeks or months. 25 Some contraindications for the ketogenic diet do exist. Screening for the deficiencies and conditions listed in Table 4 25 below becomes important for the patient who is suspected to have an inborn error of metabolism. As the ketogenic diet relies on mitochondrial fatty acid metabolism, a possibly fatal metabolic crises could occur in a patient not metabolically able to tolerate the diet. 25 Table 4. Contraindications for Use of the Ketogenic Diet Primary carnitine deficiency Carnitine palmitol transferase I or II deficiency Carnitine translocase deficiency Beta-oxidation defects Pyruvate carboxylase deficiency Porphyria 5.1.c The Ketogenic Diet, GLUT1 DS, and Absence Epilepsy While the efficacy of the ketogenic diet for GLUT1 DS patients is established, 9 some research involving the ketogenic diet has focused on absence seizures, or absence epilepsy, in particular. As cited earlier, one review has concluded that intractable absence epilepsy does appear to be effectively treated through both the ketogenic diet and the modified Atkins diet. This finding was upon review of 17 published studies in which subpopulations included absence epilepsy. 29 Additionally, a possible relationship may exist linking GLUT1 DS to refractory absence seizures in children. Byrne et al. suggested that GLUT1 DS may be causal to these seizures in a case study involving two patients. 30 As mentioned earlier, any form of intractable epilepsy, in particular early onset absence epilepsy, is one of the phenotypes that should alert practitioners to suspect GLUT1 DS The Modified Atkins Diet While the ketogenic diet has enjoyed some notoriety in recent years and is therefore more well-known, the modified Atkins diet may demand more of an introduction. The modified Atkins diet is now recognized as another ketone-based dietary intervention for intractable epilepsy and was first piloted at Johns Hopkins Hospital in The diet was developed for the purpose of producing a similar reductive effect on seizure control as the ketogenic diet, but with a less restrictive dietary protocol. Implementation of the diet, while still challenging, is clearly less rigid than the ketogenic diet and therefore an alternative for families who face obstacles in implementing and sustaining a traditional ketogenic diet. 25 Alternative ketogenic diets may also be beneficial and offer practicality for adults, as adults do reach adequate ketosis on the ketogenic diet, but find the therapy very difficult to maintain. 9 The first formal modified Atkins diet pediatric trial, published in 2006, was a prospective study of the efficacy of the diet in 20 children experiencing daily seizures resistant to control by at least 2 anticonvulsant medications. 31 The outcome of this study was >50% seizure improvement in 65% (13) of the participants and >90% seizure improvement in 35% (4 patients became seizure free). 32 Since this time, a number of prospective and retrospective studies have been conducted documenting the efficacy of the modified Atkins diet in both in children and adults, showing a similar effect on seizure reduction to the traditional ketogenic diet. 33 8

8 5.2.a The Basics of the Modified Atkins Diet The modified Atkins diet developed at Johns Hopkins Hospital consists of a 1:1 (fat : protein and carbohydrate) ratio initiated on an out-patient basis. 33 Protein, calories, and fluids are unrestricted. 28 The Atkins diet, which is a low-carbohydrate diet designed for weight loss, forms the foundation for the modified diet version. The differences between the original Atkins diet and the modified Atkins diet currently used as a therapy are outlined in Table 5 26 below. Table 5. Differences Between the Atkins and Modified Atkins Diets Atkins Diet Modified Atkins Diet (MAD) High fat foods are allowed High fat foods are strongly encouraged Carbohydrates limited to 20 grams / day for first two weeks Carbohydrates are limited to grams / day for an indefinite period Weight loss is the goal Weight loss is not the goal The classic protocol for the modified Atkins diet developed at Johns Hopkins Hospital is clearly defined and delineated as outlined in Table 6 26 below. Initially, carbohydrates for children are limited to 10 grams/day during the first month, with increases of first 15 grams, then grams/day as tolerated. Table 6. Modified Atkins Diet Protocol (Johns Hopkins Hospital) Month 1 Month 2 + Baseline CMP, CBC and lipid profile grams of carbohydrate per day Send a 2-day food record before starting No need to check ketones regularly once Go shopping (and online surfing) per week is ok Take a multivitamin and calcium Check weight weekly 10 grams of any carbohydrates per day Can reduce medications if desired --15 g/day for teens, 20 g/day for adults Start using low-carbohydrate store Eat lots of high fat foods, and plenty of products if desired carbohydrate-free foods Complete follow up visit and lab work at Check ketones twice weekly; check weight 3-4 months if diet is helping weekly Usually after 2 years, will attempt to wean Leave medications unchanged the diet --not necessarily true for teens Avoid low-carbohydrate store products in and adults the first month Call keto team in one month for update 5.2.b Additional Guidelines for the Modified Atkins Diet In practical terms for use as diet therapy, similar to the ketogenic diet, the American Dietetic Association currently does not have position papers, nor has published evidence-based guidelines for the implementation of the modified Atkins diet. However, the steps of counseling, nutritional evaluation, laboratory evaluation, and ancillary testing (optional) are not only recommended prior to initiating the ketogenic diet, but should be completed prior to all dietary therapies for epilepsy. 25 Like the ketogenic diet, the modified Atkins diet requires the patient s medications to be compounded to be carbohydrate-free. While hospital admission is not routine for initiation of the modified Atkins diet, practitioners must still be aware of the same possible short-term and long-term adverse affects of a ketone-based diet therapy; these are the same as for the ketogenic diet, as listed in Table 3 above. As with the ketogenic diet, many complications are preventable, and can be dealt with through outpatient care. Dietary support throughout the therapy is still essential, and if the therapy is discontinued, like the ketogenic diet, the modified 9

9 Atkins diet should be gradually tapered through reducing the fat: carbohydrate and protein ratio over a number of weeks or months. 25 The same contraindications for the ketogenic diet listed in Table 4 above may also apply to the modified Atkins diet. Again, screening must take place to rule these diseases and deficiencies out prior to the diet initiation. 5.2.c The Modified Atkins Diet, GLUT1 DS, and Absence Epilepsy As mentioned earlier, recent studies have highlighted the potential for seizure control with the modified Atkins diet for both GLUT1 DS patients as well as for patients with absence epilepsy. In 2008, Ito et al. published a case study documenting effectiveness of the diet in reducing symptoms in a pediatric GLUT1 DS patient. 18 Epileptic seizures and paroxysmal events also decreased in a group of six Japanese males with early-onset epilepsy diagnosed with GLUT1 DS when treated with the modified Atkins diet in a 2011 prospective study. 19 According to recent case report, another GLUT1 DS patient s paroxysmal events with reduced consciousness resolved after several months of modified Atkins diet therapy. 34 Additionally, in January 2011, Groomes et al. published a review that was the first of its kind to report the outcome of dietary therapy for idiopathic generalized epilepsy, and absence epilepsy specifically. The authors concluded that intractable absence epilepsy does appear to be effectively treated through both the ketogenic and modified Atkins diets. This was determined upon review of 17 published studies in which subpopulations included absence epilepsy. 29 No randomized controlled trial has been conducted for patient treatment with the modified Atkins diet, and questions around the long-term efficacy and side effects of this diet remain. 35 However, the diet has clearly established itself as a potentially beneficial alternative diet for the treatment of intractable epilepsy, absence epilepsy specifically, and GLUT1 DS. 5.3 The Medium-Chain Triglyceride Diet The medium-chain triglyceride diet was introduced in 1971 and created to make the ketogenic diet more palatable. 24 The diet uses medium-chain triglyceride oil as an alternative fat source. Medium chain triglycerides, in contrast to the long chain triglycerides in the ketogenic diet, yield more ketones per calorie and are absorbed more efficiently than the long-chain fatty acids the ketogenic diet provides. In the medium-chain triglyceride diet, ratios are not employed; rather a percentage of daily total calories come from fat, carbohydrate, and protein. 36 Because of the added potential for ketosis the medium-chain triglycerides in this diet have, less total fat is needed in the meal plans, and more carbohydrate and protein can be consumed. 37 As mentioned earlier, very little data is available for the use of the medium-chain triglyceride diet in GLUT1 DS patients. However, the diet has been shown to be an effective method for treating intractable epilepsy, 37 and evidence from a randomized-controlled trial further confirmed the diet s efficacy in treating drug-resistant childhood epilepsy The Low Glycemic Index Treatment The Low Glycemic Index Treatment was first reported as a treatment used for epilepsy in 2005, although it had been used as an epilepsy treatment prior to that date. 38 The diet consists of 60-70% lipids, 20-30% protein, and 10% carbohydrate. Carbohydrates are limited to grams a day. All carbohydrates are low glycemic index (Glycemic Index (GI) <50). The glycemic index refers to a measurement of how much a food tends to raise blood glucose levels compared to an equal amount of reference carbohydrate. 39 The thrust of the low glycemic index treatment is to limit foods that contain carbohydrates to those with a low impact on blood glucose, thus keeping blood glucose concentrations stable. The stabilization of blood sugar is one of the theories behind the efficacy of the ketogenic diet. 40 While the low glycemic index 10

10 treatment has not been used as a treatment for patients with GLUT1 DS, 9 a handful of studies have shown benefit for some patients with refractory epilepsy syndromes Summarizing Diet Therapy In summary, the ketogenic diet, modified Atkins diet, and medium chain triglyceride diet have been used with success in treating GLUT1 DS patients. Although the ketogenic diet is the therapy of choice, it has also been suggested that the patient s age should be considered when choosing between diet therapies, 9 likely due to issues with compliance and ability to maintain the ketogenic diet. Figure 1 9 below illustrates a type of decision tree published in a recent article addressing GLUT1 DS in clinical practice. This figure outlines not only a diagnostic approach to the disorder based on the three suggested gold standard diagnostic tests discussed above, but also serves as a guide that may be used when determining what diet to choose based on patients ages. Figure Case Study In this case study, an adolescent female patient diagnosed with intractable generalized epilepsy and absence seizures is discussed. To date, the patient has been suspected of but is undiagnosed with GLUT1 DS. She received both the modified Atkins diet and 3:1 ketogenic diet as dietary therapies at different times at the University of North Carolina Hospitals Child Neurology Clinic. In summary, during her treatment at UNCH, the patient s seizures continued at varying degrees during treatment with the modified Atkins diet but were fully controlled with the 3:1 ketogenic diet at 1 month follow up. 11

11 6.1 Description of Patient, Family Medical History The case study concerns a now 11 year, 11 month-old female born 12/29/1999 with a history of intractable seizures. The patient first came to UNCH in December of In terms of the patient s pertinent family medical history, she was the offspring of non-blood-related parents. She had a family history of afebrile seizures; fainting spells; migraine; slow development; learning difficulties; death in infancy or childhood; and kidney disease in childhood of one or more non-first degree relatives (meaning relatives other than a parent, a child, or a sibling). The patient s mother had a birth defect (unspecified), and both the mother and the patient s full sibling had attention deficit disorder. The patient also had 2 paternal aunts with a history of childhood epilepsy which remitted in adolescence, both of whom had intellectual limitations. A maternal aunt had Turner syndrome. It is unclear in the medical record which if any of the above features in the family medical history apply to or were generated by one or more of the patient s aunts. The patient s past medical history below covers what is known of the patient from birth until her first appointment with a dietitian through the UNCH Child Neurology Clinic in June Patient Medical History The patient s perinatal history was unremarkable. She was born at 42 weeks gestation, with a birth weight of 9 lbs and 1 oz. The onset of what her record refers to as drop attacks began at 2 years old. She would fall while standing or sitting, but would then return to a normal state immediately afterward. At an unspecified time in the medical record, but before the age of 4 years, the patient began Topamax for her seizures. Topamax controlled her drop attacks, but episodes of eye deviation with altered awareness continued. It is not clear from the patient s record when these episodes first began. In 2004, the Topamax was switched to Lamictal. However, as a full dose of Lamictal was approached, the patient suffered increased unspecified episodes and had drop attacks. Following this, Depakote and the modified Atkins diet were started simultaneously at an unspecified date in Three days post-initiation of the modified Atkins diet, seizure activity ceased. Depakote was weaned, and the diet continued for a year, with the patient remaining seizure-free. In 2005, over the next 6 months, the patient was transitioned off the diet, and seizure activity resumed. At this time, an attempt to re-start what is referred to in the medical record as the Atkins diet occurred. However, the patient was not compliant. Zarontin was prescribed, and was effective for a year. It was then felt that Zaronin was not working; Depakote was added and Zarontin weaned. However, the patient s seizures increased. Zarontin was then re-started, resulting in better seizure control. At age 6, both Depakote and Zarontin were weaned. Keppra was started unsuccessfully secondary to irritability and rage episodes. Vitamin B6 was recommended, but the disruptive behaviors only escalated. The patient was hospitalized in June of 2008 at the age of 8 for a 3 day video EEG, which showed absence seizures. The patient was discharged home on Depakote, but seizures were uncontrolled. She was hospitalized again in August of 2008 for initiation of a ketogenic diet at an unspecified ratio. It was noted the patient s mother was unhappy with the diet, which was described as liquid with heavy cream and soybean oil. The patient was then transitioned to what is referred to as the Atkins diet at an unspecified time. Again, it was noted the mother perceived a lack of support with the diet therapy. In December of 2009, the patient came to the UNCH Child Neurology Clinic for the first time seeking a second opinion on her seizures. She was a few weeks short of 10 years old, with 12

12 normal growth parameters of 50 th %tile for her weight, just above the 50 th % tile for her height, and between the 50 th and 70 th %tiles for her body mass index on the CDC chart for girls 2 to 20 years. The patient presented with absence seizures and another unspecified seizure type consisting of flailing arms or legs or head jerking when tired. The seizure description in the record seemed to be consistent with features of absence seizures, and notes that these seizures sometimes occurred first thing in the morning, and when the patient was tired and was hungry. Prescriptions included Depakote. The patient appeared to be following the Atkins or modified Atkins diet at this time. It was noted that the diet was not effective for the patient at that time. The visit outcome included increasing Depakote to 375 mg twice a day. The next clinic visit was in January The patient had experienced an initial improvement in seizure control but this was followed by an increase in absence seizures and occurrence of a drop attack. Over the prior several weeks, carbohydrate intake on the modified Atkins diet had increased. GABA supplementation at an unspecified dose had been introduced at home. The ketogenic diet and modified Atkins diets were discussed during this clinic visit, but a registered dietitian was not involved. It is noted the patient s mother wanted to continue the modified Atkins diet. Depakote was increased to 500 mg twice a day. Levocarnitine at 330 mg twice a day was added (in consideration of the modified Atkins diet and Depakote). In February 2010, the patient s anthropometric data per the CDC chart for girls 2 to 20 years were normal. Labs were drawn, showing normal biochemical measurements except for elevated AST, ALT, and BUN. The patient showed some improvement in seizure activity. Depakote and Levocarnitine were continued at 500 mg twice a day and 330 mg twice a day, respectively. 6.3 In-Depth Overview of Patient Timeline / Treatment Course In June 2010, the patient was first seen by a registered dietitian through the UNC Child Neurology Clinic. She saw a dietitian again in July 2011, and again in August What follows is an in-depth overview of the information related to the patient s medical course and the nutrition interventions that occurred for her over this time period, from June 2010 to August Finally, Table 7 below documents the patient s medical and nutritional course from birth until the present, with outcomes. Following the February 2010 clinic appointment, the patient was seen again in June 2010 at UNCH. During this visit, the patient s anthropometric data were as follows: weight for age was between the 50 th and 75 th %tiles; height for age was between the 50 th and 75 th %tiles, and BMI was between the 50 th and 75 th %tiles on the CDC growth chart for girls 2 to 20 years of age. All lab work was within normal limits except for urea nitrogen (High: 23 mg/dl; reference range: 5-17 mg/dl); aspartate aminotransferase (AST) (High at 50 U/L; reference range: U/L); and alanine aminotransferase (ALT) (High at 31 U/L; reference range: U/L). The patient presented with reduced seizure activity. She was also following a version of the modified Atkins diet, with no sugar, and carbohydrates limited to about 45 grams per day. The patient s mother was referred to a dietitian during the clinic visit to discuss the modified Atkins diet and the ketogenic diet. Depakote 500 mg twice daily and Levocarnitine 330 mg twice daily were continued, along with a GABA supplement Upon review, the nutrition assessment performed at this clinic visit noted the patient became hungry frequently and would become upset if she were not fed, according to her mother s report. An apparent decision was made continue the modified Atkins diet until the end of that summer, and then progress into the ketogenic diet if necessary. 13

13 The dietitian determined the patient a candidate for diet therapy based on 1) willingness of the patient; 2) the knowledge base of the patient and caregiver about the diet; and 3) food preferences. The nutrition diagnosis for the patient at this time was Food and nutrition knowledge deficits related to ketogenic diet nutrient requirements as evidenced by diet recall. Goals for the patient included: 1) Induce and maintain moderate ketosis (unclear reference range); 2) Meet calorie and protein needs for growth and development; 3) Actual nutrient requirements to be taken in: 40 kcals/kg, 0.95 grams of protein/kg, and grams of carbohydrate per day, along with 1.5 liters of free water a day. The nutrition intervention was the modified Atkins diet at grams a day, education and counseling (including, importantly, principles of modified Atkins therapy; potential side effects; home monitoring practices for ketones; meal plans; food measuring; carbohydrate sources; sick day management; and specialty products to purchase), a multivitamin, a suggestion of adding MCT oil to foods to increase ketosis, and finally, a follow up at the UNC Child Neurology clinic in 6 months. The nutrition education included printed material and a carbohydrate source book to take home. The next nutrition appointment the patient had at UNCH was in July 2011, although other UNCH Child Neurology Clinic appointments occurred before this date. In October 2010, the patient came in for a follow up appointment at the UNC Child Neurology Clinic. No specific anthropometric data is available for this visit; however, growth was noted to be within normal parameters. No lab work was completed at this time. Status of seizures was unchanged since the last clinic appointment. However, it is documented that the control of the seizures was improved; since the last visit, the patient experienced a stint of seizure control for 3 weeks. It appears Depakote 500 mg twice a day and Levocarnitine 330 mg twice daily were continued as ordered from prior visits. The patient s next follow up visit occurred in May Anthropometric data were as follows: weight for age between the 50 th and 75 th %tiles; height for age between the 50 th and 75 th %tiles; and BMI between the 50 th and 75 th %tiles on the CDC growth chart for girls 2 to 20 years of age. Vitamin D levels were included in the ordered labs due to the patient occasionally receiving a vitamin D supplement of 2,000 international units at home. All lab work, including Vitamin D, was within normal limits. The patient presented with increased absence seizures, occurring every day, in clusters, usually in the afternoon around lunchtime. It was noted the seizure clusters often occurred after the patient complained of hunger; at lunchtime, the patient seemed to be ravenous. It was noted the patient s mother felt better seizure control occurred if the patient were fed frequently. It is also noted the patient was following the modified Atkins diet at this time, although not closely. Because of the patient craving food prior to seizures a lumbar puncture was suggested to rule out GLUT1 DS. Nutrition was consulted, and a dietitian contacted the patient s mother via telephone to discuss the ketogenic diet therapy for seizure control and possible GLUT1 DS. The dietitian discussed the basics of ketogenic diet therapy and home monitoring. It appears that the patient s Depakote prescription of 500 mg twice a day and Levocarnitine at 330 mg twice daily were continued as ordered from prior visits. In July 2011, the patient was admitted to UNC Hospitals to start the ketogenic diet and undergo a lumbar puncture. Anthropometric data for the patient were as follows: weight for age was between the 50 th and 75 th %tiles; height for age was just under the 50 th %tile; and BMI was between the 50 th and 75 th %tiles on the CDC growth chart for girls 2 to 20 years of age. Labs conducted during the hospital stay were within normal limits except for the following obtained 14

14 from blood chemistry and a lumbar puncture: cerebral spinal fluid (CSF) protein (Low at < 10 mg/dl; reference range: mg/dl); CSF glucose (Low at 39 mg/dl; reference range: mg/dl); red cell distribution width (Low at 11.7%; reference range: %); absolute neutrophils (Low at 1.4 x 10 9 th /L; reference range: x 10 9 th /L); and cholesterol (High at 183 mg/dl; reference range: mg/dl). At this time of the hospital admission, the patient was 11 years old, and having multiple absence seizures daily. For evaluating GLUT1 DS, it appears that the ratio of CSF glucose to blood glucose was the diagnostic tool used. The record states the patient s CSF glucose was 48% of her serum glucose and well above the cut-off mark of 33% used as a diagnostic marker of GLUT1 DS. It was felt that this outcome made the diagnosis of GLUT1 DS very unlikely. It appears that the patient s Depakote prescription of 500 mg twice a day and Levocarnitine at 330 mg twice daily were re-ordered at this time. Also, Melatonin at 3 mg once daily was added. During the hospital stay, fluid, electrolyte, and nutrition orders were deferred to the ketogenic diet. The dietitian covering the ketogenic service initiated the diet at a 1:1 ratio and advanced to a 3:1 ratio. The nutrition assessment charted normal anthropometric measurements for the patient per the CDC growth chart for girls 2 to 20 years old. It was noted that the patient was having 1 cluster of 7-8 seizures every day, often when she was hungry. Also, it was noted that the patient had been on the modified Atkins diet at home for the past few years, but that the fat intake had been low and carbohydrates had been moderate. Furthermore, it was charted that the patient would need multivitamin supplementation and additional vitamin D and calcium on the 3:1 ketogenic diet in order to meet micronutrient recommendations. The nutrition diagnosis for this visit was Food and nutrition related knowledge deficit related to the ketogenic diet, as evidenced by admission for diet therapy. Therefore, the basis for the interventions was to change this knowledge deficit. Specifically, nutrition interventions were to initiate the ketogenic diet at a 1:1 ratio and advance to a 3:1 ratio; to supplement multivitamins, calcium, and vitamin D; and to provide recipes, ketocalculator instruction, and diet education. Monitoring and evaluation were key during this inpatient admission. The dietitian assigned a high risk level to the patient, meaning the patient was followed closely. A follow up date for 1 month out was charted. During the admission, the patient had no problems with the initiation of the ketogenic diet. No emesis was reported. Prior to discharge, the dietitian provided ketogenic recipes, recommendations for vitamins and minerals, and answered all diet questions. The final follow up date available for this patient at the time the medical record was researched was August However, the dietitian did speak on the phone to the patient s mother prior to this visit, in early August, to provide some resources related to the ketogenic diet. At the time of the call the mother stated the diet was going very well, and did not have further questions. During the August clinic visit, the patient s anthropometrics were as follows: weight for age was between the 25 th and 50 th %tiles; height for age was at the 50 th %tile; and BMI was between the 25 th and 50 th %tiles on the CDC growth chart for girls 2 to 20 years of age. All lab work was normal, except for uric acid (High at 5.9 mg/dl; reference range: mg/dl), and beta-hydroxybutyrate (High at 2.9 mmol/l (reference range: <0.4 mmol/l). At this time, the patient was seizure free and had not experienced seizures since hospital discharge. Weaning of Depakote was taking place independently at home, with seizure control. At the clinic visit, the patient was taking 250 mg in the morning, and 375 mg in the evening. Weaning down Depakote was approved with the injunction to watch the patient closely for seizures. It appears that the patient s Depakote prescription of 500 mg twice a day and Levocarnitine at 330 mg twice daily were renewed as ordered from prior visits, regardless. 15

15 At this time, it was noted that the patient s absolute CSF glucose level lab during her July 2011 hospital stay was 39 mg/dl, and at around the same time, her serum glucose was 96 mg/dl, which was noted to be somewhat of a variation in the values. A genetic test for mutations in the SLC2A1 gene causing GLUT1 DS was ordered; test results came back several weeks later as having identified a heterozygous missense change mutation, unclassified variant, in the gene. The test was deemed to not have sufficient information to definitely classify the variant as a disease-causing mutation or a benign variant. The results neither confirmed nor ruled out the diagnosis in the patient. Nutrition was also consulted and the patient saw a dietitian on the ketogenic service. The patient complained of an occasional headache and abdominal pain, but these had not been significant. She had experienced few occurrences of emesis, but only when the patient was staying overnight away from home. It was noted the patient s mother was happy with the diet therapy and the dietitian support; in addition, ketocalculator, an online computer program to make meals in ketogenic ratios, was in use at home. According to the nutrition assessment, the ketogenic diet 3:1 ratio appeared to be appropriate to continue. The lack of seizures since the patient had been discharged from the hospital after the diet initiation was noted. The dietitian discussed the fact that the patient had maintained her weight within 1 kilogram since approximately a month prior, and although the patient s BMI had dropped slightly, this was likely due to the 1 kg loss the patient had experienced. It was noted that the patient s weight would be monitored at the next follow up visit for the need to increase her total calories if needed, and that the patient was receiving 3 meals and 2 snacks a day, providing a total of total kcals; 41 grams of protein per kilogram of weight; and 2.3 grams of carbohydrates. The patient was also taking a multivitamin/multimineral, and 2 pills a day of 630 mg calcium citrate with 400 international units of Vitamin D. The nutrition goals for this patient at this time were 1) Previous inpatient goals: 3:1 ketogenic diet; 2) 1350 kcals a day for 3 meals and 2,200 kcal snacks if patient is still hungry; 3) Progress toward meeting goals: meeting; and 4) Revised goals: none continue initial goals. The nutrition interventions for this patient were to continue the ketogenic diet in the 3:1 ratio, and a statement that the dietitian would follow up with the patient at the next UNC Child Neurology Clinic appointment in 3 months. Evaluation and monitoring were therefore ongoing for this patient. The plan was for the patient to continue on the 3:1 ketogenic diet, and return to the UNC Child Neurology Clinic in 3 months. Table 7 below documents the patient s medical and nutritional course from birth until the present, with outcomes. 16