- One in 90,000 people are born with Glut 1 DS
- Prevalence is as many as 7,000 people in the United States
- Seizures are most common clinical characteristic
- Movement disorders and cognitive impairment are also common
- Ketogenic diet has proven an effective treatment
- A clinical study is under way to investigate potential of triheptanoin, a specially designed compound, as a treatment
Glucose Transporter Type 1 Deficiency Syndrome (Glut1 DS) is a rare disease with an estimated birth incidence of 1 in 90,000 (Coman, 2006). This birth incidence translates to an estimated prevalence of 3,000 to 7,000 in the U.S. Glut1 DS is a debilitating disease characterized by seizures, movement disorders and developmental delay (Pearson, 2013).
Glut1 DS is caused by a mutation in solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1), which encodes the Glut1 protein responsible for transporting glucose across the blood-brain barrier. Glucose is a carbohydrate that provides a ubiquitous energy supply to the body and is the principal fuel source for the brain. The decreased availability of glucose, as a result of the deficit to the fundamental glucose transport system across the blood-brain barrier, leads to a chronic state of energy deficiency in the brain and the manifestation of Glut1 DS.
Glut1 DS: Clinical Features
Seizures are the most common clinical characteristic of Glut 1 DS. In a comprehensive review of 87 individuals with Glut1 DS, approximately 90% experienced epilepsy defined as at least two unprovoked seizures, separated by 24 hours. The seizure type and frequency was varied with generalized tonic-clonic and absence seizures being the most commonly recorded. Other seizure types reported in Glut1 DS included complex partial, myoclonic, drop, tonic, simple partial and spasms (Pong, 2012).
In addition to seizures, most individuals affected with Glut1 DS experience movement disorders including spasticity, ataxia, chorea and dystonia. A detailed description of the movement disorder associated with Glut1 DS is provided by Pons et al (2010). The majority of subjects exhibit some kind of gait disturbance which varies in severity from mild ataxia to a spastic gait and inhibition of independent walking ability. Additionally, paroxysmal exertional dyskinesias are often observed within the Glut1 DS population.
Cognitive impairment is another common clinical feature of Glut1 DS. Deficits have been reported that range from mild learning disability to severe intellectual dysfunction (Pearson, 2013). Reports of intellectual impairment span the spectrum of mental retardation ranging from mild to moderate to severe. Delays in language skills are also observed within the Glut1 DS patient population with both receptive and expressive speech affected.
The primary neurological features of Glut1 DS, seizures, movement disorders and cognitive impairment, may occur either alone or in combination and in varying degrees. A systematic literature review (Leen, 2014) classified Glut1 DS subjects into three main categories: 1) the classic complex phenotype with intellectual disability in combination with epilepsy or movement disorder, 2) an epilepsy dominant phenotype with a paroxysmal movement disorder such as paroxysmal exercise-induced dyskinesia (PED) without intellectual disability, and 3) movement disorder dominant phenotype, mostly PED, without epilepsy and without intellectual disability. Since the initial discovery of Glut1 DS more than 20 years ago, many studies have been conducted in affected individuals from infancy to adulthood. The results of these studies suggest that, while epilepsy is the defining feature of the disease in childhood, seizures appear to attenuate or even disappear in the adolescent years. The cognitive impairment observed in childhood remains and movement disorders observed in those early years may progress to more significant mobility impairment. Movement disorders may also arise in adolescence and adulthood.
While there are currently no approved medical treatments for Glut1 DS, the ketogenic diet is the current standard of care for the management of most Glut1 DS patients. The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate diet. The ketone bodies produced from this specialized diet offer an alternative source of energy for the starving brain and prevent the glucose-induced energy crisis that defines Glut1 DS.
Management of Glut1 DS with the ketogenic diet requires discipline and commitment. When prescribed, initiation of the ketogenic diet typically involves a brief hospital admission or outpatient clinic visits for three to four consecutive days, during which fasting is induced followed by a gradual introduction of the high fat diet. Ketone levels are checked daily to ensure ketosis is established. Adherence to the diet is monitored and maintained by regular clinic visits with a dietician and neurologist every three months for the first year and every six months thereafter. Establishing ketosis with the ketogenic diet requires the elimination of sugar from the diet, allows for minimal carbohydrate consumption, and limits the intake of fruits and vegetables.
The ketogenic diet has proven an effective treatment in the management of seizures associated with Glut1 DS (Pong, 2012 and Pearson, 2013) and there is a continued effort to understand any potential protective effect on the movement disorder and cognitive abilities of Glut1 DS subjects. However, nutritional deficits encountered with strict adherence to the diet and limited information on the long term side effects of the ketogenic diet, including the potential for elevated cholesterol and renal problems, remain a concern.
Modified versions of the ketogenic diet have been proposed as more lenient management options for Glut1 DS. These modified diets should be easier to maintain but the subsequent reduced fat to nonfat ratio results in significantly lower ketosis than that induced by the classic ketogenic diet. The potential benefit of the modified Atkins diet have been described in a small six patient study (Ito, 2011); however, additional studies are needed to better understand this diet as an alternative treatment strategy for Glut1 DS. Other less stringent diets with potential for Glut1 DS include medium chain triglyceride (MCT oil) diet and low glycemic index treatment diet.
Anti-epileptic drugs (AEDs) may also be prescribed to help manage the frequency and severity of seizures however there is evidence to suggest that Glut1 DS seizures are refractory to treatment with AEDs. The retrospective study conducted by Pong et al (2012) reported that only 7 out of 73 ( about 10%) subjects treated with more than one AED achieved seizure freedom.
The ketogenic diet remains the best available management option for Glut1 DS. However, compliance with this complex regimen is difficult and concern has been raised about the long-term impact of a high fat diet on cardiovascular and renal health. There is a need for alternative therapeutic options to address the clinical manifestations of Glut1 DS and improve the quality of life of those living with Glut1 DS.
Triheptanoin is a specially designed synthetic triglyceride compound of three, seven-carbon (C7) fatty acids intended to provide patients with the medium-length, odd-chain, fatty-acid heptanoate. Triheptanoin is metabolized rapidly in the gut to form a series of energy containing metabolites, including heptanoate, which is further metabolized to 4-carbon (C4) and 5-carbon (C5) ketone bodies. Ketone bodies cross the blood-brain-barrier via the monocarboxylate transporter, bypassing the deficient Glut1 transporter and providing alternative energy sources to the brain. The metabolites also have the ability to resupply intermediates of the tricarboxylic acid (TCA) cycle (i.e., anaplerosis). UX007 is a highly purified form of triheptanoin intended for oral administration that is under development as a substrate replacement therapy for the treatment of seizures associated with Glut1 DS. If improved energy sufficiency is achieved, triheptanoin may have the potential to improve other clinical problems including cognitive problems and movement disorders that are currently not well treated with the ketogenic diet. In particular, UX007 is proposed as an alternative treatment in patients who are not on, or not compliant with, a ketogenic diet.
A global, multi-center, Phase 2 randomized, double-blind, placebo-controlled, parallel-group study is currently underway to investigate the potential of triheptanoin as a treatment for Glut1 DS (www.clinicaltrials.gov_UX007_Glut1DS_Phase2: NCI reference NCT01993186). The study will enroll approximately 50 subjects who are currently experiencing seizures and are either not being managed with a ketogenic diet or alternative high fat diet or not compliant with the regimen. Triheptanoin will be administered orally at least four times per day by mixing small amounts with food at mealtimes. The study is designed to investigate the safety and efficacy of triheptanoin compared to placebo and will evaluate the characteristic features of Glut1 DS including seizure frequency and motor and cognitive function.