What is Glut1 Deficiency?
Glucose Transporter Type 1 Deficiency Syndrome
also known as Glut1DS, G1D, De Vivo Disease
|
Glut1 Deficiency is a rare genetic condition that impairs brain metabolism. It is caused by a mutation in the SLC2A1 gene, which regulates the glucose transporter protein type 1 (Glut1). Glut1 is the principal transporter of glucose, the primary source of energy, across the blood-brain barrier. More than 100 different types of mutations and deletions of this gene have been found to date in Glut1 Deficiency patients.
Impaired glucose transport associated with Glut1 Deficiency creates a metabolic crisis in the brain and often results in seizures, speech and movement disorders, and developmental delays. Not all patients experience all symptoms, and there is a wide range of severity. Symptoms may change and evolve over time. The standard of care treatment is a ketogenic diet. This low carbohydrate, moderate protein, high fat diet causes the body to produce ketones, which are used as an energy source by the brain and other tissues when glucose is limited. The diet helps most patients with most symptoms, even in adulthood, but it is not a cure. A ketogenic diet also helps preserve brain growth and development, so early diagnosis and treatment is critical.
|
Symptoms
The hallmark symptoms of classical Glut1 Deficiency are seizures (approximately 90% of patients), a complex movement disorder, developmental delay and intellectual disability, and speech/language impairments. Not all patients experience all symptoms, and there is a great deal of variance across a wide spectrum in both the combination and severity of symptoms from one patient to another. Symptoms may also change and evolve over time as patients age.
Suggestive symptoms seen in many Glut1 Deficiency patients:
Other conditions sometimes diagnosed in patients with Glut1 Deficiency:
Suggestive symptoms seen in many Glut1 Deficiency patients:
- early onset absence seizures before the age of 3
- opsoclonus-like eye/head movements in first two years of life (aberrant gaze saccades or intermittent involuntary gaze)
- treatment resistant seizures/epilepsy at any age
- movement issues (often unique forms of ataxia, dystonia, chorea, tremor, gait abnormalities, and others)
- fluctuation of symptoms with hunger, fatigue, heat, illness, anxiety, excitement
- symptoms worse just after waking in the morning
- symptom improvement after eating
- paroxysmal neurological symptoms
(seizures, movement disturbances, hemiplegia episodes, headaches, energy levels, confusion, mood) - paroxysmal exercise-induced dystonia/dyskinesia (PED)
- developmental delays
- intellectual disabilities
Other conditions sometimes diagnosed in patients with Glut1 Deficiency:
- epilepsy
- cerebral palsy
- ataxia
- dystonia
- autism spectrum disorders
- hemolytic anemia
- ADD or ADHD
- alternating hemiplegia of childhood
- migraines
- microcephaly
Diagnosing Glut1 Deficiency
Lumbar Puncture:
When Glut1 Deficiency is suspected, glucose should be measured in the spinal fluid and in the blood simultaneously after a 4-6 hour fast. Blood samples should be drawn first to avoid stress-related hyperglycemia, and a lumbar puncture (spinal tap) should quickly follow.
Metabolic Hallmarks of Glut1 Deficiency:
Glucose Reference Ranges in Glut1 Deficiency:
Genetic Analysis:
Genetic testing can also help confirm the diagnosis by detecting a mutated SLC2A1 gene, although current testing doesn’t identify a mutation in 10-15% of patients. The combination of suggestive clinical symptoms and the characteristic CSF findings indicate a Glut1 Deficiency diagnosis, even in the absence of an identified SLC2A1 mutation.
Distinct patterns of brain glucose uptake on PET scans and specialized red blood cell uptake assays are also useful in the absence of an otherwise clear diagnosis but might be available in specialized centers only.
Dystonia 9 and 18 are associated with mutations in the SLC2A1 gene.
When Glut1 Deficiency is suspected, glucose should be measured in the spinal fluid and in the blood simultaneously after a 4-6 hour fast. Blood samples should be drawn first to avoid stress-related hyperglycemia, and a lumbar puncture (spinal tap) should quickly follow.
Metabolic Hallmarks of Glut1 Deficiency:
- low cerebrospinal fluid (CSF) glucose
- normal blood glucose
- normal cell counts
- normal CSF protein
- low to low-normal CSF lactate
Glucose Reference Ranges in Glut1 Deficiency:
- gender independent but age specific, falling at or below the 5th percentile
- fasting CSF glucose below 3.0 mmol/L or 53 mg/dl
- fasting CSF to blood glucose ratio below 60%
Genetic Analysis:
Genetic testing can also help confirm the diagnosis by detecting a mutated SLC2A1 gene, although current testing doesn’t identify a mutation in 10-15% of patients. The combination of suggestive clinical symptoms and the characteristic CSF findings indicate a Glut1 Deficiency diagnosis, even in the absence of an identified SLC2A1 mutation.
Distinct patterns of brain glucose uptake on PET scans and specialized red blood cell uptake assays are also useful in the absence of an otherwise clear diagnosis but might be available in specialized centers only.
Dystonia 9 and 18 are associated with mutations in the SLC2A1 gene.
Treatment
There is currently no cure for Glut1 Deficiency, but the recommended standard of care treatment is a medically supervised ketogenic diet, which can improve most symptoms for most patients, even in adulthood. A ketogenic diet is a high fat, moderate protein, low carbohydrate diet that provides alternative fuel to the brain with ketones instead of glucose. The earlier the diet is implemented, the better the outcomes for patients in improving seizure control, movement disorders, and cognitive abilities. Studies show that 4 out of 5 children who have epilepsy caused by Glut1 Deficiency will become seizure-free on dietary therapy.
In infancy and childhood, a classical 3:1 or 4:1 ketogenic is recommended to ensure the highest level of ketone energy to the meet the metabolic fuel demands of the developing brain. Although it is recommended to continue the classical ketogenic diet for as long as is tolerated by the patient, alternative ketogenic diet versions such as the Modified Ketogenic (2:1 and 1:1 ratios) or the Modified Atkins Diet may be more feasible for quality of life and compliance considerations and are often used by teenagers and adults.
All patients on a ketogenic diet should be under the care of an experienced dietitian and neurologist and have regular laboratory screenings to help monitor for potential side effects. Blood ketone levels, as opposed to urine, should also be monitored and can be correlated to optimal brain energy supply and symptom control.
For a small subset of patients, a ketogenic diet proves ineffective despite adequate levels of ketosis. Medications to address the symptoms of seizures or movement disorders may provide benefit, although there is currently no clear basis for specific recommendations and there are concerns to consider regarding potential harmful interactions with ketogenic diets.
In infancy and childhood, a classical 3:1 or 4:1 ketogenic is recommended to ensure the highest level of ketone energy to the meet the metabolic fuel demands of the developing brain. Although it is recommended to continue the classical ketogenic diet for as long as is tolerated by the patient, alternative ketogenic diet versions such as the Modified Ketogenic (2:1 and 1:1 ratios) or the Modified Atkins Diet may be more feasible for quality of life and compliance considerations and are often used by teenagers and adults.
All patients on a ketogenic diet should be under the care of an experienced dietitian and neurologist and have regular laboratory screenings to help monitor for potential side effects. Blood ketone levels, as opposed to urine, should also be monitored and can be correlated to optimal brain energy supply and symptom control.
For a small subset of patients, a ketogenic diet proves ineffective despite adequate levels of ketosis. Medications to address the symptoms of seizures or movement disorders may provide benefit, although there is currently no clear basis for specific recommendations and there are concerns to consider regarding potential harmful interactions with ketogenic diets.
Prevalence
The number of patients diagnosed is currently thought to number in the hundreds. Recent studies have estimated true prevalence to be at least 1:24,000, so the vast majority of patients remain undiagnosed. There’s no known susceptibility related to gender or race.
Additional Resources
Genetic Testing Resources
Behind the Seizure - no cost genetic testing for children under 96 months
Low cost genetic testing - clinical diagnostic testing services
Rare Genomes Project - research study to determine causes of genetic diseases. This is a free program, and it is ideal for suspected Glut1 Deficiency patients where mutations in the SLC2A1 gene have not been found in previous genetic testing.
Low cost genetic testing - clinical diagnostic testing services
Rare Genomes Project - research study to determine causes of genetic diseases. This is a free program, and it is ideal for suspected Glut1 Deficiency patients where mutations in the SLC2A1 gene have not been found in previous genetic testing.
|
The Rare Genomes Project is looking to enroll patients who:
● Have a condition that is suspected to be caused by a change in a single gene ● Do not yet have a genetic diagnosis ● Are currently under the care of a clinician ● Are English-speaking ● Live in the United States |
