What Is De Vivo Disease?

De Vivo disease is a rare, debilitating, neurological, and genetic disorder characterised by a dysfunctional protein called GLUT1 that transports glucose across the blood-brain barrier into the brain. As a result, it is also sometimes referred to as glucose transporter type 1 deficiency syndrome, (Glut1DS), glucose transporter protein syndrome (GTPS), or Glut1 deficiency. 

Read on to learn about what causes the GLUT1 deficiency, which age groups are most at risk, how De Vivo disease is diagnosed, whether a “keto’’ diet is as effective in controlling the neurological symptoms of De Vivo disease as claimed in the media and future directions in De Vivo disease research.

Introduction

De Vivo disease is a rare genetic disorder that mainly affects the nervous system. It is named after Dr. De Vivo who first described the disease in medical literature in 1991. It also goes by other names such as those listed above.

Causes of De Vivo disease

De Vivo disease is mainly caused by mutations or changes in the DNA sequence of the SLC2A1 gene. The SLC2A1 gene is necessary for the production of a membrane protein called glucose transporter protein type 1 (GLUT1), which functions to transport (move) glucose (a simple sugar) between cells, and across the blood-brain barrier to the brain for energy.¹ 

Due to a mutation in the SLC2A1 gene, people with De Vivo disease have little to no GLUT1 protein in their cells and therefore molecules such as glucose cannot move across the blood-brain barrier (a wall or boundary between blood vessels and brain tissue) and reach the brain. Glucose is the brain’s preferred source of metabolic fuel and without it, the brain becomes depleted of energy, resulting in the severe neurological signs and symptoms of De Vivo disease. 

De Vivo disease is usually inherited in an autosomal dominant pattern, meaning that a mutation in a single copy of the SLC2A1 gene is required to cause the disease. Rarely, De Vivo disease can be inherited in an autosomal recessive pattern, where patients have two copies of the mutated SLC2A1 gene from each parent.¹ 

Symptoms and diagnosis

The symptoms of De Vivo disease vary depending on age, and whether or not seizures or epilepsy are associated with the GLUT1 deficiency. 

There are two types of De Vivo disease:

• Epileptic encephalopathy-related GLUT1 deficiency - onsets during the first months to 3-4 years of life and is the most common form of the disease (very few individuals are diagnosed between the ages of 10-18 years old)
• Non-epileptic encephalopathy-related GLUT1 deficiency - onsets between approximately ages 10-18 years old but can sometimes develop during adulthood 

The physical and developmental symptoms of both forms of De Vivo disease are mostly overlapping, however, epileptic seizures and the after-effects of seizures are only apparent in epileptic encephalopathy-related GLUT1 deficiency and is the defining feature that distinguishes between the two forms of the disease. 

Other symptoms include:

• Rapid and irregular involuntary eye movements 
• Microcephaly (small head in babies due to insufficient glucose for proper brain and skull growth) 
• Movement disorders (ataxia)
• Muscle stiffness
• Muscle twitches (especially during periods of fasting) 
• Speech issues (dysarthria)
• Confusion 
• Lack of energy (lethargy)
• Headaches
• Learning disabilities 
• Developmental delay 

Movement disorders (such as ataxia and/or involuntary muscle tensing), tends to be more pronounced in patients with non-epileptic GLUT1 deficiency compared to those with epileptic encephalopathy-related GLUT1 deficiency.

It should also be noted that while around half of De Vivo disease patients develop learning disabilities and exhibit developmental delays, many also go on to achieve personal, educational and career successes in later adolescence and adulthood and live a good quality life despite their condition.  

Diagnostic Criteria

A healthcare provider will diagnose a suspected patient with De Vivo disease by performing a series of tests in the following order: 

• Medical history and physical examination - determines the type of GLUT1 deficiency the patient may have, and rule out other neurological diseases
• Genetic testing - checks whether the patient has a mutation in the SLC2A1 gene as it helps confirm diagnosis of De Vivo disease
• Lumbar puncture (or ‘’spinal tap test’’) - following a 4-6 hour fast, a sample of cerebrospinal fluid (CSF) from two lumber bones in your lower back is collected to assess brain function ² 
• Glucose transport test (or “Red blood cell uptake assay’’) - if the SLC2A1 genetic mutation cannot be identified via genetic testing, diagnosis of De Vivo disease can be confirmed by measuring the uptake of a form of glucose by red blood cells ³ 

Management and Treatment Options 

The main current management and treatment options for De Vivo disease are listed below.

Ketogenic Diet

The ketogenic or “keto’’ diet involves severely restricting carbohydrates whilst eating a very high amount of fat and moderate protein. As a result, the “keto’’ diet puts the body into a state of ‘’ketosis’’ whereby the body ‘burns’ fat instead of glucose for energy. It therefore provides the brain with an alternative energy source to glucose and has been used since 1991 to treat De Vivo disease. 

Multiple research studies have shown that ketogenic diets are effective in reducing seizures, movement disorders, and cognitive problems in patients with De Vivo disease. Typically, patients who are put on a keto diet at an earlier age (as early as infancy) tend to have a better outcome.³

Despite its effectiveness in managing and treating symptoms in patients with De Vivo disease, there are some risks associated with a ketogenic diet that are worth considering before starting the diet including: 

• Metabolic acidosis.  The abnormal build-up of acids within the body as a result of ketosis. If left untreated, metabolic acidosis can result in kidney disease, kidney failure, and even death. Patients should therefore never attempt a keto diet without the supervision of a healthcare provider
• Low L-carnitine intake.  Ketogenic diets tend to be low in L-carnitine which is important in fat metabolism. Patients on a ketogenic diet are therefore recommended to take a daily L-carnitine supplement at a dose of approximately 50 mg/kg/day
• Drug interactions.  Ketogenic diets may be harmful when undertaken alongside taking certain medications such as valproic acid and carbonic anhydrase inhibitors (e.g. acetazolamide). Taking these drugs whilst on a ketogenic diet may not only inhibit GLUT1 transport, thus worsening symptoms of De Vivo disease, but also increase the risk of developing Reye-like illness, kidney stones, and metabolic acidosis ³

Medical Treatments

Anti-convulsant drugs (or “anti-epileptic drugs’’ (AEDs)) are taken to manage epilepsy symptoms and reduce seizure occurrences. Research also suggests that AEDs tend to offer better De Vivo disease symptom management when taken alongside a ketogenic diet.³ 

Therapies for movement and speech difficulties such as: 

• Speech and language therapy 
• Physical therapy
• Occupational therapy  

Importance of Regular Follow-ups

Since a ketogenic diet is the current primary treatment for De Vivo disease and carries large risks, particularly metabolic acidosis, blood samples should be taken to monitor and record the concentration of blood ketones on a daily-weekly basis. The blood ketone concentration of beta-hydroxybutyrate (an acid made inside the body) in particular should be between 3-5 mmol/L (the ‘’sweet spot’’ for ketosis to work). 

Future directions

Promising treatments for de vivo disease currently undergoing treatment include:

Triheptanoin - a synthetic fat (lipid) molecule known as a triglyceride that the liver metabolises further into ketone bodies to provide an alternative energy source to glucose for the brain (ketone bodies can cross the blood-brain barrier) and has recently shown promise in decreasing seizures and improving brain performance in patients with De Vivo disease 

Gene therapy - introducing a foreign functional gene copy into cells to treat disease has only been performed in neonatal mice models, but the results (for example, increased GLUT1 protein function, CSF glucose levels, and brain size as well as decreased motor defects) promise to pave the way for gene therapy treatment in humans with De Vivo disease. ³

Continued research is therefore exceptionally important as despite its rarity, current treatment options for De Vivo disease are not only limited but carry large risks and the complications of the disease are debilitating. 

Summary 

De Vivo disease (also known as ‘glucose transporter type 1 deficiency syndrome (Glut1DS)’, ‘encephalopathy due to GLUT1 deficiency’, ‘glucose transporter protein syndrome (GTPS)’, or ‘Glut1 deficiency’) is a rare genetic disease that affects the nervous system. Caused by a mutation in a single copy of the SLC2A1 gene (important for the production of a membrane protein called GLUT1), De Vivo disease patients lack the GLUT1 transporters that move glucose across the blood-brain barrier to the brain for energy. Insufficient glucose supply to the brain affects the function, size, and cognition of patients. De Vivo disease patients may also present with seizures (epilepsy), developmental delay, and microcephaly in the first months to 3-4 years of life while movement disorders such as paroxysmal exertion-induced dystonia (PED) typically develop in 10-18-year-olds. 

De Vivo disease is mainly diagnosed using a lumbar puncture (or ‘spinal tap’), genetic testing, and/or a type of red blood cell test that measures glucose transport. Current management and treatment options for De Vivo disease include a high-fat low-carb “keto’’ diet, anti-epileptic drugs (AEDs), and different therapies including speech and language therapy, physical therapy, and/or occupational therapy. Regular monitoring of blood ketone levels is critical for patients with De Vivo disease on keto diet treatment to ensure that ketone bodies are effectively utilised by the brain for energy without inducing life-threatening side effects.