Riboflavin transporter deficiency neuronopathy is a disorder that affects nerve cells (neurons). Affected individuals typically have hearing loss caused by nerve damage in the inner ear (sensorineural hearing loss) and signs of damage to other nerves.

In addition to nerves in the inner ear, riboflavin transporter deficiency neuronopathy involves nerves found in the part of the brain that is connected to the spinal cord (the brainstem), specifically in a region of the brainstem known as the pontobulbar region. Damage to these nerves causes paralysis of the muscles controlled by them, a condition called pontobulbar palsy. Nerves in the pontobulbar region help control several voluntary muscle activities, including breathing, speaking, and moving the limbs. As a result of pontobulbar palsy, people with riboflavin transporter deficiency neuronopathy can have breathing problems; slurred speech; and muscle weakness in the face, neck, shoulders, and limbs. Affected individuals can also have muscle stiffness (spasticity) and exaggerated reflexes.

The age at which riboflavin transporter deficiency neuronopathy begins varies from infancy to young adulthood. When the condition begins in infancy, the first symptom is often breathing problems caused by nerve damage, which can be life-threatening. When the condition begins in children or young adults, sensorineural hearing loss usually occurs first, followed by signs of pontobulbar palsy.

If not treated, the signs and symptoms of riboflavin transporter deficiency neuronopathy worsen over time. Severe breathing problems and respiratory infections are the usual cause of death in people with this condition. Without treatment, affected infants typically survive less than one year. However, those who develop the condition after age 4 often survive more than 10 years.

Riboflavin transporter deficiency neuronopathy encompasses two conditions that were once considered distinct disorders: Brown-Vialetto-Van Laere syndrome (BVVLS) and Fazio-Londe disease. The two conditions have similar signs and symptoms, but Fazio-Londe disease does not include sensorineural hearing loss. Because these two conditions share a genetic cause and have overlapping features, researchers determined that they are forms of a single disorder.

Riboflavin transporter deficiency neuronopathy is caused by mutations in the SLC52A2 or SLC52A3 gene. These genes provide instructions for making related proteins called riboflavin transporters: RFVT2 is produced from the SLC52A2 gene, and RFVT3 is produced from the SLC52A3 gene. Both proteins move (transport) a vitamin called riboflavin (also called vitamin B2) across the cell membrane. Riboflavin cannot be made by the body, so it must be obtained from the food a person eats. The RFVT3 protein is found at especially high levels in cells of the small intestine and is important for absorbing riboflavin during digestion so that the vitamin can be used in the body. The RFVT2 protein is found in cells of the brain and spinal cord and is important for ensuring that these tissues have enough riboflavin for proper functioning.

In the cells of the body, riboflavin is the core component of molecules called flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN). FAD and FMN are involved in many different chemical reactions and are required for a variety of cellular processes. One important role of these molecules is in the production of energy for cells. FAD and FMN are also involved in the breakdown (metabolism) of carbohydrates, fats, and proteins.

Mutations in the SLC52A2 or SLC52A3 gene lead to an abnormal riboflavin transporter protein with impaired ability to transport riboflavin. Consequently, there is a reduction of riboflavin available in the body. However, it is unclear how these changes lead to the nerve problems characteristic of riboflavin transporter deficiency neuronopathy.

Normal Function

The SLC52A2 gene provides instructions for making a riboflavin transporter protein called RFVT2 (formerly known as RFT3). This protein moves (transports) a vitamin called riboflavin (also called vitamin B2) across the cell membrane. The RFVT2 protein is found at especially high levels in cells of the brain and spinal cord and is important for absorbing riboflavin from the bloodstream into these tissues.

In the cells of the body, including those in the brain and spinal cord, riboflavin is the core component of molecules called flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN). These molecules function as coenzymes, which means they help enzymes carry out chemical reactions. FAD and FMN are involved in many different chemical reactions and are required for a variety of cellular processes. One important role of these coenzymes is in the production of energy for cells. FAD and FMN are also involved in the breakdown (metabolism) of carbohydrates, fats, and proteins.

Health Conditions Related to Genetic Changes

Riboflavin transporter deficiency neuronopathy

At least 11 mutations in the SLC52A2 gene have been found to cause riboflavin transporter deficiency neuronopathy. This neurological condition encompasses two disorders that were previously considered to be separate: Brown-Vialetto-Van Laere syndrome and Fazio-Londe disease. Some of the gene mutations involved in riboflavin transporter deficiency neuronopathy prevent production of the RFVT2 protein. Others lead to production of an abnormal protein with impaired ability to transport riboflavin. It is unclear how these changes lead to the nerve problems that cause hearing loss, muscle weakness in the face and limbs, and breathing problems in people with the disorder.

Other Names for This Gene

• BVVLS2
• D15Ertd747e
• FLJ11856
• G protein-coupled receptor 172A
• GPCR41
• GPR172A
• hRFT3
• PAR1
• PERV-A receptor 1
• porcine endogenous retrovirus A receptor 1
• putative G-protein coupled receptor GPCR41
• RFT3
• RFVT2
• riboflavin transporter 3
• solute carrier family 52 (riboflavin transporter), member 2
• solute carrier family 52, riboflavin transporter, member 2

Genomic Location

Normal Function

The SLC52A3 gene (previously called the C20orf54 gene) provides instructions for making a riboflavin transporter protein called RFVT3 (formerly known as RFT2). This protein moves (transports) a vitamin called riboflavin (also called vitamin B2) across the cell membrane. Riboflavin cannot be made by the body, so it must be obtained from the food a person eats. The RFVT3 protein is found at especially high levels in cells of the small intestine and is important for absorbing riboflavin during digestion so that the vitamin can be used in the body.

In the cells of the body, riboflavin is the core component of molecules called flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN). These molecules function as coenzymes, which means they help enzymes carry out chemical reactions. FAD and FMN are involved in many different chemical reactions and are required for a variety of cellular processes. One important role of these coenzymes is in the production of energy for cells. FAD and FMN are also involved in the breakdown (metabolism) of carbohydrates, fats, and proteins.

Health Conditions Related to Genetic Changes

Riboflavin transporter deficiency neuronopathy

More than two dozen mutations in the SLC52A3 gene have been found to cause riboflavin transporter deficiency neuronopathy. This neurological condition encompasses two disorders that were previously considered to be separate: Brown-Vialetto-Van Laere syndrome and Fazio-Londe disease. The gene mutations involved in this condition lead to production of abnormal RFVT3 proteins. Some mutations lead to the production of an altered protein that cannot get to the cell membrane, so it is unable to transport riboflavin into the cell. Other mutations lead to a version of the protein that can get to the cell membrane, but its function as a transporter is impaired. These changes impair the absorption of riboflavin in the small intestine. The resulting shortage of riboflavin leads to a reduction of FAD and FMN. However, it is unclear how these changes lead to the nerve problems that cause hearing loss, muscle weakness in the face and limbs, and breathing problems in people with the disorder.

Other Names for This Gene

• bA371L19.1
• BVVLS
• C20orf54
• hRFT2
• MGC10698
• RFT2
• RFT2_HUMAN
• RFVT3
• riboflavin transporter 2
• solute carrier family 52 (riboflavin transporter), member 3
• solute carrier family 52, riboflavin transporter, member 3

Genomic Location

Riboflavin transporter deficiency neuronopathy usually follows an autosomal recessive pattern of inheritance, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Treatment with riboflavin therapy (high-dose supplementation of riboflavin) has been used since 2010 and appears to be effective and possibly life-saving. Therefore, treatment should begin as soon as a riboflavin transporter deficiency is suspected, and should continue unless the diagnosis is ruled out with genetic testing. Improvement of symptoms may occur within days to months after starting treatment, and starting treatment early appears to be associated with better and more rapid improvement.

Riboflavin transporter deficiency neuronopathy is a rare condition. Approximately 100 cases have been reported in the scientific literature.