Riboflavin transporter deficiency (RTD) is a rare genetic disorder that impacts the body’s ability to utilize riboflavin (vitamin B2). This condition primarily affects the nervous system, leading to progressive neurodegenerative symptoms if not addressed. Previously known as Brown-Vialetto-Van Laere syndrome (BVVL) and Fazio Londe syndrome, it was reclassified as riboflavin transporter deficiency due to a better understanding of its cause.
Understanding Riboflavin and Its Transporters
Riboflavin is a water-soluble vitamin that the human body cannot produce on its own, requiring dietary intake. This vitamin plays a role in numerous bodily functions, including the breakdown of proteins, fats, and carbohydrates, which are converted into adenosine triphosphate (ATP) for energy. ATP is the primary energy currency of cells, supporting cellular activities.
Beyond energy production, riboflavin is also involved in maintaining healthy mucous membranes in the digestive system and supporting liver function. It assists in the conversion of tryptophan into niacin and is important for healthy eyes, nerves, muscles, and skin. Riboflavin is also an antioxidant, supporting the immune system and red blood cell development.
Riboflavin transporters are specialized proteins responsible for moving riboflavin into cells, particularly in the brain and nervous system. Two specific transporters, RFVT2 and RFVT3, are significant for central nervous system function. RFVT3 is highly expressed in cells of the small intestine, facilitating the absorption of dietary riboflavin, while RFVT2 is found in cells of the brain and spinal cord, ensuring these neurological tissues receive sufficient riboflavin.
Once inside the cells, riboflavin is converted into flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). These molecules act as cofactors, assisting in many biochemical reactions, including those in the electron transport chain within mitochondria, the energy-producing centers of cells. When riboflavin transporters are not functioning correctly, intracellular levels of FMN and FAD decrease, which disrupts mitochondrial function and contributes to neurodegeneration.
Causes and Manifestations of the Deficiency
Riboflavin transporter deficiency is a genetic disorder, resulting from alterations in specific genes. It is primarily caused by mutations in genes producing riboflavin transporters. Most cases, particularly types 2 and 3, follow an autosomal recessive inheritance pattern. This means an individual must inherit two copies of the altered gene, one from each parent, to develop the condition. Parents who carry one copy of the mutated gene typically do not show symptoms themselves.
Symptoms can vary, even among siblings with the same genetic mutations, and often worsen progressively if untreated. Neurological symptoms are prominent due to impaired riboflavin transport into nerve cells. One common initial sign is sensorineural hearing loss, caused by nerve damage in the inner ear, and is often progressive and severe.
The condition can also lead to damage in nerves of the brainstem, the region connecting the brain to the spinal cord. This can result in pontobulbar palsy, causing paralysis of muscles controlled by these nerves. Symptoms of pontobulbar palsy include breathing difficulties, which can be life-threatening, especially in infants. Individuals may also experience slurred speech, difficulty chewing and swallowing, facial weakness, and muscle weakness in the neck, shoulders, and limbs.
Other manifestations include muscle stiffness, exaggerated reflexes, and an unsteady gait (ataxia). Vision problems, such as optic atrophy, can also occur. Symptom onset is highly variable, ranging from infancy to adulthood; approximately half of affected individuals develop symptoms before three years of age, with earlier onset often indicating a more severe presentation. An infection or fever may sometimes trigger or worsen the initial symptoms.
Diagnosis and Treatment Approaches
Diagnosing riboflavin transporter deficiency involves a combination of clinical evaluation, supportive laboratory tests, and genetic testing. While blood tests may show low flavin levels or abnormal acylcarnitine profiles, and urine tests may reveal abnormal organic acid analysis in about half of cases, genetic testing is the only way to confirm the diagnosis. This involves analyzing genes responsible for riboflavin transporters to identify specific mutations.
Early diagnosis is important because timely treatment can significantly alter disease progression and improve outcomes. As soon as RTD is suspected, treatment should begin immediately, even before genetic test results are available. The primary treatment is high-dose oral riboflavin supplementation, typically 10 mg to 50 mg per kilogram of body weight per day.
This high-dose supplementation aims to overcome the transport deficiency, allowing sufficient riboflavin to enter cells and support metabolism. Treatment with riboflavin can improve symptoms and clinical signs, enhance objective test results (e.g., vital capacity and nerve conduction studies), and normalize acylcarnitine levels. While high-dose riboflavin can be lifesaving and stop disease progression, it is not a cure. Individuals may still experience some residual disability, particularly if treatment is delayed.
Lifelong adherence to riboflavin supplementation is necessary. Prognosis varies considerably depending on how early treatment is initiated; individuals treated early generally experience better outcomes. Improvements in hearing loss and optic atrophy have been observed, often limited to the first 12 months of treatment, with stability in subsequent years.