NORD gratefully acknowledges Gabrielle Rushing, Neuroscience PhD Candidate, Department of Cell and Developmental Biology, Vanderbilt University, Research Director of the Thisbe and Noah Scott Foundation, for assistance in the preparation of this report.
Riboflavin transporter deficiency is a rare progressive neurodegenerative disorder. Neurodegenerative refers to disorders in which there is damage or loss of nerve cells (neurons) that transmit nerve impulses from the spinal cord or brain (central nervous system) to the nerves that serve (innervate) the muscles or glandular tissue. Riboflavin transporter deficiency is also classified as a neuronopathy, which is a disorder characterized by nerve disease that develops because of damage to motor and sensory nerve cells (neurons) of the peripheral nervous system, which is all the nerves outside of the brain and spinal cord. A motor neuron is a nerve cell that passes nerve impulses from the brain or spinal cord to the muscles or glandular tissue. Sensory nerve cells respond to external stimuli like touch, pain and temperature and convert that stimuli to nerve impulses. The loss of these nerve cells leads to weakness and degeneration (atrophy) of the muscle these nerves serve. In riboflavin transporter deficiency, the nerve cells that are affected are found in the brainstem (which is the lower part of the brain that connects to the spinal cord) and the spinal cord.
Symptoms can include breathing difficulties, facial weakness, hearing loss, abnormalities with the eyes, difficulty chewing and swallowing, muscle weakness of the arms and legs, and an unsteady or unbalanced way of walking (abnormal gait). Symptoms become progressively worse if untreated. Intelligence is not affected by this disorder.
Riboflavin is a vitamin (vitamin B2) and is essential for proper health and development of the body. Riboflavin is not readily synthesized in the body and thus, must be obtained through dietary intake. Although there is no cure, treatment is highly effective and consists of riboflavin supplementation to restore the deficient riboflavin levels. Riboflavin supplementation should be given immediately in individuals suspected of having these disorders.
Riboflavin transporter deficiency is caused by a variation (mutation) in either the SLC52A2 or SLC52A3 genes and is inherited in an autosomal recessive pattern.
Riboflavin transporter deficiency was previously referred to as Brown-Vialetto-Van Laere (BVVL) syndrome and Fazio-Londe syndrome, named after the physicians and researchers who first described the condition. Fazio-Londe syndrome was used for individuals who had similar symptoms but did not develop hearing loss. The use of these different names can be confusing for patients and caregivers. Researchers have proposed classifying the disorder as: riboflavin transporter deficiency type 2 in individuals with a variation in the SLC52A2 gene and riboflavin transporter deficiency type 3 in individuals with a variation in the SLC52A3 gene. There is also riboflavin transporter deficiency type 1, which is caused by a variation in the SLC52A1 gene, but this has only been described in one person in the medical literature. A variation in the SLC52A1 gene has been associated with maternal riboflavin deficiency leading to symptoms in a newborn infant that were resolved with riboflavin supplementation.
The onset of signs and symptoms can range from infancy to early adulthood. One person reported in the medical literature first presented symptoms at 27 years of age, but most affected individuals show symptoms within the first few years of life. Infants and children often develop normally until symptoms first begin. Sometimes, an infection or fever will occur just before symptoms first begin. The specific signs and symptoms that develop and their severity and their progression can be very different from one person to another, even among members of the same family, but for most people who are affected, the first symptom is sensorineural deafness (hearing loss due to inner ear damage). Generally, the later the onset of symptoms, the milder the disorder is. Severe forms can progress rapidly and without treatment can be life-threatening.
Pontobulbar palsy is a common symptom of riboflavin transporter deficiency. Pontobulbar refers to paralysis or impairment of the collection of nerves in the lower part of the medulla oblongata, which is the lower part of the brainstem. This includes several cranial nerves, which help to control facial expressions, hearing and balance, taste, and the muscles used to move the head, shoulders and the tongue. Pontobulbar palsy can cause weakness of facial muscles and reduced facial expressions, difficulty chewing and difficulty swallowing (dysphagia), slurring of speech or difficulty forming words (dysphonia), a high-pitched wheezing sound when breathing (stridor), and brief, spontaneous contractions (fasciculations) of the tongue and weakness of tongue, which can contribute to swallowing difficulties. Difficulties with chewing and swallowing can lead to feeding difficulties in infants, and there can be a risk of aspiration, in which food, fluid or other foreign material accidentally goes into the lungs.
When the disorder begins in infancy, one of the first signs may be a breathing (respiratory) problem. This can be a life-threatening complication if left untreated. Breathing problems result from paralysis of the diaphragm, which is a muscle that separates the chest cavity from the abdominal cavity. When taking in a breath, the diaphragm contracts and moves downward, which increases the space in the chest cavity and allows the lungs to expand when filled with air. Respiratory failure, caused by denervation of the diaphragm, is the main cause of death in patients with riboflavin transporter deficiency.
The most common symptom is sensorineural hearing loss. Sensorineural hearing loss occurs when the nerves within the ear cannot properly send sensory input (sound) to the brain, and is not caused by problems with the ear itself. The degree and production of sensorineural hearing loss can vary from one child to another, but children can experience significant hearing loss.
Some infants may experience degeneration of the main nerve of the eyes (optic nerve), which sends sensory input from the eye to the brain to form images (optic atrophy). This can result in varying degrees of vision loss. Sometimes affected individuals also experience rapid, involuntary movements of the eyes (nystagmus). Less often, drooping of the upper eyelids (ptosis) can occur.
Weakness and degeneration of the upper arm muscles (those between the elbow and the shoulder) may also occur and become progressively worse. Eventually, all muscles of the arms and the legs may be affected. There may be weakness of certain muscles of the neck. This is followed by weakness and degeneration of the muscles of the trunk, which is all of the body except for the head and arms and legs (axial muscle weakness). Some affected individuals develop sensory ataxia, in which there is a lack of control over muscle movement coordination. This can lead to an uncoordinated or unsteady manner of walking (abnormal gait). Muscle weakness can lead to an intolerance of exercise or extended activity. Some individuals eventually develop contractures. A contracture is a condition in which there is abnormal shortening of muscle. This can make muscles difficult to stretch and if a joint is involved, the joint can become permanently fixed in a bent or straightened position, completely or partially restricting the movement of the affected joint.
There are differences between riboflavin transporter deficiency types 2 and 3. Type 2 is characterized by muscle weakness that is most prominent in the arms and neck, while in type 3 muscle weakness is more generalized. Vision loss, optic atrophy, and sensory ataxia are more common in type 2 whereas vocal cord paralysis is more common in type 3.
Riboflavin transporter deficiency is caused by a variation in one of three genes – SLC52A1 gene (causing riboflavin transporter deficiency type 1), the SLC52A2 gene (riboflavin transporter deficiency type 2), and the SLC52A3 gene (riboflavin transporter deficiency type 3). Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body. The SLC52A1 and SLC52A3 proteins are primarily located in the small intestine while the SLC52A2 protein is located in the brain.
These three genes produce (encode) proteins that function as riboflavin transporters. These transporter proteins help riboflavin cross cell membranes and enter the cells. Riboflavin is also known as vitamin B2. The body does not produce riboflavin, but it can be found in many different types of food such as milk, yogurt, eggs, organ and lean meats, as well as enriched grain products. Riboflavin is an essential component of two coenzymes, flavin mononucleotide and riboflavin-5’-phosphate. Coenzymes are non-protein compounds that are necessary for the proper function of enzymes, which are specialized proteins that cause (catalyze) biochemical reactions in the body. These two coenzymes are essential for maintaining the body’s energy supply, the growth, development and function of cells, and the metabolism of carbohydrates, fats, and proteins. When there is a disease-causing (pathogenic) variation in one of these three genes, the proteins that these genes produce are abnormal and cannot transport the riboflavin across the cell membranes. It is not yet known how the abnormal riboflavin transporter proteins cause the riboflavin transporter deficiency.
The variations that cause riboflavin transporter deficiency are inherited in an autosomal recessive pattern. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
Riboflavin transporter deficiency is believed to affect females and males in equal numbers. The exact number of people who have this disorder is unknown. As of November 2017, about 165 affected individuals have been reported in the medical literature or to the Cure RTD Registry. Rare disorders like riboflavin transporter deficiency often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. Researchers believe that these disorders are underdiagnosed; one estimate suggests that at least 1 in 1,000,000 people in the general population have riboflavin transporter deficiency.
A diagnosis of riboflavin transporter deficiency is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Riboflavin transporter deficiency has yet to be detected by newborn screening. A diagnosis is confirmed by molecular genetic testing. Molecular genetic testing can detect disease-causing variations in the genes known to cause these disorders, but is available only as a diagnostic service at specialized laboratories. Because riboflavin transporter deficiency is treatable, prompt diagnosis and early treatment is essential to prevent irreversible neurological damage. Riboflavin supplementation should be given immediately in individuals suspected of having these disorders, even before confirmation through molecular genetic testing.
Clinical Testing and Workup
Affected individuals may undergo an electromyogram, which is a test that evaluates muscles and the nerves that serve those muscles. During an electromyography, a tiny needle electrode is inserted through the skin into an affected muscle. The electrode records the electrical activity of the muscle. This record shows how well a muscle responds to nerve activation and can help determine whether muscle weakness is caused by the muscles themselves or by the nerves that control those muscles.
A diagnosis of riboflavin transporter deficiency can be supported by nerve conduction studies. Nerve conduction studies determine the ability of specific nerves in the peripheral nervous system to relay nerve impulses to the brain. During a nerve conduction study, electrodes are placed over specific nerves such as those of the shoulders and arms. The electrodes stimulate the nerves and record the conduction of the signal. Doctors may also measure the sensory nerve action potentials (SNAP). A SNAP value is obtained by electronically stimulating sensory fibers and measuring the nerve action potential further along that nerve to see how well nerve impulses are being conducted. In individuals with riboflavin transporter deficiency, SNAP is often absent.
Another test measures visual evoked potential, which is the electrical response of the eye when is stimulated by light; this is often abnormal in riboflavin transporter deficiency. Doctors may also measure the brain stem audiometry evoked response (BAER). This can detect sensorineural deafness. During this test, electrodes are placed on the scalp. The electrodes measure the nerve activity from the ears to the brainstem. Some doctors may recommend an electroencephalogram (EEG), which is a test that measures the electrical activity of the brain.
Affected individuals may undergo additional tests to rule out other disorders. An advanced imaging (x-ray) technique called magnetic resonance imaging (MRI) may be recommended. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An MRI of the brain can reveal degeneration or damage to the brain. An MRI of the brain is usually normal in individuals with riboflavin transporter deficiency. However, in a small number of affected individuals, a brain MRI can show deterioration of neurons in the cerebellum (cerebellar atrophy).
Doctors may take blood to measure for the amount of dietary metabolites such as acylcarnitine. Some affected individuals (~50% reported in the literature) have displayed abnormal levels of flavin or acylcarnitine in the blood plasma. However, this is not a reliable marker for diagnosis and normal levels do not rule out riboflavin transporter deficiency. This abnormality can confuse diagnosis due to its similarity to glutaricaciduria II / multiple Acyl-CoA dehydrogenase deficiency (MADD).
The main treatment is high-dose supplementation of riboflavin. Most affected individuals improve on this therapy. Some individuals improve rapidly, while others improve gradually over 12 months. The optimum dose, best delivery method, or best frequency to take riboflavin supplementation are unknown. Treatment will be individualized. Doctors will give riboflavin supplementation in gradually increasing amounts until an optimal dose is reached for each individual. It should be noted that a small number of cases have been reported where patients do not respond or become stable and later experience symptom progression. It is unclear whether earlier intervention would have been beneficial in these cases.
Other treatments of riboflavin transporter deficiency are symptomatic and supportive. A feeding tube may be necessary to help infants who have difficulty chewing and swallowing. Infants with breathing difficulties may require mechanical assistance with a mechanical ventilator. Sometimes, affected individuals may require a tracheostomy, which is a surgical opening in the neck to gain access to the windpipe (trachea). A tube is placed into this opening to allow for breathing. In some case reports, steroids and intravenous immunoglobulins have been given with little success; typically patients experience short periods of stabilization followed by disease progression.
Speech and language therapy, occupational therapy and physical therapy can also be beneficial. Physical therapy can help to prevent contractures. Periodic reassessments and adjustment of services should be provided with all children. Some children require braces or other orthotic devices to help with walking. Severely affected individuals may require a wheelchair.
Hearing loss can be treated with hearing aids called cochlear implants. Unlike regular hearing aids that amplify sound, these hearing aids work by directly stimulating the auditory nerve. The response to a cochlear implant is individualized, but generally has been positive. Children with vision loss should receive low vision aids to help amplify remaining sight. Children with hearing loss or vision loss should also receive special education services.
Scoliosis should be treated as it would for children without riboflavin transporter deficiency. Surgery may be necessary in some individuals.
Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, physicians who specialize in diagnosing and treating disorders of brain and nervous system in children (pediatric neurologists), neurologists, physicians who specialize in diagnosing and treating disorders of the eye in children (pediatric ophthalmologists), ophthalmologists, physicians who specialize in diagnosing and treating disorders of the ears (audiologists), and other healthcare professionals may need to systematically and comprehensively plan treatment. Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.
Women who have riboflavin transporter deficiency and women who are carriers (heterozygotes) for these disorders should receive riboflavin supplementation before and during pregnancy and when breast feeding.
The Cure RTD Foundation maintains a registry for riboflavin transporter deficiency. A registry is a special database that contains information about individuals with a specific disorder or group of conditions. The collection of data about rare disorders may enable researchers to increase the understanding of such disorders, expand the search for treatments, and accelerate clinical trials into specific treatment options. For more information, visit: http://curertd.org/research/rtdregistry/.
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