What is Riboflavin Transporter Deficiency (RTD)?
RTD, also known as Brown-Vialetto-Van Laere syndrome (BVVL) and/or Fazio Londe (FL) syndrome, is a rare, progressive, neurodegenerative motor neuron disorder that specifically includes palsies (paralysis) of the cranial nerves, and is sometimes referred to as “bulbar palsy.” The BVVL arose from the physicians and researchers who described some of the first reported cases of the disease (Brown, 1894; Vialetto, 1936; and Van Laere, 1966). Due to recent research advances, the name of the disease has changed from BVVL/FL to riboflavin transporter deficiency (RTD). Riboflavin, also known as vitamin B2, is not readily synthesized in the human body and thus must be obtained through dietary intake. RTD is caused by a mutation in riboflavin transporter genes, most notably SLC52A2 (coding for RFVT2, expressed in the brain) and SLC52A3 (coding for RFVT3, expressed in the intestine) (Yao et al, 2010, J Nutr). There is a third riboflavin transporter, SLC52A1, which is less commonly mutated but also located in the small intestine (Yonezawa et al, 2008, Am J Physiol Cell Physiol). When mutated, these transporters do not function properly to intake riboflavin, thus depriving cells of a very important molecule for carbohydrate, protein and lipid metabolism (Lienhart et al, 2013, Arch Biochem Biophys).
What are symptoms of RTD?
A review of 35 publications reporting the clinical presentations of 74 patients with RTD was conducted in 2012 (Bosch et al, 2012), Orphaned Journal of Rare Diseases) reporting the most common symptoms as bulbar palsy, hearing loss, facial weakness and respiratory compromise. Sensorineural hearing loss is primary component of the syndrome however, it may not be discovered until late in children due to the mildness of the hearing loss or the more obvious symptoms that manifest first. Progressive bulbar palsy without hearing loss has previously been referred to as Favio-Londe syndrome.
The onset of symptoms varies from infancy to the third decade of life. Once diagnosed, the progression is rapid and fatal if untreated (Jaeger and Bosch, 2016, J Inherit Metab Dis). In many cases, children lead a normal life developmentally, disease-free, for years before developing symptoms. Typically, the first symptom is sensorineural deafness. Other examples of nerve degeneration include vocal cord paralysis, ptosis (droopy eyelids), facial weakness, slurred speech, dysphagia (difficulty swallowing), visual difficulty secondary to optic atrophy (loss of fibers in the optic nerve), neck and shoulder weakness, limb weakness, autonomic dysfunction (the nerves controlling involuntary bodily functions are damaged), and respiratory compromise (respiratory distress ultimately leading to respiratory failure). Respiratory failure, caused by denervation to the diaphragm, is the main cause of death.
Disease progression is variable. Up until 2010, some affected individuals gradually got worse while others had plateaus of stable disease throughout their course; however, all cases up to that point had been fatal, with only one-third of all individuals affected with RTD surviving for longer than ten years. After the discover of mutations in riboflavin transporter genes, a potential therapy of intravenous B2/riboflavin was attempted in 2010 with major clinical improvements in a small grope of patients (Bosch et al, 2012, J Inherit Metab Dis).
What is the cause of RTD?
RTD is now linked to several genes that cause riboflavin transport deficiency. In 2010, the first gene for RTD was discovered elucidating the disease as a possible riboflavin transporter gene mutation (Green et al, 2010, Am J Hum. Genet). Since then, other genes have been discovered with similar malfunction (Johnson et al, 2012, Brain).
RTD is inherited in an autosomal recessive pattern, meaning that two copies of the abnormal gene must be present to develop RTD. Several researchers continue to study the exact mechanism, including the creation of a mouse model so that we can better understand the exact cause of the disease. Gene testing is currently available for any patient suspected of having the disease through Dr. Henry Houlden's lab in the UK.
How common is RTD?
Throughout the past century, less than 100 cases of BVVL/RTD have been reported in the literature from families around the world, although those numbers are growing. We continue to have families and/or their physicians contact us through this web site, and we are learning that RTD is not near as rare as the literature suggests.
How is RTD diagnosed?
Clinical presentation of hearing loss, other cranial nerve palsies, and lower motor neuron limb involvement raises the possibility of BVVL. However, it is important to be evaluated by a pediatric neurologist who can also test for other treatable metabolic conditions that may present similarly.
Hearing tests show sensorineural hearing loss, and brainstem auditory evoked potentials (BAER) are abnormal. Magnetic resonance imaging (MRI) of the brain may show hyperintensities, especially in the brainstem, or may show nothing at all. Muscle biopsy results are typically normal or show groups of atrophic fibers suggesting denervation of muscles. Neurophysiologic tests such as EMG and nerve conduction studies also confirm denervation of muscles, both chronic and active. Cerebral spinal fluid (CSF) analysis after lumbar puncture is typical normal or only shows mildly elevated protein.
A complete diagnosis requires mutation analysis of all three riboflavin transporter genes (Bosch et al, 2012, Orphanet Journal of Rare Diseases). RTD has yet to be able to be detected by newborn screening, likely due to supplementation of riboflavin metabolites from the mother (Bosch et al, 2011, J Inherit Metab Dis). Any patient suspected of having RTD should be tested immediately for one of the RTD genes, the known riboflavin transporter gene mutations. For BVVL genetic testing, please visit http://www.ncbi.nlm.nih.gov/sites/GeneTests/?db=GeneTests, under BVVLS, where the details of the lab and services they offer can be found.
If RTD is suspected, it is important NOT TO WAIT for those results before starting trial intravenous B2/riboflavin therapy with your doctor. Patients who are treated earlier in the disease progression have shown more clinical improvement.
Is there treatment?
There is no certain effective treatment for RTD however, intravenous and oral riboflavin therapies have shown promising improvements in clinical presentation of RTD (Bosch et al, 2012, J Inherit Metab Dis, Bosch et al, 2012, Orphanet Journal of Rare Diseases). This treatment is the B2 Protocol. Early intervention is emphasized because some symptoms such as diaphragm paralysis may not be reversible (Bosch et al, 2012, J Inherit Metab Dis.) There have also been a small number of cases where patients undergoing riboflavin therapy do not improve or become stable and later experience nerve deterioration, but it is unclear if earlier intervention would have been beneficial in these cases. Future research will be critical in determining why some patients respond to B2 and why others do not.
For further information and instruction on the informal study of Riboflavin therapy, please contact one of the authors, Dr. Bosch, at the University of Amsterdam at firstname.lastname@example.org.
In some past case reports which are less promising, steroids and intravenous immunoglobulins (IVIg) have been tried with little success, typically short periods of stabilization before disease progression. Supportive care and symptomatic treatment such as tracheostomy, assisted ventilation, and gastrostomy are typically offered to patients and their families when therapy is not working.