What Is Riboflavin Transporter Deficiency?
RTD (riboflavin transporter deficiency), which is made up of RTD2 and RTD3 factors, is a rare neurological condition characterized by progressive peripheral and cranial neuropathy that results in sensory ataxia, vision loss, hearing loss, muscle weakness, and consequent respiratory compromise. On rare occasions, individuals with genetically determined riboflavin transporter deficiency may manifest symptoms during adulthood or even as late as their fifth decade. Onset is typically in infancy or childhood. Without treatment, most infants with riboflavin transporter deficiency develop an immediate need for a ventilator and die within the first ten years of life.
What Are the Signs and Symptoms of Riboflavin Transporter Deficiency?
Cranial Neuronopathy:
Most affected people initially present sensorineural hearing loss, typically severe and progressing. The interval between the onset of hearing loss and the emergence of other manifestations varies but generally is between 1 and 2 years. Some people appear to experience the onset of symptoms or a worsening of current findings in response to an intercurrent event (an injury or infection).
Motor Neuropathy:
The weakness of both proximal and distal limb muscles, often accompanied by significant distal wasting, tends to be more pronounced in the upper and lower limbs. Axional weakness, manifested as severe trunk and neck weakness requiring trunk bracing and difficulty holding the head up, results from a persistent absence of deep tendon reflexes. The diaphragm becomes paralyzed, which may lead to respiratory failure.
What Are the Diagnostic Findings of Riboflavin Transporter Deficiency?
Brain MRI:
Generally normal. But in a small number of affected people, cerebellar atrophy and abnormal T2-weighted hyperintensity are seen in the cerebellar, cortical, subcortical, and brain stem regions.
Laboratory Findings:
Although not all people with molecularly confirmed RTD have abnormal acylcarnitine profiles in their blood, remarkably, newborn screening bloodspots revealed normal acylcarnitine profiles. At the same time, children with RTD who were diagnosed in the earliest months of life have abnormal acylcarnitine profiles. This is likely because the unborn child received an adequate maternal riboflavin supply.
What Is the Management of Riboflavin Transporter Deficiency?
High-dose oral riboflavin (vitamin B2) supplementation between 10 mg and 50 mg/kg/day improves symptoms and clinical examination signs, as well as objective testing (vital capacity, brain stem evoked potentials, nerve conduction studies), and normalizes acylcarnitine levels. Although liquid riboflavin is available, it is frequently challenging to obtain. As a result, riboflavin capsules are commonly opened and mixed with food, like yogurt. The dosage of riboflavin supplementation varies based on the severity of the disease and the individual's response to treatment. The reaction may be very positive if riboflavin supplementation is administered earlier in the disease course. If issued later in the disease course, the answer may be less favorable due to the impact of pre-existing neuronal damage.
Oral riboflavin supplementation should start as soon as a riboflavin transporter deficiency is suspected and continue for the rest of one's life unless molecular genetic testing cannot detect pathogenic variants. Supportive care consists of breathing assistance, physiotherapy to prevent contractures, occupational therapy to support daily activities, orthotics for limb and trunk bracing, speech and language therapy to avoid choking and respiratory issues, wheelchairs as needed, low vision aids as required, routine management of scoliosis to prevent long-term respiratory problems and routine control of depression.
Follow-up physical and neurological exams, measurement of blood riboflavin or FAD or FMN, and analysis of blood acylcarnitine profile are all routinely performed three to six months after initiating riboflavin supplementation. Follow-up visits are typically biannual for older people and more frequent for younger kids. To determine the ideal dose for oral riboflavin supplementation, doses should be increased gradually:
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Riboflavin 10 mg/kg/day, divided into three doses, for a month.
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Riboflavin 20 mg/kg/day was administered in three doses for a month.
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Three doses of 30 mg/kg of riboflavin daily for a month.
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Three doses of 40 mg/kg of riboflavin daily for a month.
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Riboflavin is 50 mg/kg/day in three doses for a month.
What Is the Differential Diagnosis of Riboflavin Transporter Deficiency?
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BSCL2 or GARS1- related distal hereditary motor neuropathy (HMN) - Upper limb-predominant involvement in axonal neuropathy.
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Achalasia-addisonianism-alacrimia syndrome (AAAS) - Prominent bulbar features, but the main manifestations are alacrimia, adrenal issues, achalasia and autonomic symptoms.
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Neonatal-onset multiple acyl-CoA dehydrogenase deficiency (MADD) - Usually fatal, large amounts of metabolites derived from fatty acids and amino acids are excreted along with severe hypoketotic hypoglycemia, multisystem involvement (biochemical profile similar to RTD), and metabolic acidosis.
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Spinal muscular atrophy with respiratory distress 1 (SMARD1) - Typically, the onset is early (infantile onset is most common) in severe axonal polyneuropathy characterised by distal muscle and lower-limb weakness, as well as respiratory failure caused by diaphragmatic paralysis with or without autonomic involvement, hypotonia and pneumonia.
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Amyotrophic lateral sclerosis - A progressive, fatal neurodegenerative disease that affects both the brain and the spinal cord. The most common cause of death is respiratory muscle failure. RTD and ALS affect the bulbar and LMN (lower motor neuron).
What Should Be Avoided In Riboflavin Transporter Deficiency?
Avoidants include restricting riboflavin in the diet and engaging in vigorous exercise. It is appropriate to conduct molecular genetic testing on an affected person's older and younger siblings when the family's SLC52A2 or SLC52A3 pathogenic variants are known. This will help identify those affected as early as possible and who will benefit from early treatment with riboflavin supplementation and monitoring for potential disorder complications. Gestational management includes women with RTD or who are heterozygous for a pathogenic variant in either SLC52A2 or SLC52A3 are advised to consume a diet high in riboflavin. To prevent riboflavin deficiency in the unborn child, supplements should be taken before, during, and after breastfeeding, if necessary.
Conclusion:
Positive clinical response to treatment may occur with some latency. Thus, riboflavin therapy should continue in all suspected or genetically diagnosed RTD cases, even if no apparent clinical improvement is observed. There is a better response when the treatment is given earlier in life or earlier in the disease course. Adult-onset or late treatment is frequently associated with non-improvement, likely due to neuronal damage.
