Riboflavin transporter deficiency

Other Names: Pontobulbar palsy and neurosensory deafness; BVVLS; Pontobulbar palsy with deafness; Progressive bulbar palsy with sensorineural deafness; Brown-Vialetto-van Laere syndrome

Riboflavin transporter deficiency is a progressive neurodegenerative disease characterized by paralysis of the cranial nerves, sensorineural deafness, and signs of damage to other nerves. Symptoms may begin from infancy to early adulthood and worsen over time.

Epidemiology

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

Cause

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.

Inheritance

Autosomal recessive inheritance, a 25% chance

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.

Signs and symptoms

When the condition begins in infancy, the first symptom often is breathing problems, which can be life-threatening. When it begins in childhood or early adulthood, sensorineural deafness is usually the first symptom. Other signs and symptoms may include vocal cord paralysis, droopy eyelids, facial weakness, slurred speech, difficulty swallowing, visual problems, autonomic dysfunction, breathing difficulties, and weakness of the neck, shoulder, and limbs.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Bulbar palsy
• Progressive hearing impairment

30%-79% of people have these symptoms

• Abnormality of eye movement(Abnormal eye movement)
• Dysarthria(Difficulty articulating speech)
• Dysphagia(Poor swallowing)
• Facial palsy(Bell's palsy)
• Hyporeflexia(Decreased reflex response)
• Limb muscle weakness(Limb weakness)
• Muscular hypotonia(Low or weak muscle tone)
• Myoclonus
• Ptosis(Drooping upper eyelid)
• Respiratory insufficiency(Respiratory impairment)
• Skeletal muscle atrophy(Muscle degeneration)

5%-29% of people have these symptoms

• Abnormal autonomic nervous system physiology
• Abnormality of macular pigmentation
• Aggressive behavior(Aggression)
• Ataxia
• Cachexia(Wasting syndrome)
• Cerebral cortical atrophy(Decrease in size of the outer layer of the brain due to loss of brain cells)
• Color vision defect(Abnormal color vision)
• Diabetes insipidus
• Gynecomastia(Enlarged male breast)
• Hallucinations(Hallucination)
• Hypertension
• Hypogonadism(Decreased activity of gonads)
• Intellectual disability(Mental deficiency)
• Iris hypopigmentation(Light eye color)
• Optic disc pallor
• Seizure
• Sleep apnea (Pauses in breathing while sleeping)
• Tremor
• Visual impairment(Impaired vision)

Diagnosis

The diagnosis of riboflavin transporter deficiency neuronopathy is based on clinical, neurophysiologic, neuroimaging, and laboratory findings as well as the identification of biallelic pathogenic variants in either SLC52A2 or SLC52A3 on molecular genetic testing.

Clinical features consist of progressive childhood onset* of the following:

Motor neuronopathy:

• Affecting upper limbs more than lower limbs, resulting in weakness, involving proximal and distal limb musculature, often with severe distal wasting. Deep tendon reflexes are consistently absent.
• Resulting in axial weakness, manifest as severe trunk and neck weakness requiring trunk bracing and difficulty with holding the head up
• Resulting in paralysis of the diaphragm which can result in respiratory insufficiency
• Sensory neuronopathy manifesting as gait ataxia

Cranial neuronopathy: Typically affecting cranial nerves II (optic atrophy variably associated nystagmus), VIII (sensorineural hearing loss), IX and X (bulbar palsy), and XII (tongue fasciculations, weakness, and atrophy) Occasionally affecting cranial nerves III (ptosis) and VII (facial weakness) Cognition is usually preserved.

Neurophysiologic studies

• Electromyogram shows chronic partial denervation.
• Nerve conduction studies show a sensory > motor axonal neuronopathy. Motor nerve conduction velocities are usually normal.
• Sensory nerve action potentials are often absent.
• Visual evoked potentials are frequently abnormal.
• Brain stem audiometry evoked response has universally shown sensorineural deafness.
• EEG (electroencephalogram) may show an excess of theta activity or slow waves [Rosemberg et al 1982].
• Brain MRI is usually normal; however, in a small number of affected individuals cerebellar atrophy and hyperintense areas in the brain stem and cerebral peduncles are observed.

Laboratory findings. Acylcarnitine profile in blood is abnormal with accumulation of short and medium-chain (and sometimes long-chain) acylcarnitines in some but not all individuals with genetically confirmed riboflavin transporter deficiency neuronopathy.

Treatment

High-dose oral supplementation of riboflavin between 10 mg and 50 mg/kg/day improves symptoms and signs on clinical examination, improves objective testing (vital capacity, brain stem evoked potentials, nerve conduction studies), and normalizes acylcarnitine levels. The optimal dose is as yet unknown.

Because oral riboflavin supplementation is effective (and possibly lifesaving), it should begin as soon as a riboflavin transporter deficiency neuronopathy is suspected and continued lifelong unless the diagnosis is excluded by molecular genetic testing.

Supportive care includes: respiratory support; physiotherapy to avoid contractures; occupational therapy to support activities of daily living; orthotics for limb and trunk bracing; speech and language therapy to avoid choking and respiratory problems; wheelchair as needed; low vision aids as needed; routine management of scoliosis to avoid long-term respiratory problems; and routine management of depression.

NIH genetic and rare disease info

• NIH info on Riboflavin transporter deficiency

Riboflavin transporter deficiency is a rare disease.

Riboflavin transporter deficiency Resources
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