Clinical description: Riboflavin transporter deficiency (RTD), comprising RTD2 and RTD3 (caused by biallelic pathogenic variants in SLC52A2 and SLC52A3, respectively) is a rare neurologic condition characterized by progressive peripheral and cranial neuronopathy that causes muscle weakness (and consequent respiratory compromise), vision loss, deafness, and sensory ataxia. Onset is usually in infancy or in childhood; however, on occasion individuals with genetically confirmed RTD present as adults and even as late as the fifth decade. When untreated, most infants with riboflavin transporter deficiency rapidly become ventilator dependent and die in the first decade of life.

In the majority of affected individuals, the initial finding is sensorineural hearing loss, which is usually progressive and severe. The time between the onset of hearing loss and the development of other manifestations varies but is usually one to two years. In some individuals an intercurrent event, usually an injury or infection, appears to precipitate the initial manifestations or worsen existing findings.

One case report (which requires additional confirmation) suggests that biallelic expression of pathogenic variants in SLC52A1 (i.e., RTD1) is associated with infantile-onset of riboflavin-responsive seizures associated with hyperammonemia.

Diagnosis/testing: The diagnosis of RTD2 and RTD3 is established in an individual with suggestive findings and biallelic pathogenic variants in either SLC52A2 or SLC52A3, respectively, identified on molecular genetic testing.

Management: Treatment of manifestations: High-dose oral supplementation of riboflavin (vitamin B₂) 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. Liquid riboflavin is available but is often difficult to obtain; therefore, riboflavin capsules are often opened and mixed with food such as yogurt. The amount of riboflavin supplementation varies depending on the severity of the disease and response of the individual to the treatment. When riboflavin supplementation is given earlier in the disease course, the response can be very good; if given later in the disease course, the response is less, likely reflecting the effect of existing neuronal damage.

Because oral riboflavin supplementation is effective (and possibly lifesaving), it should begin as soon as a riboflavin transporter deficiency is suspected and continued lifelong unless molecular genetic testing fails to identify biallelic pathogenic variants in either SLC52A2 or SLC52A3.

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.

Surveillance: At three months and six months after initiation of riboflavin supplementation, routine follow-up physical and neurologic examinations, measurement of blood riboflavin/FAD/FMN, and analysis of blood acylcarnitine profile. Thereafter, follow up is usually biannually in older individuals and more frequently in younger children.

Agents/circumstances to avoid: Dietary restriction of riboflavin and strenuous physical activity.

Evaluation of relatives at risk: When the SLC52A2 or SLC52A3 pathogenic variants in the family are known, it is appropriate to perform molecular genetic testing on the older and younger sibs of an affected individual to identify as early as possible those who are affected and would benefit from early treatment with riboflavin supplementation and monitoring for potential complications of the disorder.

Pregnancy management: A diet rich in ribolflavin is recommended for women who have RTD or are heterozygous for a pathogenic variant in either SLC52A2 or SLC52A3. If necessary, riboflavin supplements should be taken before and during pregnancy and when breast feeding to avoid inducing riboflavin deficiency in the baby.

Genetic counseling: RTD caused by biallelic pathogenic variants in either SLC52A2 (RTD2) or SLC52A3 (RTD3) is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an RTD-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the familial RTD-causing pathogenic variants. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible if both RTD-causing pathogenic variants have been identified in an affected family member.