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.

Suggestive Findings

Riboflavin transporter deficiency 2 (RTD2) and riboflavin transporter deficiency 3 (RTD3) should be suspected in individuals with the following clinical, neurophysiologic, brain MRI, and laboratory findings.

Clinical features. Progressive, usually childhood onset (range: a few months to early teen years; very rarely adulthood) of the following:

• Cranial neuronopathy
  • Very frequently affecting cranial nerves II (optic atrophy with bilateral symmetric optic nerve pallor, variably associated nystagmus) and VIII (sensorineural hearing loss is one of the initial findings)
  • Frequently affecting cranial nerves IX and X (bulbar palsy), and XII (tongue fasciculations, weakness, and atrophy)
  • Occasionally affecting cranial nerves III (ptosis) and VII (facial weakness)
• Motor neuropathy
  • 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 neuropathy manifesting as gait ataxia

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. Usually normal; however, in a small number of affected individuals cerebellar atrophy and abnormal T₂-weighted hyperintensity in the cerebellar, cortical, subcortical, and brain stem regions are observed.

Laboratory findings

• Acylcarnitine profile in blood is abnormal with accumulation of short- and medium-chain (and sometimes long-chain) acylcarnitine in some but not all individuals with molecularly confirmed RTD [Bosch et al 2012, Foley et al 2014].
• Note: Even in children with RTD diagnosed in the first months of life with abnormal acylcarnitine profiles, newborn screening bloodspots demonstrated normal acylcarnitine profiles, probably due to sufficient maternal riboflavin supply to the unborn infant [Bosch et al 2011].

Riboflavin transporter deficiency 1 should be considered (based on preliminary observations) in an infant with recurrent seizures with unexplained hyperammonemia [Kang et al 2020].

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

Establishing the Diagnosis

The diagnosis of riboflavin transporter deficiency (RTD) is established in a proband with suggestive clinical, neurophysiologic, neuroimaging, and laboratory findings and biallelic pathogenic (or likely pathogenic) variants in either SLC52A2 (RTD2) or SLC52A3 (RTD3) on molecular genetic testing (Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of either biallelic SLC52A2 or SLC52A3 variants of uncertain significance (or of one known SLC52A2 or SLC52A3 pathogenic variant and one SLC52A2 or SLC52A3 variant of uncertain significance) does not establish or rule out a diagnosis of the disorder. (3) In the only child reported to date with presumed RTD1, the complex genotype requires further investigation (see Molecular Genetics).

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using multigene panel testing (see Option 1), whereas those in whom the diagnosis of RTD has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Riboflavin transporter deficiency 2 (caused by biallelic SLC52A2 pathogenic variants) and riboflavin transporter deficiency 3 (caused by biallelic SLC52A3 pathogenic variants) are clinically characterized by motor neuropathy, sensory neuropathy, and cranial neuronopathy [Bandettini Di Poggio et al 2014, Foley et al 2014, Manole et al 2014]. Motor neuropathy manifests as proximal and distal limb weakness (often with severe distal wasting and breathing problems due to paralysis of the diaphragm), sensory neuropathy as gait ataxia, and cranial neuronopathy as optic atrophy, sensorineural hearing loss, and bulbar palsy.

In contrast, RTD1 (possibly caused by biallelic SLC52A1 pathogenic variants), reported in a single case report, may manifest in infancy as generalized or focal tonic-clonic seizures, metabolic acidosis, and hyperammonemia, responsive to riboflavin supplementation [Kang et al 2020].

Genotype-Phenotype Correlations

See Table 2 for a comparison of select clinical findings by gene.

Nomenclature

Other terms used to refer to riboflavin transporter deficiency:

• Brown-Vialetto-Van Laere (BVVL) syndrome (corresponding with either SLC52A3- or SLC52A2-related disease) and Fazio-Londe syndrome (a BVVL-like syndrome without deafness caused by SLC52A3 pathogenic variants)
• SLC52A2-related riboflavin transporter deficiency may be referred to as spinocerebellar ataxia with blindness and deafness type 2 (SCABD2)[Babanejad et al 2018].

Prevalence

Although riboflavin transporter deficiency (RTD) is relatively rare, the advent of molecular genetic testing has improved diagnostic capabilities, making RTD appear more prevalent than previously thought [Foley et al 2014].

It is difficult to establish the prevalence of RTD. It may be underdiagnosed and misdiagnosed; however, it is estimated that RTD affects one in 1,000,000 people in the general population.

SLC52A2. The founder pathogenic variant c.916G>A;p.Gly306Arg has been described in the Lebanese population [Foley et al 2014, Srour et al 2014].

SLC52A3. No founder variants have been reported.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with riboflavin transporter deficiency, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

High-dose supplementation of riboflavin (vitamin B₂). Riboflavin supplementation is effective and possibly lifesaving. It is recommended that treatment begin as soon as RTD is suspected and continue lifelong unless molecular genetic testing fails to identify biallelic pathogenic variants in either SLC52A2 or SLC52A3. Before initiating riboflavin supplementation, perform the assessments in Table 4.

High-dose supplementation of riboflavin (10-50 mg/kg/day) has been effective in individuals with molecularly confirmed riboflavin transporter deficiency and, also in some individuals in whom the genetic basis of riboflavin transporter deficiency has not been established.

The amount of riboflavin given varies depending on the severity and response of the individual to the treatment. It has been reported that doses <10 mg/kg/day are ineffective [O'Callaghan et al 2019], whereas doses >80 mg/kg/day may have minimal side effects.

Oral riboflavin supplementation should be given in gradually increasing doses in order to establish the optimal dose:

1.

Riboflavin 10 mg/kg/day in 3 doses for 1 month

2.

Riboflavin 20 mg/kg/day in 3 doses for 1 month

3.

Riboflavin 30 mg/kg/day in 3 doses for 1 month

4.

Riboflavin 40 mg/kg/day in 3 doses for 1 month

5.

Riboflavin 50 mg/kg/day in 3 doses for 1 month

Note: Theoretically, parenteral administration of riboflavin may increase uptake and effect [Gorcenco et al 2019].

Side effects reported after high-dose riboflavin supplementation, when present, can include diarrhea, increased urination, and urine discoloration. Allergic reactions have been described rarely. Side effects, problems, or deterioration at any point require discussion with the treating clinician.

Open-label studies have reported improvement of motor symptoms or neurophysiologic measurements or hearing level in a third of individuals treated with up to 500 mg riboflavin three times per day. However, no randomized controlled trials have been performed [Foley et al 2014, Jaeger & Bosch 2016].

Positive clinical response to the treatment could occur with some latency; thus, riboflavin therapy should be continued in all suspected or genetically diagnosed RTD cases even when there is no apparent initial clinical improvement [O'Callaghan et al 2019].

Better response to the treatment is reported when given earlier in life or in the disease course. Adulthood-onset or late treatment are frequently associated with non-improvement, likely reflecting neuronal damage.

Supportive care by multidisciplinary specialists including the following are recommended: pulmonology; orthopedics, rehabilitation medicine, physical therapy and occupational therapy; speech and language therapy; feeding team including gastroenterology, nutritionists; low vision specialist; and mental health specialists (see Table 5).

Surveillance

Agents/Circumstances to Avoid

Avoid dietary restriction of riboflavin and consume riboflavin-rich foods such as meat, eggs, and milk.

Metabolic stress caused by increased physical activity can decrease levels of riboflavin; therefore, excessive exercise should be limited.

Evaluation of Relatives at Risk

When the SLC52A2 or SLC52A3 pathogenic variants in the family are known (or if a proband is found to have biallelic SLC52A1 pathogenic variants presumed to be associated with RTD1), it is appropriate to perform molecular genetic testing on the older and younger sibs of a proband with RTD to identify those with biallelic pathogenic variants who would benefit from early treatment with riboflavin supplementation and monitoring for potential complications of the disorder.

If the pathogenic variants are not known, riboflavin should be administered for both diagnostic and therapeutic purposes if a younger sib of a proband presents with typical symptoms or signs of RTD.

See Pregnancy Management for information about riboflavin supplementation in women who are heterozygous for an SLC52A1, SLC52A2, or SLC52A3 pathogenic variant.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Females with biallelic RTD-causing pathogenic variants. Females who have riboflavin transporter deficiency with biallelic pathogenic variants in either SLC52A2 or SLC52A3 should take riboflavin supplements before and during pregnancy and when breast feeding to avoid inducing riboflavin deficiency in the fetus and infant. Recommended dose during pregnancy is 10 mg/kg/day.

Females heterozygous for an RTD-causing pathogenic variant. The authors recommend a diet rich in riboflavin during pregnancy for females who are heterozygous for an RTD-related pathogenic variant. Young women heterozygous for an RTD-causing pathogenic variant should also receive counseling regarding the possibility of further riboflavin supplementation, if necessary, during pregnancy and when breastfeeding, to avoid risks of riboflavin deficiency in both mother and offspring.

• Transient neonatal riboflavin deficiency (see Differential Diagnosis) has been reported in offspring of a mother heterozygous for an SLC52A1 pathogenic variant who became riboflavin deficient during pregnancy; her riboflavin-deficient newborn experienced neonatal seizures responsive to riboflavin supplementation. It is unknown if the offspring of females heterozygous for a SLC52A2 or SLC52A3 pathogenic variant may also be at increased risk for neonatal riboflavin deficiency.
• Although no data are available, heterozygous females may be at increased risk of developing symptoms due to an increased demand for riboflavin during pregnancy.

Few studies have evaluated for adverse fetal outcomes after excessive maternal riboflavin intake during pregnancy. Riboflavin deficiency during pregnancy, however, has been associated with an increased risk of maternal preeclampsia and preterm delivery [Carmichael et al 2013].

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Riboflavin transporter deficiency 2 (RTD2) and RTD3 – caused by biallelic pathogenic variants in SLC52A2 or SLC52A3, respectively – are inherited in an autosomal recessive manner.

Preliminary data from a single case report suggests that RTD1 is caused by biallelic pathogenic variants in SLC25A1 and inherited in an autosomal recessive manner [Kang et al 2020]. Because further study is needed to confirm this observation, RTD1 is not discussed further in this section.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one SLC52A2 or one SLC52A3 pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an SLC52A2 or SLC52A3 pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Most heterozygous individuals do not have manifestations of RTD. Theoretically, heterozygotes may have manifestations of RTD if other conditions that lead to riboflavin depletion (e.g., dietary restriction, malnourishment, pregnancy, and/or illness) co-occur (see Pregnancy Management). Preliminary research data suggest that in some individuals heterozygous pathogenic variants in SLC52A3 may be associated with RTD in the absence of conditions that lead to riboflavin depletion; however, this hypothesis requires further research [Khani et al 2021].

Sibs of a proband

• If both parents are known to be heterozygous for an SLC52A2 or SLC52A3 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-related pathogenic variants.
• Most heterozygous individuals do not have manifestations of RTD. Theoretically, heterozygotes may have manifestations of RTD if other conditions that lead to riboflavin depletion (e.g., dietary restriction, malnourishment, pregnancy, and/or illness) co-occur (see Pregnancy Management).Preliminary research data suggest that in some individuals heterozygous pathogenic variants in SLC52A3 may be associated with RTD in the absence of conditions that lead to riboflavin depletion; however, this hypothesis requires further research [Khani et al 2021].

Offspring of a proband. Unless an affected individual's reproductive partner also has RTD or is a carrier, offspring will be obligate heterozygotes (carriers) for an SLC52A2 or SLC52A3 pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an SLC52A2 or SLC52A3 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the SLC52A2 or SLC52A3 pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• Young women with RTD should receive counseling regarding riboflavin supplementation both before and during pregnancy and when breast feeding to avoid inducing riboflavin deficiency in the fetus and infant (see Pregnancy Management).
• Women found to be heterozygous (carriers) for a pathogenic variant in SLC52A1 are recommended a diet rich in riboflavin during pregnancy, and should receive counseling regarding the possibility of riboflavin supplementation before and during pregnancy and when breastfeeding to avoid neonatal riboflavin deficiency. Although no data are available, the same approach should be considered in women who are heterozygous for a pathogenic variant in SLC52A2 or SLC52A3 to avoid the possibility of riboflavin deficiency in the fetus and infant.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Once the SLC52A2 or SLC52A3 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

SLC52A1, SLC52A2, and SLC52A3 encode the transmembrane proteins (hRFVT1, hRFVT2, and hRFVT3, respectively) that mediate cellular uptake of riboflavin (vitamin B₂) in the intestine (as well as in the stomach, duodenum, colon, and rectum) and reabsorption in the kidney [Subramanian et al 2015, Udhayabanu et al 2016, Mosegaard et al 2020]. SLC52A1 is highly expressed in the placenta and hRFVT1 is the only one of the three proteins to transport riboflavin to the fetus. The water-soluble vitamin riboflavin is then converted to the coenzymes flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which are essential for mitochondrial function and electron transfer in oxidation-reduction reactions [Udhayabanu et al 2016].

Mechanism of disease causation. Loss of function. The pathogenic variants in SLC52A2 and SLC52A3 that cause loss of function may include missense, nonsense, frameshift, and splice site variants that reduce riboflavin uptake or riboflavin transporter protein expression [Haack et al 2012, Foley et al 2014, Manole et al 2017].

Author Notes

MRC Centre for Neuromuscular Diseases

The authors are interested in neuromuscular diseases, channelopathies, and neurodevelopmental disorders; their work involves both the genetics and the functional aspects of these disorders.

Emails for correspondence: ku.ca.lcu@ilac.e and ku.ca.lcu@nedluoh.h

Acknowledgments

The authors would like to thank the patients and their families for their essential help with this work. This study was supported by the Medical Research Council UK, the Wellcome Trust, and the Brain Research Trust (BRT). This study was also supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre (NIHR-UCLH-BRC).

Revision History

• 8 April 2021 (bp) Comprehensive update posted live
• 11 June 2015 (me) Review posted live
• 2 September 2014 (am) Original submission

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