Riboflavin Transporter Deficiency

Elisa Cali; Natalia Dominik; Andreea Manole; Henry Houlden

Riboflavin Transporter Deficiency

Cali E, Dominik N, Manole A, et al.

Publication Details

Estimated reading time: 34 minutes

Summary

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.

GeneReview Scope

Riboflavin transporter deficiency (RTD), comprising RTD2 and RTD3 (caused by biallelic pathogenic variants in SLC52A2 and SLC52A3, respectively) is a well-defined phenotypic continuum of motor, sensory, and cranial nerve neuronopathy that encompasses the previously recognized phenotypes Brown-Vialetto-Van Laere (BVVL) syndrome and Fazio-Londe syndrome [Green et al 2010, Johnson et al 2010, Johnson et al 2012, Foley et al 2014].

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 [Kang et al 2020].

Diagnosis

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).

Option 1

Hearing loss panels, myopathy panels, motor neuron disease panels, inborn error of metabolism panels, neuropathy panels and other multigene panels now include SLC52A2 and SLC52A3 along with other genes of interest (see Differential Diagnosis). Multigene panels are most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Riboflavin Transporter Deficiency (RTD)

Clinical Characteristics

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].

Riboflavin Deﬁciency 2 and 3

While most individuals with RTD2 or RTD3 (caused by biallelic pathogenic variants in SLC52A2 or SLC52A3, respectively) present early in life, late onset (ages 10-30 years) has been reported in persons with RTD3. Males and females are equally affected. Table 2 summarizes the frequency of select features in 136 individuals with molecularly confirmed RTD2 and RTD3.

Table 2.

Riboflavin Transporter Deficiency 2 and 3: Select Features

The phenotype of individuals with riboflavin deﬁciency 2 and 3 at onset usually includes hearing impairment and/or sensory ataxia, followed by progressive upper limb weakness, optic atrophy, bulbar weakness, and respiratory failure.The time between the disease onset 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 [Bandettini Di Poggio et al 2014].

Note: When the onset occurs in infancy, after a symptom-free first few weeks (or in some cases months) of life, infants become floppy with failure to thrive and rapidly developing respiratory insufficiency due to paralysis of the diaphragm, followed (in order of appearance) by:

Infantile- or early childhood-onset nystagmus
Early childhood-onset sensory (gait) ataxia
Early-childhood onset progressive and severe sensorineural hearing loss
Weakness and atrophy of the upper limbs (first distally then proximally)
Weakness of neck extensors and later trunk muscles
Tongue fasciculations and atrophy with increased swallowing problems
Respiratory insufficiency due to muscle weakness

Other initial presenting features can include stridor, slurring of speech, and facial weakness. Visual problems due to optic atrophy are common [Bandettini Di Poggio et al 2014, Foley et al 2014, Manole et al 2014, Srour et al 2014, Bamaga et al 2018, Amir et al 2020, Kranthi et al 2020].

Motor neuropathy has been described in 80% of affected individuals. Limb weakness is frequently accompanied by atrophy and involves the upper extremities more than the lower extremities in RTD2. Many also developed axial weakness, with severe weakness of neck extensor and trunk muscles.

Electrophysiologic studies, when performed, were suggestive of peripheral neuropathy in most individuals with RTD, showing chronic denervation and anterior horn dysfunction. Nerve conduction studies suggest an axonal rather than demyelinating neuropathy.

Sensory neuropathy was reported in 34% of individuals. However, most individuals with gait abnormalities/ataxia had RTD2, while only 13% of those with RTD3 had sensory symptoms. Vibration and proprioception are the most severely affected.

Ophthalmologic involvement, the result of optic nerve atrophy, usually manifests as reduced visual acuity and visual field impairment; a few individuals also experience color blindness. Vision loss can progress rapidly or slowly [Bamaga et al 2018, Gorcenco et al 2019, Kranthi et al 2020].

When present, torsional/horizontal nystagmus is one of the early signs of optic atrophy prior to vision loss; thus, RTD should be considered in children with new-onset nystagmus [Amir et al 2020].

Facial weakness. Fifty-five per cent of individuals with RTD3 presented with facial weakness caused by degeneration of cranial nerve VII; this feature was rarely observed in RTD2.

Hearing loss, a presenting manifestation in many individuals, falls within the auditory neuropathy spectrum disorder (ANSD) and is a consequence of cranial nerve VIII degeneration. Otoacoustic emissions (OAE) are usually present while auditory brain stem reflexes (ABR) are abnormal or absent. The hearing loss is usually progressive and severe and can result in complete bilateral deafness (hearing loss >81 decibels). The time between the onset of ANSD and the development of other manifestations of RTD varies but is usually one to two years. Very rarely affected individuals do not develop any hearing impairment, and sometimes it appears later in the disease course [Anderson et al 2019, Mutlu et al 2019, Amir et al 2020].

Bulbar palsy. Signs and symptoms of bulbar palsy are common, being reported in more than 50% of individuals. Most individuals report dysarthria and feeding difficulties resulting from dysphagia. Tongue wasting/fasciculations are common on neurologic examination.

Respiratory involvement, a consequence of neurogenic diaphragm paralysis, is often an early manifestation. Many affected individuals present with breath-holding spells within the first year of the disease course. Therefore, respiratory insufficiency, secondary to muscle weakness, can also be one of the late manifestations of untreated RTD. Artificial respiratory support may be required.

Other features variably seen:

Epilepsy. Some affected individuals had a single seizure-like episode that resolved before the diagnosis of RTD was established and before beginning treatment with riboflavin [Pillai et al 2020, Rabbani et al 2020].
Progressive mental and motor regression [Shi et al 2019, Pillai et al 2020]
Anemia. Although two individuals had riboflavin-responsive severe macrocytic anemia, riboflavin deficiency had been previously associated with mild-moderate anemia [Amir et al 2020, Pillai et al 2020].
Depression. To date, only associated with RTD3 [Rabbani et al 2020, Khani et al 2021]

While the RTD2 and RTD3 phenotypes are difficult to differentiate, in RTD2 early-onset weakness in the upper limbs and neck is almost invariable, in contrast to RTD3 or genetically unclassified Brown-Vialetto-Van Laere (BVVL) syndrome, in which the onset of weakness is often more generalized [Green et al 2010, Bosch et al 2011, Bosch et al 2012, Foley et al 2014].

Life expectancy. Untreated, most infants diagnosed with RTD rapidly become ventilator dependent (often for some years at home or in intensive care units) and most die before age 12 years [Bandettini Di Poggio et al 2014, Foley et al 2014, Manole et al 2014].

Previous data suggest that in 70% of individuals receiving riboflavin supplementation, muscle strength, motor abilities, respiratory function, and cranial nerve deficits improve [O'Callaghan et al 2019]. Death was reported in some individuals if the treatment was discontinued or started too late in the disease course [Jaeger & Bosch 2016].

With improved disease management and riboflavin treatment (see Management), life span is likely to increase; however, the experience with riboflavin supplementation has only been since 2010 [Bosch et al 2011, Horvath 2012, Bandettini Di Poggio et al 2014, Foley et al 2014, Manole et al 2014].

Pathology. Few pathologic descriptions are available. Sural nerve biopsies in individuals with RTD2 and RTD3 previously showed axonal neuropathy and degeneration. In one study, clinical manifestations and MRI findings supported neuronal loss and degeneration in cranial nerve nuclei and tracts and in the brain stem, cerebellum, and spinal cord of individuals with RTD3 [O'Callaghan et al 2019].

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.

Genetically Related (Allelic) Disorders

No phenotypes other than those discussed in this GeneReview are known (or presumed) to be associated with biallelic germline pathogenic variants in SLC52A1, SLC52A2, or SLC52A3.

Sporadic tumors (including esophageal squamous cell carcinomas) occurring as single tumors in the absence of any other findings of riboflavin transporter deficiency frequently harbor somatic pathogenic variants in SLC52A3 that are not present in the germline; thus, predisposition to these tumors is not heritable.

Differential Diagnosis

Table 3.

Genes and Disorders of Interest in the Differential Diagnosis of Riboflavin Transporter Deficiency

Transient neonatal riboflavin deficiency. In the reports of transient riboflavin deficiency in two newborns of mothers heterozygous for an SLC52A1 pathogenic variant, the mothers were asymptomatic whereas the infants had clinical and biochemical features of multiple acyl-CoA dehydrogenase deficiency (MADD) that resolved with riboflavin supplementation. When riboflavin supplementation was discontinued, children both showed normal psychomotor development. In the report of Ho et al [2011] only the mother was heterozygous for the SLC52A1 variant, whereas in the report of Mosegaard et al [2017], both the mother and infant were heterozygous.

Disorders of unknown cause to consider in the differential diagnosis of riboflavin transporter deficiency include the following:

Nathalie syndrome (OMIM 255990) has no lower cranial nerve signs but includes deafness and weakness in addition to spinal muscular atrophy (SMA), cataracts, hypogonadism, and cardiac conduction defects.
Madras motor neuron disease (MMND) (also referred to as Madras pattern motor neuron disease), a rare disorder with early-onset progressive neuromuscular disease with a relatively benign course, has predominantly been observed in southern India. Multiple cranial nerve palsies involve predominately the seventh and ninth to 12th cranial nerves. Hearing impairment is present in all; optic atrophy is present in some. While the majority are simplex cases (i.e., a single occurrence in a family), a few familial cases have been reported. The etiology is unknown; pathogenic variants in SLC52A2 and SLC52A3 as well as C9orf72 have been excluded [Nalini et al 2013].
Facial-onset sensory motor neuronopathy (FOSMN) is a rare, slowly progressive, lower motor neuron disease with sensory compromise, involving mainly the face, bulbar region, and upper limbs. FOSMN syndrome represents a primary neurodegenerative variant of motor neuron disease with TAR DNA-binding protein (TDP)-43 aggregation. While most individuals have an insidious clinical course over the fifth to seventh decades of life, childhood and juvenile onset have been reported [Pinto et al 2019].

Management

No clinical practice guidelines for riboflavin transporter deficiency have been published.

Note: Because SLC25A1-related riboflavin-responsive hyperammonemic seizures have been described in a single individual to date [Kang et al 2020], current information is insufficient to provide management recommendations.

When riboflavin transporter deficiency is suspected during the diagnostic evaluation, begin oral riboflavin supplementation (see Treatment of Manifestations) immediately and continue it lifelong unless the diagnosis is excluded by molecular genetic testing.

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.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with Riboflavin Transporter Deficiency 2 and 3

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).

Table 5.

Supportive Care for Individuals with Riboflavin Transporter Deficiency 2 and 3

Educational Services for Those with Motor and Language Disabilities

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

IEP services:
- An IEP provides specially designed instruction and related services to children who qualify.
- IEP services will be reviewed annually to determine whether any changes are needed.
- Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
- Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
- PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
- As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Surveillance

Table 6.

Recommended Surveillance for Individuals with Riboflavin Transporter Deficiency 2 and 3

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

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.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Cure RTD Foundation
Phone: 403-244-4549
Email: [email protected]
www.curertd.org
MedlinePlus
Riboflavin transporter deficiency neuronopathy
Cure RTD Registry
www.curertd.org/research/rtdregistry

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Riboflavin Transporter Deficiency: Genes and Databases

Table B.

OMIM Entries for Riboflavin Transporter Deficiency (View All in OMIM)

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].

Table 7.

Riboflavin Transporter Deficiency: Gene-Specific Laboratory Technical Considerations

Table 8.

Riboflavin Transporter Deficiency: Notable Pathogenic Variants by Gene

Chapter Notes

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: [email protected] and [email protected]

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

References

Literature Cited

Abbas Q, Jafri SK, Ishaque S, Rahman AJ. Brown-Vialetto-Van Laere syndrome: a novel diagnosis to a common presentation. BMJ Case Rep. 2018;2018:bcr2018224958. [PMC free article: PMC6040568] [PubMed: 29950502]
Amir F, Atzinger C, Massey K, Greinwald J, Hunter LL, Ulm E, Kettler M. The clinical journey of patients with riboflavin transporter deficiency type 2. J Child Neurol. 2020;35:283–90. [PubMed: 31868069]
Anderson P, Schaefer S, Henderson L, Bruce IA. Cochlear implantation in children with auditory neuropathy: lessons from Brown-Vialetto-Van Laere syndrome. Cochlear Implants International. 2019;20:31–8. [PubMed: 30332915]
Babanejad M, Adeli OA, Nikzat N, Beheshtian M, Azarafra H, Sadeghnia F, Mohseni M, Najmabadi H, Kahrizi K. SLC52A2 mutations cause SCABD2 phenotype: a second report. Int J Pediatr Otorhinolaryngol. 2018;104:195–9. [PubMed: 29287867]
Bamaga AK, Maamari RN, Culican SM, Shinawi M, Golumbek PT. Child neurology: Brown-Vialetto-Van Laere syndrome: dramatic visual recovery after delayed riboflavin therapy. Neurology. 2018;91:938–41. [PMC free article: PMC6260193] [PubMed: 30420458]
Bandettini Di Poggio M, Monti Bragadin M, Reni L, Doria-Lamba L, Cereda C, Pardini M, Roccatagliata L, Rossi A, Schenone A. Brown-Vialetto-Van Laere syndrome: clinical and neuroradiological findings of a genetically proven patient. Amyotroph Lateral Scler Frontotemporal Degener. 2014;15:141–4. [PubMed: 24079556]
Bosch AM, Abeling NG, Ijlst L, Knoester H, van der Pol WL, Stroomer AE, Wanders RJ, Visser G, Wijburg FA, Duran M, Waterham HR. Brown-Vialetto-Van Laere and Fazio Londe syndrome is associated with a riboflavin transporter defect mimicking mild MADD: a new inborn error of metabolism with potential treatment. J Inherit Metab Dis. 2011;34:159–64. [PMC free article: PMC3026695] [PubMed: 21110228]
Bosch AM, Stroek K, Abeling NG, Waterham HR, Ijlst L, Wanders RJ. The Brown-Vialetto-Van Laere and Fazio Londe syndrome revisited: natural history, genetics, treatment and future perspectives. Orphanet J Rare Dis. 2012;7:83. [PMC free article: PMC3517535] [PubMed: 23107375]
Carmichael SL, Yang W, Shaw GM. National Birth Defects Prevention Study: maternal dietary nutrient intake and risk of preterm delivery. Am J Perinatol. 2013;30:579–88. [PMC free article: PMC4041277] [PubMed: 23208764]
Carreau C, Benoit C, Ahle G, Cauquil C, Roubertie A, Lenglet T, Cosgrove J, Meunier I, Veauville-Merllié A, Acquaviva-Bourdain C, Nadjar Y. Late-onset riboflavin transporter deficiency: a treatable mimic of various motor neuropathy aetiologies. J Neurol Neurosurg Psychiatry. 2020. Epub ahead of print. [PubMed: 33087424]
Flokas ME, Tomani M, Agdere L, Brown B. Triple A syndrome (Allgrove syndrome): improving outcomes with a multidisciplinary approach. Pediatric Health Med Ther. 2019;10:99–106. [PMC free article: PMC6718240] [PubMed: 31695556]
Foley AR, Menezes MP, Pandraud A, Gonzalez MA, Al-Odaib A, Abrams AJ, Sugano K, Yonezawa A, Manzur AY, Burns J, Hughes I, McCullagh BG, Jungbluth H, Lim MJ, Lin JP, Megarbane A, Urtizberea JA, Shah AH, Antony J, Webster R, Broomfield A, Ng J, Mathew AA, O'Byrne JJ, Forman E, Scoto M, Prasad M, O'Brien K, Olpin S, Oppenheim M, Hargreaves I, Land JM, Wang MX, Carpenter K, Horvath R, Straub V, Lek M, Gold W, Farrell MO, Brandner S, Phadke R, Matsubara K, McGarvey ML, Scherer SS, Baxter PS, King MD, Clayton P, Rahman S, Reilly MM, Ouvrier RA, Christodoulou J, Züchner S, Muntoni F, Houlden H. Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2. Brain. 2014;137:44–56. [PMC free article: PMC3891447] [PubMed: 24253200]
Garg M, Kulkarni SD, Hegde AU, Shah KN. Riboflavin treatment in genetically proven Brown-Vialetto-Van Laere syndrome. J Pediatr Neurosci. 2018;13:471–3. [PMC free article: PMC6413615] [PubMed: 30937093]
Gayathri S, Gowda VK, Udhayabanu T, O'Callaghan B, Efthymiou S, Varalakshmi P, Benakappa N, Houlden H, Ashokkumar B. Brown-Vialetto-Van Laere and Fazio-Londe syndromes: SLC52A3 mutations with puzzling phenotypes and inheritance. Eur J Neurol. 2021;28:945–54. [PubMed: 33325104]
González-Pérez P, Lu Y, Chian RJ, Sapp PC, Tanzi RE, Bertram L, McKenna-Yasek D, Gao FB, Brown RH Jr. Association of UBQLN1 mutation with Brown-Vialetto-Van Laere syndrome but not typical ALS. Neurobiol Dis. 2012;48:391–8. [PMC free article: PMC4245016] [PubMed: 22766032]
Gorcenco S, Vaz FM, Tracewska-Siemiatkowska A, Tranebjærg L, Cremers FPM, Ygland E, Kicsi J, Rendtorff ND, Möller C, Kjellström U, Andréasson S, Puschmann A. Oral therapy for riboflavin transporter deficiency - what is the regimen of choice? Parkinsonism Relat Disord. 2019;61:245–7. [PubMed: 30343981]
Green P, Wiseman M, Crow YJ, Houlden H, Riphagen S, Lin JP, Raymond FL, Childs AM, Sheridan E, Edwards S, Josifova DJ. Brown-Vialetto-Van Laere syndrome, a ponto-bulbar palsy with deafness, is caused by mutations in c20orf54. Am J Hum Genet. 2010;86:485–9. [PMC free article: PMC2833371] [PubMed: 20206331]
Haack TB, Makowski C, Yao Y, Graf E, Hempel M, Wieland T, Tauer U, Ahting U, Mayr JA, Freisinger P, Yoshimatsu H, Inui K, Strom TM, Meitinger T, Yonezawa A, Prokisch H. Impaired riboflavin transport due to missense mutations in SLC52A2 causes Brown-Vialetto-Van Laere syndrome. J Inherit Metab Dis. 2012;35:943–8. [PMC free article: PMC3470687] [PubMed: 22864630]
Ho G, Yonezawa A, Masuda S, Inui K, Sim KG, Carpenter K, Olsen RK, Mitchell JJ, Rhead WJ, Peters G, Christodoulou J. Maternal riboflavin deficiency, resulting in transient neonatal-onset glutaric aciduria Type 2, is caused by a microdeletion in the riboflavin transporter gene GPR172B. Hum Mutat. 2011;32:E1976–84. [PubMed: 21089064]
Horvath R. Update on clinical aspects and treatment of selected vitamin-responsive disorders II (riboflavin and CoQ 10). J Inherit Metab Dis. 2012;35:679–87. [PubMed: 22231380]
Jaeger B, Bosch AM. Clinical presentation and outcome of riboflavin transporter deficiency: mini review after five years of experience. J Inherit Metab Dis. 2016;39:559–64. [PMC free article: PMC4920840] [PubMed: 26973221]
Johnson JO, Gibbs JR, Megarbane A, Urtizberea JA, Hernandez DG, Foley AR, Arepalli S, Pandraud A, Simón-Sánchez J, Clayton P, Reilly MM, Muntoni F, Abramzon Y, Houlden H, Singleton AB. Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease. Brain. 2012;135:2875–82. [PMC free article: PMC3437022] [PubMed: 22740598]
Johnson JO, Gibbs JR, Van Maldergem L, Houlden H, Singleton AB. Exome sequencing in Brown-Vialetto-van Laere syndrome. Am J Hum Genet. 2010;87:567–9. [PMC free article: PMC2948797] [PubMed: 20920669]
Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519–22. [PubMed: 28959963]
Kang U, Yang DH, Nam SO, Lee Y-J, Yeon GM. Riboflavin transporter 1 deficiency caused by a homozygous single exonal deletion of SLC52A1. Ann Child Neurol. 2020;28:160–3.
Khani M, Shamshiri H, Taheri H, Hardy J, Bras JT, Carmona S, Moazzeni H, Alavi A, Heshmati A, Taghizadeh P, Nilipour Y, Ghazanfari T, Shahabi M, Okhovat AA, Rohani M, Valle G, Boostani R, Abdi S, Eshghi S, Nafissi S, Elahi E. BVVL/ FL: features caused by SLC52A3 mutations; WDFY4 and TNFSF13B may be novel causative genes. Neurobiol Aging. 2021;99:102.e1–102.e10. [PubMed: 33189404]
Kranthi P, Garuda BR, Gopi S, Kumar TS. Brown-Vialetto-Van Laere syndrome: a rare case report of MND mimic. Neurol India. 2020;68:1217–9. [PubMed: 33109881]
Manole A, Fratta P, Houlden H. Recent advances in bulbar syndromes: genetic causes and disease mechanisms. Curr Opin Neurol. 2014;27:506–14. [PubMed: 25159929]
Manole A, Jaunmuktane Z, Hargreaves I, Ludtmann MHR, Salpietro V, Bello OD, Pope S, Pandraud A, Horga A, Scalco RS, Li A, Ashokkumar B, Lourenço CM, Heales S, Horvath R, Chinnery PF, Toro C, Singleton AB, Jacques TS, Abramov AY, Muntoni F, Hanna MG, Reilly MM, Revesz T, Kullmann DM, Jepson JEC, Houlden H. Clinical, pathological and functional characterization of riboflavin-responsive neuropathy. Brain. 2017;140:2820–37. [PMC free article: PMC5808726] [PubMed: 29053833]
Mosegaard S, Bruun GH, Flyvbjerg KF, Bliksrud YT, Gregersen N, Dembic M, Annexstad E, Tangeraas T, Olsen RKJ, Andresen BS. An intronic variation in SLC52A1 causes exon skipping and transient riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency. Mol Genet Metab. 2017;122:182–8. [PubMed: 29122468]
Mosegaard S, Dipace G, Bross P, Carlsen J, Gregersen N, Olsen RKJ. Riboflavin deficiency-implications for general human health and inborn errors of metabolism. Int J Mol Sci. 2020;21:3847. [PMC free article: PMC7312377] [PubMed: 32481712]
Mutlu B, Topçu MT, Çiprut A. A case with Brown-Vialetto-Van Laere syndrome: a sudden onset auditory neuropathy spectrum disorder. Turk Arch Otorhinolaryngol. 2019;57:201–5. [PMC free article: PMC7032554] [PubMed: 32128519]
Nalini A, Pandraud A, Mok K, Houlden H. Madras motor neuron disease (MMND) is distinct from the riboflavin transporter genetic defects that cause Brown-Vialetto-Van Laere syndrome. J Neurol Sci. 2013;334:119–22. [PMC free article: PMC4068726] [PubMed: 24139842]
O'Callaghan B, Bosch AM, Houlden H. An update on the genetics, clinical presentation, and pathomechanisms of human riboflavin transporter deficiency. J Inherit Metab Dis. 2019;42:598–607. [PubMed: 30793323]
Pagnamenta AT, Kaiyrzhanov R, Zou Y, Da'as SI, Maroofian R, Donkervoort S, Dominik N, Lauffer M, Ferla MP, Orioli A, Giess A, Tucci A, Beetz C, Sedghi M, Ansari B, Barresi R, Basiri K, Cortese A, Elgar G, Fernandez-Garcia MA, Yip J, Foley AR, Gutowski N, Jungbluth H, Lassche S, Lavin T, Marcelis C, Marks P, Marini-Bettolo C, Medne L, Moslemi AR, Sarkozy A, Reilly MM, Muntoni F, Millan F, Muraresku CC, Need AC, Nemeth AH, Neuhaus SB, Norwood F, O'Donnell M, O'Driscoll M, Rankin J, Yum SW, Zolkipli-Cunningham Z, Brusius I, Wunderlich G; Genomics England Research Consortium, Karakaya M, Wirth B, Fakhro KA, Tajsharghi H, Bönnemann CG, Taylor JC, Houlden H. An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy. 2021;144:584-600. [PMC free article: PMC8263055] [PubMed: 33559681]
Pillai NR, Amin H, Gijavanekar C, Liu N, Issaq N, Broniowska KA, Bertuch AA, Sutton VR, Elsea SH, Scaglia F. Hematologic presentation and the role of untargeted metabolomics analysis in monitoring treatment for riboflavin transporter deficiency. Am J Med Genet A. 2020;182:2781–7. [PubMed: 32909658]
Pinto WBVR, Naylor FGM, Chieia MAT, de Souza PVS, Oliveira ASB. New findings in facial-onset sensory and motor neuronopathy (FOSMN) syndrome. Rev Neurol (Paris). 2019;175:238–46. [PubMed: 30293881]
Rabbani B, Bakhshandeh MK, Navaeifar MR, Abbaskhanian A, Soveizi M, Geravandpoor S, Mahdieh N. Brown-Vialetto-Van Laere syndrome and Fazio-Londe syndrome: a novel mutation and in silico analyses. J Clin Neurosci. 2020;72:342–9. [PubMed: 31959559]
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
Rosemberg S, Lancellotti CL, Arita F, Campos C, de Castro NP Jr. Progressive bulbar paralysis of childhood (Fazio-Londe disease) with deafness. Case report with clinicopathologic correlation. Eur Neurol. 1982;21:84–9. [PubMed: 7094955]
Rossor AM, Kalmar B, Greensmith L, Reilly MM. The distal hereditary motor neuropathies. J Neurol Neurosurg Psychiatry. 2012;83:6–14. [PubMed: 22028385]
Saladini M, Nizzardo M, Govoni A, Taiana M, Bresolin N, Comi GP, Corti S. Spinal muscular atrophy with respiratory distress type 1: clinical phenotypes, molecular pathogenesis and therapeutic insights. J Cell Mol Med. 2020;24:1169–78. [PMC free article: PMC6991628] [PubMed: 31802621]
Shi K, Shi Z, Yan H, Wang X, Yang Y, Xiong H, Gu Q, Wu Y, Jiang Y, Wang J. A Chinese pedigree with Brown-Vialetto-Van Laere syndrome due to two novel mutations of SLC52A2 gene: clinical course and response to riboflavin. BMC Med Genet. 2019;20:76. [PMC free article: PMC6505200] [PubMed: 31064337]
Spagnoli C, Pitt MC, Rahman S, de Sousa C. Brown-Vialetto-van Laere syndrome: a riboflavin responsive neuronopathy of infancy with singular features. Eur J Paediatr Neurol. 2014;18:231–4. [PubMed: 24206674]
Srour M, Putorti ML, Schwartzentruber J, Bolduc V, Shevell MI, Poulin C, O'ferrall E, Buhas D, Majewski J, Brais B, et al. Mutations in riboflavin transporter present with severe sensory loss and deafness in childhood. Muscle Nerve. 2014;50:775–9. [PubMed: 24616084]
Subramanian VS, Kapadia R, Ghosal A, Said HM. Identification of residues/sequences in the human riboflavin transporter-2 that is important for function and cell biology. Nutr Metab (Lond). 2015;12:13. [PMC free article: PMC4367879] [PubMed: 25798182]
Udhayabanu T, Subramanian VS, Teafatiller T, Gowda VK, Raghavan VS, Varalakshmi P, Said HM, Ashokkumar B. SLC52A2 [p.P141T] and SLC52A3 [p.N21S] causing Brown-Vialetto-Van Laere syndrome in an Indian patient: first genetically proven case with mutations in two riboflavin transporters. Clin Chim Acta. 2016;462:210–4. [PMC free article: PMC5521005] [PubMed: 27702554]
Yedavalli VS, Patil A, Shah P. Amyotrophic lateral sclerosis and its mimics/variants: a comprehensive review. J Clin Imaging Sci. 2018;8:53. [PMC free article: PMC6302559] [PubMed: 30652056]

Publication Details

Author Information and Affiliations

Elisa Cali, MD

MRC Centre for Neuromuscular Diseases
UCL Queen Square Institute of Neurology
London, United Kingdom

Email: [email protected]

Natalia Dominik, BSc, MSc

MRC Centre for Neuromuscular Diseases
UCL Queen Square Institute of Neurology
London, United Kingdom

Email: [email protected]

Andreea Manole, BSc, PhD

MRC Centre for Neuromuscular Diseases
UCL Queen Square Institute of Neurology and National Hospital for Neurology and Neurosurgery
London, United Kingdom

Email: [email protected]

Henry Houlden, MD, PhD

Department of Molecular Neurosciences and MRC Centre for Neuromuscular Diseases
UCL Queen Square Institute of Neurology and National Hospital for Neurology and Neurosurgery
London, United Kingdom

Email: [email protected]

Publication History

Initial Posting: June 11, 2015; Last Update: April 8, 2021.

Copyright

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2024 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Publisher

University of Washington, Seattle, Seattle (WA)

NLM Citation

Cali E, Dominik N, Manole A, et al. Riboflavin Transporter Deficiency. 2015 Jun 11 [Updated 2021 Apr 8]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

Gene ¹	Proportion of RTD Attributed to Pathogenic Variants in Gene ²	Proportion of Probands with a Pathogenic Variant ³ Detectable by Method
Gene ¹		Sequence analysis ⁴	Gene-targeted deletion/duplication analysis ⁵
SLC52A2	~44%	60/60 probands ⁷	No large deletions/duplications ⁸
SLC52A3	~56%	76/76 probands ⁹	No large deletions/duplications ⁸

Feature		% of Persons w/Feature
Feature		RTD2 (n=60)	RTD3 (n=76)	RTD2 & RTD3 (n=136)
Age of onset		Mean 3.2 yrs	Mean 8.5 yrs
Peripheral neuropathy		92%	84%	80%-90%
Motor neuropathy (weakness, hypotonia)		77%	80%	80%
Sensory neuropathy (gait abnormality, ataxia)		60%	13%	34%
Cranial neuronopathy	Optic nerve atrophy / ophthalmoplegia	43%	19%
	Facial weakness	34%	55%
	Hearing loss	85%	82%
	Bulbar palsy	55%	62%
Respiratory involvement		48%	57%
Feeding difficulties		23%	41%
Abnormal cranial MRI		19% (7/37)	22% (13/60)

Gene(s)	Disorder	MOI	Clinical Features	Distinguishing Features
AAAS	Achalasia-addisonianism-alacrimia syndrome (AAAS) (OMIM 231550)	AR	Prominent bulbar features; however, achalasia, alacrimia, adrenal problems & autonomic symptoms are the primary manifestations. ¹	Persons w/AAAS have an abnormal, small fissured tongue similar to that in ALS. ²
BSCL2 GARS1	BSCL2- or GARS1-related distal hereditary motor neuropathy (HMN)	AD	Axonal neuropathy w/upper limb-predominant involvement	BSCL2- & GARS1-related distal HMN are not assoc w/optic atrophy, hearing loss, or bulbar dysfunction. ³
C9orf72 FUS SOD1 TARDBP UBQLN2 ⁴ (~30 genes ⁵)	Amyotrophic lateral sclerosis (ALS)	AD AR XL ⁶	Progressive, fatal, neurodegenerative disease involving both brain & spinal cord. Death most often results from failure of respiratory muscles. RTD has been described as an AR juvenile form of ALS since both RTD & ALS have bulbar & LMN involvement.	ALS features that differentiate it from RTD: absence of hearing loss, less prominent bulbar presentations, later onset, asymmetric early presentations, & usually more rapid progression ⁷
ETFA ETFB ETFDH	Neonatal-onset multiple acyl-CoA dehydrogenase deficiency (MADD)	AR	Usually fatal; severe hypoketotic hypoglycemia, metabolic acidosis, multisystem involvement, & excretion of large amts of fatty acid- & amino acid-derived metabolites (biochemical profile similar to RTD)	MADD usually presents w/metabolic decompensation or muscle weakness. Hearing loss has not been described in MADD.
IGHMBP2	Spinal muscular atrophy with respiratory distress 1 (SMARD1) (OMIM 604320)	AR	Typically early-onset (infantile onset is most common) severe axonal polyneuronopathy w/distal muscle & lower-limb weakness & respiratory failure due to diaphragmatic paralysis; ± autonomic involvement, pneumonia, & hypotonia	Deafness has not been described in SMARD1. ⁸
SMN1	Spinal muscular atrophy	AR	Muscle weakness & atrophy due to progressive degeneration & irreversible loss of anterior horn cells in spinal cord & brain stem nuclei. Onset of weakness ranges from before birth to adulthood; weakness is symmetric, proximal > distal, & progressive.	RTD is limited to lower cranial nerves & progresses to death in 1-5 yrs if not treated.
VWA1	10-bp repeat expansion in VWA1 assoc w/HMN	AR	Axonal motor neuropathy w/upper & lower limb involvement, distal & proximal wasting, & tongue fasciculations/atrophy ⁹	Unlike RTD, which has predominantly upper limb involvement, VWA1-assoc HMN more frequently affects lower limbs (upper limb involvement is usually secondary) & most affected persons present w/foot deformities. VWA1-assoc HMN is not assoc w/other bulbar manifestations, optic atrophy, or hearing loss. ⁹

System/Concern	Evaluation	Comment
Constitutional	Measure height, weight, & head circumference.	Weight loss reported in some persons
Motor/sensory neuropathy	Neuromuscular specialist	Assess proximal & distal muscle strength (Rankins scale, MRC strength scale), sensory loss, & gait disturbance (SARA ataxia scale).
Epilepsy	Medical history; EEG
Musculoskeletal	Orthopedics / physical medicine & rehab / PT & OT eval	To assess: Gross motor & fine motor skills Spine for scoliosis Mobility, ADL, & need for bracing &/or adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Optic atrophy	Experienced ophthalmologist	Assess extraocular movement, best corrected visual acuity, color vision testing (Farnsworth test), visual field testing (Goldman perimetry), visual evoked potentials, OCT, fundus exam
Optic atrophy	Vision specialist	Assess for need for visual aids, preferential seating in school.
Sensorineural hearing impairment	Audiologic exam	Incl: ABRs to confirm pathology & provide baseline Evoked OAEs to identify type of hearing impairment Speech discrimination tests Behavioral tests
Speech & language	Speech & language assessment	As indicated
Bulbar dysfunction		Assess for swallowing disorder (dysphagia).
Gastrointestinal/ Feeding	Gastroenterology / nutrition / feeding team eval	Assess aspiration risk & nutritional status; consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
Autonomic dysfunction	Physical exam, medical history	Assess heart rate, temperature, medical history for syncope.
Respiratory involvement	Pulmonary consultation	Sleep study / polysomnography
Depression	Psychiatric consultation	If present
Genetic counseling	By genetics professionals ¹	To inform affected persons & their families re nature, MOI, & implications of riboflavin transporter deficiency in order to facilitate medical & personal decision making
Family support & resources	Assess need for: Community or online resources such as Parent to Parent; Social work involvement for parental support; Home nursing referral.

Manifestation/ Concern	Treatment	Considerations/Other
Poor weight gain / Failure to thrive	Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues.	Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia
Dysphagia		Determine exact cause of swallowing malfunction; modify food types & consistency, head positioning during swallowing, & exercises to improve swallowing. Attn to oral hygiene & dental care, as dysphagia may → impaired clearance of organisms & pathogenic colonization
Musculoskeletal	Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls	Consider need for orthotics for limb & trunk bracing, positioning & mobility devices, & disability parking placard.
Reduced vision	Low vision aids; per ophthalmologist & low vision specialist	Community vision services through early intervention or school district
Ptosis	Per treating ophthalmologist
Sensorineural hearing impairment	Treatment of SNHL depends on degree of hearing impairment. ¹	Educational intervention for the hearing impaired; cochlear implants or hearing aids may be required.
Dysarthria	Speech-language pathologist	Help maintain vocal control; improve speech, breathing techniques, & communication in general
Depression	Depending on severity, treatment may be required.
Epilepsy	Standardized treatment w/ASM by experienced neurologist	Many ASMs may be effective; no one ASM has been demonstrated effective specifically for RTD. Education of parents/caregivers ²
Family needs / social support	Educational services; home nursing care; palliative care consultation

System/Concern	Evaluation	Frequency
Riboflavin supplementation	Discussion of any problems w/riboflavin supplementation Blood sample for riboflavin/FAD/FMN; acylcarnitine analysis (if previous/y abnormal) to determine if they are normalizing	3 mos, 6 mos, & 12 mos after initiation of riboflavin supplementation, then annually or as needed
Neurologic exam	Focused on motor/sensory findings
Musculoskeletal	Orthopedic eval of spine/scoliosis Physical medicine & rehab; OT/PT eval of fine & gross motor skills, ADL
Sensorineural hearing impairment	Audiogram
Epilepsy	Assess new episodes; EEG.
Autonomic dysfunction	Physical exam
Vision loss	Ophthalmologic exam
Speech & language	Eval by speech-language pathologist; consider need for alternative communication.	As needed
Bulbar dysfunction	Assess safety of oral feeding vs need for gastrostomy tube.
Feeding	Assess nutrition, dietary needs.
Respiratory involvement	Assess need for ventilation.
Family support/ resources	Discussion of any problems

Gene	Chromosome Locus	Protein	Locus-Specific Databases	HGMD	ClinVar
SLC52A1	17p13.2	Solute carrier family 52, riboflavin transporter, member 1	SLC52A1 @ LOVD	SLC52A1	SLC52A1
SLC52A2	8q24.3	Solute carrier family 52, riboflavin transporter, member 2	SLC52A2 database	SLC52A2	SLC52A2
SLC52A3	20p13	Solute carrier family 52, riboflavin transporter, member 3	SLC52A3 database	SLC52A3	SLC52A3

211500	FAZIO-LONDE DISEASE
211530	BROWN-VIALETTO-VAN LAERE SYNDROME 1; BVVLS1
607882	SOLUTE CARRIER FAMILY 52 (RIBOFLAVIN TRANSPORTER), MEMBER 2; SLC52A2
607883	SOLUTE CARRIER FAMILY 52 (RIBOFLAVIN TRANSPORTER), MEMBER 1; SLC52A1
613350	SOLUTE CARRIER FAMILY 52 (RIBOFLAVIN TRANSPORTER), MEMBER 3; SLC52A3
614707	BROWN-VIALETTO-VAN LAERE SYNDROME 2; BVVLS2
615026	RIBOFLAVIN DEFICIENCY; RBFVD

Gene ¹	Special Consideration
SLC52A1	While a heterozygous multiexon deletion combined w/homozygous exon 3 deletion was reported in association w/RTD1, this observation may require further investigation [Kang et al 2020].
SLC52A2	To date only nonsynonymous pathogenic variants in the homozygous or compound heterozygous state have been reported in RTD2 [Bosch et al 2012, Spagnoli et al 2014].
SLC52A3	Numerous pathogenic variants have been reported in the homozygous & compound heterozygous state in RTD3. Preliminary data suggest that in some persons heterozygous pathogenic variants in SLC52A3 may be assoc w/RTD in the absence of conditions that lead to riboflavin depletion; however, this hypothesis requires further investigation [Khani et al 2021].

Gene	Reference Sequences	DNA Nucleotide Change	Predicted Protein Change	Comment [Reference]
SLC52A2	NM_024531.4 NP_078807.1	c.916G>A	p.Gly306Arg	Founder variant in the Lebanese population [Foley et al 2014, Srour et al 2014]
SLC52A3	NM_033409.3 NP_212134.3	c.710C>T	p.Ala237Val	Variant w/an unusual pattern of inheritance in 2 related persons of Indian ancestry [Gayathri et al 2021]
SLC52A3	NM_033409.3 NP_212134.3	c.986A>G	p.Tyr329Cys	Preliminary data suggest that some persons heterozygous for this variant may manifest RTD in the absence of circumstances that cause riboflavin depletion, but this hypothesis requires further investigation [Khani et al 2021].