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Riboflavin Transporter Deficiency Neuronopathy

, BSc and , MD, PhD.

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Estimated reading time: 25 minutes

Summary

Clinical description.

Riboflavin transporter deficiency neuronopathy is characterized by motor neuronopathy (manifest as proximal and distal limb weakness, often with severe distal wasting and breathing problems due to paralysis of the diaphragm), sensory neuronopathy (manifest as gait ataxia), and cranial neuronopathy (manifest as optic atrophy, sensorineural deafness, and bulbar palsy). Onset is usually in infancy or in childhood before age eight years; however, on occasion individuals with genetically confirmed disease present in the third decade. When untreated, most infants with riboflavin transporter deficiency rapidly become ventilator dependent and die in the first years of life. In the majority of affected individuals the initial finding is sensorineural deafness, which is usually progressive and severe. The time between the onset of deafness 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.

Diagnosis/testing.

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

Management.

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

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

Supportive care includes: respiratory support; physiotherapy to avoid contractures; occupational therapy to support activities of daily living; orthotics for limb and trunk bracing; speech and language therapy to avoid choking and respiratory problems; wheel chair 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: follow-up physical and neurologic examinations, and measurement of blood riboflavin/FAD/FMN and acylcarnitine analysis. Thereafter, follow up should be biannual in older individuals and more frequent in younger children.

Agents/circumstances to avoid: Dietary restriction of riboflavin.

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 would benefit from early treatment with riboflavin supplementation and monitoring for potential complications of the disorder.

Pregnancy management: Females who have riboflavin transporter neuronopathy or are heterozygous for a pathogenic variant in SLC52A2 or SLC52A3 should have riboflavin supplements before and during pregnancy and when breast feeding to avoid inducing riboflavin deficiency in the baby.

Genetic counseling.

Riboflavin transporter deficiency neuronopathy is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic heterozygote (carrier), and a 25% chance of being unaffected and not a carrier. Heterozygote (carrier) testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the SLC52A2 or SLC52A3 pathogenic variants in the family are known.

GeneReview Scope

Riboflavin Transporter Deficiency Neuronopathy: Included Phenotypes
  • Brown-Vialetto-Van Laere (BVVL) syndrome
  • Fazio-Londe syndrome

For synonyms and outdated names see Nomenclature.

Diagnosis

Riboflavin transporter deficiency neuronopathy is a phenotypic continuum of motor, sensory, and cranial nerve neuronopathy caused by pathogenic variants in either SLC52A2 or SLC52A3 and including the following previously recognized disorders [Fazio 1892, Londe 1894, Dipti et al 2005, Green et al 2010, Johnson et al 2010, Johnson et al 2012, Foley et al 2014]:

  • Brown-Vialetto-Van Laere (BVVL) syndrome
  • Fazio-Londe syndrome; similar to BVVL syndrome but lacking cranial nerve VIII involvement (i.e., deafness)

Suggestive Findings

Riboflavin transporter deficiency neuronopathy should be suspected in individuals with the following clinical, neurophysiologic, neuroimaging, and laboratory findings of motor, sensory, and cranial nerve neuronopathy [Gomez et al 1962, Alexander et al 1976, McShane et al 1992, Sathasivam et al 2000, Dipti et al 2005, Sathasivam 2008, Bosch et al 2011, Horvath 2012, Bandettini Di Poggio et al 2014, Foley et al 2014, Manole et al 2014].

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

  • Motor neuronopathy:
    • Affecting upper limbs more than lower limbs, resulting in weakness, involving proximal and distal limb musculature, often with severe distal wasting. Deep tendon reflexes are consistently absent.
    • Resulting in axial weakness, manifest as severe trunk and neck weakness requiring trunk bracing and difficulty with holding the head up
    • Resulting in paralysis of the diaphragm which can result in respiratory insufficiency
  • Sensory neuronopathy manifesting as gait ataxia
  • Cranial neuronopathy:
    • Typically affecting cranial nerves II (optic atrophy variably associated nystagmus), VIII (sensorineural hearing loss), IX and X (bulbar palsy), and XII (tongue fasciculations, weakness, and atrophy)
    • Occasionally affecting cranial nerves III (ptosis) and VII (facial weakness)

Cognition is usually preserved.

*Note: Onset age range is a few months to early teen years, and very rarely in adulthood.

Neurophysiologic studies

  • Electromyogram shows chronic partial denervation.
  • Nerve conduction studies show a sensory > motor axonal neuronopathy. Motor nerve conduction velocities are usually normal.
  • Sensory nerve action potentials are often absent.
  • Visual evoked potentials are frequently abnormal.
  • Brain stem audiometry evoked response has universally shown sensorineural deafness.
  • EEG (electroencephalogram) may show an excess of theta activity or slow waves [Rosemberg et al 1982].

Brain MRI is usually normal; however, in a small number of affected individuals cerebellar atrophy and hyperintense areas in the brain stem and cerebral peduncles are observed.

Laboratory findings. Acylcarnitine profile in blood is abnormal with accumulation of short and medium-chain (and sometimes long-chain) acylcarnitines in some but not all individuals with genetically confirmed riboflavin transporter deficiency neuronopathy [Bosch et al 2012, Foley et al 2014].

It should be noted that even in children 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].

Establishing the Diagnosis

The diagnosis of riboflavin transporter deficiency neuronopathy is based on the clinical, neurophysiologic, neuroimaging, and laboratory findings described above as well as the identification of biallelic pathogenic variants in either SLC52A2 or SLC52A3 on molecular genetic testing (Table 1).

Molecular testing approaches can include single-gene testing and use of a multigene panel:

  • Single-gene testing. Simultaneous sequence analysis of SLC52A2 and SLC52A3 is performed first and followed by gene-targeted deletion/duplication analysis if only one pathogenic variant is found in either SLC52A2 or SLC52A3. Note: Although subtle differences are observed in the phenotype of individuals with pathogenic variants in SLC52A2 compared with the phenotype of individuals with pathogenic variants in SLC52A3, the phenotypes are sufficiently similar that both genes should be tested at the same time rather than sequentially.
  • A multigene panel that includes SLC52A2 and SLC52A3 as well as other genes of interest selected on potentially similar clinical presentations (see Differential Diagnosis) may also be used. Multigene panels have been developed to include SLC52A1, SLC52A2, SLC52A3, ETFA, ETFB, ETFDH, IGHMBP, ALSIN, ALADIN, and UBQLN1 [Manole et al 2014, Angelini 2015]. 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; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (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.

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

Table 1.

Molecular Genetic Testing Used in Riboflavin Transporter Deficiency Neuronopathy

Gene 1Proportion of Riboflavin Transporter Deficiency Neuronopathy Attributed to Pathogenic Variants in GeneProportion of Probands with a Pathogenic Variant 2 Detectable by Method
Sequence analysis 3, 4Gene-targeted deletion/duplication analysis 5
SLC52A2~30%13/13 probands 6No large deletions/duplications 7
SLC52A3~70%18/18 probands 8No large deletions/duplications 7
Unknown 9Unknown
1.
2.

See Molecular Genetics for information on allelic variants.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

All variants have been detected using Sanger sequencing or next-generation exome sequencing and then Sanger sequencing confirmation.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Foley et al [2014] provide the most extensive screening of SLC52A2: 13 of 72 probands with cranial neuronopathy, sensorimotor neuronopathy, and respiratory insufficiency were found to have biallelic pathogenic variants. Other smaller case series and individual families have been reported as well.

7.

No large deletions/duplications identified using chromosome microarray analysis (CMA) [Manole et al, unpublished data]

8.

Manole [unpublished data] provides the most extensive screening of SLC52A3: Eighteen of 116 individuals with cranial neuropathy and sensorimotor neuropathy ± respiratory insufficiency were found to have biallelic pathogenic variants. Other smaller series and individual families have been reported as well.

9.

A number of individuals with cranial neuropathy and sensorimotor neuropathy ± respiratory insufficiency have not had pathogenic variants identified using exome sequencing and Sanger sequencing [Manole unpublished data]. In a number of individuals large deletions/duplications in SLC52A1, SLC52A2, and SLC52A3 (see Molecular Genetics) were excluded using CMA [Manole et al, unpublished data].

Clinical Characteristics

Clinical Description

Riboflavin transporter deficiency neuronopathy is characterized by motor neuronopathy (manifest as proximal and distal limb weakness, often with severe distal wasting [Bandettini Di Poggio et al 2014, Foley et al 2014, Manole et al 2014] and breathing problems), sensory neuronopathy (manifest as gait ataxia), and cranial neuronopathy (manifest as optic atrophy, sensorineural deafness, and bulbar palsy).

Onset is usually in infancy or in childhood before age eight years, although on occasion individuals with genetically confirmed disease present in the third decade.

Typically, 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
  • Childhood onset sensorineural deafness
  • 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 [Gomez et al 1962, Alexander et al 1976, Summers et al 1987, Abarbanel et al 1991, Dipti et al 2005, Nemoto et al 2005, Descatha et al 2006, Malheiros et al 2007, Miao et al 2007, Dakhil et al 2010, Green et al 2010, Bosch et al 2011, Bandettini Di Poggio et al 2014, Foley et al 2014, Manole et al 2014, Srour et al 2014].

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

In the majority of affected individuals presenting after infancy the initial finding is sensorineural deafness, which is usually progressive and severe. The time between the onset of deafness and the development of other symptoms varies but is usually one to two years. Very rarely affected individuals do not develop deafness, and sometimes deafness appears later in the disease course.

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

In some individuals an intercurrent event, usually an injury or infection, appears to precipitate the initial symptoms or worsen existing symptoms [Gallai et al 1981, Voudris et al 2002, Bandettini Di Poggio et al 2014].

Other neurologic features can include: occasional sensory involvement, retinitis pigmentosa and macular hyperpigmentation, autonomic dysfunction, and epilepsy.

The phenotypes caused by pathogenic variants in SLC52A2 are difficult to differentiate from those caused by pathogenic variants in SLC52A3; however, in individuals with pathogenic variants in SLC52A2 early-onset weakness in the upper limbs and neck is almost invariable – in contrast to those with pathogenic variants in SLC52A3 or genetically unclassified Brown-Vialetto-Van Laere (BVVL) syndrome, in whom the onset of weakness is often more generalized [Green et al 2010, Bosch et al 2011, Bosch et al 2012, Foley et al 2014].

Other neurophysiologic studies. Electrocardiogram showed incomplete right bundle branch block in one individual [Mégarbané et al 2000].

Sleep studies demonstrated predominantly central sleep apnea with minimal obstructive sleep apnea in one individual [Miao et al 2007].

CSF protein is often raised but <1 g/dL [Foley et al 2014].

Pathology. Few pathologic descriptions of riboflavin transporter deficiency neuronopathy are available. The authors know of only one pathologic description of an archival genetically confirmed case; however, findings were similar to those in individuals who had not undergone molecular genetic testing [Johnson et al 2010]. There was usually neuronal injury and loss in cranial nerve nuclei III, V, VI and lower cranial nerve nuclei (VII – XII); depletion of spinal anterior horn cells, lateral columns, and pyramidal tracts; and degeneration of cerebellar Purkinje cells and basal ganglia [Rosemberg et al 1982, Summers et al 1987, Abarbanel et al 1991].

Genotype-Phenotype Correlations

To date no genotype-phenotype correlations have been identified in SLC52A2 or SLC52A3 [Author, personal observation].

Nomenclature

Childhood-onset progressive bulbar palsy developing in the first and second decade of life was traditionally separated into Brown-Vialetto-Van Laere (BVVL) syndrome and Fazio-Londe syndrome (a BVVL-like syndrome without deafness). It is now known that Brown-Vialetto-Van Laere syndrome and Fazio-Londe syndrome are caused by biallelic pathogenic variants in either SLC52A2 or SLC52A3.

Bosch et al [2012] and Foley et al [2014] have proposed new BVVL syndrome nomenclature to clarify the specific mechanism of disease: riboflavin transporter deficiency neuronopathy, type 2 (corresponding with SLC52A2-associated disease) and riboflavin transporter deficiency neuronopathy, type 3 (corresponding with SLC52A3-associated disease).

BVVL syndrome was first reported in 1894 by Charles Brown as an "infantile" form of ALS with associated hearing loss [Brown 1894]. The male index case manifested an acute onset of bulbar weakness, hearing loss and respiratory insufficiency at age 12 years, with rapid progression of symptoms and later involvement of the upper limbs as well as "general arrest of development and emaciation." The report of three sibs with pontobulbar paralysis and associated hearing loss by Dr. Ernesto Vialetto in 1936 [Vialetto 1936] followed by the report of three sisters with similar clinical features by MJ Van Laere in 1966 resulted in the term BVVL syndrome being used to describe this pontobulbar palsy [Van Laere 1966].

Hereditary progressive bulbar palsy without deafness has also been described and referred to as Fazio-Londe syndrome [Fazio 1892, Londe 1894]; it was initially described in a mother and her son and later reported in two brothers with a more rapidly progressive syndrome.

Prevalence

Although riboflavin transporter deficiency neuronopathy is a relatively rare condition, it appears to be more prevalent than previously thought given the advent of molecular genetic testing, which has improved diagnostic capabilities [Foley et al 2014]. Based on the number of individuals screened for pathogenic variants in SLC52A2 and SLC52A3, the authors estimate 70 new diagnoses worldwide per year; however, it is difficult to provide a precise figure at this stage [Manole et al, unpublished data based on genetic referral numbers].

Differential Diagnosis

Multiple acyl-CoA dehydrogenase deficiency (MADD) (also known as glutaric acidemia II or glutaric aciduria II) (OMIM 231680) can be caused by biallelic pathogenic variants in at least three different genes: ETFA, ETFB, and ETFDH. These genes are all involved in electron transfer in the mitochondrial respiratory chain [Olsen et al 2007, Law et al 2009].

The clinical features of MADD are grouped into three types:

  • Neonatal-onset form with congenital anomalies (type I)
  • Neonatal-onset form without congenital anomalies (type II)
  • Late-onset form (type III)

The neonatal-onset forms, which are usually fatal, are characterized by severe hypoketotic hypoglycemia, metabolic acidosis, multisystem involvement, and excretion of large amounts of fatty acid- and amino acid-derived metabolites.

Symptoms and age at presentation of late-onset MADD are highly variable and characterized by proximal muscle weakness, recurrent episodes of lethargy, vomiting, hypoglycemia, metabolic acidosis, and hepatomegaly often preceded by metabolic stress [Law et al 2009]. Neuronopathy is not observed in MADD.

In MADD acylcarnitine analysis usually reveals increased concentrations of several short-chain, medium-chain, and long-chain acylcarnitines. In individuals with late-onset disease, abnormalities may be mild, atypical, or only detectable during decompensation.

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) (OMIM 604320) is an "SMA plus" syndrome caused by biallelic pathogenic variants in IGHMBP2 (encoding immunoglobulin mu-binding protein 2), usually leading to early-onset severe axonal polyneuronopathy with distal muscle and lower-limb weakness and respiratory failure due to diaphragmatic paralysis. Infantile onset is most common. There may also be autonomic involvement, pneumonia, and hypotonia; deafness has not been described [Yiu et al 2008].

Spinal muscular atrophy (caused by pathogenic variants in SMN1) mostly involves the anterior horn cells of motor neurons; however, some affected individuals may have peripheral motor and sensory nerve involvement [Yiu et al 2008].

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 [Cremers et al 1975, Sathasivam 2008].

Madras motor neuron disease (MMND) (also referred to as Madras pattern motor neuron disease), a rare young age-onset progressive neuromuscular disease with a relatively benign course, has predominantly been observed in southern India. Multiple cranial nerve palsies particularly involve the seventh and ninth to 12th cranial nerves. Hearing impairment is present in all patients; optic atrophy is present in some. Although the majority are simplex cases (i.e., a single occurrence in a family), a few familial cases have been reported. The etiology is unknown; mutation of SLC52A2 and SLC52A3 as well as C9orf72 has been excluded [Valmikinathan et al 1973, Shankar et al 2000, Nalini et al 2013].

Facial onset sensory motor neuronopathy (FOSMN) is a recently described under-recognized, rare, slowly progressive bulbar onset motor and sensory neuronopathy [Vucic et al 2012]. Although there are marked similarities to classic bulbar-onset motor neuron disease, FOSMN differs clinically by the striking facial-onset sensory deficits with subsequent development of motor deficits, slow evolution in a rostral-caudal direction, and a much better prognosis. The finding of TDP-43 pathology in an individual with FOSMN suggests an overlap with motor neuron disease, although further evidence and studies are needed. The heterozygous variant Asp90Ala was identified in SOD1 in a patient with FOSMN [Dalla Bella et al 2014]; its role in causation of MND is unclear.

Allgrove or triple A syndrome (OMIM 231550), caused by pathogenic variants in ALADIN, is a rare autosomal recessive disorder that has prominent bulbar features, although achalasia, alacrima, and adrenal problems are the primary manifestations [Houlden et al 2002]. Of note, affected individuals also have an abnormal, small fissured tongue similar to that of individuals with amyotrophic lateral sclerosis (ALS) [Houlden 2009, Manole et al 2014].

Amyotrophic lateral sclerosis (ALS) is characterized by adult-onset degeneration of motor neurons in the corticospinal tract and brain stem, and the anterior horn cells of the spinal cord. Patients have upper motor neuron (UMN) and lower motor neuron (LMN) limb signs with progressive muscle weakness and wasting, fasciculations, and spasticity. Patients often die of respiratory paralysis [Hardiman et al 2011]. BVVL has been described as an autosomal recessive juvenile form of ALS since both BVVL and ALS have bulbar and LMN involvement. BVVL differs from ALS in that BVVL includes deafness and has an earlier age of onset and a more irregular disease course; UMN limb signs are not invariably present [Hardiman et al 2011].

Of note, pathogenic variants in UBQLN2 (encoding ubiquilin 2) have been identified as a rare cause of ALS; a recent study has identified a heterozygous variant in a related gene (UBQLN1) previously linked to neurodegeneration in an individual with BVVL and an atypical early-onset ALS with bulbar palsy and hearing loss. Although the pathogenicity of this variant remains uncertain, this finding highlights the overlap of the BVVL and ALS phenotypes [González-Pérez et al 2012].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with riboflavin transporter deficiency neuronopathy, the following are recommended:

  • Evaluation by a neuromuscular specialist with attention to possible weakness, sensory loss, gait disturbance, and need for bracing
  • Sleep study and pulmonary consultation
  • Ophthalmologic evaluation with attention to visual acuity and possible optic atrophy
  • Audiologic assessment
  • Other consultations depending on clinical problems; for example, orthopedic consultation if scoliosis is present or psychiatry consultation if depression is present
  • Rehabilitation assessments: physiotherapy, occupational therapy, orthotics, speech and language therapy, wheel chair clinic
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Medications

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

High-dose supplementation of riboflavin between 10 mg and 50 mg/kg/day has been effective in patients with genetically confirmed riboflavin transporter deficiency neuronopathy and also in some patients in whom the genetic basis of riboflavin transporter deficiency neuronopathy has not been established.

Although no formal placebo control trial has been conducted and the longest course of riboflavin supplementation has been 36 months, riboflavin supplementation: improves symptoms and signs on clinical examination; improves objective testing (vital capacity, brain stem evoked potentials, nerve conduction studies), and normalizes acylcarnitine levels [Foley et al 2014].

Before initiating riboflavin supplementation, perform the assessments in Evaluations Following Initial Diagnosis.

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

  • Riboflavin 10 mg/kg per day in 3 doses for 1 month
  • Riboflavin 20 mg/kg per day in 3 doses for 1 month
  • Riboflavin 30 mg/kg per day in 3 doses for 1 month
  • Riboflavin 40 mg/kg per day in 3 doses for 1 month
  • Riboflavin 50 mg/kg per day in 3 doses for 1 month

Note: Some patients are on doses up to 70 mg/kg/day.

Side effects, problems, or deterioration at any point require discussion with the treating clinician.

See Surveillance for recommended follow up of individuals treated with riboflavin supplementation.

Note: Treatments attempted before the basis of riboflavin transporter deficiency neuronopathy was known have included the following:

  • Intravenous immunoglobulin (IVIG) has been tried in a number of patients with reports of improvement as well as reports of no or non-sustained response [Bandettini Di Poggio et al 2014].
  • Some patients have reported additional improvement with other multivitamins and coenzyme Q10.

Supportive Care

The following are appropriate:

  • Respiratory support
  • Physiotherapy to avoid contractures
  • Occupational therapy for support in activities of daily living
  • Orthotics for limb and trunk bracing
  • Hearing aids and appropriate educational intervention for those with sensorineural hearing loss
  • Speech and language therapy to avoid choking and respiratory problems
  • Wheel chair as needed
  • Low vision aids for those with decreased visual acuity
  • Routine management of scoliosis to avoid long term respiratory problems
  • Routine management of depression

Surveillance

Recommended follow up at three months and six months after initiation of riboflavin supplementation:

  • General examination
  • Neurologic examination
  • Discussion of any problems with riboflavin supplementation
  • Ideally, obtaining a blood sample for riboflavin/FAD/FMN, acylcarnitine analysis (if previous evaluation demonstrated abnormalities) to determine if these levels are normalizing

After one year of riboflavin supplementation, repeat examination/investigations as detailed in Evaluation Following Initial Diagnosis except for consultation with a medical geneticist/genetic counselor.

Agents/Circumstances to Avoid

Avoid dietary restriction of riboflavin. If not possible to avoid dietary restriction, provide riboflavin supplements.

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 a proband with riboflavin transporter deficiency neuronopathy to identify as early as possible those with biallelic pathogenic variants who would benefit from early treatment with riboflavin supplementation and monitoring for potential complications of the disorder.

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

Pregnancy Management

Females who have riboflavin transporter deficiency neuronopathy 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 doses during pregnancy are 10 mg/kg/day.

Few studies have evaluated for adverse fetal outcome 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 [Wacker et al 2000, Carmichael et al 2013].

Note: Although no data are available, the authors recommend a diet rich in riboflavin during pregnancy for females who are heterozygous for a pathogenic variant in either SLC52A2 or SLC52A3 as it is unknown if they are at increased risk of developing symptoms due to an increased demand for riboflavin during pregnancy.

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, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Riboflavin transporter deficiency neuronopathy is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one SLC52A2 or one SLC52A3 pathogenic variant).
  • Under normal dietary conditions carriers have no symptoms. Theoretically, carriers could have symptoms of riboflavin transporter deficiency neuronopathy if other conditions that lead to riboflavin depletion (e.g., dietary restriction, malnourishment, pregnancy, and/or illness) co-occur (see Pregnancy Management).

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Under normal dietary conditions carriers have no symptoms. Theoretically, carriers could have symptoms of riboflavin transporter deficiency neuronopathy if other conditions that lead to riboflavin depletion (e.g., dietary restriction, malnourishment, pregnancy, and/or illness) co-occur (see Pregnancy Management).

Offspring of a proband. The offspring of an individual with riboflavin transporter deficiency neuronopathy are 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 (Heterozygote) 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

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the SLC52A2 or SLC52A3 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

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.

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 Neuronopathy: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

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

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

Molecular Pathogenesis

SLC52A2 and SLC52A3 encode transmembrane proteins (hRFVT2 and hRFVT3, respectively) that mediate cellular uptake of riboflavin. The water-soluble vitamin riboflavin is converted to the coenzymes flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), and is essential for normal cellular functions. These coenzymes are essential in a number of cellular processes such as normal mitochondrial function.

Although a third member of this gene family, SLC52A1 encoding hRFVT1, has not been implicated directly in riboflavin transporter deficiency neuronopathy to date [Chiong et al 2007; Ho et al 2011; Manole, unpublished data on 116 cases], a de novo heterozygous SLC52A1 deletion of exons 2 and 3 was identified in the mother of a child with multiple neurologic and systemic abnormalities [Ho et al 2011].

Early-onset weakness in the upper limbs and neck is almost invariably seen in persons with biallelic pathogenic variants in SLC52A2 in contrast to those with biallelic pathogenic variants in SLC52A3 or genetically unclassified BVVL syndrome, in whom the onset of weakness is often more generalized [Green et al 2010, Bosch et al 2011, Bosch et al 2012, Foley et al 2014]. This observation could be explained by the tissue distribution of the transporters: hRFVT1 and hRFVT3 are mainly localized in the small intestinal epithelial cells and may be complimentary. In particular, hRFVT3 may transport sufficient riboflavin to prevent profound RF deficiency when there is haploinsufficiency of hRFVT1. Expression of hRFVT2 is primarily in the brain, explaining the normal circulating levels of flavins, but transport of riboflavin into the brain is impaired in hRFVT2 deficiency resulting in abnormal metabolism [Yonezawa & Inui 2013].

SLC52A2

Gene structure. SLC52A2 produces a 1900-bp transcript, four coding exons of 445 amino acids (NM_024531.4). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Pathogenic variants in SLC52A2 are distributed throughout the gene in regions encoding transmembrane, intracellular, and extracellular loops [Dezfouli et al 2012, Foley et al 2014]. Only nonsynonymous pathogenic variants in the homozygous or compound heterozygous state have been reported in SLC52A2 to date [Bosch et al 2012, Spagnoli et al 2014].

An SLC52A2 founder pathogenic variant has been described (NM_024531.4:c.916G>A; p.Gly306Arg) in the Lebanese population [Foley et al 2014, Srour et al 2014].

No large insertions or deletions have been found to date [Johnson et al 2012, Green et al 2010, Johnson et al 2010, Foley et al 2014].

See Table 2 (pdf) for information on pathogenic variants in SLC52A2.

In vitro analysis of specific SLC52A2 pathogenic variants

  • Reduced riboflavin uptake was observed when the SLC52A2 p.Leu123Pro and p.Leu339Pro pathogenic variants were expressed in HEK293 cells [Haack et al 2012].
  • Riboflavin uptake was reduced in fibroblasts of a patient with the SLC52A2 pathogenic variants p.[Gly419Ser];[Ser52Phe]; residual activity was 29% of controls when cells were grown in low riboflavin medium (0.4 nM) [Ciccolella et al 2013]. In this patient, SLC52A2 mRNA expression was significantly reduced (45%), while SLC52A1 mRNA expression was unaffected; however, the protein levels of both RFVT1 and RFVT2 were undetectable. In vitro studies of the parents' fibroblasts suggested that the p.Ser52Phe variant may impair SLC52A2 mRNA stability, while the p.Gly419Ser variant may affect protein function.
  • Foley et al [2014] determined the 3H-riboflavin transport activities and protein expression in HEK293 cells transiently expressing the following SLC52A2 variants: p.Trp31Ser, p.Gln234Stop, p.Ala284Asp, p.Tyr305Cys, p.Gly306Arg, p.Leu312Pro, and p.Leu339Pro. Cells expressing the variants displayed the greatest reduction in riboflavin uptake. The expression levels of all SLC52A2 pathogenic variants were reduced, except p.Trp31Ser, for which expression remained near wild-type levels in the plasma membrane [Foley et al 2014].

Normal gene product. SLC52A2 encodes solute carrier family 52, riboflavin transporter, member 2 (also known as riboflavin transporter 2 [hRFVT2]) comprising 445 amino acid residues.

Abnormal gene product. See Molecular Pathogenesis; see Table 2 (pdf) for a summary of in vitro expression studies of SLC52A2 pathogenic variants.

SLC52A3

Gene structure. SLC52A3 produces a 2716-bp transcript, four coding exons of 469 amino acids (NM_033409.3). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Pathogenic variants in SLC52A3 are distributed throughout the gene in regions encoding the transmembrane, intracellular, and extracellular loops [Dezfouli et al 2012, Foley et al2014].

Thus far, nonsynonymous, stop-gain, frameshift, and splice-site altering pathogenic variants have been identified in the homozygous or compound heterozygous state [Bosch et al 2012]. No large insertions or deletions have been identified to date [Green et al 2010, Johnson et al 2010, Johnson et al 2012, Foley et al 2014].

See Table 2 (pdf) for pathogenic variants in SLC52A3.

Normal gene product. SLC52A3 encodes solute carrier family 52, riboflavin transporter, member 3 (also known as riboflavin transporter 3 [hRFVT3]) comprising 469 amino acid residues.

Abnormal gene product. The following SLC52A3 pathogenic variants have been shown to cause reduced riboflavin uptake: Trp17Arg, Pro28Thr, Glu36Lys, Glu71Lys, and Arg132Trp. Confocal imaging of these mutated proteins showed that they were retained within the endoplasmic reticulum as opposed to the cell surface [Nabokina et al 2012].

Cancer and Benign Tumors

Genome-wide association studies (GWAS) have shown that sporadic esophageal squamous cell carcinomas are associated with rs13042395 and rs3746804 in SLC52A3 [Ji et al 2012, Palmer et al 2012, Piao et al 2014].

References

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Chapter Notes

Author Notes

MRC Centre for Neuromuscular Diseases

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

Emails for correspondence: ku.ca.lcu@31.elonam.aeerdna 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 (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre (BRC).

Revision History

  • 11 June 2015 (me) Review posted live
  • 2 September 2014 (am) Original submission
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