Riboflavin Transporter Deficiency (Brown-Vialetto-Van Laere and Fazio-Londe)

Deficiency of the RFVT2 and RFVT3 transporters (SLC52A2 and SLC52A3 genes), with maternal RFVT1 (SLC52A1) deficiency as a related form

Literature and regulatory information updated: 1 November 2026.

0. Initial Reference Table

1. Introduction

1.1 Definition and scope

Riboflavin transporter deficiency (RTD) is a progressive hereditary neuronopathy affecting the cranial nerves, the motor neurons of the anterior horn of the spinal cord and the sensory neurons of the dorsal root ganglia. It results from insufficient uptake of riboflavin (vitamin B2) through plasma membrane transporters. GeneReviews defines the disease as a phenotypic continuum of motor, sensory and cranial neuronopathy caused by biallelic variants in SLC52A2 (RTD2) or SLC52A3 (RTD3), encompassing the historical entities known as Brown-Vialetto-Van Laere (BVVL) syndrome and Fazio-Londe syndrome [2]. Orphanet classifies it as a rare genetic motor neuron disease with peripheral and cranial neuropathy, neuronal loss in the anterior horns and atrophy of the spinal sensory tracts, leading to muscle weakness, sensory loss, diaphragmatic palsy with respiratory failure and cranial nerve deficits such as sensorineural hearing loss, bulbar signs and visual loss due to optic atrophy [5].

This article covers the complete class of riboflavin transport deficiencies. The two main forms are RTD2, linked to the RFVT2 transporter, which predominates in nervous tissue, and RTD3, linked to the intestinal transporter RFVT3. The third entity is maternal riboflavin deficiency, due to haploinsufficiency of the placental and intestinal transporter RFVT1 (SLC52A1), which causes transient metabolic decompensation in the newborn [5, 15]. Defects of intracellular flavin metabolism, such as FAD synthase deficiency (FLAD1) and mitochondrial FAD transporter deficiency (SLC25A32), produce myopathy with a multiple acyl-CoA dehydrogenase deficiency (MADD) profile and form part of the differential diagnosis [15].

The disease has a targeted, low-cost and generally well-tolerated treatment: high-dose oral riboflavin supplementation. Without treatment, most infants become ventilator-dependent and die in the first decade; with treatment, about 70% to 90% of patients improve, and the response depends on how early treatment is started [2, 21].

1.2 Historical overview

The first case was described by Charles Henry Brown in 1894 as "infantile amyotrophic lateral sclerosis of the family type". This was followed by descriptions of familial cases with a pattern consistent with autosomal recessive inheritance by Ernesto Vialetto in 1936, by Van Laere in 1966 and by Boudin and colleagues in 1971; most of the early familial cases occurred in girls [3]. In the same year, 1894, Londe described two brothers aged 5 and 6 years, children of first cousins, with progressive infantile familial bulbar palsy; Marinesco described in 1915 a 12-year-old girl and her 8-year-old brother without pyramidal involvement, and the cases attributed to Fazio were, according to Gomez and colleagues (1962), a mother and her son aged 4 and a half years [4]. The eponym Fazio-Londe came to designate progressive bulbar palsy of childhood without deafness, and the eponym Brown-Vialetto-Van Laere pontobulbar palsy with sensorineural deafness [3, 4].

Gallai and colleagues published in 1981 the clinical and neuropathological description of three cases, including a girl who became deaf at 2 years of age and developed multiple cranial and spinal palsies at 14 years [3]. In 1990, Hawkins, Nevin and Harding described a family in which the father, a paternal uncle and possibly a cousin had sensorineural deafness and a paternal aunt had the full picture, and raised the hypothesis of genetic heterogeneity with autosomal recessive and dominant or X-linked forms [22]. In 2005, Dipti and colleagues described four Pakistani siblings born to consanguineous parents: two presented with stridor in the first 16 months and died of respiratory failure before 2 years of age without apparent deafness, and were diagnosed with Fazio-Londe; the other two developed bulbar palsy at 5 and 7 years, followed by deafness and anterior horn neuropathy with corticospinal signs. The authors proposed that BVVL and Fazio-Londe were a single disease, a juvenile form of amyotrophic lateral sclerosis (ALS) [23].

1.3 Molecular discovery

In 2010, Green and colleagues identified, by autozygosity mapping in a consanguineous Pakistani family, variants in the C20orf54 gene, later named SLC52A3, and found eight variants in nine patients from seven families [8, 24]. In the same year, Johnson and colleagues confirmed the gene by exome sequencing in a Turkish family with three affected members [25]. Bosch and colleagues linked the defect to metabolism in 2011: three infants with progressive weakness and diaphragmatic palsy had plasma acylcarnitine and urinary organic acid profiles suggestive of mild MADD and profound plasma flavin deficiency despite normal dietary intake; C20orf54 sequencing showed pathogenic variants, and high-dose riboflavin rapidly improved the clinical and biochemical picture, which inaugurated targeted treatment [26]. Two of these patients were siblings homozygous for the same variant, one with a Fazio-Londe picture and the other with BVVL, which confirmed the identity of the two entities [27].

In 2012, Johnson and colleagues identified, by linkage analysis and exome sequencing in an extended Lebanese family negative for SLC52A3, a variant in SLC52A2, the second gene of the riboflavin transporter family; among 44 patients screened they found the same variant in one additional case and two cases with SLC52A3 variants, and none in SLC52A1 [28]. In the same year, Haack and colleagues described biallelic missense variants in SLC52A2 that reduced transporter activity [29]. In 2014, Foley and colleagues characterised 18 patients from 13 families with RTD2 and documented sustained clinical and biochemical responses to high-dose riboflavin [16]. The first human genetic defect of riboflavin transport had been described in 2011, in a mother with a de novo deletion of exons 2 and 3 of SLC52A1 whose newborn had transient MADD [14].

1.4 Nomenclature and reclassifications

Bosch and colleagues proposed in 2012 renaming the disease according to its mechanism, as riboflavin transporter deficiency types 1, 2 and 3 [27]. GeneReviews adopted the designations RTD2 (SLC52A2) and RTD3 (SLC52A3) and lists the synonyms BVVL (for either gene) and Fazio-Londe (BVVL-type syndrome without deafness, caused by SLC52A3) [2]. OMIM retains the historical numbering in the reverse order of the transporters: BVVLS1 (211530) corresponds to SLC52A3 and BVVLS2 (614707) to SLC52A2; Fazio-Londe disease (211500) is linked to SLC52A3 with the provisional relationship symbol, because it is based on a single family [1, 3, 4]. The designation spinocerebellar ataxia with blindness and deafness (SCABD) was assigned in 2000 to an Arab-Israeli family wrongly linked to chromosome 6p21; Guissart and colleagues showed in 2016 that this family carried the SLC52A2 variant p.(Gly306Arg) in the homozygous state and proposed the term SCABD2 for SLC52A2-related disease, reserving SCABD1 for the PEX6-related form. The 2019 consensus classification of recessive ataxias listed SLC52A2-related ataxia as SCAR3/BVVLS2, and OMIM retains SCAR3 as a former title in both entries [1, 30]. Some recent publications swap the correspondence between eponyms and genes, assigning BVVL to SLC52A2 and Fazio-Londe to SLC52A3 [31]; this article follows the correspondence used by OMIM and GeneReviews.

2. Molecular Genetics and Pathophysiology

2.1 Riboflavin metabolism

Riboflavin is a water-soluble vitamin that the human body does not synthesise; milk and dairy products are important dietary sources in Western diets [15]. It is the precursor of flavin mononucleotide (FMN), a cofactor of respiratory chain complex I, and of flavin adenine dinucleotide (FAD), a cofactor of complex II and of many dehydrogenation reactions, including the acyl-CoA dehydrogenases of mitochondrial beta-oxidation, electron transfer flavoprotein (ETF) and its dehydrogenase (ETFDH) [15, 26]. Within the cell, riboflavin is phosphorylated to FMN, which is converted to FAD by FAD synthase, which has a mitochondrial isoform (FADS1) and a cytoplasmic isoform (FADS2) generated by alternative splicing; FAD enters the mitochondrion through the mitochondrial folate and FAD transporter (SLC25A32), and the existence of a mitochondrial riboflavin transporter has been postulated but not proven [15]. Flavins are also involved in the conversion of vitamins B6 and B9 into their active forms, which may explain the haematological abnormalities observed in some patients [31, 32].

Three transporters of the SLC52 family mediate cellular riboflavin uptake. RFVT1 (SLC52A1) and RFVT3 (SLC52A3) are responsible for intestinal absorption; RFVT2 (SLC52A2) ensures transport into the tissues, particularly the brain [15]. GeneReviews adds that all three transporters act in the stomach, duodenum, colon and rectum and in renal reabsorption, and that RFVT1, highly expressed in the placenta, is the only one that transports riboflavin to the fetus [2].

2.2 The genes and proteins

Table sources: [2, 7–10, 15]. The SLC52A2 and SLC52A1 genes were first identified as receptors 1 and 2 for porcine endogenous retrovirus subgroup A, with implications for xenotransplantation, before their transporter function was known [7, 9]. In comparative studies in transfected HEK293 cells, all three transporters took up riboflavin in a time- and concentration-dependent manner, independently of extracellular sodium and chloride; uptake was abolished by excess unlabelled riboflavin or lumiflavin and modestly inhibited by FMN; only RFVT3 lost activity when extracellular pH rose from 5.4 to 8.4, and only RFVT2 was inhibited, slightly, by FAD [9].

2.3 Disease mechanism

The mechanism is loss of function. Missense, nonsense, frameshift and splice variants reduce riboflavin uptake or transporter protein expression [2]. In the functional studies of Foley and colleagues, SLC52A2 variants reduced or abolished labelled riboflavin uptake in HEK293 cells and decreased protein expression: p.(Gly306Arg) caused a moderate but significant reduction, and p.(Leu339Pro), p.(Ala284Asp) and p.(Tyr305Cys) abolished uptake [7, 16]. In fibroblasts from a patient with p.(Ser52Phe) and p.(Gly419Ser), RFVT2 messenger RNA was at 45% of normal, the protein was undetectable and riboflavin transport was at 29% [7].

In RTD3, the intestinal transporter defect reduces absorption and produces systemic deficiency, documented in the first patients by low plasma concentrations of riboflavin, FMN and FAD [26]. In RTD2, intestinal absorption is maintained by the RFVT1 and RFVT3 transporters, and plasma concentrations are often normal; the deficit lies mainly in entry into nervous tissue [1, 16, 32]. Intracellular FAD deficiency compromises the acyl-CoA dehydrogenases and complex II, which explains the acylcarnitine profile resembling mild MADD found in about half to 60% of patients [15, 18]. The efficacy of high-dose riboflavin is attributed to increased intracellular riboflavin, FMN and FAD through residual transporter activity and passive diffusion [21].

The selective vulnerability of neurons of the auditory and optic pathways, motor neurons and sensory ganglia remains unexplained. Studies in motor neurons derived from induced pluripotent stem cells (iPSC) from patients with RTD2 show reduced expression of neuronal markers, less developed neuronal networks and shorter neurites, and earlier studies by the same group described abnormalities of the cytoskeleton, antioxidant response and calcium metabolism, partially corrected by riboflavin and antioxidants [33]. Tolomeo and colleagues showed in 2026 that RFVT2 forms homodimers and that pathogenic variants impair dimerisation, with signs of endoplasmic reticulum stress in motor neurons and mitochondrial and calcium-signalling dysfunction in fibroblasts, without a reduction in FAD content; the authors propose an additional proteotoxic mechanism, so far restricted to cell models [34]. The available neuropathology shows neuronal loss and degeneration in the cranial nerve nuclei and tracts, brainstem, cerebellum and spinal cord in RTD3, and axonal neuropathy with loss of large myelinated fibres without regeneration in the sural nerve in RTD2 [2, 16]. At the autopsy of a patient with RTD3, Johnson and colleagues described replacement gliosis of the cranial nuclei, mainly at the bulbopontine level, with mild anterior horn involvement [3].

2.4 Inheritance pattern

RTD2 and RTD3 are transmitted in an autosomal recessive manner [1–3]. The sources nevertheless record observations that do not fit this model completely. Hawkins and colleagues suggested in 1990 a dominant form in a family with deafness in several relatives [22]. Several patients with a compatible phenotype have only one identified variant in SLC52A3: an 18-year-old French woman with a juvenile ALS picture, subclinical auditory neuropathy and marked improvement with riboflavin [35]; a 68-year-old Portuguese woman with onset at 12 years and slow progression [11]; and carriers of p.(Tyr329Cys) studied by Khani and colleagues [2]. Li and colleagues described in 2025 a Chinese family in which a heterozygous carrier of p.(Asn21Ser) had optic nerve dysfunction and considered incomplete penetrance and possible dominant transmission [12]. In an Indian family, homozygosity for p.(Ala237Val) in mother and son produced a pseudodominant pattern explained by consanguinity [36]. The 2026 systematic review included a patient with one variant in SLC52A2 and another in SLC52A3 who responded to riboflavin [21]. Overall, recessive inheritance is established; manifestation in isolated heterozygotes remains a hypothesis with preliminary data, and an undetected second variant (deep intronic, regulatory or structural) has not been excluded in these cases. Maternal RFVT1 deficiency is different: the heterozygous mother has haploinsufficiency (classified as autosomal dominant by Orphanet), and the newborn suffers a transient deficiency [5, 14].

2.5 Variant spectrum

Up to 2021, GeneReviews recorded 60 probands with RTD2 and 76 with RTD3; in all, sequencing identified the variants, and no large deletions or duplications had been described [2]. In RTD2 only non-synonymous variants in the homozygous or compound heterozygous state had been described; in RTD3, the spectrum includes missense, nonsense, splice and frameshift variants [2]. The following table brings together the most frequently cited variants, described according to Human Genome Variation Society (HGVS) nomenclature and normalised in VariantValidator to the MANE Select transcript, with the ClinVar classification consulted on 1 November 2026. For SLC52A2, the coding numbering of NM_024531.4 matches that of the MANE transcript NM_001363118.2 for all variants checked [10].

Table sources: [2, 6–8, 10, 16, 17, 36–39]. Two nomenclature corrections result from validation. The V413A variant, described in OMIM as 1237T>C, does not match the reference sequence at that position, and the correct notation is c.1238T>C p.(Val413Ala) [10, 37]. OMIM states that L339P is also designated c.968T>C p.(Leu323Pro) in NM_024531.4, but the two descriptions correspond to different genomic positions (g.144360604T>C and g.144360460T>C) and are not synonymous [7, 10]. p.(Gly306Arg) may result from c.916G>A or c.916G>C, both classified as pathogenic [31, 37]. For SLC52A1, OMIM describes the exon 4 intronic variant as c.234+11G>A on a non-existent transcript; identifier rs141935493 and ClinVar correspond to NM_017986.4:c.1134+11G>A (NC_000017.11:g.5033250C>T), a notation confirmed in VariantValidator [9, 10, 37].

2.6 Genotype-phenotype correlations, penetrance and expressivity

The differences between the genes are statistical and do not allow the genotype to be predicted from the clinical picture. In RTD2, early weakness of the upper limbs and neck is almost invariable and sensory ataxia is frequent (60%), whereas in RTD3 weakness is more generalised, facial weakness is more common (55% versus 34%) and sensory ataxia is rare (13%) [2]. Within the same gene, truncating variants are associated with earlier onset: in the Arabian Peninsula study, patients homozygous for c.1325_1326del developed symptoms at 6 and 8 months, and those homozygous for c.634C>T between 7 and 23 years [17]. Expressivity varies even between siblings with the same genotype: in the Omani cohort, the age at onset of symptomatic individuals overlapped with the age of the oldest asymptomatic carrier, 21 years, suggesting interaction with environmental factors or modifiers [17]. Reduced riboflavin intake can precipitate the disease, as shown by three previously healthy young adults who became ill after reducing their consumption of meat and dairy products [40], and intercurrent events such as infections or trauma can trigger or aggravate the manifestations [2].

2.7 Allelic disorders and modifiers

GeneReviews does not recognise other germline allelic disorders of SLC52A1, SLC52A2 or SLC52A3 [2]. Sporadic oesophageal squamous cell carcinomas frequently carry somatic SLC52A3 variants, without hereditary predisposition, and OMIM records a pending association of common SLC52A3 variation with susceptibility to oesophageal squamous cell carcinoma and gastric cardia adenocarcinoma [2, 8]. The association of a UBQLN1 variant with a clinical BVVL picture is of uncertain pathogenicity [2, 3]. A child with RTD2 due to paternal uniparental isodisomy of chromosome 8, which renders homozygous a variant inherited from a single parent, has been described [41].

3. Clinical Spectrum and Manifestations by Organ System

3.1 Overview and frequency of manifestations

RTD2 and RTD3 present with motor neuropathy, sensory neuropathy and cranial neuronopathy [2]. Motor neuropathy results in proximal and distal limb weakness, often with severe distal atrophy and diaphragmatic palsy; sensory neuropathy results in gait ataxia; and cranial neuronopathy results in optic atrophy, sensorineural hearing loss and bulbar palsy [2]. Cognition is generally preserved [2, 16]. The most common initial presentation is hearing loss or sensory ataxia, followed, usually within one to two years, by progressive upper limb weakness, optic atrophy, bulbar weakness and respiratory failure; an intercurrent event, such as an infection or trauma, can precipitate the manifestations [2]. The following table summarises the frequency of manifestations in 136 patients with a molecular diagnosis, compiled by O'Callaghan, Bosch and Houlden in 2019 [2, 42].

Before the molecular era, Bosch and colleagues reviewed 74 patients with onset before 18 years of age published up to 2012 (23 male, 51 female), diagnosed on clinical grounds only. The most frequent manifestations were bulbar palsy (92%), hearing loss (81%), facial weakness (77%) and respiratory compromise (64%). In those with onset between 0 and 3 years, respiratory compromise and bulbar palsy predominated (86% each), with weakness and hearing loss in 67%; between 4 and 10 years, bulbar palsy was present in all, facial weakness in 95% and hearing loss in 90%; between 11 and 17 years, bulbar palsy, hearing loss and facial weakness were the most frequent (89%, 86% and 82%) [27]. GeneReviews indicates that both sexes are equally affected, despite the excess of girls in the early series [2, 27].

3.2 Auditory nervous system

Hearing loss is often the first manifestation and falls within the auditory neuropathy spectrum disorder (ANSD), owing to degeneration of cranial nerve VIII: otoacoustic emissions are usually present and brainstem auditory evoked potentials (BAEP) are abnormal or absent [2]. Hearing loss is usually progressive and severe and may reach complete bilateral deafness (greater than 81 dB); rarely there is no hearing loss, or it appears late in the course [2]. It may develop over weeks: a 12-year-old girl described by Hawkins developed sensorineural deafness within a few weeks, and a Turkish patient had sudden hearing loss at 10 years of age [3]. In the Chinese auditory neuropathy cohort, hearing loss in patients with RTD2 began between 6 months and 4 years and ranged from mild to profound [38]. In a series of ten children with RTD2 in the USA, hearing loss had been recognised in only 40% before diagnosis [43].

3.3 Visual system

Optic atrophy results in reduced visual acuity and visual field, and some patients have dyschromatopsia; visual loss may progress quickly or slowly [2]. Torsional or horizontal nystagmus may be an early sign of optic atrophy, before recognised visual loss, so RTD should be considered in children with new-onset nystagmus [2]. Optic atrophy was present in 93% of Foley's 18 patients with RTD2 [1]. In three children with RTD2 studied by optical coherence tomography, the retinal ganglion cell layer and retinal nerve fibre layer were thin but measurable 7 years after onset, with acuities of 20/30 and 20/60 and preserved colour vision [44]. Ptosis and ophthalmoplegia occur occasionally, mainly in RTD3 [2, 15].

3.4 Lower cranial nerves and bulbar function

Bulbar palsy occurs in more than 50% of patients and manifests as dysarthria, dysphagia, and tongue atrophy and fasciculations; facial diparesis is more frequent in RTD3 (55%) [2]. Stridor due to vocal cord palsy may be the presentation, especially in infants and in RTD3 [2, 4]. In the Arabian Peninsula cohort, with 13 symptomatic patients with RTD3, facial diparesis was present in 12, dysarthria in 10, hearing loss in 10 and vocal cord paresis in 8 [17].

3.5 Peripheral neuromuscular system

Weakness affects the upper limbs more than the lower limbs, with severe distal atrophy, claw hand and consistently absent tendon reflexes; axial weakness of the neck and trunk requires orthoses and prevents head control [1, 2]. In RTD2, Foley and colleagues described as the core phenotype a rapidly progressive axonal sensorimotor neuropathy, with sensory ataxia, severe weakness of the upper limbs and axial muscles and relatively preserved lower limb strength [16]. Sensory ataxia is due to severe loss of vibration and proprioceptive sensation and was the most common presentation (9 of 18 patients) [1, 16]. A Lebanese family homozygous for G306R presented mainly with severe progressive sensory loss, with hearing loss in childhood and marked weakness and atrophy of the upper limbs [45]. Upper motor neuron signs (hyperreflexia, clonus, Babinski sign) are rare but have been described [3, 32].

3.6 Respiratory system

Neurogenic diaphragmatic palsy is often early and is the main cause of death [2, 27]. Many patients have apnoeic episodes or respiratory arrest in the first year of illness, and nocturnal hypoventilation with daytime sleepiness often precedes overt respiratory failure [2, 3]. In Foley's RTD2 cohort, 13 of 18 patients developed respiratory failure, and one died at 3 and a half years of subacute respiratory failure despite ventilation [16]. In the Sydney series of children with RTD2, obstructive sleep apnoea was documented in four patients, three of whom required continuous positive airway pressure overnight [32].

3.7 Extraneurological and other manifestations

Severe riboflavin-responsive macrocytic or megaloblastic anaemia and, in Chinese children, pure red cell aplasia as the presenting form of RTD2 have been described [2, 43, 46–48]. In the Sydney series, six of ten children assessed had microcytosis and three had microcytic anaemia at some point, which the authors relate to the dependence of vitamin B6 on riboflavin to form pyridoxal 5'-phosphate, a cofactor in haem synthesis [32]. Other occasional manifestations are an isolated seizure, psychomotor regression and depression, the latter described only in RTD3 [2, 17]. Scoliosis occurred in 8 of 11 children with RTD2, with a median age at diagnosis of 11 and a half years [32]. Magnetic resonance imaging is usually normal; a small number of patients have cerebellar atrophy and T2 hyperintensity in the cerebellum, cortex, subcortical regions and brainstem [2].

3.8 Forms by age at onset

In the infantile form, after weeks or months without symptoms, the child becomes hypotonic, with faltering growth and rapidly developing respiratory failure due to diaphragmatic palsy, followed by nystagmus, sensory ataxia, severe hearing loss, weakness of the upper limbs (first distal, then proximal), neck extensors and trunk, tongue fasciculations and dysphagia [2]. Bosch's cases exemplify this form: a 6-month-old boy with apnoeic episodes, head lag and complete diaphragmatic palsy, and his 3-month-old sister with faltering growth and axial weakness [26].

In the childhood form, the most frequent presentation in RTD2 is sensory ataxia at around 2 to 3 years of age, followed by hearing loss and nystagmus [32, 43]. In Amir's American series, abnormal gait or ataxia was present in 70% in the first year, nystagmus in 50% and upper limb weakness in 40%; the mean diagnostic delay was 27.6 months and mitochondrial disease was the most common suspicion before diagnosis (30%) [43].

Adolescent and adult forms are more frequent in RTD3, with onset between 10 and 30 years and cases up to the fifth decade [2]. Carreau and colleagues brought together six French patients with motor neuropathy beginning after 10 years of age and 19 cases from the literature: 56% had a picture resembling ALS or distal hereditary motor neuropathy, 16% multiple mononeuropathy with cranial nerve involvement, 8% a picture resembling Guillain-Barré syndrome and 20% mixed motor and sensory neuronopathy (only with SLC52A2); deafness preceded motor neuropathy in 44%, but 16% began with motor neuropathy alone, and classic pontobulbar palsy was not constant [49]. In the Arabian Peninsula, patients homozygous for c.634C>T developed symptoms at a median of 13 years (range 9 to 23 years), none required ventilation and the manifestations were mainly craniofacial [17]. Late and slowly progressive forms have been described: a European man developed neuropathy in his twenties and was alive at 57 years without respiratory compromise [8], and a Portuguese woman developed hearing loss at 12 years and at 68 years had facial diparesis, dysarthrophonia, stridor and tongue atrophy, on nocturnal non-invasive ventilation [11].

3.9 Natural history without and with treatment

The natural history without treatment is severe. In Bosch's review, 28 of 61 untreated patients died (46%), with a mean age at death of 11.6 years (median 9.3; range 0.9 to 42 years) and a mean interval of 5 years between presentation and death; mortality was 85% (11/13) in those with onset before 4 years, with a mean age at death of 1.9 years, 53% (9/17) between 4 and 10 years and 19% (5/27) between 11 and 17 years; in all cases with a known cause, death was due to respiratory failure [27]. In Jaeger and Bosch's review of the first 70 patients with a molecular diagnosis, all 31 untreated patients deteriorated and 15 had died at the time of publication, with a mean interval of 7.1 years between onset and death [18]. Individual reports illustrate this course: in a consanguineous Lebanese family, three siblings with RTD2 died at 11, 7 and 4 years, one of them of respiratory failure [1, 50], and a boy with RTD2 with onset at 2 years died at 3 years of acute respiratory failure [1, 51]. GeneReviews summarises that, without treatment, most infants become ventilator-dependent, often for years, and die before 12 years of age [2].

With treatment, no deaths were described after the start of riboflavin among the 39 treated patients in the 2016 review or the 94 in the 2023 review, and 71% to 81% improved, while the remainder stabilised [18, 52]. Improvement is not cure: in the follow-up of eleven children with RTD2 for up to ten years, ataxia progressed, forced vital capacity (FVC) fell by 12.5% over nine years even in patients treated early, and all were left with residual disability [32]. These data distinguish a lethal disease in its natural history from a chronic disease with sequelae when treated, and the outcome depends on the interval between symptom onset and treatment (sections 7 and 11).

3.10 Maternal riboflavin deficiency (RFVT1)

Maternal deficiency manifests in the newborn within the first 24 hours, with hypoglycaemia, hyperammonaemia, acidosis and organic aciduria typical of MADD; the abnormalities resolve with riboflavin and do not recur after it is stopped [15]. The mother has persistent riboflavin deficiency and a heterozygous SLC52A1 variant, and Orphanet describes maternal hyperemesis gravidarum without other signs of deficiency [5, 15]. The two cases that defined the entity illustrate the picture. Chiong and colleagues described in 2007 a newborn girl with poor sucking, hypoglycaemia and metabolic acidosis shortly after birth, dicarboxylic aciduria and raised plasma acylcarnitines, initially interpreted as MADD; oral riboflavin completely resolved the clinical and biochemical picture, primary MADD was excluded by genetic testing, supplementation was stopped at 15 months and development was normal. The mother had had severe vomiting and a restricted diet during pregnancy, without other signs of deficiency; on a normal diet she maintained raised serum acylcarnitines, which normalised with riboflavin. Ho and colleagues identified in her a de novo heterozygous 1.9 kb deletion of SLC52A1, removing exons 2 and 3 and causing haploinsufficiency, absent in the daughter; a second pregnancy on oral riboflavin resulted in an unaffected son [9, 13, 14]. Mosegaard and colleagues described in 2017 a female infant conceived by in vitro fertilisation with an anonymous donor, whose mother had had hyperemesis gravidarum with a 20 kg weight loss, without signs of riboflavin deficiency (painful mucous membranes, photophobia or dermatitis) and with whole-blood riboflavin at the lower limit of normal (307 nmol/L; reference 300 to 509 nmol/L). At 4 days of life, the infant had lethargy, hypotonia, poor peripheral perfusion, hypothermia and lactic acidosis, with a MADD acylcarnitine profile; after haemofiltration and riboflavin, the acylcarnitines on repeat newborn screening at 8 and 10 days were within the reference range. Riboflavin was continued for 30 months and carnitine for 12 months, and psychomotor development was normal at 3 years. Mother and daughter were heterozygous for the c.1134+11G>A variant, which increases binding of the splicing factor HNRNPA1 and exon 4 skipping in HeLa and HEK293 cells; the allele frequency in ExAC was 0.2% [9, 13, 39]. Heterozygous carriers may also have symptoms of their own: a 62-year-old woman with mild hyperammonaemia and MADD-type acylcarnitines after gastroenteritis (p.(Ser23Tyr)), and a 7-month-old infant with recurrent seizures and hypsarrhythmia with a normal metabolic work-up (loss of the initiation codon) [6]. A single case of biallelic SLC52A1 deficiency with riboflavin-responsive seizures and hyperammonaemia requires confirmation [2].

4. Clinical Recognition and Warning Signs

4.1 When to suspect the diagnosis

Suspicion rests on the combination of auditory neuropathy with signs of other cranial nerves or peripheral neuropathy. GeneReviews indicates suspicion in the presence of progressive onset, usually in childhood, of cranial neuronopathy (II and VIII very frequently; IX, X and XII frequently; III and VII occasionally), motor neuropathy predominantly affecting the upper limbs, axial weakness and diaphragmatic palsy, and sensory neuropathy with ataxia [2]. In Saudubray's syndromic approaches, riboflavin transporter deficiency appears in the differential diagnosis of cranial nerve and bulbar palsy, syndromic sensorineural deafness and hypotonia with abnormal acylcarnitines in children, among the "vitamin-responsive" disorders whose recognition can be life-saving [53], and, in adults, among the metabolic causes of axonal neuropathy and motor neuron disease, with presentations of motor and sensory neuropathy, distal motor neuropathy, multiple mononeuropathy with cranial nerve involvement, a Guillain-Barré-like picture or ALS mimicry [54]. Fennessy and colleagues recommend maintaining a high index of suspicion in children with auditory neuropathy, ataxia, optic atrophy with nystagmus or upper limb weakness [32].

4.2 Red flags requiring urgent action

Respiratory failure due to diaphragmatic palsy is the main emergency. Tachypnoea, shallow breathing, use of accessory muscles, paradoxical abdominal breathing, orthopnoea, apnoeic episodes and stridor indicate impending ventilatory failure [2, 57]. Dysphagia with choking and weight loss requires airway protection and tube feeding [2, 57]. In this setting, GeneReviews recommends starting oral riboflavin as soon as the diagnosis is suspected, without waiting for the molecular result, and continuing it unless testing fails to identify biallelic variants [2, 18]. In the case described by Ali and colleagues, empirical riboflavin started on the fifth day of admission, before genetic confirmation, was followed by respiratory improvement within a few days [57].

4.3 Newborn screening

There is no newborn screening. The newborn screening cards of children diagnosed in the first months of life with abnormal acylcarnitines had normal profiles, probably because maternal riboflavin supply during pregnancy is sufficient [2, 26]. A normal newborn screen does not exclude the disease [27]. Presymptomatic diagnosis is achieved through cascade testing of the siblings of an index case (section 8).

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Diagnostic criterion

The diagnosis of RTD2 or RTD3 is established in a proband with suggestive clinical, neurophysiological, imaging and laboratory findings and biallelic pathogenic or likely pathogenic variants in SLC52A2 or SLC52A3 [2]. Biallelic variants of uncertain significance (VUS), or one pathogenic variant with a VUS, neither establish nor exclude the diagnosis [2]. There are no formal validated clinical criteria, and no non-molecular test confirms the disease; biochemistry may be normal, and the diagnosis can only be made or rejected by molecular analysis [18, 27].

5.2 Neurophysiology

Electromyography shows chronic partial denervation, and nerve conduction studies show an axonal neuronopathy that is more sensory than motor, with generally normal motor conduction velocities and often absent sensory action potentials [2]. In RTD2, the studies are consistent with axonal sensorimotor neuropathy [16]. In adults, the patterns range from pure motor neuronopathy to multiple mononeuropathy and mixed neuronopathy [49]. In a patient with juvenile-onset RTD3, conduction studies showed a predominantly motor axonal neuropathy with reduced amplitudes and normal velocities, and electromyography showed chronic and active denervation in the bulbar, cervical and lumbosacral myotomes; repetitive stimulation at 3 Hz showed no decrement [57]. Visual evoked potentials are frequently abnormal, and BAEP show sensorineural deafness in all patients assessed; the electroencephalogram may show excess theta or slow activity [2].

5.3 Audiological and ophthalmological assessment

The combination of preserved otoacoustic emissions (or cochlear microphonics) with absent or markedly abnormal BAEP defines auditory neuropathy and suggests a postsynaptic lesion [2, 38]. Speech discrimination tests are disproportionately impaired relative to pure-tone thresholds [32, 58]. The Chinese auditory neuropathy guideline includes SLC52A3 among the genes with a definitive association, although it prioritises OTOF (41.2% of childhood auditory neuropathy) and AIFM1 (18.6% of late-onset auditory neuropathy) in genetic screening [59]. Ophthalmological assessment includes best-corrected visual acuity, colour vision (Farnsworth test), visual fields, visual evoked potentials, optical coherence tomography and fundoscopy [2, 44].

5.4 Biochemical biomarkers

Acylcarnitines and organic acids are useful screening tests, but a normal result does not exclude the disease [18, 32]. In Bosch's first patient, acylcarnitines showed C4 of 0.65 µmol/L (reference 0.07 to 0.58), C5 of 0.29 (0.04 to 0.22), C6 of 0.27 (0.02 to 0.12) and C14 of 0.14 (less than 0.08), with normal glutarylcarnitine, and urine showed ethylmalonic acid of 62 mmol/mol creatinine (less than 15), adipate of 70 (2 to 26) and normal glutaric acid, unlike MADD due to an ETFDH defect [26]. Plasma flavins are measured by high-performance liquid chromatography with fluorescence detection; they normalised within weeks of riboflavin and fell again when it was stopped [26]. All the initial biochemical abnormalities normalise with riboflavin, which makes acylcarnitines a marker of treatment adherence [15, 32].

5.5 Genetic tests in order

When the picture is suggestive, a multigene panel including SLC52A2 and SLC52A3 is the preferred test; these genes are included in panels for hearing loss, motor neuron disease, neuropathy, myopathy and inborn errors of metabolism [2]. When the diagnosis has not been considered, exome or genome sequencing is more likely to identify it [2]. In the Lebanese series, the diagnosis was made only by exome sequencing, at a median of 5 years, because the clinical and biochemical picture was inconsistent, and the authors suggest next-generation sequencing as the first-line test [60]. Panels targeting mitochondrial disease or hereditary myopathies may not include these genes, as happened in a patient whose diagnosis was only obtained by targeted Sanger sequencing [57]. Maternal deficiency requires SLC52A1 sequencing and deletion analysis in the mother, because the lesion initially described was a deletion of exons 2 and 3 detected by quantitative polymerase chain reaction (PCR) [14].

5.6 Test limitations

Sequencing identified the variants in all 136 probands compiled up to 2021, and no large deletions or duplications in SLC52A2 or SLC52A3 have been described by chromosomal microarray; however, this proportion reflects published cases with a molecular diagnosis and is not an estimate of clinical sensitivity [2]. Deep intronic variants (such as SLC52A1 c.1134+11G>A, which creates an hnRNP A1 binding site and causes exon 4 skipping) and exon deletions (SLC52A1) have already been described in the gene family and escape conventional exome sequencing [14, 39]. A single variant in a patient with a typical phenotype should prompt a search for copy number variants (CNV), RNA analysis or genome sequencing before a dominant mechanism is accepted [11, 35]. Conversely, identification of a single heterozygous variant is not diagnostic: in an Indian series of five patients with heterozygous variants, some had no functional effect, and two variants that reduced transport were also present in an asymptomatic father, making them unlikely to be causal [61]. Uniparental isodisomy explains some cases in which only one parent is a carrier [2, 41]. Several recurrent variants, such as SLC52A3 p.(Arg212Cys) and p.(Asn21Ser) and SLC52A2 p.(Pro134Leu), have conflicting classifications in ClinVar, and the clinical response to riboflavin has been used as functional evidence in the face of a VUS [17, 37, 56].

5.7 Content of the genetic report

The report should state the gene, the reference transcript with version (MANE Select NM_001363118.2 for SLC52A2, NM_033409.4 for SLC52A3, NM_017986.4 for SLC52A1), the coding and protein HGVS nomenclature, the zygosity, the class according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) standards and, when the literature uses another notation, the historical notation [2, 10]. Segregation in the parents confirms the phase of the variants and distinguishes compound heterozygosity from variants in cis [2].

5.8 Diagnostic algorithm

1. Clinical suspicion (section 4): start oral riboflavin immediately, after drawing blood for acylcarnitines, urinary organic acids and plasma riboflavin, FMN and FAD, without waiting for the results [2, 18, 32].
2. Targeted assessment: nerve conduction and electromyography, BAEP with otoacoustic emissions, visual evoked potentials and fundoscopy, magnetic resonance imaging, assessment of respiratory function and polysomnography [2].
3. Molecular testing: panel with SLC52A2 and SLC52A3 or exome/genome; if a single variant is found with a typical phenotype, look for CNV, intronic variants and isodisomy [2, 35].
4. Biallelic pathogenic or likely pathogenic variants: continue riboflavin lifelong and test the siblings; negative result and alternative diagnosis: stop riboflavin [2].
5. Newborn with a transient riboflavin-responsive MADD profile: measure maternal riboflavin and test SLC52A1 [14, 15].

5.9 Prenatal and preimplantation diagnosis

When both familial variants are known, prenatal diagnosis and preimplantation genetic testing are possible [2]. In two reports, prenatal diagnosis led to maternal supplementation during pregnancy and treatment from birth, with children free of manifestations (section 8) [17, 62].

6. Differential Diagnosis

6.1 Comparative table

6.2 Main differential diagnoses

In the infantile form, the central differential diagnosis is spinal muscular atrophy. The Oxford Desk Reference recommends that, in an infant with a severe spinal muscular atrophy picture in the first months without a homozygous SMN1 deletion, IGHMBP2-related SMARD and Brown-Vialetto-Van Laere syndrome should be considered, the latter causing progressive respiratory failure with hypotonia and bulbar palsy and potentially responding to riboflavin [55]. Bosch's patients had had spinal muscular atrophy and SMARD excluded by genetic testing before diagnosis [26]. Diaphragmatic palsy is common to both entities; deafness and optic atrophy, when present, point towards RTD, but may appear later [2, 3].

In adolescents and adults, the differential diagnosis is ALS and the motor neuropathies. RTD has been described as a recessive juvenile form of ALS, because both involve bulbar and lower motor neuron involvement [2, 23]. Sensorineural hearing loss is the most useful clue, and the absence of pontobulbar palsy does not exclude RTD [49, 57]. Carreau and colleagues recommend discussing a trial of high-dose riboflavin in any young-onset motor neuron disease [35].

The biochemical similarity to MADD is the main metabolic pitfall. Nyhan's Atlas includes the riboflavin transporter defect in the differential diagnosis of MADD, based on Bosch's three patients with an attenuated MADD profile and riboflavin, FMN and FAD deficiency [63]. Urinary glutarate and glutarylcarnitine, markedly raised in ETFDH-related MADD, were normal in the patients with RTD [26]. FLAD1 and SLC25A32 deficiencies likewise produce riboflavin-responsive MADD, but with lipid storage myopathy and complex II deficiency, without cranial neuronopathy [15].

In the differential diagnosis of auditory neuropathy with neurological signs, the Chinese auditory neuropathy guideline lists OTOF, AIFM1, OPA1, WFS1 and SLC52A3 among the definitive genes [59]. AIFM1-related disorders, the most frequent genetic cause of late-onset auditory neuropathy in that guideline, combine auditory neuropathy with peripheral neuropathy and are a relevant differential diagnosis [59].

Pictures that mimic acquired diseases delay diagnosis: a child with ptosis and bulbar weakness was treated as seronegative myasthenia with corticosteroids, pyridostigmine, salbutamol and intravenous immunoglobulin without response until homozygous SLC52A3 p.(Phe224Leu) was identified [56], and a Saudi child was initially treated as chronic inflammatory demyelinating polyneuropathy [64]. Conversely, other diseases mimic RTD, such as adult Sandhoff disease and a patient with a TNRC18 variant and a Fazio-Londe picture [65, 66].

7. Treatment and Risk Management Strategies

7.1 Principles and sources of the recommendations

There is no formal clinical practice guideline for RTD; GeneReviews, revised in 2021 by experts from the Centre for Neuromuscular Diseases at University College London, is the reference guidance document, and the recommendations rest on open series and case reports, without randomised trials [2]. In 2026, a European Delphi panel of 36 experts from 18 countries classified riboflavin as an essential nutritional therapy product for riboflavin transporter deficiencies (SLC52A2 and SLC52A3), with level 3 evidence on the Oxford Centre for Evidence-Based Medicine scale [67]. The systematic review by Jaeger and colleagues, from the same year, classified riboflavin as effective in RTD2 and RTD3, with a positive response in 85 of 94 genetically confirmed patients (90.4%) [21]. The principle common to all sources is to start riboflavin as soon as the disease is suspected, without waiting for molecular confirmation, and to continue it for life [2, 18, 27, 32].

7.2 High-dose riboflavin

Riboflavin (vitamin B2) is the targeted treatment. The proposed mechanism is an increase in intracellular riboflavin, FMN and FAD concentrations through residual transporter activity and through passive diffusion when the extracellular concentration is high [21]. In RTD2, the intestinal transporters RFVT1 and RFVT3 remain functional and ensure absorption, but saturation of these transporters limits the amount absorbed with each dose [16].

Reference dose. GeneReviews recommends 10 to 50 mg/kg/day orally, divided into three doses, with progressive titration to find the effective dose: 10 mg/kg/day for one month, then 20, 30, 40 and 50 mg/kg/day, each step for one month [2]. Doses below 10 mg/kg/day have been described as ineffective, and doses above 80 mg/kg/day have had minimal adverse effects [2]. The dose depends on severity and on individual response [2]. Saudubray reports doses of 10 to 80 mg/kg/day with minimal adverse effects, and the medicines table in the same book gives 100 to 400 mg/day in two to three doses for riboflavin-responsive disorders in general, with up to 80 mg/kg/day in RFVT2 and RFVT3 deficiencies [15, 68].

The published doses vary widely: 7 to 60 mg/kg/day in the 39 treated patients of the 2016 review, and 1.7 to 80 mg/kg/day or 20 to 1500 mg/day in the 94 patients of the 2026 review [18, 21]. The first patients responded to 10 mg/kg/day [26, 27], and 10 mg/kg/day is also the dose given in Nyhan's Atlas [63]. In young adults with disease unmasked by a dietary change, 20 to 40 mg/kg/day partly reversed the symptoms [40]. In a pharmacokinetic study in a 35-year-old Swedish man with RTD2, taking 500 mg three times a day produced low plasma levels in the morning, with a peak up to 4 hours after the dose; the change to 250 mg six times a day made the levels more constant and 27% higher over 24 hours, with slight improvement in gait, sitting balance, visual acuity and colour vision after one year, without demonstration of clinical superiority over other regimens [1, 69]. The parenteral route could theoretically increase uptake [2]; two of the first patients received intravenous riboflavin, and one case of gastrointestinal intolerance occurred only with the intravenous route and resolved on changing to the oral route [21, 27].

Formulation and administration. Liquid riboflavin exists but is difficult to obtain; capsules are often opened and the contents mixed with food such as yoghurt [2]. Orange-yellow urine is expected and serves as a patient-reported marker of adherence [2, 57].

Adverse effects and their management. The adverse effects described are diarrhoea, increased urine output and discolouration of the urine; allergic reactions are rare [2]. In the systematic review that brought together 780 patients treated with riboflavin for inherited metabolic diseases, adverse effects were recorded in 10 (1.3%), mainly gastrointestinal (vomiting in four) [21]. In RTD, three patients had gastrointestinal symptoms among 39 treated [18]. In one of Bosch's patients, the parents reduced the dose because of suspected gastrointestinal effects, and the patient subsequently deteriorated with new cranial nerve palsies and ventilator dependence [26]. Gastrointestinal effects are managed by splitting the dose into more administrations, giving it with food and titrating more slowly, never by stopping treatment [2, 69].

Duration and discontinuation. Treatment is lifelong. Discontinuation has caused rapid deterioration, and deaths have been described when treatment was interrupted or started late [2]. In one of Bosch's patients, withdrawal of riboflavin at 4 years of age caused deterioration with vomiting, fatigue and a rise in lactate, transaminases and creatine kinase, reversed by reintroduction of 50 mg twice a day [26]. The response may take time: some patients improve within days and others, especially the most severely affected, over more than 12 months, so riboflavin should be continued even without apparent initial improvement [2, 27].

Monitoring. Acylcarnitines, when initially abnormal, normalise with adequate doses, in some patients two weeks after the first dose, and recurrence of the abnormalities suggests poor adherence; plasma riboflavin, FMN and FAD rise with treatment [16, 32]. The monitoring schedule is in section 11.

Adjuvant therapies. Coenzyme Q10 and carnitine were added when levels were low in the Omani cohort, and some Sydney patients took FMN, coenzyme Q10, L-carnitine and fish oil on their own initiative; there are no data on the benefit of these combinations [17, 32]. The initial treatment for MADD with a low-fat diet, carnitine, glycine and 3-hydroxybutyrate was withdrawn without problems after metabolic normalisation in the first report [26]. As monotherapy, riboflavin accounted for 91.8% of the positive responses in the 2026 review [21].

7.3 Efficacy: series and reviews

Sources for the table: [16–18, 21, 27, 32, 52, 70].

These data have limitations. No study is randomised or controlled; the comparisons with untreated patients use historical controls from different periods with different diagnostic criteria, and the 2012 review included patients diagnosed on clinical grounds alone [2, 27]. The reviews aggregate case reports with publication bias in favour of positive responses, the classification of the response depended on the opinion of the original authors, and riboflavin was often combined with other supplements [21]. The proportions of improvement (71% to 90%) are not comparable between reviews, because the denominators, the response criteria and the overlap of patients differ. Clinical improvement coexists with long-term progression in some domains, and the editorial comment on the Sydney series stressed that riboflavin does not halt progression in RTD2 [32, 71]. There are also negative results: in the 2026 review, seven patients did not respond (two had started treatment decades after onset), four patients with long-standing hearing loss did not recover hearing after 24 months, whereas two treated within the first year of hearing loss improved, and in a Chinese family with SLC52A3 variants correction of serum riboflavin brought no clinical improvement [12, 21]. A Portuguese patient with a single variant in SLC52A3 did not improve with 10 mg/kg/day for three years, started at the age of 63 years [11].

7.4 Early treatment and presymptomatic treatment

The response is better when treatment starts early in life and early in the course, and onset in adulthood or late treatment is often associated with absence of improvement because of established neuronal damage [2]. In Foley's patients with RTD2, the mean time between onset and treatment was 7.4 years in those who improved and 19.2 years in those who stabilised [18]. Bosch's index patient, treated at 6 months with 10 mg/kg/day, walked unaided at 22 months, had the tracheostomy closed at 4 years and at 9 years had a normal neurological examination and normal strength; his sister, treated at 3 months, had normal tone within 7 days [18, 26]. In the Sydney series, patients treated shortly after onset had better outcomes for hearing, optic atrophy, lung function, strength and balance than those diagnosed late, but reversal of neuronal damage was confined to the first 12 months [32]. In the Turkish family with p.(Pro134Leu), the patient treated 8 months after onset recovered completely, with resolution of the neurogenic changes within a year, and the patient treated 13 years after onset stabilised without electrophysiological improvement [70].

Treatment of siblings identified by cascade screening before symptoms prevents or delays the disease. In the Arabian Peninsula cohort, nine of ten patients treated presymptomatically remained free of symptoms during follow-up, and the only one who became ill admitted to not taking the riboflavin [17]. In the Turkish family, the two siblings treated before symptoms still had normal nerve conduction and electromyography after about five years [70]. An asymptomatic sibling treated from molecular diagnosis had normal vision and optical coherence tomography 7 years later [44], and two American siblings treated with riboflavin and coenzyme Q10 had stable visual and neurological status 7.5 years after starting [72]. The ideal dose for presymptomatic individuals is not defined; the Omani authors used 5 to 10 mg/kg/day when the genotype was associated with late onset, and they question whether lower doses improve adherence [17].

7.5 Regulatory status

Sources for the table: [73–76]. The European Delphi panel stresses that many of these products work as medicines but are regulated as foods, which limits access, reimbursement and regularity of supply; riboflavin is already on the World Health Organization list of essential medicines, but with a generic indication [67]. The systematic review concludes that access to riboflavin is crucial for these patients [21]. The recommended dose is, in any case, that of the expert documents and not that of a label, because no label carries an indication for RTD; no label of the available products contains doses of 10 to 50 mg/kg/day [2, 73].

7.6 Multidisciplinary supportive care

Respiratory. Assessment includes spirometry with FVC, maximal respiratory pressures, peak cough flow and polysomnography [2, 11, 32]. Nocturnal non-invasive ventilation is indicated in hypoventilation, and some patients need invasive ventilation through a tracheostomy [2, 32]. In Lourenço's Portuguese patient, FVC remained normal (101.5% of predicted) while maximal inspiratory pressure fell to 20.7 cmH2O within a year; nocturnal non-invasive ventilation was started in bilevel mode, and peak cough flow rose from 210 to 312 L/min with air-stacking manoeuvres (15 repetitions, three times a day), with mechanical insufflation-exsufflation available; the authors note that respiratory care in BVVL is adapted from other neuromuscular diseases with a better evidence base [11]. Riboflavin may allow support to be reduced: in the four tracheostomised patients of the 2012 review, ventilation was reduced or withdrawn, and the patient in section 10 was extubated 10 days after starting treatment [16, 27].

Swallowing and nutrition. Dysphagia requires assessment of the cause, modification of food consistency, head positioning and exercises, oral hygiene care and a low threshold for a radiological swallow study; gastrostomy is necessary in persistent feeding difficulties [2]. Dietary restriction of riboflavin should be avoided and rich foods, such as meat, eggs and milk, favoured [2].

Hearing. Treatment depends on the degree of loss: hearing aids or cochlear implantation and educational intervention [2]. In the auditory neuropathy of RTD, the benefit of hearing aids is often small. A 31-year-old Brazilian patient with auditory neuropathy and no benefit from hearing aids received bilateral cochlear implants at 21 and 23 years of age; five years later she had a mean free-field threshold of 28 dB and recognised 64% of disyllables and 100% of trisyllables [58]. In the review of implanted patients with RTD2, thresholds improved in some, but functional speech recognition was often limited, which is attributed to postsynaptic involvement of the auditory nerve [38]. The Brazilian scoping review of hearing in BVVL found only case reports, with sensorineural hearing loss, auditory neuropathy and rehabilitation by cochlear implant as the main findings [77]. Since hearing improvement with riboflavin is concentrated in the first 12 months, implantation may be considered at that point, when further recovery is unlikely [32].

Vision. Low-vision aids, school adaptations and ophthalmological follow-up; ptosis is treated by the ophthalmologist [2].

Motor and orthopaedic. Physiotherapy with stretching to prevent contractures and falls, occupational therapy, limb and trunk orthoses, mobility devices and surveillance for scoliosis, which may require surgery [2, 32]. A Brazilian patient with intrinsic hand weakness regained function six months after supercharged end-to-side nerve transfer from the anterior interosseous nerve to the motor branch of the ulnar nerve, with benefit maintained at five years; this is an isolated case [78].

Speech, epilepsy and mental health. Speech therapy for dysarthria and augmentative communication when needed; conventional antiepileptic drugs for epilepsy, with no specific agent; treatment of depression; social support, home care and palliative care when indicated [2].

Education. Early intervention from 0 to 3 years with therapies, an individual education plan with vision and hearing consultants at school age, and a transition plan in adolescence [2].

7.7 Agents and circumstances to avoid

GeneReviews recommends avoiding dietary restriction of riboflavin and limiting excessive physical exercise, because the metabolic stress of exertion may lower riboflavin levels [2]. Vegetarian or vegan diets without adequate supplementation are a risk: three young adults became ill after reducing meat and dairy products [40]. Interruption of riboflavin, through intolerance, lack of access or the patient's decision, is the circumstance of greatest risk [2, 17, 26].

7.8 Pregnancy, lactation and the perinatal period

Women with RTD should continue riboflavin before and during pregnancy and while breastfeeding, to avoid inducing deficiency in the fetus and the infant; the dose recommended in pregnancy is 10 mg/kg/day [2]. Heterozygous women should have a diet rich in riboflavin and be counselled about supplementation if needed, because demand increases in pregnancy; riboflavin deficiency in pregnancy has been associated with a higher risk of pre-eclampsia and preterm birth, and there are few studies of excessive maternal intake [2]. In carriers of SLC52A1 variants, supplementation before and during pregnancy and while breastfeeding is recommended to prevent neonatal deficiency [2]. In two reports, maternal supplementation during a pregnancy with a fetus affected by RTD3, followed by riboflavin from birth, resulted in children without manifestations (one asymptomatic at 2 years) [17, 62].

7.9 The perioperative period and intercurrent illness

The sources do not describe specific perioperative protocols. The principles derive from the pathophysiology and from the general recommendations: continue riboflavin without interruption during fasting (by nasogastric tube if necessary), assess respiratory function and swallowing before anaesthesia and plan for non-invasive ventilation postoperatively in patients with diaphragmatic weakness [2, 11]. Infections and trauma may precipitate or worsen the disease, which justifies closer monitoring in those periods [2, 26].

7.10 Transition to adulthood

In the Sydney series, patients were followed annually until transition to adult services [32]. Transition must ensure continuity of access to riboflavin, respiratory and hearing surveillance, and reproductive counselling, including supplementation in pregnancy [2, 32].

7.11 Gene therapy and other investigational therapies

Gene therapy for RTD is at the preclinical stage. It is classified as gene augmentation therapy, suited to a recessive loss-of-function disease: the aim is to introduce a functional copy of SLC52A2 into nerve cells, without correcting the endogenous gene [33]. Mei and colleagues used an adeno-associated virus serotype 2/9 (AAV9) vector carrying codon-optimised human SLC52A2 complementary DNA, chosen for the neurotropism of AAV9, for stable expression in post-mitotic cells and for low immunogenicity [33]. The methodology consisted of differentiating iPSCs from two patients with RTD2 (with the variants c.155C>T and c.935T>C, and a two-nucleotide deletion with c.505C>T) into mature motor neurons, positive for HB9, through a three-dimensional and two-dimensional protocol with embryoid bodies; since AAV9 transduces cultured cells poorly, the neurons were pretreated with sialidase (1.25 U/mL for 3 hours), which removes surface sialic acid and increased transduction efficiency, and were then exposed to the vector at a multiplicity of infection of 10⁷ viral genomes per cell [33]. The patients' motor neurons had shorter neurites and less developed neuronal networks than controls; after transduction, neurite length increased significantly in both lines, measured by automated imaging over 15 days [33]. There are no results in animal models or in humans, nor registered clinical trials, and the authors present the work as a step preceding in vivo studies [33]. The safety and biodistribution of in vivo administration were not assessed in this cell model, and an advantage over riboflavin, which is cheap and effective in most patients, would have to be demonstrated above all in patients who progress despite treatment [32, 33]. A disease-specific functional scale, the RTD Pediatric Scale, derived from the CMTPedS, has been developed as an outcome measure for future trials [32, 79]. GeneReviews records no clinical trials [2].

7.12 Developments in the past 12 months

Between November 2025 and November 2026 the following were published: the largest RTD3 cohort, with 23 patients from Oman and Saudi Arabia and the longest cumulative follow-up of patients treated before symptoms (retrospective observational study) [17]; the systematic review of the efficacy of riboflavin in inherited metabolic diseases, which classifies it as effective in RTD2 and RTD3 (review of published series) [21]; the European Delphi consensus that considers it an essential product (expert consensus) [67]; the five-year follow-up of a Turkish family with p.(Pro134Leu), which relates reversibility to the interval before treatment (case series) [70]; a Chinese auditory neuropathy cohort with four RTD2 patients and a worldwide review of 178 alleles (series and review) [38]; the study of RFVT2 dimerisation in cell models (preclinical) [34]; and reports of presentation as seronegative myasthenia, pure red cell aplasia and a rapid respiratory response in a young adult (case reports) [47, 56, 57]. No marketing authorisation applications, regulatory opinions or clinical trials of medicinal products for RTD were identified in the sources consulted.

8. Reproductive Options and Family Counselling

8.1 Recurrence risks

RTD2 and RTD3 are transmitted in an autosomal recessive manner. The parents of an affected child are, in principle, obligate heterozygotes, and molecular testing of the parents is recommended to confirm carrier status and calculate the recurrence risk reliably [2]. If only one parent is a carrier, the possibilities are a de novo variant in the proband, a postzygotic variant in a mosaic parent or uniparental isodisomy of the chromosome carrying the variant [2]; paternal isodisomy of chromosome 8 has been documented in RTD2 [41].

Most heterozygotes have no manifestations. Theoretically, a carrier may have symptoms if situations of riboflavin depletion coexist, such as dietary restriction, malnutrition, pregnancy or illness, and preliminary data suggest that some SLC52A3 heterozygotes may have disease without these conditions, a hypothesis yet to be demonstrated [2, 11, 12]. In consanguineous families, homozygosity in two generations can mimic vertical transmission (pseudodominance) [36].

8.2 Cascade testing of siblings and presymptomatic treatment

When the familial variants are known, testing of the older and younger siblings of a proband is indicated, to identify affected individuals who benefit from early riboflavin [2]. If the variants are not known and a younger sibling presents with typical signs, riboflavin should be given for diagnostic and therapeutic purposes [2]. Foley and colleagues recommended rapid screening of the siblings of patients with RTD2, considering that presymptomatic identification would create a therapeutic opportunity [16]. This strategy has shown results: nine of ten Omani siblings treated before symptoms remained free of symptoms, two Turkish siblings treated presymptomatically had normal neurophysiology after about five years and an American brother treated from diagnosis had normal vision and optical coherence tomography 7 years later [17, 44, 70]. This is a situation in which genetic testing of asymptomatic minors is justified, because there is an effective intervention that must start before symptoms [2, 17].

8.3 Carriers and family planning

Carrier testing in at-risk relatives requires prior identification of both familial variants [2]. Young women with RTD should be counselled about supplementation before and during pregnancy and while breastfeeding; carriers of SLC52A1 variants should have a riboflavin-rich diet and be informed of the possibility of supplementation, and the same approach should be considered in carriers of SLC52A2 or SLC52A3 variants, to avoid deficiency in the fetus and infant [2]. The best time to determine genetic risk and discuss prenatal diagnosis and preimplantation genetic testing is before pregnancy, and genetic counselling should be offered to young adults who are carriers or at risk of being carriers [2].

8.4 Prenatal and preimplantation diagnosis

With both variants known, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing are possible [2]. In RTD, prenatal diagnosis also has therapeutic value. Elks and colleagues described two brothers with RTD3: the elder was diagnosed at 11 months with severe respiratory compromise and regression and improved with riboflavin; the younger was diagnosed by prenatal genetic analysis, received riboflavin in utero via the mother and after birth, and at 2 years was asymptomatic [62]. The Omani cohort describes another pregnant woman treated during the pregnancy of an affected fetus, with a newborn free of manifestations [17]. Differing perspectives on the use of prenatal diagnosis should be discussed with the family [2].

8.5 Maternal riboflavin deficiency

In RFVT1 deficiency, the relevant genotype is that of the mother. A woman heterozygous for a loss-of-function SLC52A1 variant, if she has riboflavin deficiency during pregnancy, may have a newborn with transient MADD, which corrects with riboflavin and does not require lifelong treatment [14, 15, 39]. Maternal malnutrition and riboflavin deficiency in pregnancy appear to be determining factors [39]. Carriers should not be regarded as permanently healthy, because symptoms have been described in a heterozygous infant and in a 62-year-old woman after gastroenteritis [6]. Recurrence in subsequent pregnancies is prevented by maternal supplementation and surveillance of the newborn [2].

9. Special Considerations: Population Diversity and Epidemiology

9.1 Prevalence and what each figure measures

The prevalence of RTD is difficult to establish; GeneReviews estimates about 1 in 1,000,000 in the general population and considers underdiagnosis likely [2]. Orphanet places the disease in the prevalence class below 1 in 1,000,000 and records 109 cases or families, based on the 2019 review [5]. These values do not come from population studies: the GeneReviews estimate is an approximation and the Orphanet and review figures count published cases. Cumulative counts have grown with the spread of sequencing: 58 patients with clinical BVVL published up to 2008, about 110 cases with a molecular diagnosis up to 2019, about 200 RTD2 cases up to 2025 and fewer than 500 genetically confirmed cases, according to a 2025 estimate [11, 27, 31, 60]. An automated text-mining study of the clinical records of 2,288,901 patients at Amsterdam University Medical Centers between 2004 and 2021 identified 13 patients with possible RTD without an alternative diagnosis; six accepted testing and all were negative, and all previously known patients were detected, suggesting that prevalence is low and that the risk of unrecognised cases in that hospital is limited, although seven patients were not tested [80].

9.2 Founder populations and geographical distribution

The SLC52A2 variant c.916G>A p.(Gly306Arg) is a founder variant in the Lebanese population: three homozygous Lebanese families shared the same haplotype across 11 polymorphisms [7, 16], and in a Lebanese series from 2018 to 2023 the six patients from three families were homozygous [60]. The same variant was found in the homozygous state in an Arab-Israeli family and a Scottish child, and in compound heterozygosity in European families [7, 16]. In the 2026 worldwide review, p.(Gly306Arg) accounted for 41.6% of the 178 published RTD2 alleles, whereas the variants of Chinese patients were scattered across the gene, without hotspots [38]. In RTD3, the c.634C>T p.(Arg212Cys) variant was found in the homozygous state in 20 patients from six unrelated Omani families, with a frequency of 0.000008 in gnomAD and 0.00038 in a local database, suggesting a founder effect; c.1325_1326del was shared by two Saudi families [17]. In India, the SLC52A3 variant c.62A>G p.(Asn21Ser) is recurrent [36]. Consanguinity is frequent in the series from the Middle East, Pakistan and India [17, 24, 36].

9.3 United States and Europe

In the USA, a Cincinnati series brought together ten children with RTD2 and a mean diagnostic delay of 27.6 months, and a Philadelphia series characterised the ophthalmological findings [43, 44]. In Europe, the founding work comes from the Netherlands (Amsterdam), the United Kingdom (London and Leeds), Germany and Italy [16, 24, 26, 29]. In France, six adults with late-onset motor neuropathy were brought together in a national series [49], and in Poland two sisters with RTD2 were described [31]. Foley's study included patients from 21 centres in England (originating from Pakistan, India, Saudi Arabia, Kuwait, Iran and Turkey) and from centres in Wales, Scotland, Northern Ireland, Ireland, France, Belgium, the Netherlands, Greece, Malta, Russia, Lebanon, Iceland, Australia and the USA [16].

9.4 Portugal and Brazil

In Portugal, Lourenço and colleagues, from Hospital Pedro Hispano (Matosinhos), described in 2025 a 68-year-old woman with hearing loss since 12 years of age, facial diparesis, dysarthrophonia, stridor and tongue atrophy with fasciculations, with a single heterozygous SLC52A3 variant identified at 63 years; the diagnosis was considered after discussion with a reference centre, riboflavin (10 mg/kg/day) brought no improvement over three years, and the patient remains on nocturnal non-invasive ventilation and airway clearance techniques [11]. In Brazil, a case of bilateral cochlear implantation in a patient with RTD3 (Ribeirão Preto), a scoping review of the audiological findings (Brasília) and a case of nerve transfer for intrinsic hand dysfunction (Ribeirão Preto) have been published [58, 77, 78]. The sources consulted do not provide prevalence data for Portugal or Brazil.

9.5 Sex and special populations

The early series showed an excess of female patients (51 of 74 in the 2012 review; 16 of 23 in the Omani and Saudi cohort), but GeneReviews considers both sexes equally affected [2, 17, 27]. Pregnant women with RTD and carriers have increased riboflavin requirements (section 7.8) [2]. Patients on restrictive, vegetarian or vegan diets without supplementation, or with malnutrition, are at risk of decompensation [2, 40]. Madras motor neuron disease, in southern India, is a distinct entity, with SLC52A2 and SLC52A3 excluded [2].

9.6 Reference networks and patient associations

In Europe, patients fall within the European Reference Network for rare neuromuscular diseases (EURO-NMD) and the network for inherited metabolic diseases (MetabERN) [19, 20]. The Cure RTD Foundation, based in Calgary (Canada), maintains information for families and clinicians, an international patient registry (Cure RTD Registry), an SLC52 variant database and a research funding programme [2, 81]. MedlinePlus Genetics has a page on riboflavin transporter deficiency neuronopathy [2].

10. Illustrative Clinical Case

10.1 Infant with RTD2 and respiratory failure reversed by riboflavin

The case is patient I1 of the cohort of Foley and colleagues, published in 2014 in Brain [16]. He was a boy of Irish origin, compound heterozygous in SLC52A2 for the variants c.914A>G p.(Tyr305Cys) and c.916G>A p.(Gly306Arg), described on transcript NM_024531.4, whose numbering matches that of the MANE transcript NM_001363118.2 [10, 16]. Both variants are classified as pathogenic in ClinVar, and in the functional studies of the same work p.(Tyr305Cys) abolished riboflavin uptake and p.(Gly306Arg) reduced it moderately [7, 16, 37].

At 22 months he was assessed with a history of nystagmus for 6 months, ataxic gait for 4 months and rapidly progressive bilateral hand and bulbar weakness for 3 weeks. On examination he could neither walk nor hold his bottle. He then developed respiratory failure and inability to swallow. Ophthalmological examination showed bilateral optic atrophy, visual evoked potentials showed visual loss and BAEP revealed bilateral sensorineural hearing loss. The plasma acylcarnitine profile showed elevation of the C6, C8, C10 and C14:1 species [16].

Riboflavin was started within 8 days of presentation, at 10 mg/kg/day, and increased to 50 mg/kg/day over 4 weeks. Ten days after the start he was extubated and remained off respiratory support. Within four weeks he was feeding orally, holding his head up, reaching for and grasping toys and walking with trunk support. The acylcarnitine profile repeated two weeks after the start was normal [16]. Figure 3A of the article, a photograph of this patient aged 1.8 years, illustrates severe weakness of neck extension and of the upper limbs with less weakness of the lower limbs; the legend was read in the full text available in PubMed Central (PMC3891447) [16].

10.2 Interpretation

The case brings together the characteristic elements of RTD2: onset with nystagmus and sensory ataxia before weakness, a weakness pattern predominantly affecting the upper limbs and neck, optic atrophy and auditory neuropathy, a mild MADD-type acylcarnitine profile and rapidly developing respiratory failure [2, 16]. The authors attributed the recovery, which they considered life-saving, to the short interval between symptom onset and treatment [16]. The titration from 10 to 50 mg/kg/day over four weeks was faster than the monthly steps later proposed by GeneReviews, justified by the severity of the picture; riboflavin started before molecular confirmation corresponds to the current recommendation [2, 16]. The case does not represent the course of all patients: in the long-term follow-up of other children with RTD2 treated early, progression of ataxia, slow decline in respiratory function and residual disability persisted [32].

10.3 Complementary case: RTD3 in a young adult

A case published in 2026 illustrates late-onset RTD3. A South Asian man, in his late teens or early twenties, born to consanguineous parents, had progressive bilateral hearing loss for 4 to 5 years, progressive dysphagia for 6 months, mild distal weakness and, over the previous 10 days, dyspnoea progressing to dyspnoea at rest with orthopnoea; two siblings had died in their early twenties with the same sequence of hearing loss, dysphagia, weakness and respiratory failure [57]. He had tongue atrophy and fasciculations, thenar atrophy, facial diparesis, mild ptosis, a reduced gag reflex, paradoxical breathing and profound sensorineural hearing loss; nerve conduction showed a predominantly motor axonal neuropathy, electromyography chronic and active denervation, and repetitive stimulation, cerebrospinal fluid, magnetic resonance imaging, creatine kinase and the metabolic work-up were normal [57]. Empirical riboflavin was started at 40 mg/kg/day in three doses on the fifth day, before confirmation of a homozygous frameshift variant in SLC52A3 (the variant is not specified in the report), with a nasogastric tube and nocturnal non-invasive ventilation; FVC rose from 35% to 50% predicted within a week, strength improved, at 8 weeks he had gained 3 kg and at 6 months he was walking unaided, without electrophysiological progression, and required only nocturnal ventilation [57]. The authors acknowledge that the response of a single patient does not demonstrate efficacy, because ventilatory and nutritional support may have contributed [57].

11. Prognosis and Long-Term Follow-Up

11.1 Prognosis

Without treatment, RTD is a progressive disease with high mortality from respiratory failure: 46% of the 61 untreated patients in the 2012 review had died, with mortality of 85% when onset occurred before 4 years, 53% between 4 and 10 years and 19% between 11 and 17 years [27]. Among the 31 untreated patients with a molecular diagnosis compiled in 2016, all deteriorated and 15 had died, with a mean interval of 7.1 years between onset and death [18]. GeneReviews indicates that most untreated infants die before 12 years of age [2].

With riboflavin, no deaths after the start of treatment were described in the 2016 and 2023 reviews, and 71% to 90% of patients improve, strength being the most responsive domain [18, 21, 52]. Vision and hearing recover less, and only when treatment is early [21, 32]. In the follow-up of eleven children with RTD2 in Sydney, the total CMTPedS score remained stable in the group but progressed in some children; ataxia progressed, 6-minute walk distance decreased in most, grip strength stabilised or improved in those treated early, FVC decreased by 12.5% over nine years, three patients came to require nocturnal continuous positive airway pressure, two continuous invasive ventilation and gastrostomy (both treated late) and all were left with residual disability [32]. Patients treated before symptoms remained free of symptoms during follow-up of several years [17, 70]. The life expectancy of treated patients is not known, because experience with riboflavin dates only from 2010 [2]. Slowly progressive late-onset forms may have long survival even without response to treatment, as in the 68-year-old Portuguese woman [11].

The poor prognostic factors described are onset before 4 years without treatment, a long interval between onset and treatment, truncating SLC52A3 variants with onset in infancy, interruption of riboflavin and poor adherence [2, 17, 18, 27, 70].

11.2 Initial assessment after diagnosis

The initial assessment recommended by GeneReviews includes anthropometry; neuromuscular assessment of proximal and distal strength (Rankin and Medical Research Council scales), sensory loss and gait (SARA scale for ataxia); history of epilepsy with electroencephalogram; orthopaedic and physical medicine assessment (scoliosis, mobility, activities of daily living, orthoses); ophthalmology (ocular motility, best-corrected acuity, colour vision, visual fields, visual evoked potentials, optical coherence tomography and fundoscopy) and low vision; audiology (BAEP, otoacoustic emissions, speech discrimination and behavioural tests); speech and language therapy and swallowing assessment; gastroenterology and nutrition (aspiration risk, need for gastrostomy); autonomic assessment (heart rate, temperature, syncope); respiratory medicine with polysomnography; psychiatry if depression is present; genetic counselling; and assessment of family support needs [2].

11.3 Surveillance

The GeneReviews summary indicates six-monthly follow-up in older patients and more frequent follow-up in young children, and the surveillance table of the same document proposes assessments at 3, 6 and 12 months after starting riboflavin and then annually or as needed [2]. The Sydney series used annual intervals until transition and proposed a surveillance protocol with the RTD Pediatric Scale and the clinical measures described, also as a basis for registries and trials [32]. Patients treated before symptoms were followed up six-monthly in the Omani cohort, with indirect laryngoscopy and audiometry [17].

12. Summary and Final Considerations

Riboflavin transporter deficiency brings together under a common mechanism the Brown-Vialetto-Van Laere and Fazio-Londe syndromes, described since 1894 as forms of pontobulbar palsy with or without deafness. Biallelic variants in SLC52A2 (RTD2), the nervous tissue transporter, or in SLC52A3 (RTD3), the intestinal transporter, cause a neuronopathy affecting the cranial nerves, motor neurons and sensory neurons, with auditory neuropathy, optic atrophy, bulbar palsy, weakness of the upper limbs and neck, sensory ataxia and diaphragmatic palsy. RTD2 begins at a mean age of 3 years, with frequent sensory ataxia and optic atrophy, and RTD3 at a mean age of 8.5 years, with more facial weakness and cases of adult onset. Maternal RFVT1 deficiency causes transient decompensation in the newborn.

The diagnosis is molecular. Mild MADD-type acylcarnitines and low plasma flavins help when present, but are normal in about half of patients, and newborn screening does not detect the disease. Suspicion should arise in the presence of auditory neuropathy associated with another neurological sign, a spinal muscular atrophy picture without SMN1 deletion or a young-onset motor neuron disease.

Without treatment, the disease kills, through respiratory failure, most patients with onset before 4 years of age. High-dose oral riboflavin, 10 to 50 mg/kg/day in three doses with progressive titration, started as soon as the disease is suspected and continued lifelong, improves about 70% to 90% of patients, and no deaths after the start of treatment have been described in the published series. The response depends on how early treatment begins: hearing and visual recovery is concentrated in the first year, patients treated late stabilise without recovering, and those treated before symptoms remain asymptomatic for years. Even with early treatment, slow progression of ataxia, decline in respiratory function and residual disability persist, which requires multidisciplinary surveillance and sustains interest in additional therapies, such as AAV9 gene augmentation, still at the cell-model stage.

Riboflavin is not authorised as a medicine for this indication in the USA, the European Union, Portugal or Brazil, and is obtained as a supplement or compounded preparation, which makes continuous access a clinical issue. Cascade testing of siblings, preconception counselling and supplementation in pregnancy complete the approach to one of the few hereditary neuronopathies with an effective treatment.

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