RARE DISEASE
RFVT3-related riboflavin transporter deficiency
RFVT3-related riboflavin transporter deficiency
RFVT3-related riboflavin transporter deficiency
Synonyms: RTD3, Riboflavin transporter deficiency 3
Synonyms: RTD3, Riboflavin transporter deficiency 3
Synonyms: RTD3, Riboflavin transporter deficiency 3
Drug discovery
0
drugs
With orphan designations
Overview
RFVT3-Related Riboflavin Transporter Deficiency
RFVT3-related riboflavin transporter deficiency, caused by biallelic SLC52A3 mutations, impairs riboflavin absorption and metabolism, leading to cellular flavin deficiency. Key features include progressive sensorineural hearing loss, pontobulbar palsy, generalized muscle weakness, optic atrophy, and respiratory compromise. Onset ranges from infancy to adulthood, with symptom severity inversely related to age. Early high-dose riboflavin supplementation (20–60 mg/kg/day) can stabilize or reverse symptoms, emphasizing the need for prompt diagnosis to mitigate irreversible neurological damage [3][4][5][6].
Burden
Mortality: Untreated cases often fatal due to respiratory failure; no deaths reported in riboflavin-treated cohorts [2][5].
Morbidity: Persistent deficits (e.g., hearing loss, gait abnormalities) despite treatment; lifelong dependency on assistive devices in severe cases [3][6].
Diagnostic challenges: Normal biochemical markers in ~50% of cases require genetic confirmation, delaying treatment [5][9].
Therapies
High-dose riboflavin: 10–90 mg/kg/day in divided doses, often combined with CoQ10 or carnitine for mitochondrial support [1][6][9].
Early intervention: Critical to prevent irreversible neurodegeneration; stabilization/improvement seen in 60–80% of treated patients [2][6].
Adjuvant care: Respiratory support, gastrostomy, and cochlear implants for advanced cases [5][6].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare neurological diseases, rare ophthalmic disorders, rare otorhinolaryngological diseases
Research Papers
48 drug discovery papers about RFVT3-related riboflavin transporter deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
48 drug discovery papers about RFVT3-related riboflavin transporter deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-27 | Biomarker-Guided Diagnosis of Riboflavin Transporter Deficiency Presenting as Seronegative Myasthenia Gravis: A Short Report from a Consanguineous Family.
Brown-Vialetto-Van Laere syndrome (BVVLS) is a rare, treatable neurodegenerative disorder caused by riboflavin transporter gene variants (SLC52A2, SLC52A3). Early symptoms can mimic neuromuscular junction disorders, causing diagnostic delays. A 3.5-year-old girl from consanguineous parents presented at 2.5 years with isolated bilateral ptosis, later developing dysphagia, dysphonia, facial diplegia, stridor, and respiratory compromise. Examination revealed tongue atrophy with fasciculations and bulbar weakness but normal limb strength. Diagnosed with seronegative myasthenia gravis, she failed to respond to corticosteroids, pyridostigmine, salbutamol, and intravenous immunoglobulin. Absence of fatigability, lower motor neuron signs, and a sibling history of hearing loss and bulbar palsy prompted genetic testing revealed a homozygous missense variant in SLC52A3 (c.670T > C; p.Phe224Leu). High-dose riboflavin (up to 50 mg/kg/day) led to gradual improvement in bulbar function, resolution of stridor, and respiratory stabilization, though ptosis and tongue fasciculations persisted. This report is novel in using clinical response to riboflavin as a functional biomarker for riboflavin transporter deficiency (RTD) in a patient with a variant of uncertain significance, unlike prior cases with definitive genetics. Empiric riboflavin challenge offers a practical framework when genetic results are ambiguous. RTD should be suspected in children with treatment-resistant, non-fluctuating ptosis and bulbar weakness, particularly with consanguinity or family history of hearing loss and bulbar palsy. Early high-dose riboflavin prevents decline, while immunosuppression is ineffective and potentially harmful.
2025-11-26 | Riboflavin Transporter Deficiency as a Cause of Progressive Encephalopathy.
Background/Objective: Riboflavin transporter deficiency (RTD) is a rare neurodegenerative disease, with under 500 cases genetically confirmed since the early 2000s. Thus far, three separate subtypes of RTD2 are described-type 1, 2 and 3-but, previously, RTD was classified as two separate genetic defects: Brown-Vialetto-Van Laere syndrome and Fazio-Londe syndrome, caused by mutations in the SLC52A2 and SLC52A3 genes, respectively. The most prominent symptoms found in patients include encephalopathy, expressed as peripheral and cranial nerve neuropathy, which in turn lead to a series of complications: decreased muscle strength, hypotonia, visual impairment, sensorineural hearing loss, bulbar palsy, sensory ataxia and respiratory insufficiency secondary to diaphragmatic paresis. At the cellular level, riboflavin is modified into active flavin cofactors: FMN, mediating riboflavin phosphorylation through riboflavin kinase, and FAD, involved in FMN adenylation through the flavin dinucleotide 1 synthesis. FMN and FAD are two of approximately 100 proteins collectively described as the 'flavoproteome'. Most of them are mitochondrial oxidoreductases, catalyzing the electron transport in many metabolic reactions, as well as regulating important cell processes, such as the production of reactive oxygen species, protein conformation and damage repair. FMN and FAD are also responsible for the conversion of B6 and B9 vitamins into their active forms, which allows for healthy cell growth and immune function. Methods: In this article, the authors describe two children, a 6-year-old girl and her 5-year-old sister, both presenting with RTD2 caused by mutations in the SLC52A2 gene (c.916G>C (p.Gly306Arg); c.477C>G (p.Cys159Trp)), in whom the disease progression was successfully inhibited by vitamin B2 supplementation in varying doses. Results: Their clinical image consists of psychomotor developmental delay, ataxia, horizontal nystagmus, hearing loss and a lack of visual fixation. Conclusions: The phenotype and clinical signs presented by the described sisters are further discussed in relation to the previously published reports of RTD2 cases.
2024-12-15 | Development of a riboflavin-responsive model of riboflavin transporter deficiency in zebrafish.
Riboflavin transporter deficiency (RTD) is a rare and progressive neurodegenerative disease resulting from the disruption of RFVT2- and RFVT3- mediated riboflavin transport caused by biallelic mutations in SLC52A2 and SLC52A3, respectively. The resulting impaired mitochondrial metabolism leads to sensorimotor neurodegeneration and symptoms including muscle weakness, respiratory difficulty, and sensorineural deafness. Although over 70% of patients with RTD improve following high-dose riboflavin supplementation, remaining patients either stabilise or continue to deteriorate. This may be due to the rapid excretion of central nervous system (CNS) riboflavin by organic anion transporter 3 (OAT-3), highlighting the need for alternative or supplemental RTD treatments. Probenecid is a promising therapeutic candidate for RTD due to its known inhibitory effect on OAT-3. Therefore, this study aimed to generate morpholino-mediated knockdowns of human SLC52A3 ortholog slc52a3 in zebrafish larvae for use in therapeutic screening of riboflavin and probenecid. Knockdown of slc52a3 resulted in an RTD-like phenotype indicative of altered neurodevelopment, hearing loss, and reduced mobility. This RTD-like phenotype overlaps with the phenotype of CRISPR/Cas9-mediated knockout of slc52a3 in zebrafish, is maintained following slc52a3 morpholino + p53 morpholino co-injection, and is rescued following slc52a3 morpholino + human SLC52A3 mRNA co-injection, indicating specificity of the knockdown. Riboflavin treatment alone ameliorates locomotor activity and hearing ability in slc52a3 morphants. Riboflavin and probenecid co-treatment provides an additional small benefit to hearing but not to locomotion. Our findings demonstrate that this model recapitulates both the RTD phenotype and the riboflavin-responsiveness of RTD patients, and possible therapeutic benefit conferred by probenecid warrants further investigation.
2024-11-15 | Child Neurology: Five-Year Update on Siblings With Riboflavin Transporter Deficiency: Stable Visual and Neurologic Status With Continued Riboflavin Therapy.
Riboflavin transporter deficiency (RTD), previously referred to as Brown-Vialetto-Van Laere syndrome, is caused by pathogenic variants in the SLC52A1, SLC52A2, or SLC52A3 genes, resulting in RTD types 1, 2, and 3, respectively. Researchers estimate an occurrence of approximately 1 in 1,000,000. There is only one case of type 1 described in medical literature. Type 2 is characterized by muscle weakness in the arms and neck, vision loss, hearing impairment, and sensory ataxia. In type 3, vocal cord paralysis is more common and muscle weakness is more generalized. In 2018, we described a case of a 6-year-old girl with RTD type 2 who made remarkable visual recovery after initiation of treatment with oral riboflavin and coenzyme Q10 supplementation. The patient's younger brother began the same treatment regimen after genetic testing confirmed that he carried the same genetic variant. In this report, we update the visual and neurologic status in these siblings 5 years after our initial report and 7.5 years after initiation of riboflavin treatment.
2024-10-28 | Acute proximal weakness after cochlear implant: Riboflavin transporter deficiency onset in child
Riboflavin transporter deficiencies (RTDs) are treatable progressive neurodegenerative disorders that present with symptoms including weakness, ataxia and neurosensory hearing loss. Once converted to the flavin cofactor, riboflavin plays a pivotal role in redox metabolic reactions. Similarly to classical mitochondrial diseases, stress may act as a trigger for disease progression. The subject is a 3-year-old girl with initially normal development who experienced language regression due to sensorineural deafness at 20 months old. One year later, the patient experienced an acute episode of asymmetric proximal weakness following cochlear implant surgery. All metabolic, immunological, and neuroimaging studies were normal. Serial electromyography studies revealed a rapidly progressive axonal sensory-motor neuropathy affecting the upper limbs. In search of treatable conditions, riboflavin was initiated, and later on, compound heterozygous pathogenic variants in SLC52A2 were identified. This report describes the clinical and electromyography findings of this patient during the four years following diagnosis.
small molecules
2026-09-27 | Biomarker-Guided Diagnosis of Riboflavin Transporter Deficiency Presenting as Seronegative Myasthenia Gravis: A Short Report from a Consanguineous Family.
Brown-Vialetto-Van Laere syndrome (BVVLS) is a rare, treatable neurodegenerative disorder caused by riboflavin transporter gene variants (SLC52A2, SLC52A3). Early symptoms can mimic neuromuscular junction disorders, causing diagnostic delays. A 3.5-year-old girl from consanguineous parents presented at 2.5 years with isolated bilateral ptosis, later developing dysphagia, dysphonia, facial diplegia, stridor, and respiratory compromise. Examination revealed tongue atrophy with fasciculations and bulbar weakness but normal limb strength. Diagnosed with seronegative myasthenia gravis, she failed to respond to corticosteroids, pyridostigmine, salbutamol, and intravenous immunoglobulin. Absence of fatigability, lower motor neuron signs, and a sibling history of hearing loss and bulbar palsy prompted genetic testing revealed a homozygous missense variant in SLC52A3 (c.670T > C; p.Phe224Leu). High-dose riboflavin (up to 50 mg/kg/day) led to gradual improvement in bulbar function, resolution of stridor, and respiratory stabilization, though ptosis and tongue fasciculations persisted. This report is novel in using clinical response to riboflavin as a functional biomarker for riboflavin transporter deficiency (RTD) in a patient with a variant of uncertain significance, unlike prior cases with definitive genetics. Empiric riboflavin challenge offers a practical framework when genetic results are ambiguous. RTD should be suspected in children with treatment-resistant, non-fluctuating ptosis and bulbar weakness, particularly with consanguinity or family history of hearing loss and bulbar palsy. Early high-dose riboflavin prevents decline, while immunosuppression is ineffective and potentially harmful.
2025-11-26 | Riboflavin Transporter Deficiency as a Cause of Progressive Encephalopathy.
Background/Objective: Riboflavin transporter deficiency (RTD) is a rare neurodegenerative disease, with under 500 cases genetically confirmed since the early 2000s. Thus far, three separate subtypes of RTD2 are described-type 1, 2 and 3-but, previously, RTD was classified as two separate genetic defects: Brown-Vialetto-Van Laere syndrome and Fazio-Londe syndrome, caused by mutations in the SLC52A2 and SLC52A3 genes, respectively. The most prominent symptoms found in patients include encephalopathy, expressed as peripheral and cranial nerve neuropathy, which in turn lead to a series of complications: decreased muscle strength, hypotonia, visual impairment, sensorineural hearing loss, bulbar palsy, sensory ataxia and respiratory insufficiency secondary to diaphragmatic paresis. At the cellular level, riboflavin is modified into active flavin cofactors: FMN, mediating riboflavin phosphorylation through riboflavin kinase, and FAD, involved in FMN adenylation through the flavin dinucleotide 1 synthesis. FMN and FAD are two of approximately 100 proteins collectively described as the 'flavoproteome'. Most of them are mitochondrial oxidoreductases, catalyzing the electron transport in many metabolic reactions, as well as regulating important cell processes, such as the production of reactive oxygen species, protein conformation and damage repair. FMN and FAD are also responsible for the conversion of B6 and B9 vitamins into their active forms, which allows for healthy cell growth and immune function. Methods: In this article, the authors describe two children, a 6-year-old girl and her 5-year-old sister, both presenting with RTD2 caused by mutations in the SLC52A2 gene (c.916G>C (p.Gly306Arg); c.477C>G (p.Cys159Trp)), in whom the disease progression was successfully inhibited by vitamin B2 supplementation in varying doses. Results: Their clinical image consists of psychomotor developmental delay, ataxia, horizontal nystagmus, hearing loss and a lack of visual fixation. Conclusions: The phenotype and clinical signs presented by the described sisters are further discussed in relation to the previously published reports of RTD2 cases.
2024-12-15 | Development of a riboflavin-responsive model of riboflavin transporter deficiency in zebrafish.
Riboflavin transporter deficiency (RTD) is a rare and progressive neurodegenerative disease resulting from the disruption of RFVT2- and RFVT3- mediated riboflavin transport caused by biallelic mutations in SLC52A2 and SLC52A3, respectively. The resulting impaired mitochondrial metabolism leads to sensorimotor neurodegeneration and symptoms including muscle weakness, respiratory difficulty, and sensorineural deafness. Although over 70% of patients with RTD improve following high-dose riboflavin supplementation, remaining patients either stabilise or continue to deteriorate. This may be due to the rapid excretion of central nervous system (CNS) riboflavin by organic anion transporter 3 (OAT-3), highlighting the need for alternative or supplemental RTD treatments. Probenecid is a promising therapeutic candidate for RTD due to its known inhibitory effect on OAT-3. Therefore, this study aimed to generate morpholino-mediated knockdowns of human SLC52A3 ortholog slc52a3 in zebrafish larvae for use in therapeutic screening of riboflavin and probenecid. Knockdown of slc52a3 resulted in an RTD-like phenotype indicative of altered neurodevelopment, hearing loss, and reduced mobility. This RTD-like phenotype overlaps with the phenotype of CRISPR/Cas9-mediated knockout of slc52a3 in zebrafish, is maintained following slc52a3 morpholino + p53 morpholino co-injection, and is rescued following slc52a3 morpholino + human SLC52A3 mRNA co-injection, indicating specificity of the knockdown. Riboflavin treatment alone ameliorates locomotor activity and hearing ability in slc52a3 morphants. Riboflavin and probenecid co-treatment provides an additional small benefit to hearing but not to locomotion. Our findings demonstrate that this model recapitulates both the RTD phenotype and the riboflavin-responsiveness of RTD patients, and possible therapeutic benefit conferred by probenecid warrants further investigation.
2024-11-15 | Child Neurology: Five-Year Update on Siblings With Riboflavin Transporter Deficiency: Stable Visual and Neurologic Status With Continued Riboflavin Therapy.
Riboflavin transporter deficiency (RTD), previously referred to as Brown-Vialetto-Van Laere syndrome, is caused by pathogenic variants in the SLC52A1, SLC52A2, or SLC52A3 genes, resulting in RTD types 1, 2, and 3, respectively. Researchers estimate an occurrence of approximately 1 in 1,000,000. There is only one case of type 1 described in medical literature. Type 2 is characterized by muscle weakness in the arms and neck, vision loss, hearing impairment, and sensory ataxia. In type 3, vocal cord paralysis is more common and muscle weakness is more generalized. In 2018, we described a case of a 6-year-old girl with RTD type 2 who made remarkable visual recovery after initiation of treatment with oral riboflavin and coenzyme Q10 supplementation. The patient's younger brother began the same treatment regimen after genetic testing confirmed that he carried the same genetic variant. In this report, we update the visual and neurologic status in these siblings 5 years after our initial report and 7.5 years after initiation of riboflavin treatment.
2024-10-28 | Acute proximal weakness after cochlear implant: Riboflavin transporter deficiency onset in child
Riboflavin transporter deficiencies (RTDs) are treatable progressive neurodegenerative disorders that present with symptoms including weakness, ataxia and neurosensory hearing loss. Once converted to the flavin cofactor, riboflavin plays a pivotal role in redox metabolic reactions. Similarly to classical mitochondrial diseases, stress may act as a trigger for disease progression. The subject is a 3-year-old girl with initially normal development who experienced language regression due to sensorineural deafness at 20 months old. One year later, the patient experienced an acute episode of asymmetric proximal weakness following cochlear implant surgery. All metabolic, immunological, and neuroimaging studies were normal. Serial electromyography studies revealed a rapidly progressive axonal sensory-motor neuropathy affecting the upper limbs. In search of treatable conditions, riboflavin was initiated, and later on, compound heterozygous pathogenic variants in SLC52A2 were identified. This report describes the clinical and electromyography findings of this patient during the four years following diagnosis.
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