{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T17:29:45Z","timestamp":1791826185065,"version":"4.3.4"},"reference-count":47,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T00:00:00Z","timestamp":1761264000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Statutory Project of Medical University of Silesia","award":["1180K4K"],"award-info":[{"award-number":["1180K4K"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>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\u2014type 1, 2 and 3\u2014but, previously, RTD was classified as two separate genetic defects: Brown\u2013Vialetto\u2013Van Laere syndrome and Fazio\u2013Londe 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 \u2018flavoproteome\u2019. 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&gt;C (p.Gly306Arg); c.477C&gt;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.<\/jats:p>","DOI":"10.3390\/metabo15110688","type":"journal-article","created":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T07:41:35Z","timestamp":1761291695000},"page":"688","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Riboflavin Transporter Deficiency as a Cause of Progressive Encephalopathy"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1794-8546","authenticated-orcid":false,"given":"Justyna","family":"Paprocka","sequence":"first","affiliation":[{"name":"Department of Pediatric Neurology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-752 Katowice, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Karpierz","sequence":"additional","affiliation":[{"name":"Students\u2019 Scientific Society, Department of Pediatric Neurology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-752 Katowice, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0399-7542","authenticated-orcid":false,"given":"Micha\u0142","family":"Hutny","sequence":"additional","affiliation":[{"name":"Students\u2019 Scientific Society, Department of Pediatric Neurology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-752 Katowice, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8259-1304","authenticated-orcid":false,"given":"Jagoda","family":"Hofman-Hutna","sequence":"additional","affiliation":[{"name":"Students\u2019 Scientific Society, Department of Pediatric Neurology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, 40-752 Katowice, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Artur","family":"Dobosz","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Faculty of Medicine, Jagiellonian University Medical College, 31-008 Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,24]]},"reference":[{"key":"ref_1","unstructured":"Mahabadi, N., Bhusal, A., and Banks, S.W. (2021). Riboflavin Deficiency. StatPearls, StatPearls Publishing."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.abb.2013.02.015","article-title":"The Human Flavoproteome","volume":"535","author":"Lienhart","year":"2013","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_3","unstructured":"Peechakara, B.V., Sina, R.E., and Gupta, M. (2025). Vitamin B2 (Riboflavin), National Library of Medicine."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), Turck, D., Bresson, J.-L., Burlingame, B., Dean, T., Fairweather-Tait, S., Heinonen, M., Hirsch-Ernst, K.I., and Mangelsdorf, I. (2017). Dietary Reference Values for Riboflavin. EFSA J., 15, e04919.","DOI":"10.2903\/j.efsa.2017.4919"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Kennedy, D.O. (2016). B Vitamins and the Brain: Mechanisms, Dose and Efficacy\u2014A Review. Nutrients, 8.","DOI":"10.3390\/nu8020068"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Mosegaard, S., Dipace, G., Bross, P., Carlsen, J., Gregersen, N., and Olsen, R.K.J. (2020). Riboflavin Deficiency\u2014Implications for General Human Health and Inborn Errors of Metabolism. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21113847"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/s41419-020-02929-5","article-title":"Flavin Dependency Undermines Proteome Stability, Lipid Metabolism and Cellular Proliferation during Vitamin B2 Deficiency","volume":"11","author":"Calloni","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1136\/jclinpath-2018-205048","article-title":"Laboratory Assessment of Folate (Vitamin B9) Status","volume":"71","author":"Harrington","year":"2018","journal-title":"J. Clin. Pathol."},{"key":"ref_9","unstructured":"Brown, M.J., Ameer, M.A., Daley, S.F., and Beier, K. (2025). Vitamin B6 Deficiency, National Library of Medicine."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1007\/s10545-016-9950-0","article-title":"Riboflavin Transport and Metabolism in Humans","volume":"39","author":"Barile","year":"2016","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1093\/ajcn\/77.6.1352","article-title":"Riboflavin (Vitamin B-2) and Health","volume":"77","author":"Powers","year":"2003","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.eja.2006.04.009","article-title":"Variability of B Vitamin Concentrations in Wheat Grain, Milling Fractions and Bread Products","volume":"25","author":"Batifoulier","year":"2006","journal-title":"Eur. J. Agron."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"23","DOI":"10.5539\/jfr.v3n6p23","article-title":"Riboflavin in Nutrition, Food Processing, and Analysis\u2014A Review","volume":"3","author":"Golbach","year":"2014","journal-title":"J. Food Res."},{"key":"ref_14","unstructured":"Cali, E., Dominik, N., Manole, A., and Houlden, H. (2015). Riboflavin Transporter Deficiency. GeneReviews\u00ae, University of Washington."},{"key":"ref_15","unstructured":"Cali, E., Dominik, N., Manole, A., and Houlden, H. (2015). Riboflavin Transporter Deficiency, National Library of Medicine."},{"key":"ref_16","first-page":"233","article-title":"Riboflavin Transporter Deficiency in Young Adults Unmasked by Dietary Changes","volume":"65","author":"Jaeger","year":"2024","journal-title":"JIMD Rep."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Udhayabanu, T., Manole, A., Rajeshwari, M., Varalakshmi, P., Houlden, H., and Ashokkumar, B. (2017). Riboflavin Responsive Mitochondrial Dysfunction in Neurodegenerative Diseases. J. Clin. Med., 6.","DOI":"10.3390\/jcm6050052"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1007\/s10545-016-9924-2","article-title":"Clinical Presentation and Outcome of Riboflavin Transporter Deficiency: Mini Review after Five Years of Experience","volume":"39","author":"Jaeger","year":"2016","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1111\/dmcn.16083","article-title":"Long-term Outcomes in Children with Riboflavin Transporter Deficiency and Surveillance Recommendations","volume":"67","author":"Fennessy","year":"2025","journal-title":"Dev. Med. Child. Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1186\/s13023-024-03428-y","article-title":"Riboflavin Transporter Deficiency, the Search for the Undiagnosed: A Retrospective Data Mining Study","volume":"19","author":"Jaeger","year":"2024","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Zhang, L., and Thyagarajan, D. (2022). Two Rare Cases of Long Surviving Riboflavin Transporter Deficiency with Co-Existing Adenosine Monophosphate Deaminase (AMP) Deficiency. Brain Sci., 12.","DOI":"10.3390\/brainsci12121605"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/1750-1172-7-83","article-title":"The Brown-Vialetto-Van Laere and Fazio Londe Syndrome Revisited: Natural History, Genetics, Treatment and Future Perspectives","volume":"7","author":"Bosch","year":"2012","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1111\/dmcn.13084","article-title":"Auditory Neuropathy in Brown\u2013Vialetto\u2013Van Laere Syndrome Due to Riboflavin Transporter RFVT2 Deficiency","volume":"58","author":"Menezes","year":"2016","journal-title":"Dev. Med. Child. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s40673-018-0091-0","article-title":"Successful Treatment of a Genetic Childhood Ataxia Due to Riboflavin Transporter Deficiency","volume":"5","author":"Fan","year":"2018","journal-title":"Cerebellum Ataxias"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.jclinepi.2017.04.026","article-title":"CARE Guidelines for Case Reports: Explanation and Elaboration Document","volume":"89","author":"Riley","year":"2017","journal-title":"J. Clin. Epidemiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1111\/head.12246","article-title":"The CARE Guidelines: Consensus-Based Clinical Case Reporting Guideline Development","volume":"53","author":"Gagnier","year":"2013","journal-title":"Headache"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1016\/j.addr.2008.05.001","article-title":"The Mitochondrial Cocktail: Rationale for Combined Nutraceutical Therapy in Mitochondrial Cytopathies","volume":"60","author":"Tarnopolsky","year":"2008","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1002\/jimd.12053","article-title":"An Update on the Genetics, Clinical Presentation, and Pathomechanisms of Human Riboflavin Transporter Deficiency","volume":"42","author":"Bosch","year":"2019","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2820","DOI":"10.1093\/brain\/awx231","article-title":"Clinical, Pathological and Functional Characterization of Riboflavin-Responsive Neuropathy","volume":"140","author":"Manole","year":"2017","journal-title":"Brain"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/1750-1172-3-9","article-title":"Brown-Vialetto-Van Laere Syndrome","volume":"3","author":"Sathasivam","year":"2008","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s10545-010-9242-z","article-title":"Brown-Vialetto-Van Laere and Fazio Londe Syndrome Is Associated with a Riboflavin Transporter Defect Mimicking Mild MADD: A New Inborn Error of Metabolism with Potential Treatment","volume":"34","author":"Bosch","year":"2011","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1111\/j.1469-8749.2011.04142.x","article-title":"Early Use of High-dose Riboflavin in a Case of Brown\u2013Vialetto\u2013Van Laere Syndrome","volume":"54","author":"Anand","year":"2012","journal-title":"Dev. Med. Child. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1002\/ajh.26573","article-title":"Thirteen-Month-Old Girl with Hyporegenerative Macrocytic Anemia Due to Brown\u2013Vialetto\u2013Van Laere Syndrome 2","volume":"97","author":"Naami","year":"2022","journal-title":"Am. J. Hematol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/j.cca.2021.10.031","article-title":"BVVLS2 Overlooked for 3 Years in a Pediatric Patient Caused by Novel Compound Heterozygous Mutations in SLC52A2 Gene","volume":"523","author":"Liu","year":"2021","journal-title":"Clin. Chim. Acta"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"314","DOI":"10.24953\/turkjped.2021.02.016","article-title":"Brown Vialetto Van Laere Syndrome: Presenting with Left Ventricular Non-Compaction and Mimicking Mitochondrial Disorders","volume":"63","author":"Ceylaner","year":"2021","journal-title":"Turk. J. Pediatr."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.4103\/0028-3886.299175","article-title":"Brown\u2013Vialetto\u2013Van Laere Syndrome: A Rare Case Report of MND Mimic","volume":"68","author":"Kranthi","year":"2020","journal-title":"Neurol. India"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2781","DOI":"10.1002\/ajmg.a.61851","article-title":"Hematologic Presentation and the Role of Untargeted Metabolomics Analysis in Monitoring Treatment for Riboflavin Transporter Deficiency","volume":"182","author":"Pillai","year":"2020","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1080\/14670100.2018.1534035","article-title":"Cochlear Implantation in Children with Auditory Neuropathy: Lessons from Brown\u2013Vialetto\u2013Van Laere Syndrome","volume":"20","author":"Anderson","year":"2019","journal-title":"Cochlear Implant. Int."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.spen.2017.03.001","article-title":"Genetic, Radiologic, and Clinical Variability in Brown-Vialetto-van Laere Syndrome","volume":"26","author":"Woodcock","year":"2018","journal-title":"Semin. Pediatr. Neurol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1002\/ajmg.a.38530","article-title":"Riboflavin Transporter Deficiency Mimicking Mitochondrial Myopathy Caused by Complex II Deficiency","volume":"176","author":"Nimmo","year":"2018","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"a000265","DOI":"10.1101\/mcs.a000265","article-title":"Sustained Therapeutic Response to Riboflavin in a Child with a Progressive Neurological Condition, Diagnosed by Whole-Exome Sequencing","volume":"1","author":"Shashi","year":"2015","journal-title":"Mol. Case Stud."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"a000257","DOI":"10.1101\/mcs.a000257","article-title":"Exome Sequencing Results in Successful Riboflavin Treatment of a Rapidly Progressive Neurological Condition","volume":"1","author":"Petrovski","year":"2015","journal-title":"Mol. Case Stud."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1016\/j.clinph.2015.05.012","article-title":"Pathophysiology of Motor Dysfunction in a Childhood Motor Neuron Disease Caused by Mutations in the Riboflavin Transporter","volume":"127","author":"Menezes","year":"2016","journal-title":"Clin. Neurophysiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1002\/mus.24224","article-title":"Mutations in Riboflavin Transporter Present with Severe Sensory Loss and Deafness in Childhood","volume":"50","author":"Srour","year":"2014","journal-title":"Muscle Nerve"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1007\/s10545-012-9513-y","article-title":"Impaired Riboflavin Transport Due to Missense Mutations in SLC52A2 Causes Brown-Vialetto-Van Laere Syndrome","volume":"35","author":"Haack","year":"2012","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e209969","DOI":"10.1212\/WNL.0000000000209969","article-title":"Child Neurology: Five-Year Update on Siblings With Riboflavin Transporter Deficiency","volume":"103","author":"Culican","year":"2024","journal-title":"Neurology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1111\/dmcn.16106","article-title":"Riboflavin Supplementation in Children with Riboflavin Transporter Deficiency Type 2 Does Not Stop Disease Progression Based on Long-term Follow-up","volume":"67","author":"Bertini","year":"2024","journal-title":"Dev. Med. Child. Neurol."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/15\/11\/688\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T07:54:07Z","timestamp":1761292447000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/15\/11\/688"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,24]]},"references-count":47,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["metabo15110688"],"URL":"https:\/\/doi.org\/10.3390\/metabo15110688","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,24]]}}}