{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T06:25:21Z","timestamp":1761719121805,"version":"build-2065373602"},"reference-count":37,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,29]],"date-time":"2022-01-29T00:00:00Z","timestamp":1643414400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Recessive hereditary methemoglobinemia (RHM) due to NADH-cytochrome b5 reductase deficiency is a rare disease caused by pathogenic variants in CYB5R3. Unlike type I, in RHM type II (RHM2), the enzymatic defect affects erythrocytes and all body tissues, thus resulting in cyanosis and neurological impairment. Although the first description of RHM2 dates back to the mid-1950s, detailed clinical and neuroimaging information are available for only a few patients. Here, we describe a new patient with RHM2 that harbors an unreported homozygous 31 Kb deletion involving part of CYB5R3, and showing a peculiar neuroimaging pattern resembling a ponto-cerebellar hypoplasia-like condition. A careful review of the available literature was performed with the aim of better delineating neurological and neuroimaging as well as the genotypic spectra of this extremely rare disease.<\/jats:p>","DOI":"10.3390\/brainsci12020182","type":"journal-article","created":{"date-parts":[[2022,1,29]],"date-time":"2022-01-29T23:02:06Z","timestamp":1643497326000},"page":"182","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Neurological and Neuroimaging Features of CYB5R3-Related Recessive Hereditary Methemoglobinemia Type II"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5612-821X","authenticated-orcid":false,"given":"Francesco","family":"Nicita","sequence":"first","affiliation":[{"name":"Unit of Neuromuscular and Neurodegenerative Disorders, Genetics and Rare Diseases Research Division, Department of Neurosciences, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8168-6352","authenticated-orcid":false,"given":"Letizia","family":"Sabatini","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"},{"name":"Department of Pediatrics, University of Rome Tor Vergata, 00146 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7514-5683","authenticated-orcid":false,"given":"Viola","family":"Alesi","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Ges\u00f9 Children 5 Hospital and Research Institute, IRCCS, 00146 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giulia","family":"Lucignani","sequence":"additional","affiliation":[{"name":"Unit of Neuroradiology, Department of Radiology, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ester","family":"Sallicandro","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Ges\u00f9 Children 5 Hospital and Research Institute, IRCCS, 00146 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonella","family":"Sferra","sequence":"additional","affiliation":[{"name":"Unit of Neuromuscular and Neurodegenerative Disorders, Genetics and Rare Diseases Research Division, Department of Neurosciences, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9276-4590","authenticated-orcid":false,"given":"Enrico","family":"Bertini","sequence":"additional","affiliation":[{"name":"Unit of Neuromuscular and Neurodegenerative Disorders, Genetics and Rare Diseases Research Division, Department of Neurosciences, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6367-1843","authenticated-orcid":false,"given":"Ginevra","family":"Zanni","sequence":"additional","affiliation":[{"name":"Unit of Neuromuscular and Neurodegenerative Disorders, Genetics and Rare Diseases Research Division, Department of Neurosciences, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Palumbo","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00146 Rome, Italy"},{"name":"Department of Pediatrics, University of Rome Tor Vergata, 00146 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1002\/humu.23973","article-title":"Mutation update: Variants of the CYB5R3 gene in recessive congenital methemoglobinemia","volume":"41","author":"Gupta","year":"2020","journal-title":"Hum. Mutat."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Siendones, E., Ballesteros, M., and Navas, P. (2018). Cellular and molecular mechanisms of recessive hereditary methaemoglobinaemia type II. J. Clin. Med., 7.","DOI":"10.3390\/jcm7100341"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1042\/bj3550529","article-title":"Transcriptional and translational mechanisms of cytochrome b5 reductase isoenzyme generation in humans","volume":"355","author":"Leroux","year":"2001","journal-title":"Biochem. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2\u2212\u0394\u0394CT method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1111\/cge.13562","article-title":"Heterozygous missense variants of SPTBN2 are a frequent cause of congenital cerebellar ataxia","volume":"96","author":"Nicita","year":"2019","journal-title":"Clin. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1111\/j.1600-0609.1978.tb02472.x","article-title":"Heterogeneity of hereditary methaemoglobinaemia: A study of 4 cuban families with NADH-methaemoglobin reductase deficiency including a new variant (Santiago de Cuba Variant)","volume":"20","author":"Estrada","year":"1978","journal-title":"Scand. J. Haematol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1182\/blood.V75.7.1408.1408","article-title":"Serine-proline replacement at residue 127 of NADH-cytochrome b5 reductase causes hereditary methemoglobinemia, generalized type","volume":"75","author":"Kobayashi","year":"1990","journal-title":"Blood"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1002\/ajh.2830400411","article-title":"New variant of cytochrome b5 reductase deficiency (b5RKurashiki) in red cells, platelets, lymphocytes, and cultured fibroblasts with congenital methemoglobinemia, mental and neurological retardation, and skeletal anomalies","volume":"40","author":"Yawata","year":"1992","journal-title":"Am. J. Hematol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5952","DOI":"10.1016\/S0021-9258(17)37554-3","article-title":"An in-frame deletion of codon 298 of the NADH-cytochrome b5 reductase gene results in hereditary methemoglobinemia type II (generalized type). A functional implication for the role of the COOH-terminal region of the enzyme","volume":"269","author":"Shirabe","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2254","DOI":"10.1182\/blood.V85.8.2254.bloodjournal8582254","article-title":"Four new mutations in the NADH-cytochrome b5 reductase gene from patients with recessive congenital methemoglobinemia type II","volume":"85","author":"Vieira","year":"1995","journal-title":"Blood"},{"key":"ref_11","first-page":"302","article-title":"A novel point mutation in a 3\u2032 splice site of the NADH-cytochrome b5 reductase gene results in immunologically undetectable enzyme and impaired NADH-dependent ascorbate regeneration in cultured fibroblasts of a patient with type II hereditary methemoglobinemia","volume":"57","author":"Shirabe","year":"1995","journal-title":"Am. J. Hum. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3208","DOI":"10.1182\/blood.V88.8.3208.bloodjournal8883208","article-title":"Two novel mutations in the reduced nicotinamide adenine dinucleotide (NADH)-cytochrome b5 reductase gene of a patient with generalized type, hereditary methemoglobinemia","volume":"88","author":"Manabe","year":"1996","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1023\/A:1005379730729","article-title":"Recessive congenital methaemoglobinaemia type II, a new mutation which causes incorrect splicing in the NADH-cytochrome b5 reductase gene","volume":"20","author":"Owen","year":"1997","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1046\/j.1365-2141.1998.01123.x","article-title":"Molecular basis of hereditary methaemoglobinaemia, types I and II: Two novel mutations in the NADH-cytochrome b5 reductase gene","volume":"103","author":"Higasa","year":"1998","journal-title":"Br. J. Haematol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/1098-1004(200007)16:1<18::AID-HUMU4>3.0.CO;2-N","article-title":"A case of methemoglobinemia type II due to NADH-cytochrome b5 reductase deficiency: Determination of the molecular basis","volume":"16","author":"Aalfs","year":"2000","journal-title":"Hum. Mutat."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1002\/humu.31","article-title":"Molecular basis of recessive congenital methemoglobinemia, types I and II: Exon skipping and three novel missense mutations in the NADH-cytochrome b5 reductase (diaphorase 1) gene","volume":"17","author":"Kugler","year":"2001","journal-title":"Hum. Mutat."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/s00431-004-1409-x","article-title":"Severe neurological impairment in hereditary methaemoglobinaemia type 2","volume":"163","author":"Toelle","year":"2004","journal-title":"Eur. J. Pediatr."},{"key":"ref_18","first-page":"187","article-title":"A rare cause of mental motor retardation: Recessive congenital methemoglobinemia type II","volume":"51","author":"Yilmaz","year":"2009","journal-title":"Turk. J. Pediatr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1002\/ajmg.a.30467","article-title":"A novel mutation in the DIA1 gene in a patient with methemoglobinemia type II","volume":"133A","author":"Yilmaz","year":"2005","journal-title":"Am. J. Med. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.pediatrneurol.2005.02.009","article-title":"A case with quadriparetic cerebral palsy and cyanosis: Congenital methemoglobinemia","volume":"33","author":"Gokalp","year":"2005","journal-title":"Pediatr. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1093\/brain\/awm337","article-title":"Recessive hereditary methaemoglobinaemia, type II: Delineation of the clinical spectrum","volume":"131","author":"Ewenczyk","year":"2008","journal-title":"Brain"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.bcmd.2008.02.002","article-title":"Recessive hereditary methemoglobinemia: Two novel mutations in the NADH-cytochrome b5 reductase gene","volume":"41","author":"Fermo","year":"2008","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1177\/0883073809336136","article-title":"A novel mutation in type II methemoglobinemia","volume":"25","author":"Hudspeth","year":"2010","journal-title":"J. Child Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.braindev.2010.06.015","article-title":"Cerebellar atrophy in a child with hereditary methemoglobinemia type II","volume":"33","author":"Fusco","year":"2011","journal-title":"Brain Dev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1002\/ajh.21956","article-title":"Severe mental retardation and recessive congenital methemoglobinemia in three Indian patients: Compound heterozygous for NADH-cytochrome b5 reductase gene mutations","volume":"86","author":"Kedar","year":"2011","journal-title":"Am. J. Hematol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1097\/MPH.0b013e318257a492","article-title":"Methemoglobin reductase deficiency: Novel mutation is associated with a disease phenotype of intermediate severity","volume":"34","author":"Percy","year":"2012","journal-title":"J. Pediatr. Hematol. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1111\/cge.12326","article-title":"Clinical spectrum and molecular basis of recessive congenital methemoglobinemia in India","volume":"87","author":"Warang","year":"2015","journal-title":"Clin. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.ymgmr.2015.10.002","article-title":"A novel nine base deletion mutation in NADH-cytochrome b5 reductase gene in an Indian family with recessive congenital methemoglobinemia-type-II","volume":"5","author":"Warang","year":"2015","journal-title":"Mol. Genet. Metab. Reports"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1002\/pbc.25791","article-title":"Congenital methemoglobinemia type II-clinical improvement with short-term methylene blue treatment","volume":"63","author":"Cooper","year":"2016","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1002\/ccr3.1310","article-title":"Congenital methemoglobinemia type II in a 5-year-old boy","volume":"6","author":"Mannino","year":"2018","journal-title":"Clin. Case Rep."},{"key":"ref_31","first-page":"626","article-title":"Two Novel C-Terminal Frameshift Mutations in the CYB5R3 gene lead to global growth and developmental delay associated with recessive congenital methemoglobinemia type II","volume":"6","author":"Gupta","year":"2018","journal-title":"JMSCR"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1136\/jmg.19.3.204","article-title":"Alteration of NADH-diaphorase and cytochrome b5 reductase activities of erythrocytes, platelets, and leucocytes in hereditary methaemoglobinaemia with and without mental retardation","volume":"19","author":"Takeshita","year":"1982","journal-title":"J. Med. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1111\/j.1600-0609.2004.00388.x","article-title":"Prenatal diagnosis of recessive congenital methaemoglobinaemia type II: Novel mutation in the NADH-cytochrome b5 reductase gene leading to stop codon read-through","volume":"74","author":"Leroux","year":"2005","journal-title":"Eur. J. Haematol."},{"key":"ref_34","first-page":"687","article-title":"Heterogeneity of the molecular biology of methemoglobinemia: A study of eight consecutive patients","volume":"90","author":"Maran","year":"2005","journal-title":"Haematologica"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.1002\/ajh.26340","article-title":"Recommendations for diagnosis and treatment of methemoglobinemia","volume":"96","author":"Iolascon","year":"2021","journal-title":"Am. J. Hematol."},{"key":"ref_36","unstructured":"Bahi-Buisson, N., and Maillard, C. (2021, December 29). Tubulinopathies Overview. GeneReviews, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK350554\/."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1007\/s12311-020-01135-5","article-title":"Pontocerebellar Hypoplasia: A pattern recognition approach","volume":"19","author":"Kottke","year":"2020","journal-title":"Cerebellum"}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/12\/2\/182\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:11:02Z","timestamp":1760134262000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/12\/2\/182"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,29]]},"references-count":37,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["brainsci12020182"],"URL":"https:\/\/doi.org\/10.3390\/brainsci12020182","relation":{},"ISSN":["2076-3425"],"issn-type":[{"type":"electronic","value":"2076-3425"}],"subject":[],"published":{"date-parts":[[2022,1,29]]}}}