This review summarises progress in the research of homocystinuria (HCU) in the past three decades. HCU due to cystathionine β-synthase (CBS) was discovered in 1962, and Prof. Jan Peter Kraus summarised developments in the field in the first-ever Komrower lecture in 1993. In the past three decades, significant advancements have been achieved in the biology of CBS, including gene organisation, tissue expression, 3D structures, and regulatory mechanisms. Renewed interest in CBS arose in the late 1990s when this enzyme was implicated in biogenesis of H2S. Advancements in genetic and biochemical techniques enabled the identification of several hundreds of pathogenic CBS variants and the misfolding of missense mutations as a common mechanism. Several cellular, invertebrate and murine HCU models allowed us to gain insights into functional and metabolic pathophysiology of the disease. Establishing the E-HOD consortium and patient networks, HCU Network Australia and HCU Network America, offered new possibilities for acquiring clinical data in registries and data on patients' quality of life. A recent analysis of data from the E-HOD registry showed that the clinical variability of HCU is broad, extending from severe childhood disease to milder (late) adulthood forms, which typically respond to pyridoxine. Pyridoxine responsiveness appears to be the key factor determining the clinical course of HCU. Increased awareness about HCU played a role in developing novel therapies, such as gene therapy, correction of misfolding by chaperones, removal of methionine from the gut and enzyme therapies that decrease homocysteine or methionine in the circulation.

Department of Pediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czechia

Department of Pharmacology Faculty of Science and Medicine University of Fribourg Fribourg Switzerland

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Zechmeister L, Cholnoky L. Principles and Practice of Chromatography. Chapman and Hall; 1943.

Kraus JP. Komrower lecture. Molecular basis of phenotype expression in homocystinuria. J Inherit Metab Dis. 1994;17:383‐390. doi:10.1007/BF00711354

Olson KR, Straub KD. The role of hydrogen sulfide in evolution and the evolution of hydrogen sulfide in metabolism and signaling. Physiology (Bethesda). 2016;31:60‐72. doi:10.1152/physiol.00024.2015

Brimblecombe P. Biogeochemical cycles | Sulfur cycle. In: Holton JR, ed. Encyclopedia of Atmospheric Sciences. Academic Press; 2002:213‐220.

Kutney G. Sulfur: History, Technology, Applications and Industry. 3rd ed. ChemTec Publishing; 2023.

Butz LW, Vigneaud V. The formation of a homologue of cystine by the decomposition of methionine with sulfuric acid. J Biol Chem. 1932;99:135‐142.

Finkelstein JD. Homocysteine: a history in progress. Nutr Rev. 2000;58:193‐204. doi:10.1111/j.1753‐4887.2000.tb01862.x

Carson NA, Neill DW. Metabolic abnormalities detected in a survey of mentally backward individuals in Northern Ireland. Arch Dis Child. 1962;37:505‐513. doi:10.1136/adc.37.195.505

Gerritsen T, Vaughn JG, Waisman HA. The identification of homocystine in the urine. Biochem Biophys Res Commun. 1962;9:493‐496. doi:10.1016/0006‐291x(62)90114‐6

Carson NA, Cusworth DC, Dent CE, Field CM, Neill DW, Westall RG. Homocystinuria: a new inborn error of metabolism associated with mental deficiency. Arch Dis Child. 1963;38:425‐436. doi:10.1136/adc.38.201.425

Komrower GM, Wilson VK. Homocystinuria. Proc R Soc Med. 1963;56:996‐997.

Mudd SH, Finkelstein JD, Irreverre F, Laster L. Homocystinuria: an enzymatic defect. Science. 1964;143:1443‐1445.

Komrower GM, Lambert AM, Cusworth DC, Westall RG. Dietary treatment of homocystinuria. Arch Dis Child. 1966;41:666‐671.

Barber GW, Spaeth GL. Pyridoxine therapy in homocystinuria. Lancet. 1967;289:337. doi:10.1016/S0140‐6736(67)91290‐1

Turner B. Pyridoxine treatment in homocystinuria. Lancet. 1967;2:1151.

Bickel H. Recent advances in the early detection and treatment of inborn errors with brain damage. Neuropadiatrie. 1969;1:1‐11. doi:10.1055/s‐0028‐1091859

Mudd SH, Skovby F, Levy HL, et al. The natural history of homocystinuria due to cystathionine beta‐synthase deficiency. Am J Hum Genet. 1985;37:1‐31.

Kozich V, Kraus JP. Screening for mutations by expressing patient cDNA segments in E. coli: homocystinuria due to cystathionine beta‐synthase deficiency. Hum Mutat. 1992;1:113‐123. doi:10.1002/humu.1380010206

Kraus JP, Oliveriusová J, Sokolová J, et al. The human cystathionine β‐synthase (CBS) gene: complete sequence, alternative splicing, and polymorphisms. Genomics. 1998;52:312‐324. doi:10.1006/geno.1998.5437

Chasse JF, Paul V, Escanez R, Kamoun P, London J. Human cystathionine beta‐synthase: gene organization and expression of different 5′ alternative splicing. Mamm Genome. 1997;8:917‐921.

Uhlen M, Fagerberg L, Hallstrom BM, et al. Proteomics. Tissue‐based map of the human proteome. Science. 2015;347:1260419. doi:10.1126/science.1260419

Krijt J, Kopecka J, Hnizda A, et al. Determination of cystathionine beta‐synthase activity in human plasma by LC‐MS/MS: potential use in diagnosis of CBS deficiency. J Inherit Metab Dis. 2011;34:49‐55. doi:10.1007/s10545‐010‐9178‐3

Alcaide P, Krijt J, Ruiz‐Sala P, et al. Enzymatic diagnosis of homocystinuria by determination of cystathionine‐ß‐synthase activity in plasma using LC‐MS/MS. Clin Chim Acta. 2015;438:261‐265. doi:10.1016/j.cca.2014.09.009

Zuhra K, Augsburger F, Majtan T, Szabo C. Cystathionine‐beta‐synthase: molecular regulation and pharmacological inhibition. Biomolecules. 2020;10:10. doi:10.3390/biom10050697

McCorvie TJ, Kopec J, Hyung SJ, et al. Inter‐domain communication of human cystathionine beta‐synthase: structural basis of S‐adenosyl‐L‐methionine activation. J Biol Chem. 2014;289:36018‐36030. doi:10.1074/jbc.M114.610782

Ereno‐Orbea J, Majtan T, Oyenarte I, Kraus JP, Martinez‐Cruz LA. Structural insight into the molecular mechanism of allosteric activation of human cystathionine beta‐synthase by S‐adenosylmethionine. Proc Natl Acad Sci USA. 2014;111:E3845‐E3852. doi:10.1073/pnas.1414545111

Taoka S, Lepore BW, Kabil O, Ojha S, Ringe D, Banerjee R. Human cystathionine beta‐synthase is a heme sensor protein. Evidence that the redox sensor is heme and not the vicinal cysteines in the CXXC motif seen in the crystal structure of the truncated enzyme. Biochemistry. 2002;41:10454‐10461.

Meier M, Janosik M, Kery V, Kraus JP, Burkhard P. Structure of human cystathionine beta‐synthase: a unique pyridoxal 5′‐phosphate‐dependent heme protein. EMBO J. 2001;20:3910‐3916. doi:10.1093/emboj/20.15.3910

Ereno‐Orbea J, Majtan T, Oyenarte I, Kraus JP, Martinez‐Cruz LA. Structural basis of regulation and oligomerization of human cystathionine beta‐synthase, the central enzyme of transsulfuration. Proc Natl Acad Sci USA. 2013;110:E3790‐E3799. doi:10.1073/pnas.1313683110

McCorvie TJ, Adamoski D, Machado RAC, et al. Architecture and regulation of filamentous human cystathionine beta‐synthase. Nat Commun. 2024;15:2931. doi:10.1038/s41467‐024‐46864‐x

Kraus JP. Cystathionine beta‐synthase (human). Methods Enzymol. 1987;143:388‐394. doi:10.1016/0076‐6879(87)43068‐1

Meister A, Morris HP, Tice SV. Effect of vitamin B6 defiency on hepatic transaminase and cysteine desulfhydrase systems. Proc Soc Exp Biol Med. 1953;82:301‐304. doi:10.3181/00379727‐82‐20100

Abe K, Kimura H. The possible role of hydrogen sulfide as an endogenous neuromodulator. J Neurosci. 1996;16:1066‐1071.

Hosoki R, Matsuki N, Kimura H. The possible role of hydrogen sulfide as an endogenous smooth muscle relaxant in synergy with nitric oxide. Biochem Biophys Res Commun. 1997;237:527‐531.

Wang R. Physiological implications of hydrogen sulfide: a whiff exploration that blossomed. Physiol Rev. 2012;92:791‐896. doi:10.1152/physrev.00017.2011

Singh S, Padovani D, Leslie RA, Chiku T, Banerjee R. Relative contributions of cystathionine beta‐synthase and gamma‐cystathionase to H2S biogenesis via alternative trans‐sulfuration reactions. J Biol Chem. 2009;284:22457‐22466. doi:10.1074/jbc.M109.010868

Ditroi T, Nagy A, Martinelli D, Rosta A, Kozich V, Nagy P. Comprehensive analysis of how experimental parameters affect H2S measurements by the monobromobimane method. Free Radic Biol Med. 2019;136:146‐158. doi:10.1016/j.freeradbiomed.2019.04.006

Olson KR, DeLeon ER, Liu F. Controversies and conundrums in hydrogen sulfide biology. Nitric Oxide. 2014;41:11‐26. doi:10.1016/j.niox.2014.05.012

Majtan T, Krijt J, Sokolová J, et al. Biogenesis of hydrogen sulfide and thioethers by cystathionine beta‐synthase. Antioxid Redox Signal. 2018;28:311‐323. doi:10.1089/ars.2017.7009

Kraus JP, Janosik M, Kozich V, et al. Cystathionine beta‐synthase mutations in homocystinuria. Hum Mutat. 1999;13:362‐375.

Linnebank M, Janosik M, Kozich V, et al. The cystathionine beta‐synthase (CBS) mutation c.1224‐2A>C in Central Europe: vitamin B6 nonresponsiveness and a common ancestral haplotype. Hum Mutat. 2004;24:352‐353. doi:10.1002/humu.9280

Vyletal P, Sokolova J, Cooper DN, et al. Diversity of cystathionine beta‐synthase haplotypes bearing the most common homocystinuria mutation c.833T>C: a possible role for gene conversion. Hum Mutat. 2007;28:255‐264. doi:10.1002/humu.20430

Janošík M, Oliveriusová J, Janošík B, et al. Impaired heme binding and aggregation of mutant cystathionine β‐synthase subunits in homocystinuria. Am J Hum Genet. 2001;68:1506‐1513. doi:10.1086/320597

Janosik M, Sokolova J, Janosikova B, Krijt J, Klatovska V, Kozich V. Birth prevalence of homocystinuria in Central Europe: frequency and pathogenicity of mutation c.1105C>T (p.R369C) in the cystathionine beta‐synthase gene. J Pediatr. 2009;154:431‐437. doi:10.1016/j.jpeds.2008.09.015

Kozich V, Sokolova J, Klatovska V, et al. Cystathionine beta‐synthase mutations: effect of mutation topology on folding and activity. Hum Mutat. 2010;31:809‐819. doi:10.1002/humu.21273

Singh LR, Chen X, Kozich V, Kruger WD. Chemical chaperone rescue of mutant human cystathionine beta‐synthase. Mol Genet Metab. 2007;91:335‐342. doi:10.1016/j.ymgme.2007.04.011

Maclean KN, Gaustadnes M, Oliveriusova J, et al. High homocysteine and thrombosis without connective tissue disorders are associated with a novel class of cystathionine beta‐synthase (CBS) mutations. Hum Mutat. 2002;19:641‐655. doi:10.1002/humu.10089

Collard R, Majtan T. Genetic and pharmacological modulation of cellular proteostasis leads to partial functional rescue of homocystinuria‐causing cystathionine‐beta synthase variants. Mol Cell Biol. 2023;43:664‐674. doi:10.1080/10985549.2023.2284147

Casique L, Kabil O, Banerjee R, Martinez JC, De Lucca M. Characterization of two pathogenic mutations in cystathionine beta‐synthase: different intracellular locations for wild‐type and mutant proteins. Gene. 2013;531:117‐124. doi:10.1016/j.gene.2013.08.021

Ismail HM, Krishnamoorthy N, Al‐Dewik N, et al. In silico and in vivo models for Qatari‐specific classical homocystinuria as basis for development of novel therapies. Hum Mutat. 2019;40:230‐240. doi:10.1002/humu.23682

Majtan T, Liu L, Carpenter JF, Kraus JP. Rescue of cystathionine beta‐synthase (CBS) mutants with chemical chaperones: purification and characterization of eight CBS mutant enzymes. J Biol Chem. 2010;285:15866‐15873. doi:10.1074/jbc.M110.107722

Hnízda A, Jurga V, Raková K, Kožich V. Cystathionine beta‐synthase mutants exhibit changes in protein unfolding: conformational analysis of misfolded variants in crude cell extracts. J Inherit Metab Dis. 2012;35:469‐477. doi:10.1007/s10545‐011‐9407‐4

Hnizda A, Majtan T, Liu L, et al. Conformational properties of nine purified cystathionine beta‐synthase mutants. Biochemistry. 2012;51:4755‐4763. doi:10.1021/bi300435e

Gupta S, Wang L, Kruger WD. The c.797 G>a (p.R266K) cystathionine beta‐synthase mutation causes homocystinuria by affecting protein stability. Hum Mutat. 2017;38:863‐869. doi:10.1002/humu.23240

Gupta S, Kuhnisch J, Mustafa A, et al. Mouse models of cystathionine beta‐synthase deficiency reveal significant threshold effects of hyperhomocysteinemia. FASEB J. 2009;23:883‐893. doi:10.1096/fj.08‐120584

Gupta S, Wang L, Hua X, Krijt J, Kožich V, Kruger WD. Cystathionine β‐synthase p.S466L mutation causes hyperhomocysteinemia in mice. Hum Mutat. 2008;29:1048‐1054. doi:10.1002/humu.20773

Wang L, Chen X, Tang B, Hua X, Klein‐Szanto A, Kruger WD. Expression of mutant human cystathionine beta‐synthase rescues neonatal lethality but not homocystinuria in a mouse model. Hum Mol Genet. 2005;14:2201‐2208. doi:10.1093/hmg/ddi224

Kopecka J, Krijt J, Rakova K, Kozich V. Restoring assembly and activity of cystathionine beta‐synthase mutants by ligands and chemical chaperones. J Inherit Metab Dis. 2011;34:39‐48. doi:10.1007/s10545‐010‐9087‐5

Melenovska P, Kopecka J, Krijt J, et al. Chaperone therapy for homocystinuria: the rescue of CBS mutations by heme arginate. J Inherit Metab Dis. 2015;38:287‐294. doi:10.1007/s10545‐014‐9781‐9

Shan X, Kruger WD. Correction of disease‐causing CBS mutations in yeast. Nat Genet. 1998;19:91‐93. doi:10.1038/ng0598‐91

Kim CE, Gallagher PM, Guttormsen AB, et al. Functional modeling of vitamin responsiveness in yeast: a common pyridoxine‐responsive cystathionine beta‐synthase mutation in homocystinuria. Hum Mol Genet. 1997;6:2213‐2221.

Sun S, Weile J, Verby M, et al. A proactive genotype‐to‐patient‐phenotype map for cystathionine beta‐synthase. Genome Med. 2020;12:13. doi:10.1186/s13073‐020‐0711‐1

Vozdek R, Hnizda A, Krijt J, Kostrouchova M, Kozich V. Novel structural arrangement of nematode cystathionine beta‐synthases: characterization of Caenorhabditis elegans CBS‐1. Biochem J. 2012;443:535‐547. doi:10.1042/BJ20111478

Prabhudesai S, Koceja C, Dey A, et al. Cystathionine beta‐synthase is necessary for axis development in vivo. Front Cell Dev Biol. 2018;6:14. doi:10.3389/fcell.2018.00014

Dey A, Prabhudesai S, Zhang Y, et al. Cystathione β‐synthase regulates HIF‐1α stability through persulfidation of PHD2. Sci Adv. 2020;6:6. doi:10.1126/sciadv.aaz8534

Flores‐Flores M, Moreno‐Garcia L, Castro‐Martinez F, Nahmad M. Cystathionine beta‐synthase deficiency impairs vision in the fruit fly, Drosophila melanogaster. Curr Eye Res. 2021;46:600‐605. doi:10.1080/02713683.2020.1818262

Majtan T, Kožich V, Kruger WD. Recent therapeutic approaches to cystathionine beta‐synthase‐deficient homocystinuria. Br J Pharmacol. 2023;180:264‐278. doi:10.1111/bph.15991

Kruger WD. Cystathionine beta‐synthase deficiency: of mice and men. Mol Genet Metab. 2017;121:199‐205. doi:10.1016/j.ymgme.2017.05.011

Watanabe M, Osada J, Aratani Y, et al. Mice deficient in cystathionine beta‐synthase: animal models for mild and severe homocyst(e)inemia. Proc Natl Acad Sci USA. 1995;92:1585‐1589.

Maclean KN, Sikora J, Kozich V, et al. Cystathionine beta‐synthase null homocystinuric mice fail to exhibit altered hemostasis or lowering of plasma homocysteine in response to betaine treatment. Mol Genet Metab. 2010;101:163‐171. doi:10.1016/j.ymgme.2010.06.007

Gupta S, Gallego‐Villar L, Wang L, et al. Analysis of the Qatari R336C cystathionine beta‐synthase protein in mice. J Inherit Metab Dis. 2019;42:831‐838. doi:10.1002/jimd.12140

Gupta S, Wang L, Anderl J, Slifker MJ, Kirk C, Kruger WD. Correction of cystathionine beta‐synthase deficiency in mice by treatment with proteasome inhibitors. Hum Mutat. 2013;34:1085‐1093. doi:10.1002/humu.22335

Nakladal D, Lambooy SPH, Mišúth S, et al. Homozygous whole body Cbs knockout in adult mice features minimal pathology during ageing despite severe homocysteinemia. FASEB J. 2022;36:e22260. doi:10.1096/fj.202101550R

Majtan T, Hulkova H, Park I, et al. Enzyme replacement prevents neonatal death, liver damage, and osteoporosis in murine homocystinuria. FASEB J. 2017;31:5495‐5506. doi:10.1096/fj.201700565R

Perla‐Kajan J, Utyro O, Rusek M, Malinowska A, Sitkiewicz E, Jakubowski H. N‐Homocysteinylation impairs collagen cross‐linking in cystathionine beta‐synthase‐deficient mice: a novel mechanism of connective tissue abnormalities. FASEB J. 2016;30:3810‐3821. doi:10.1096/fj.201600539

Dayal S, Chauhan AK, Jensen M, et al. Paradoxical absence of a prothrombotic phenotype in a mouse model of severe hyperhomocysteinemia. Blood. 2012;119:3176‐3183. doi:10.1182/blood‐2011‐09‐380568

Skvorak K, Mitchell V, Teadt L, et al. An orally administered enzyme therapeutic for homocystinuria that suppresses homocysteine by metabolizing methionine in the gastrointestinal tract. Mol Genet Metab. 2023;139:107653. doi:10.1016/j.ymgme.2023.107653

Lee HO, Salami CO, Sondhi D, Kaminsky SM, Crystal RG, Kruger WD. Long‐term functional correction of cystathionine β‐synthase deficiency in mice by adeno‐associated viral gene therapy. J Inherit Metab Dis. 2021;44:1382‐1392. doi:10.1002/jimd.12437

Majtan T, Jones W Jr, Krijt J, et al. Enzyme replacement therapy ameliorates multiple symptoms of murine homocystinuria. Mol Ther. 2018;26:834‐844. doi:10.1016/j.ymthe.2017.12.014

Singh LR, Gupta S, Honig NH, Kraus JP, Kruger WD. Activation of mutant enzyme function in vivo by proteasome inhibitors and treatments that induce Hsp70. PLoS Genet. 2010;6:e1000807. doi:10.1371/journal.pgen.1000807

Moorthie S, Cameron L, Sagoo GS, Bonham JR, Burton H. Systematic review and meta‐analysis to estimate the birth prevalence of five inherited metabolic diseases. J Inherit Metab Dis. 2014;37:889‐898. doi:10.1007/s10545‐014‐9729‐0

Gaustadnes M, Ingerslev J, Rütiger N. Prevalence of congenital homocystinuria in Denmark. N Engl J Med. 1999;340:1513. doi:10.1056/nejm199905133401915

Weber Hoss GR, Sperb‐Ludwig F, Schwartz IVD, Blom HJ. Classical homocystinuria: a common inborn error of metabolism? An epidemiological study based on genetic databases. Mol Genet Genomic Med. 2020;8:e1214. doi:10.1002/mgg3.1214

Skovby F, Gaustadnes M, Mudd SH. A revisit to the natural history of homocystinuria due to cystathionine beta‐synthase deficiency. Mol Genet Metab. 2010;99:1‐3. doi:10.1016/j.ymgme.2009.09.009

Barber GW, Spaeth GL. The successful treatment of homocystinuria with pyridoxine. J Pediatr. 1969;75:463‐478.

Moat SJ, Bonham JR, Tanner MS, Allen JC, Powers HJ. Recommended approaches for the laboratory measurement of homocysteine in the diagnosis and monitoring of patients with hyperhomocysteinaemia. Ann Clin Biochem. 1999;36(3):372‐379. doi:10.1177/000456329903600311

Morris AA, Kozich V, Santra S, et al. Guidelines for the diagnosis and management of cystathionine beta‐synthase deficiency. J Inherit Metab Dis. 2017;40:49‐74. doi:10.1007/s10545‐016‐9979‐0

Kožich V, Sokolová J, Morris AAM, et al. Cystathionine β‐synthase deficiency in the E‐HOD registry‐part I: pyridoxine responsiveness as a determinant of biochemical and clinical phenotype at diagnosis. J Inherit Metab Dis. 2021;44:677‐692. doi:10.1002/jimd.12338

Fowler B. Recent advances in the mechanism of pyridoxine‐responsive disorders. J Inherit Metab Dis. 1985;8(1):76‐83.

Stabler SP, Korson M, Jethva R, et al. Metabolic profiling of total homocysteine and related compounds in hyperhomocysteinemia: utility and limitations in diagnosing the cause of puzzling thrombophilia in a family. JIMD Rep. 2013;11:149‐163. doi:10.1007/8904_2013_235

Magner M, Krupkova L, Honzik T, Zeman J, Hyanek J, Kozich V. Vascular presentation of cystathionine beta‐synthase deficiency in adulthood. J Inherit Metab Dis. 2011;34:33‐37. doi:10.1007/s10545‐010‐9146‐y

Tada K, Yoshida T, Arakawa T. Free amino acid pattern in the liver from the patients with amino acid disorders: postmortem diagnosis of inborn errors of amino acid metabolism. Tohoku J Exp Med. 1970;101:223‐226.

Curtius HCH, Martenet AC, Anders PW. Bestimmung von freien aminosäuren im augenkammerwasser des menschen bei homocystinurie‐patienten und kontrollfällen. Clin Chim Acta. 1968;19:469‐476. doi:10.1016/0009‐8981(68)90274‐X

Tada K, Yoshida T, Hirono H, Arakawa T. Homocystinuria: amino acid pattern of the liver. Tohoku J Exp Med. 1967;92:325‐332.

Stabler SP, Lindenbaum J, Savage DG, Allen RH. Elevation of serum cystathionine levels in patients with cobalamin and folate deficiency. Blood. 1993;81:3404‐3413.

Jakubowski H. Proteomic exploration of cystathionine β‐synthase deficiency: implications for the clinic. Expert Rev Proteom. 2020;17:751‐765. doi:10.1080/14789450.2020.1865160

Kozich V, Kraus JP, Majtan T. Cystathionine Beta‐Synthase (CBS) Deficiency: Genetics. eLS. John Wiley and Sons; 2018.

Kožich V, Morris AAM, Blom HJ. Disorders of sulfur amino acid MetabolismSulfur amino acid metabolism. In: Saudubray J‐M, Baumgartner MR, García‐Cazorla Á, Walter J, eds. Inborn Metabolic Diseases: Diagnosis and Treatment. Springer Berlin Heidelberg; 2022:407‐422.

Naughten ER, Yap S, Mayne PD. Newborn screening for homocystinuria: Irish and world experience. Eur J Pediatr. 1998;157(2):S84‐S87.

Yap S, Naughten E. Homocystinuria due to cystathionine beta‐synthase deficiency in Ireland: 25 years' experience of a newborn screened and treated population with reference to clinical outcome and biochemical control. J Inherit Metab Dis. 1998;21:738‐747.

Mulvihill A, Yap S, O'Keefe M, Howard PM, Naughten ER. Ocular findings among patients with late‐diagnosed or poorly controlled homocystinuria compared with a screened, well‐controlled population. J AAPOS. 2001;5:311‐315. doi:10.1067/mpa.2001.118219

Mulvihill A, O'Keeffe M, Yap S, Naughten E, Howard P, Lanigan B. Ocular axial length in homocystinuria patients with and without ocular changes: effects of early treatment and biochemical control. J AAPOS. 2004;8:254‐258. doi:10.1016/j.jaapos.2004.01.010

Yap S, Rushe H, Howard PM, Naughten ER. The intellectual abilities of early‐treated individuals with pyridoxine‐nonresponsive homocystinuria due to cystathionine beta‐synthase deficiency. J Inherit Metab Dis. 2001;24:437‐447.

Yap S, Naughten ER, Wilcken B, Wilcken DE, Boers GH. Vascular complications of severe hyperhomocysteinemia in patients with homocystinuria due to cystathionine beta‐synthase deficiency: effects of homocysteine‐lowering therapy. Semin Thromb Hemost. 2000;26:335‐340. doi:10.1055/s‐2000‐8100

Loeber JG, Platis D, Zetterström RH, et al. Neonatal screening in Europe revisited: an ISNS perspective on the current state and developments since 2010. Int J Neonatal Screen. 2021;7:7. doi:10.3390/ijns7010015

Chace DH, Hillman SL, Millington DS, Kahler SG, Adam BW, Levy HL. Rapid diagnosis of homocystinuria and other hypermethioninemias from newborns' blood spots by tandem mass spectrometry. Clin Chem. 1996;42:349‐355.

Turgeon CT, Magera MJ, Cuthbert CD, et al. Determination of total homocysteine, methylmalonic acid, and 2‐methylcitric acid in dried blood spots by tandem mass spectrometry. Clin Chem. 2010;56:1686‐1695. doi:10.1373/clinchem.2010.148957

Huemer M, Kožich V, Rinaldo P, et al. Newborn screening for homocystinurias and methylation disorders: systematic review and proposed guidelines. J Inherit Metab Dis. 2015;38:1007‐1019. doi:10.1007/s10545‐015‐9830‐z

Keller R, Chrastina P, Pavlikova M, et al. Newborn screening for homocystinurias: recent recommendations versus current practice. J Inherit Metab Dis. 2019;42:128‐139. doi:10.1002/jimd.12034

Levy HL. Early development of newborn screening for HCU and current challenges. Int J Neonatal Screen. 2021;7:7. doi:10.3390/ijns7040067

Pickens CA, Courtney E, Isenberg SL, Cuthbert C, Petritis K. Multiplexing homocysteine into first‐tier newborn screening mass spectrometry assays using selective thiol derivatization. Clin Chem. 2023;69:470‐481. doi:10.1093/clinchem/hvad007

Levy HL, Sahai I. Is more effective newborn screening for homocystinuria on the horizon? Clin Chem. 2023;69:433‐434. doi:10.1093/clinchem/hvad027

Schnabel E, Kolker S, Gleich F, et al. Combined newborn screening allows comprehensive identification also of attenuated phenotypes for Methylmalonic acidurias and Homocystinuria. Nutrients. 2023;15:15. doi:10.3390/nu15153355

Morrison T, Bösch F, Landolt MA, Kožich V, Huemer M, Morris AAM. Homocystinuria patient and caregiver survey: experiences of diagnosis and patient satisfaction. Orphanet J Rare Dis. 2021;16:124. doi:10.1186/s13023‐021‐01764‐x

Gupta S, Lee HO, Wang L, Kruger WD. Examination of two different proteasome inhibitors in reactivating mutant human cystathionine β‐synthase in mice. PLoS One. 2023;18:e0286550. doi:10.1371/journal.pone.0286550

Perreault M, Means J, Gerson E, et al. The live biotherapeutic SYNB1353 decreases plasma methionine via directed degradation in animal models and healthy volunteers. Cell Host Microbe. 2024;32:382‐395.e310. doi:10.1016/j.chom.2024.01.005

Bublil EM, Majtan T, Park I, et al. Enzyme replacement with PEGylated cystathionine beta‐synthase ameliorates homocystinuria in murine model. J Clin Invest. 2016;126:2372‐2384. doi:10.1172/JCI85396

Majtan T, Park I, Cox A, et al. Behavior, body composition, and vascular phenotype of homocystinuric mice on methionine‐restricted diet or enzyme replacement therapy. FASEB J. 2019;33:12477‐12486. doi:10.1096/fj.201901203R

Van Hove JLK, Freehauf CL, Ficicioglu C, et al. Biomarkers of oxidative stress, inflammation, and vascular dysfunction in inherited cystathionine beta‐synthase deficient homocystinuria and the impact of taurine treatment in a phase 1/2 human clinical trial. J Inherit Metab Dis. 2019;42:424‐437. doi:10.1002/jimd.12085

Maclean KN, Jiang H, Phinney WN, Keating AK, Hurt KJ, Stabler SP. Taurine alleviates repression of betaine‐homocysteine S‐methyltransferase and significantly improves the efficacy of long‐term betaine treatment in a mouse model of cystathionine beta‐synthase‐deficient homocystinuria. FASEB J. 2019;33:6339‐6353. doi:10.1096/fj.201802069RR

Huemer M, Diodato D, Schwahn B, et al. Guidelines for diagnosis and management of the cobalamin‐related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency. J Inherit Metab Dis. 2017;40:21‐48. doi:10.1007/s10545‐016‐9991‐4

Barić I, Staufner C, Augoustides‐Savvopoulou P, et al. Consensus recommendations for the diagnosis, treatment and follow‐up of inherited methylation disorders. J Inherit Metab Dis. 2017;40:5‐20. doi:10.1007/s10545‐016‐9972‐7

Huemer M, Buerer C, Jesina P, et al. Clinical onset and course, response to treatment and outcome in 24 patients with the cblE or cblG remethylation defect complemented by genetic and in vitro enzyme study data. J Inherit Metab Dis. 2015;38:957‐967. doi:10.1007/s10545‐014‐9803‐7

Chiku T, Padovani D, Zhu W, Singh S, Vitvitsky V, Banerjee R. H2S biogenesis by human cystathionine gamma‐lyase leads to the novel sulfur metabolites lanthionine and homolanthionine and is responsive to the grade of hyperhomocysteinemia. J Biol Chem. 2009;284:11601‐11612. doi:10.1074/jbc.M808026200