Cystathionine β-synthase (CBS) deficiency has a wide clinical spectrum, ranging from neurodevelopmental problems, lens dislocation and marfanoid features in early childhood to adult onset disease with predominantly thromboembolic complications. We have analysed clinical and laboratory data at the time of diagnosis in 328 patients with CBS deficiency from the E-HOD (European network and registry for Homocystinurias and methylation Defects) registry. We developed comprehensive criteria to classify patients into four groups of pyridoxine responsivity: non-responders (NR), partial, full and extreme responders (PR, FR and ER, respectively). All groups showed overlapping concentrations of plasma total homocysteine while pyridoxine responsiveness inversely correlated with plasma/serum methionine concentrations. The FR and ER groups had a later age of onset and diagnosis and a longer diagnostic delay than NR and PR patients. Lens dislocation was common in all groups except ER but the age of dislocation increased with increasing responsiveness. Developmental delay was commonest in the NR group while no ER patient had cognitive impairment. Thromboembolism was the commonest presenting feature in ER patients, whereas it was least likely at presentation in the NR group. This probably is due to the differences in ages at presentation: all groups had a similar number of thromboembolic events per 1000 patient-years. Clinical severity of CBS deficiency depends on the degree of pyridoxine responsiveness. Therefore, a standardised pyridoxine-responsiveness test in newly diagnosed patients and a critical review of previous assessments is indispensable to ensure adequate therapy and to prevent or reduce long-term complications.

Department of Clinical Genetics Center for Lysosomal and Metabolic Diseases Erasmus Medical Center Rotterdam Netherlands

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

Department of Pediatrics Landeskrankenhaus Bregenz Bregenz Austria

Department of Probability and Mathematical Statistics Charles University Faculty of Mathematics and Physics Prague Czech Republic

Division of Metabolism and Children's Research Center University Children's Hospital Zurich Switzerland

Division of Metabolism Bambino Gesù Children's Research Hospital IRCCS Rome Italy

Division of Neuropaediatrics and Metabolic Medicine Centre for Paediatric and Adolescent Medicine University Hospital Heidelberg Germany

Manchester Centre for Genomic Medicine Manchester University Hospitals NHS Trust Manchester UK

University of Zürich Zürich Switzerland

Zobrazit více v PubMed

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. 10.1136/adc.38.201.425. PubMed DOI PMC

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

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

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

Skovby F, Krassikoff N, Francke U. Assignment of the gene for cystathionine beta‐synthase to human chromosome 21 in somatic cell hybrids. Hum Genet. 1984;65:291‐294. PubMed

Kraus JP, Le K, Swaroop M, et al. Human cystathionine beta‐synthase cDNA: sequence, alternative splicing and expression in cultured cells. Hum Mol Genet. 1993;2:1633‐1638. PubMed

Kraus JP, Oliveriusova J, Sokolova J, et al. The human cystathionine beta‐synthase (CBS) gene: complete sequence, alternative splicing, and polymorphisms. Genomics. 1998;52:312‐324. PubMed

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. PubMed

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

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. PubMed PMC

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. 10.1016/j.ymgme.2009.09.009. PubMed DOI PMC

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. 10.1007/8904_2013_235. PubMed DOI PMC

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

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. 10.1002/jimd.12034. PubMed DOI

Gan‐Schreier H, Kebbewar M, Fang‐Hoffmann J, et al. Newborn population screening for classic homocystinuria by determination of total homocysteine from Guthrie cards. J Pediatr. 2010;156:427‐432. 10.1016/j.jpeds.2009.09.054. PubMed DOI

Huemer M, Kozich 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. 10.1007/s10545-015-9830-z. PubMed DOI PMC

Okun JG, Gan‐Schreier H, Ben‐Omran T, et al. Newborn screening for vitamin B6 non‐responsive classical homocystinuria: Systematical evaluation of a two‐tier strategy. JIMD Rep. 2017;32:87‐94. 10.1007/8904_2016_556. PubMed DOI PMC

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. 10.1007/s10545-016-9979-0. PubMed DOI PMC

Huemer M, Diodato D, Martinelli D, et al. Phenotype, treatment practice and outcome in the cobalamin‐dependent remethylation disorders and MTHFR deficiency: data from the E‐HOD registry. J Inherit Metab Dis. 2019;42:333‐352. 10.1002/jimd.12041. PubMed DOI

Walter JH, Wraith JE, White FJ, Bridge C, Till J. Strategies for the treatment of cystathionine beta‐synthase deficiency: the experience of the Willink biochemical genetics unit over the past 30 years. Eur J Pediatr. 1998;157:S71‐S76. PubMed

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(Pt 3):372‐379. 10.1177/000456329903600311. PubMed DOI

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. 10.1016/j.cca.2014.09.009. PubMed DOI

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. 10.1007/s10545-010-9178-3. PubMed DOI PMC

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. 10.1007/s10545-010-9146-y. PubMed DOI PMC

Raskob GE, Angchaisuksiri P, Blanco AN, et al. Thrombosis: a major contributor to global disease burden. Semin Thromb Hemost. 2014;40:724‐735. 10.1055/s-0034-1390325. PubMed DOI

Sabapathy CA, Djouonang TN, Kahn SR, Platt RW, Tagalakis V. Incidence trends and mortality from childhood venous thromboembolism: a population‐based cohort study. J Pediatr. 2016;172:175‐180 e171. 10.1016/j.jpeds.2016.02.017. PubMed DOI

Siegal DM, Eikelboom JW, Lee SF, et al. Variations in incidence of venous thromboembolism in low‐, middle‐ and high‐income countries. Cardiovasc Res. 2020. 10.1093/cvr/cvaa044. PubMed DOI

Majors AK, Pyeritz RE. A deficiency of cysteine impairs fibrillin‐1 deposition: implications for the pathogenesis of cystathionine beta‐synthase deficiency. Mol Genet Metab. 2000;70:252‐260. 10.1006/mgme.2000.3024. PubMed DOI

Brenton DP. Skeletal abnormalities in homocystinuria. Postgrad Med J. 1977;53:488‐494; discussion 495‐486. 10.1136/pgmj.53.622.488. PubMed DOI PMC

Poloni S, Spritzer PM, Mendes RH, et al. Leptin concentrations and SCD‐1 indices in classical homocystinuria: evidence for the role of sulfur amino acids in the regulation of lipid metabolism. Clin Chim Acta. 2017;473:82‐88. 10.1016/j.cca.2017.08.005. PubMed DOI

Purcell O, Coughlan A, Grant T, et al. Growth patterns in the Irish pyridoxine nonresponsive homocystinuria population and the influence of metabolic control and protein intake. J Nutr Metab. 2017;2017:8570469‐8570467. 10.1155/2017/8570469. PubMed DOI PMC

Elshorbagy AK, Smith AD, Kozich V, Refsum H. Cysteine and obesity. Obesity (Silver Spring). 2012;20:473‐481. 10.1038/oby.2011.93. PubMed DOI

Gupta S, Kruger WD. Cystathionine beta‐synthase deficiency causes fat loss in mice. PLoS One. 2011;6:e27598. 10.1371/journal.pone.0027598. PubMed DOI PMC

Majtan T, Park I, Bublil EM, Kraus JP. Enzyme replacement therapy prevents loss of bone and fat mass in murine homocystinuria. Hum Mutat. 2018;39:210‐218. 10.1002/humu.23360. PubMed DOI

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. 10.1096/fj.201901203R. PubMed DOI PMC

Gupta S, Wang L, Kruger WD. Betaine supplementation is less effective than methionine restriction in correcting phenotypes of CBS deficient mice. J Inherit Metab Dis. 2016;39:39‐46. 10.1007/s10545-015-9883-z. PubMed DOI PMC

Cystathionine β-Synthase Deficiency in the E-HOD Registry-Part II: Dietary and Pharmacological Treatment

Deciphering pathophysiological mechanisms underlying cystathionine beta-synthase-deficient homocystinuria using targeted metabolomics, liver proteomics, sphingolipidomics and analysis of mitochondrial function

Recent therapeutic approaches to cystathionine beta-synthase-deficient homocystinuria

Homocystinuria patient and caregiver survey: experiences of diagnosis and patient satisfaction