CBS – Classic Homocystinuria

Classic homocystinuria is an autosomal recessive disorder caused by biallelic pathogenic variants in cystathionine beta-synthase (CBS), leading to deficient conversion of homocysteine to cystathionine. Affected individuals present with ectopia lentis, intellectual disability, skeletal abnormalities and a high risk of thromboembolism (HP:0001083, HP:0001249, HP:0002156, HP:0000924, HP:0001907). The biochemical hallmark is markedly elevated plasma homocysteine, which may be responsive to pyridoxine (vitamin B6) in a subset of patients.

Inheritance is autosomal recessive. A study of 24 Saudi Arabian patients found that 19 had one or more affected relatives, confirming familial segregation and supporting AR transmission ([PMID:17341972]). More than 268 unrelated probands have been reported worldwide, with consistent segregation in over 50 families ([PMID:14722927]).

The variant spectrum exceeds 130 distinct mutations, predominantly missense changes but also including frameshift, splice-site, and exon-deletion alleles. The canonical I278T (c.833T>C (p.Ile278Thr)) variant accounts for approximately 41% of alleles in pyridoxine-responsive patients ([PMID:7611293]). Founder alleles such as G307S are prevalent in Celtic populations, while population-specific alleles (e.g., p.Arg336Cys in Qatar) reflect geographic diversity.

Functional assays demonstrate that many missense mutations destabilize CBS or impair cofactor binding. Yeast complementation shows five of six tested variants lack activity under low pyridoxine, but R266K retains function in high-vitamin conditions, mirroring clinical responsiveness ([PMID:9361025]). In vitro studies reveal defective heme binding and aggregation for several pathogenic subunits, supporting a loss-of-function mechanism.

Animal models corroborate pathogenicity: Cbs−/− mice expressing human I278T or I278T/T424N survive neonatal lethality despite hyperhomocysteinemia, indicating non-enzymatic roles for CBS protein ([PMID:15972722]). Treatment of I278T and S466L mouse models with proteasome inhibitors restores mutant protein levels and lowers plasma homocysteine, illustrating potential therapeutic avenues ([PMID:23592311]).

Newborn screening by tandem mass spectrometry of total homocysteine from dried blood spots identified 14 Qatari cases (incidence ~1:1,800), whereas methionine alone would miss half of the patients, underscoring the need for homocysteine-based assays ([PMID:19914636]). Early diagnosis enables tailored therapy, including pyridoxine, dietary methionine restriction, and betaine supplementation.

Integration of extensive genetic and functional data establishes CBS-related homocystinuria as a definitive gene-disease association. Clinical utility spans diagnostic confirmation, family screening, newborn screening optimization, and potential small-molecule rescue. Key take-home: genotyping of CBS informs prognosis and guides personalized management, especially regarding vitamin responsiveness and thromboembolic risk.

References

• Human molecular genetics • 1994 • Identical genotypes in siblings with different homocystinuric phenotypes: identification of three mutations in cystathionine beta-synthase using an improved bacterial expression system. PMID:7981678
• American journal of human genetics • 1995 • A missense mutation (I278T) in the cystathionine beta-synthase gene prevalent in pyridoxine-responsive homocystinuria and associated with mild clinical phenotype. PMID:7611293
• Human mutation • 2004 • The molecular basis of cystathionine beta-synthase (CBS) deficiency in UK and US patients with homocystinuria. PMID:14722927
• Human molecular genetics • 1997 • Functional modeling of vitamin responsiveness in yeast: a common pyridoxine-responsive cystathionine beta-synthase mutation in homocystinuria. PMID:9361025
• Journal of the College of Physicians and Surgeons--Pakistan : JCPSP • 2018 • Classical Homocystinuria in a Juvenile Patient. PMID:29848432
• Human mutation • 2013 • Correction of cystathionine β-synthase deficiency in mice by treatment with proteasome inhibitors PMID:23592311
• The Journal of pediatrics • 2010 • Newborn population screening for classic homocystinuria by determination of total homocysteine from Guthrie cards. PMID:19914636
• Annals of Saudi medicine • 1998 • Saudi experience with classic homocystinuria. PMID:17341972

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