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Study Objective: A phase 1/2 clinical trial was performed in individuals with cystathionine β synthase (CBS) deficient homocystinuria with aims to: (a) assess pharmacokinetics and safety of taurine therapy, (b) evaluate oxidative stress, inflammation, and vascular function in CBS deficiency, and (c) evaluate the impact of short-term taurine treatment., Methods: Individuals with pyridoxine-nonresponsive CBS deficiency with homocysteine >50 μM, without inflammatory disorder or on antioxidant therapy were enrolled. Biomarkers of oxidative stress and inflammation, endothelial function (brachial artery flow-mediated dilation [FMD]), and disease-related metabolites obtained at baseline were compared to normal values. While maintaining current treatment, patients were treated with 75 mg/kg taurine twice daily, and treatment response assessed after 4 hours and 4 days., Results: Fourteen patients (8-35 years; 8 males, 6 females) were enrolled with baseline homocysteine levels 161 ± 67 μM. The study found high-dose taurine to be safe when excluding preexisting hypertriglyceridemia. Taurine pharmacokinetics showed a rapid peak level returning to near normal levels at 12 hours, but had slow accumulation and elevated predosing levels after 4 days of treatment. Only a single parameter of oxidative stress, 2,3-dinor-8-isoprostaglandin-F2α, was elevated at baseline, with no elevated inflammatory parameters, and no change in FMD values overall. Taurine had no effect on any of these parameters. However, the effect of taurine was strongly related to pretreatment FMD values; and taurine significantly improved FMD in the subset of individuals with pretreatment FMD values <10% and in individuals with homocysteine levels >125 μM, pertinent to endothelial function., Conclusion: Taurine improves endothelial function in CBS-deficient homocystinuria in patients with preexisting reduced function., (© 2019 SSIEM.)

Homocystinuria (HCU) due to deficiency of cystathionine beta-synthetase is associated with increased plasma levels of homocysteine and methionine and is characterized by developmental delay, intellectual impairment, ocular defects, thromboembolism and skeletal abnormalities. HCU has been associated with increased risk for osteoporosis in some studies, but the natural history of HCU-related bone disease is poorly understood. The objective of this study was to characterize bone mineral density (BMD) measured by dual energy X-ray absorptiometry (DXA) in a multi-center, retrospective cohort of children and adults with HCU. We identified 19 subjects (9 males) aged 3.5 to 49.2 years who had DXA scans performed as a part of routine clinical care from 2002-2010. The mean lumbar spine (LS) BMD Z-score at the time of first DXA scan in this cohort was -1.2 (± SD of 1.3); 38% of participants had low BMD for age (as defined by a Z-score ≤-2). Homocysteine and methionine were positively associated with LS BMD Z-score in multiple linear regression models. Our findings suggest that low BMD is common in both children and adults with HCU and that routine assessment of bone health in this patient population is warranted. Future studies are needed to clarify the relationship between HCU and BMD., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Cystathionine beta-synthase (CBS) deficient homocystinuria (HCU) is an inherited metabolic defect that if untreated, typically results in cognitive impairment, connective tissue disturbances, atherosclerosis and thromboembolic disease. In recent years, chronic inappropriate expression of the inflammatory response has emerged as a major driving force of both thrombosis and atherosclerotic lesion development. We report here a characterization of the abnormalities in cytokine expression induced in both a mouse model of HCU and human subjects with the disease in the presence and absence of homocysteine lowering therapy. HCU mice exhibited highly significant induction of the pro-inflammatory cytokines Il-1alpha, Il-1beta and TNF-alpha. Similarly, in untreated/poorly compliant human subjects with HCU we observed constitutive induction of multiple pro-inflammatory cytokines (IL-1alpha, IL-6, TNF-alpha, Il-17 and IL-12(p70)) and chemotactic chemokines (fractalkine, MIP-1alpha and MIP-1beta) compared to normal controls. These HCU patients also exhibited significant induction of IL-9, TGF-alpha and G-CSF. The expression levels of anti-inflammatory cytokines were unaffected in both HCU mice and human subjects with the disease. In the human subjects, homocysteine lowering therapy was associated with either normalization or significant reduction of all of the pro-inflammatory cytokines and chemokines investigated. We conclude that HCU is a disease of chronic inflammation and that aberrant cytokine expression has the potential to contribute to multiple aspects of pathogenesis. Our findings indicate that anti-inflammatory strategies could serve as a useful adjuvant therapy for this disease., (Copyright © 2011 Elsevier Inc. All rights reserved.)