Publications

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Classical homocystinuria: From cystathionine beta-synthase deficiency to novel enzyme therapies.
Genetic defects in cystathionine beta-synthase (CBS), a key enzyme of organic sulfur metabolism, result in deficiency of CBS activity and a rare inborn error of metabolism called classical homocystinuria (HCU). HCU is characterized by massive accumulation of homocysteine, an intermediate of methionine metabolism, and multisystemic clinical symptoms. Current treatment options for HCU are very limited and often inefficient, partially due to a low patient compliance with very strict dietary regimen. Novel therapeutic approaches are needed to cope with the toxic accumulation of homocysteine and restoration of a healthy metabolic balance. » Read More
Behavior, body composition, and vascular phenotype of homocystinuric mice on methionine-restricted diet or enzyme replacement therapy.
Classic homocystinuria (HCU) is an inherited disorder characterized by elevated homocysteine (Hcy) in plasma and tissues resulting from cystathionine β-synthase (CBS) deficiency. There is no cure, and patients are predominantly managed by methionine-restricted diet (MRD) to limit the production of Hcy. In this study, we used the I278T mouse model of HCU to evaluate the long-term impact of a novel enzyme replacement therapy [truncated human CBS C15S mutant modified with linear 20-kDa N-hydroxysuccinimide ester polyethylene glycol (OT-58)] on clinical end points relevant to human patients with HCU. » Read More
Characteristics Of Patients Participating In A Study Of Homocystinuria Due To Cystathionine Beta-synthase Deficiency
This interim analysis assessed baseline and longitudinal characteristics, including demographics, medical and family histories, medications, dietary information, ophthalmologic findings, plasma total Hcy (tHcy) and other sulfur metabolites, and laboratory values. The interim results demonstrate that despite being seen at centers of excellence and being prescribed a natural protein-restricted diet and/or a Met-free L-amino acid mixture and supplements, many patients have: plasma tHcy values 5 to 40 times the ULN for tHcy, hypermethioninemia (≥600 μM) in 33% of patients (36% pediatric, 33% adult), ocular deficits, signs of inflammation, protein metabolism and/or liver dysfunction. These data indicate that current diet and therapeutic interventions are poorly effective and/or that most patients are not able to remain compliant, leading to high tHcy levels, even in patients being frequently monitored at centers of excellence. » Read More
Homocysteine Is Negatively Correlated With Cognition In Homocystinuria Due To Cystathionine Beta-synthase Deficiency
Study CBS-HCY-NHS-01 is a multicenter (8 sites), international, observational, prospective, natural history study of HCU that enrolled 55 pediatric and adult patients to characterize the clinical course of HCU in patients under current clinical management practices over 3 years. This interim analysis assessed patients’ Cognitive function at baseline and every 6 months using the age-normalized NIH Toolbox Cognition Battery (NIHCB). tHcy levels were measured in plasma. This study highlights the overall cognitive impairment in many HCU patients. Patients with lower plasma tHcy levels performed better on measures of executive functioning, extending prior studies showing that controlling tHcy levels is essential for maintaining intellectual functioning within average range. As expected, lower Met levels, which reflect a better control of sulfur-amino acid metabolism, are associated with better cognition. The results of this study have practical implications for the management of HCU. Neuropsychological evaluations should be considered an important component of medical care for HCU patients, and assessment of executive functioning (including response inhibition) should be included as part of those evaluations. » Read More
Skeletal Fragility In A Natural History Study Of Homocystinuria Due To Cystathionine Beta-synthase Deficiency Patients
Study CBS-HCY-NHS-01 is a multicenter (8 sites), international, observational, prospective, natural history study of HCU that enrolled 55 pediatric (5-17 years of age) and adult (>18 years of age) patients to characterize the clinical course of HCU in patients under current clinical management practices over 3 years. This interim analysis assessed patient Bone Mineral Density (BMD) at baseline and 1 year at three locations (the hip, lumbar spine, and whole body) by dual-energy X-ray absorptiometry (DXA). Results indicate patients with plasma tHcy levels <100 µM had much greater skeletal fragility than those with levels >100 µM. BMD improves with greater total dietary protein intake, as shown by a positive correlation between BMD at all three locations and total dietary protein intake. This study shows that most HCU patients have skeletal fragility despite a relatively young age. For each patient, BMD results and Z-scores were stable over 12 months. Therefore, BMD and Z-scores assessed by DXA scan be considered a reliable endpoint to assess the efficacy of investigational treatments in future clinical trials in HCU patients. Bone health in this population is correlated with higher total dietary protein intake and higher tHcy levels, suggesting that, by chronically restricting their total protein intake to control their tHcy levels, patients may be increasing their skeletal fragility » Read More
Claims-Based Analysis of Homocysteine Testing, Elevated Homocysteine Levels, and Homocystinuria Diagnosis in the U.S.
This study examined the all-cause healthcare costs and resource utilization between HCU and PKU patients using the Administrative claims in the IBM® MarketScan® Commercial and Medicare Supplemental Databases from January 1, 2010 through December 31, 2016. HCU patients had higher rates of all-cause healthcare utilization in nearly all components of care captured compared to their PKU counterparts. Additionally, HCU patients incurred higher monthly all-cause medical costs. compared to PKU patients, with more than half of the medical costs for HCU patients attributable to IP admissions. » Read More