Homocystinuria Research Articles

High clinical burden of classical homocystinuria in the United States: a retrospective analysis

BackgroundClassical homocystinuria (HCU) is a rare genetic metabolic disorder resulting in elevated homocysteine and methionine levels. The clinical characteristics and associated complications of HCU are well documented. However, there is limited published research on the clinical burden of patients with HCU, especially stratified by total homocysteine (tHcy) levels. This study aimed to describe the overall clinical burden of patients with HCU in the United States and key clinical events by tHcy levels using administrative claims data.MethodsThis non-interventional retrospective cohort analysis from January 01, 2016, through September 30, 2021, used Optum’s de-identified Market Clarity Data. Patients who had 1 or more International Classification of Diseases, Tenth Revision code for homocystinuria (E72.11) or the signs, disease, and symptoms term homocystinuria in the natural language processing dataset were included. To obtain a study population most likely to have HCU, stratifications by tHcy levels, clinical characteristics, and phenotypic expressions were applied to refine the cohort. Included patients were then stratified by highest tHcy level. Clinical burden was measured by category of HCU-related events. Descriptive statistics were reported.ResultsSix hundred thirty-three patients met the inclusion criteria, and 601 patients had a tHcy level: < 50 µM (n = 278), 50 to < 100 µM (n = 212), and ≥ 100 µM (n = 111). Among the 601 patients with a tHcy level, almost one-half (n = 297, 49.4%) had at least one thrombotic/thromboembolic, skeletal, ocular, or neurological event and 14.1% (n = 85) had multiple events. Thrombotic/thromboembolic events (n = 186, 30.9%) were the most common type of events, followed by skeletal (n = 100, 16.6%), ocular (n = 63, 10.5%), and neurological events (n = 50, 8.3%). During follow-up, 5.7% (n = 34) of the patients died. All events assessed were more prevalent in the 50 to < 100 µM group and ≥ 100 µM group compared with those in the < 50 µM group.ConclusionsAs has been believed, patients with tHcy ≥ 100 µM carried a substantial clinical burden, but the burden is also very high in those whose levels were ≥ 50 µM. Thrombotic/thromboembolic events were more common than skeletal, ocular, or neurological events. Meaningfully lowered tHcy levels may help to reduce significant clinical events.

Genotypic Spectrum in a Cohort of Sri Lankan Patients With Homocystinuria.

Homocystinuria due to cystathionine beta-synthase (CBS) deficiency is a rare metabolic disorder inherited as an autosomal recessive trait. Spectrum of genetic variants in CBS gene and their correlation with the phenotypes of homocystinuria in Sri Lankan patients have not been reported to date. The objective of this study was to identify the genotypes and genotype-phenotype correlations in a cohort of Sri Lankan patients with homocystinuria due to CBS deficiency. We determined the variants in CBS gene in 14 Sri Lankan patients with homocystinuria, from 9 unrelated families. The clinical features and the biochemical response to pyridoxine were studied for further correlations. Among the 14 patients, the common clinical features were ectopia lentis (100%), intellectual disability (92%) and marfanoid features (78%) at presentation while three of them had developed osteoporosis (21%). Median age at diagnosis was 8 years (range 2-12). Three pathogenic variants (c.1006C>T, c.785C>T and c.19del) and two likely pathogenic variants (c.869C>T, c.772G>A) in CBS gene were identified. Thirteen patients with homozygous genotypes were non-responsive to pyridoxine while the only patient with the compound heterozygous genotype (c.869C>T/c.772G>A) responded to pyridoxine treatment. The genotypic spectrum observed in Sri Lankan patients is unique and mostly associated with pyridoxine non-responsiveness. The majority of the patients were identified clinically at a later stage of the disease due to lack of a screening programme in the country. Therefore, it is important to improve the awareness of the disease among the clinicians in the interest of early diagnosis and early commencement of metabolic treatment.

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

ABSTRACTCystathionine β‐synthase (CBS) deficiency (classical homocystinuria) has a wide range of severity. Mildly affected patients typically present as adults with thromboembolism and respond to treatment with pyridoxine. Severely affected patients usually present during childhood with learning difficulties, ectopia lentis and skeletal abnormalities; they are pyridoxine non‐responders (NR) or partial responders (PR) and require treatment with a low‐methionine diet and/or betaine. The European network and registry for Homocystinurias and methylation Defects (E‐HOD) has published management guidelines for CBS deficiency and recommended keeping plasma total homocysteine (tHcy) concentrations below 100 μmol/L. We have now analysed data from 311 patients in the registry to see how closely treatment follows the guidelines. Pyridoxine‐responsive patients generally achieved tHcy concentrations below 50 μmol/L, but many NRs and PRs had a mean tHcy considerably above 100 μmol/L. Most NRs were managed with betaine and a special diet. This usually involved severe protein restriction and a methionine‐free amino acid mixture, but some patients had a natural protein intake substantially above the WHO safe minimum. Work is needed on the methionine content of dietary protein as estimates vary widely. Contrary to the guidelines, most NRs were on pyridoxine, sometimes at dangerously high doses. tHcy concentrations were similar in groups prescribed high or low betaine doses and natural protein intakes. High tHcy levels were probably often due to poor compliance. Comparing time‐to‐event graphs for NR patients detected by newborn screening and those ascertained clinically showed that treatment could prevent thromboembolism (risk ratio 0.073) and lens dislocation (risk ratio 0.069).

Oxidative damage and mitochondrial dysfunction in cystathionine beta-synthase deficiency

Cystathionine beta-synthase deficiency (CBSD) is the most prevalent inherited disorder of homocysteine metabolism in the transsulphuration pathway. Research have suggested oxidative stress and inflammation as candidate pathogenic mechanisms in CBSD. This study aims to evaluate mitochondrial dysfunction and oxidative stress biomarkers in cystathionine beta-synthase deficiency (CBSD) patients, which may aid in understanding the pathogenesis of CBSD and improving treatment. The study group comprised 23 patients with a diagnosis of CBSD and healthy controls. We analysed serum levels of NAD+ and NADH by fluorometric assay, FGF-21 and GDF-15 by ELISA, mitochondrial DAMPs by real time qRT-PCR, total homocysteine levels in plasma by enzymatic test and compared the results in CBSD group with healthy controls. In patient group, a positive correlation was found between the total homocysteine level and both GDF-15 and NAD+/NADH levels. Furthermore, there was a negative correlation between total homocysteine levels and both total NAD++NADH and NADH levels. The alterations in NAD+, FGF-21, GDF-15 levels, and NAD+/NADH ratio in patients suggest that oxidative damage coexists with mitochondrial dysfunction in CBSD. Assessment of oxidative damage and addition of anti-oxidant therapy together with mitochondrial support may have additional benefits in reducing long-term morbidity in CBSD patients.

Impact of primary sequence changes on the self-association properties of mammalian cystathionine beta-synthase enzymes.

Cystathionine beta-synthase (CBS) is an evolutionarily conserved enzyme that plays a key role in mammalian sulfur amino acid biochemistry, mutations in which are the cause of classical homocystinuria (HCU), an inborn error of metabolism. Although there is agreement in the literature that CBS is a homomultimer, its precise structure is a source of confusion. Here, we performed a series of experiments examining the quaternary structure of various wild-type and mutant CBS enzymes using a combination of native gel electrophoresis, in situ activity assays, analytical ultracentrifugation, and gel filtration. Our data show that recombinantly expressed and purified full-length wild-type human CBS enzyme (hCBS) and HCU-causing variants (p.P422L, p.I435T, and p.R125Q CBS) form high molecular weight assemblies that are consistent with the properties expected of a filament. The filament is enzymatically active, and its size is sensitive to protein concentration. This behavior contrasts sharply with hCBS enzymes containing small deletions within the Bateman domain, which form stable tetramers and octamers regardless of concentration. Examination of liver lysates from humans and mice confirms the existence of enzymatically active high molecular weight aggregates in vivo, but also shows that these aggregates are specific to human CBS and do not occur in mice. Molecular modeling using AlphaFold2 suggests that these experimentally observed differences may be explained by subtle differences in the interaction mediated by the Bateman domains. Our results show that small differences in amino acid sequence can cause large differences in the size and shape of CBS multimers.

Clinical, biochemical and molecular characteristics of classic homocystinuria in Saudi Arabia and the impact of newborn screening on prevention of the complications: A tertiary center experience.

Classic homocystinuria (HCU) is a rare inborn metabolic disease that is generally asymptomatic at birth. If untreated, it can cause a wide range of complications including intellectual disability, lens dislocation, and thromboembolism. This study aimed to describe the natural history and the molecular findings of patients with HCU, and to assess the importance of early diagnosis. This study retrospectively collected data on patients attending the metabolic unit at Prince Sultan Military Medical City, Riyadh, Saudi Arabia from 2011 to 2024. Demographic, clinical, and molecular data was extracted from the electronic medical records. Among the 33 patients with HCU enrolled, 5/33 (15%) were diagnosed by newborn screening and the rest were diagnosed on clinical grounds. The complication profile was vast, with neuropsychiatric, musculoskeletal, ophthalmic, and thromboembolic morbidities complicating the disease course in 28/33 (85%) of the patients. None of the newborn screened patients had complications while all of the non-newborn screened patients had at least one complication, p < 0.0001. The majority of parents in this cohort were highly consanguineous, with 90% had first or second cousin marriage. Seven previously reported variants were detected in this cohort and one novel variant was found in three patients (c.828+2-828+ 3 delins ACACTTGCATCC, p.?). The known pathogenic variant (c.969G>A, p. (Trp323*)) was seen in most of the patients, with all of them coming from one tribe. This cohort gives further evidence that the newborn screening for HCU is likely to prevent the complications associated with the disease at least in the first few years of life. Therefore, newborn screening for HCU should be encouraged. Our molecular studies revealed the presence of a founder variant, detected in patients from a single tribe. This suggests that specific mutation testing may be cost-effective for individuals from certain ethnicities.

Mechanism of action and impact of thiol homeostasis on efficacy of an enzyme replacement therapy for classical homocystinuria

Homocystinuria (HCU) due to cystathionine beta-synthase (CBS) deficiency is characterized by elevated plasma and tissue homocysteine levels. There is no cure, but HCU is typically managed by methionine/protein restriction and vitamin B6 supplementation. Enzyme replacement therapy (ERT) based on human CBS has been developed and has shown significant efficacy correcting HCU phenotype in several mouse models by bringing plasma total homocysteine below the clinically relevant 100 μM threshold. As the reactive nature of homocysteine promotes disulfide formation and protein binding, and ERT is unable to normalize plasma total homocysteine levels, the mechanism of action of ERT in HCU remains to be further characterized. Here we showed that only a reduced homocysteine serves as a substrate for CBS and its availability restricts the homocysteine-degrading capacity of CBS. We also demonstrated that cells export homocysteine in its reduced form, which is efficiently metabolized by CBS in the culture medium. Availability of serine, a CBS co-substrate, was not a limiting factor in our cell-based model. Biological reductants, such as N-acetylcysteine, MESNA or cysteamine, increased the availability of the reduced homocysteine and thus promoted its subsequent CBS-based elimination. In a transgenic I278T mouse model of HCU, administration of biological reductants significantly increased the proportion of protein-unbound homocysteine in plasma, which improved the efficacy of the co-administered CBS-based ERT, as evidenced by significantly lower plasma total homocysteine levels. These results clarify the mechanism of action of CBS-based ERT and unveil novel pharmacological approaches to further increase its efficacy.

Anticipare il futuro (di circa otto anni) per provare a cambiarlo

A 14-day-old infant was diagnosed with classical homocystinuria through extended newborn screening after detecting hypermethioninemia and elevated homocysteine levels. The infant exhibited feeding difficulties and poor general health. Following a low-methionine diet and pharmacological therapy, his condition improved rapidly. Early diagnosis enabled therapeutic intervention in the first month of life, advancing the typical diagnosis by approximately eight years.

Komrower Memorial Lecture 2023. Molecular basis of phenotype expression in homocystinuria: Where are we 30 years later?

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.

Engineered Carbon Nanocatalysts for Homocysteine Catabolism

Cystathionine-β-synthase (CBS) deficiency or homocystinuria (HCU) is a rare inherited disorder with main clinical features of osteoporosis, dislocation of the optic lenses, learning difficulties and thromboembolism. CBS is a key enzyme in methionine catabolism pathway. CBS deficiency impairs the conversion of homocysteine (Hcy) to cystathionine, which leads to extracellular buildup of Hcy in toxic concentrations. Patients with CBS deficiency have elevated plasma Hcy and methionine.Currently, there is no FDA approved drug for CBS deficiency. Clinical treatment options are low-protein diet and betaine for severely affected patients, and vitamin supplementation for mildly affected adults. Artificial protein-based enzymes for Hcy treatment are in clinical trials. However, protein-based artificial enzymes can be immunogenic, prone to intracellular modifications, and the treatment may not be viable after few months.We propose a novel nanotechnology-based approach for the treatment of CBS deficiency. Carbon nanomaterials with multiple unsaturated carbons provide an excellent scaffold for engineering enzyme mimicking catalysts. We have designed carbon nanomaterial based catalytic artificial enzymes (CAEs) by surface engineering to mimic metabolic enzymes that catabolize Hcy under physiological conditions. Using a combination of paper chromatography and H1-NMR, our lab has shown that CAE can breakdown homocysteine and produce hydrogen sulfide similar to CGL enzyme. The degree of surface functionalization as well as surface curvature has profound effect on specificity and catalysis. We have shown that CAE can enter cells and lower homocysteine levels in cellular models. In preliminary studies, CAE was able to lower serum homocysteine levels in a murine model. Further studies will involve safety assessments of CAE as a treatment for HCU.

Cellular turnover and degradation of the most common missense cystathionine beta-synthase variants causing homocystinuria.

Homocystinuria (HCU) due to cystathionine beta-synthase (CBS) deficiency is the most common inborn error of sulfur amino acid metabolism. Recent work suggests that missense pathogenic mutations-regardless of their topology-cause instability of the C-terminal regulatory domain, which likely translates into CBS misfolding, impaired assembly, and loss of function. However, it is unknown how instability of the regulatory domain translates into cellular CBS turnover and which degradation pathways are involved in CBS proteostasis. Here, we developed a human HEK293-based cellular model lacking intrinsic CBS and stably overexpressing wild-type (WT) CBS or its 10 most common missense HCU mutants. We found that HCU mutants, except the I278T variant, expressed similarly or better than CBS WT, with some of them showing impaired oligomerization, activity and response to allosteric activator S-adenosylmethionine. Cellular stability of all HCU mutants, except P49L and A114V, was significantly lower than the stability of CBS WT, suggesting their increased degradation. Ubiquitination analysis of CBS WT and two representative CBS mutants (T191M and I278T) showed that proteasomal degradation is the major pathway for CBS disposal, with a minor involvement of lysosomal-autophagic and endoplasmic reticulum-associated degradation (ERAD) pathways for HCU mutants. Proteasomal inhibition significantly increased the half-life and activity of T191M and I278T CBS mutants. Lysosomal and ERAD inhibition had only a minor impact on CBS turnover, but ERAD inhibition rescued the activity of T191M and I278T CBS mutants similarly as proteasomal inhibition. In conclusion, the present study provides new insights into proteostasis of CBS in HCU.

Real-time detection of enzymatically formed hydrogen sulfide by pathogenic variants of cystathionine beta-synthase using hemoglobin I of Lucina pectinata as a biosensor

Classical homocystinuria is a rare disease caused by mutations in cystathionine β-synthase (CBS) gene (OMIM 613381). CBS catalyzes the first step of the transsulfuration pathway that converts homocysteine (Hcy) into cystathionine (Cysta) via a number of co-substrates and mechanisms. Formation of Cysta by condensation of Hcy and cysteine (Cys) produces a molar equivalent of hydrogen sulfide (H2S). H2S plays important roles in cognitive and vascular functions. Clinically, patients with CBS deficiency present with vascular, ocular, neurological and skeletal impairments. Biochemically, CBS deficiency manifests with elevated Hcy and reduced concentration of Cysta in plasma and urine. A number of pathogenic variants of human CBS have been characterized by their residual enzymatic activity, but very few studies have examined H2S production by pathogenic CBS variants, possibly due to technical hurdles in H2S detection and quantification. We describe a method for the real-time, continuous quantification of H2S formed by wild-type and pathogenic variants of human recombinant CBS, as well as by fibroblast extracts from healthy controls and patients diagnosed with CBS deficiency. The method takes advantage of the specificity and high affinity of hemoglobin I of the clam Lucina pectinata toward H2S and is based on UV–visible spectrophotometry. Comparison with the gold-standard, end-point H2S quantification method employing monobromobimane, as well as correlations with CBS enzymatic activity determined by LC-MS/MS showed agreement and correlation, and permitted the direct, time-resolved determination of H2S production rates by purified human recombinant CBS and by CBS present in fibroblast extracts. Rates of H2S production were highest for wild-type CBS, and lower for pathogenic variants. This method enables the examination of structural determinants of CBS that are important for H2S production and its possible relevance to the clinical outcome of patients.

Dysregulation of hepatic one-carbon metabolism in classical homocystinuria: Implications of redox-sensitive DHFR repression and tetrahydrofolate depletion for pathogenesis and treatment.

Cystathionine beta-synthase-deficient homocystinuria (HCU) is a life-threatening disorder of sulfur metabolism. HCU can be treated by using betaine to lower tissue and plasma levels of homocysteine (Hcy). Here, we show that mice with severely elevated Hcy and potentially deficient in the folate species tetrahydrofolate (THF) exhibit a very limited response to betaine indicating that THF plays a critical role in treatment efficacy. Analysis of a mouse model of HCU revealed a 10-fold increase in hepatic levels of 5-methyl -THF and a 30-fold accumulation of formiminoglutamic acid, consistent with a paucity of THF. Neither of these metabolite accumulations were reversed or ameliorated by betaine treatment. Hepatic expression of the THF-generating enzyme dihydrofolate reductase (DHFR) was significantly repressed in HCU mice and expression was not increased by betaine treatment but appears to be sensitive to cellular redox status. Expression of the DHFR reaction partner thymidylate synthase was also repressed and metabolomic analysis detected widespread alteration of hepatic histidine and glutamine metabolism. Many individuals with HCU exhibit endothelial dysfunction. DHFR plays a key role in nitric oxide (NO) generation due to its role in regenerating oxidized tetrahydrobiopterin, and we observed a significant decrease in plasma NOx (NO2 + NO3) levels in HCU mice. Additional impairment of NO generation may also come from the HCU-mediated induction of the 20-hydroxyeicosatetraenoic acid generating cytochrome CYP4A. Collectively, our data shows that HCU induces dysfunctional one-carbon metabolism with the potential to both impair betaine treatment and contribute to multiple aspects of pathogenesis in this disease.

Classical Homocystinuria (HCU): Overview and dietary management

Classical Homocystinuria (HCU): Overview and dietary management

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

BackgroundCystathionine β-synthase (CBS)-deficient homocystinuria (HCU) is an inherited disorder of sulfur amino acid metabolism with varying severity and organ complications, and a limited knowledge about underlying pathophysiological processes. Here we aimed at getting an in-depth insight into disease mechanisms using a transgenic mouse model of HCU (I278T). MethodsWe assessed metabolic, proteomic and sphingolipidomic changes, and mitochondrial function in tissues and body fluids of I278T mice and WT controls. Furthermore, we evaluated the efficacy of methionine-restricted diet (MRD) in I278T mice. ResultsIn WT mice, we observed a distinct tissue/body fluid compartmentalization of metabolites with up to six-orders of magnitude differences in concentrations among various organs. The I278T mice exhibited the anticipated metabolic imbalance with signs of an increased production of hydrogen sulfide and disturbed persulfidation of free aminothiols. HCU resulted in a significant dysregulation of liver proteome affecting biological oxidations, conjugation of compounds, and metabolism of amino acids, vitamins, cofactors and lipids. Liver sphingolipidomics indicated upregulation of the pro-proliferative sphingosine-1-phosphate signaling pathway. Liver mitochondrial function of HCU mice did not seem to be impaired compared to controls. MRD in I278T mice improved metabolic balance in all tissues and substantially reduced dysregulation of liver proteome. ConclusionThe study highlights distinct tissue compartmentalization of sulfur-related metabolites in normal mice, extensive metabolome, proteome and sphingolipidome disruptions in I278T mice, and the efficacy of MRD to alleviate some of the HCU-related biochemical abnormalities.

Visual functions, ocular characteristics and visual quality of life in patients with homocystinuria

ABSTRACT Background Homocystinuria (HCU) is a rare metabolic disease that affects many organs, including the eyes. Aims: to assess visual functions, ocular characteristics, visual quality of life and time from the onset of ocular manifestations to HCU-diagnosis in patients with HCU. Material and methods Eighteen patients underwent ophthalmological examinations and visual quality of life questionnaires. Results Best corrected decimal visual acuity was median 1.0 (range amaurosis - 1.3) right eye and 1.0 (range amaurosis -1.3) left eye. Five patients presented with severe myopia as first HCU manifestation, duration to HCU diagnosis was mean 13.6 years (range 2-25). Two patients had suffered ectopia lentis as first HCU manifestation, HCU diagnosis was established mean 8.0 years (range 7-9) later. One patient had suffered both from thrombosis and ectopia lentis prior to diagnosis. Another four patients suffered thromboembolic events before diagnosis. Median VFQ-25 composite score was 93 (68-98). Conclusions The prevalence of myopia, ectopia lentis and monocular blindness was high in HCU-patients, which was reflected in their visual quality of life. Diagnosis was often delayed after the first ocular manifestation, increasing the risk of other severe non-ocular complications.

Pegtibatinase, an investigational enzyme replacement therapy, for the treatment of classical homocystinuria (HCU): Design of the harmony Phase 3 study

Pegtibatinase, an investigational enzyme replacement therapy, for the treatment of classical homocystinuria (HCU): Design of the harmony Phase 3 study

Economic burden of classical homocystinuria in the United States

Economic burden of classical homocystinuria in the United States

Polymorphic substitutions in folate cycle genes as predictors of hyperhomocysteinemia in children

Introduction. Mutant alleles of genes of folate cycle enzymes can lead to the significant deterioration of its function and varying severity of pathology. Several defects in these genes lead to severe hyperhomocysteinemia, the most common form of which is a deficiency of cystathionine beta-synthase B. &#x0D; Aim: to establish polymorphic substitutions in the genes of folate cycle enzymes that contribute to the formation of hyperhomocysteinemia in children.&#x0D; Materials and methods. Two hundred seventy one children aged of 13–18 years were examined. The analysis of genetic polymorphisms of the folate cycle was carried out using a molecular genetic method. Quantitative determination of the blood homocysteine and folic acid level was performed by chemiluminescent immunoassay on microparticles. Statistical data processing was carried out using Statistica 6.1 application programs (StatSoft Inc., USA). &#x0D; Results. The frequency of the T allele of the MTHFR 677 gene was revealed to be higher in adolescents of the main group compared with the control (p = 0.043). The frequency of the homozygous genotype 66 AA of the MTRR gene in children of the comparison group was significantly higher (p = 0.049), however, the heterozygous genotype 66 AG of the MTRR gene was significantly more often detected in adolescents of the main group (p = 0.008). The average concentrations of homocysteine in children of the main group were 11.6 mmol/L, in adolescents of the control group 9.3 mmol/L (p = 0.021). Hyperhomocysteinemia in children of the main group was detected in 217 (80.1%) adolescents, and in 57 (49.6%) children of the control group (p &lt; 0.001). The baseline serum folate level was determined in the children of the main group. The average amount of vitamin B9 in the blood of children of the main group was 3.7 ng/ml, and in 145 (53.5%) children this indicator was significantly reduced.&#x0D; Conclusion. Low levels of folic acid contribute to an increase in homocysteine in blood plasma. Taking vitamin B9 and vitamin folate complexes significantly reduces the level of homocysteine in blood plasma (p &lt; 0.001).

The live biotherapeutic SYNB1353 decreases plasma methionine via directed degradation in animal models and healthy volunteers

Methionine is an essential proteinogenic amino acid, but its excess can lead to deleterious effects. Inborn errors of methionine metabolism resulting from loss of function in cystathionine β-synthase (CBS) cause classic homocystinuria (HCU), which is managed by a methionine-restricted diet. Synthetic biotics are gastrointestinal tract-targeted live biotherapeutics that can be engineered to replicate the benefits of dietary restriction. In this study, we assess whether SYNB1353, an E.coli Nissle 1917 derivative, impacts circulating methionine and homocysteine levels in animals and healthy volunteers. In both mice and nonhuman primates (NHPs), SYNB1353 blunts the appearance of plasma methionine and plasma homocysteine in response to an oral methionine load. A phase 1 clinical study conducted in healthy volunteers subjected to an oral methionine challenge demonstrates that SYNB1353 is well tolerated and blunts plasma methionine by 26%. Overall, SYNB1353 represents a promising approach for methionine reduction with potential utility for the treatment of HCU.