Materiały źródłowe

• #1 Homocystinuria/Homocysteinemia: Overview, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/1115062-overview

  Homocystinuria is a disorder of methionine metabolism, leading to an abnormal accumulation of homocysteine and its metabolites (homocystine, homocysteine-cysteine complex, and others) in blood and urine. Homocystinuria is an autosomal recessively inherited defect in the transsulfuration pathway (homocystinuria I) or methylation pathway (homocystinuria II and III). […] The accumulation of homocysteine and its metabolites is caused by disruption of any of the three interrelated pathways of methionine metabolismdeficiency in the cystathionine B-synthase (CBS) enzyme, defective methylcobalamin synthesis, or abnormality in methylene tetrahydrofolate reductase (MTHFR). […] Homocysteinemia theoretically could be a result of defects at any of these three locations. These abnormalities could arise from solely a genetic predisposition or from a genetic predisposition worsened by comorbid conditions and/or nutritional and environmental factors.

• #2 Homocystinuria: pathogenetic mechanisms – PubMed

  https://pubmed.ncbi.nlm.nih.gov/324277/

  Homocystinuria with elevated plasma homocysteine and methionine levels is the result of deficient activity of cystathionine synthetase, the enzyme catalyzing conversion of homocysteine to cystathionine. […] The major clinical manifestations result from the elevated plasma homocysteine level. The excitotoxic effect of homocysteic acid accounts for mental retardation and seizures. Interference with collagen cross-linking by sulfhydryl groups of homocysteine causes ectopia lentis and skeletal deformities. Sulfation factor-like effects contribute to disruption of vascular endothelium, which is followed by platelet thrombosis and widespread arterial and venous occlusions. […] Low methionine homocystinuria, with deficient remethylation of homocysteine, results from deranged vitamin B(12) metabolism and from deficient 5,10-methylene-tetrahydrofolate reductase. Administration of azaribine produces homocystinuria by mechanism not yet elucidated.

• #3 Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency – GeneReviews® – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK1524/

  Homocystinuria caused by cystathionine -synthase (CBS) deficiency is characterized by involvement of the eye (ectopia lentis and/or severe myopia), skeletal system (excessive height, long limbs, scoliosis, and pectus excavatum), vascular system (thromboembolism), and CNS (developmental delay/intellectual disability). […] Classic homocystinuria is caused by deficiency of cystathionine -synthase (CBS), a pyridoxine (vitamin B6)-dependent enzyme. […] Because homocysteine is at the branch point between transsulfuration and methionine remethylation in the methionine metabolic cycle, a block at CBS limits transsulfuration and results in both increased homocysteine and increased methionine, the latter caused by enhanced remethylation. […] The diagnosis of classic homocystinuria is established in a proband by measurement of plasma total homocysteine (tHcy) and amino acids in plasma and/or by identification of biallelic pathogenic variants in CBS through molecular genetic testing. […] Most pathogenic variants affect the active core of cystathionine -synthase. Pathogenic variants may also impair the binding of adenosine derivatives (e.g., AMP, ATP, S-adenosylmethionine), thus interfering with cellular energy.

• #4 Homocystinuria: a commentary | Journal of Clinical Pathology

  https://jcp.bmj.com/content/76/3/153

  Homocysteine (HCY) is a non-essential sulfur containing amino acid under normal circumstances is converted into cysteine (transulfuration pathway) or remethylated (remethylation pathway) forming methionine. […] While free HCY is pathogenic, it is difficult to measure, is unstable and is an insensitive marker as it only becomes detectable when total-HCY (tHCY) is above 5060 mol/L(90% CI 15 to 100 mol/L). […] Measurement of urinary HCY is also insensitive as it only becomes detectable once plasma tHCY exceed approximately 150 mol/L. […] Developments in assays particularly in HPLC (high-performance liquid chromatography) made it possible to measure the lower tHCY concentrations in plasma. […] Such immunoassays are available on automated random access immunoassay analysers, which increases the availability of HCY to less specialist laboratories as well as potentially decreasing the.

• #5 Homocystinuria diagnosis and management: it is not all classical | Journal of Clinical Pathology

  https://jcp.bmj.com/content/75/11/744

  Homocystinuria (HCU) refers to a group of inherited disorders of homocysteine metabolism associated with high blood homocysteine concentration, thromboembolic tendency and neurocognitive symptoms. […] The most prevalent inherited disorder of homocysteine metabolism is classical HCU caused by deficiency of the pyridoxine-dependent enzyme, cystathione beta-synthase, which converts homocysteine to cystathionine in the transsulphuration pathway. An alternative route for homocysteine metabolism is its remethylation to methionine by the cobalamin-dependent enzyme, methionine synthase, using the folate derivative, methyltetrahydrofolate, as a methyl donor. […] Primary genetic disorders affecting function of CBS (classical HCU) or enzymes involved in remethylation impair metabolism of HCy causing it to rise in plasma from a reference concentration below 15 mol/L to at least 40 mol/L and usually over 100 mol/L.

• #6 Homocystinuria, Diagnosis and Treatment – Labpedia.net

  https://labpedia.net/homocystinuria-diagnisis-and-treatment/

  It is an autosomal recessive inherited disorder. […] It results from the enzyme cystathionine-beta-synthetase deficiency, which catalyzes cystathionine formation from homocystine and serine. […] This is a disorder of methionine metabolism which leads to: Accumulation of homocysteine and its metabolites in the blood and urine. […] Basically, there is a deficiency of the cystathionine beta-synthase enzyme deficiency. […] This metabolic disorder results from a deficiency in the cystathionine beta-synthase enzyme, which is responsible for methionine and homocysteine metabolism. […] The concentration of homocystine in the urine is not detectable but decreased homocysteine conversion to cystathionine by cystathionine beta-synthase enzyme or back to methionine leads to homocystinuria. […] There is an excess of homocysteine and methionine in the blood.

• #7 Homocystinuria diagnosis and management: it is not all classical | Journal of Clinical Pathology

  https://jcp.bmj.com/content/75/11/744

  In HCU, remethylation is the only route available for HCy metabolism, and consequently, methionine is high and cystine, distal to the defective CBS enzyme, is low. Conversely, in remethylation disorders, CBS is the only route available for HCy metabolism, therefore, methionine is low. […] The CBS enzyme uses pyridoxal 5-phosphate as a cofactor. Approximately 50% of patients with HCU respond partially or wholly to high-dose pyridoxine (vitamin B6). Pyridoxine responsiveness is thought to depend on the extent to which the CBS mutations affect the cofactor binding site. […] In non-pyridoxine-responsive HCU and some partially responsive patients, target tHCy can only be attained by additionally following a protein restricted diet to limit intake of the essential amino acid, methionine, the precursor to HCy production in the transsulphuration pathway. […] Remethylation defects are caused by MTHFR deficiency (known as 'MTHFR’) and disorders of cobalamin metabolism. […] Cobalamin disorders directly or indirectly impair methionine synthase activity resulting in high tHCy accompanied by a low or low/normal methionine.

• #8 Homocystinuria | Radiology Reference Article | Radiopaedia.org

  https://radiopaedia.org/articles/homocystinuria?lang=us

  A deficiency of the enzyme cystathionine–synthase causes classical homocystinuria whereby the metabolism of homocysteine to methionine is affected. This is due to a mutation of the CBS gene on chromosome 21q22.3 and is inherited in an autosomal recessive fashion. […] Other forms of secondary homocystinuria can be seen in other rare inborn metabolism disorders (e.g. methylenetetrahydrofolate reductase deficiency).

• #9 The Spectrum of Mutations of Homocystinuria in the MENA Region

  https://www.mdpi.com/2073-4425/11/3/330

  Approximately 87% of all CBS mutations are missense and do not target the CBS catalytic site, but rather result in unstable misfolded proteins lacking the normal biological function, designating them for degradation. […] The main aim is to keep the plasma homocysteine as close to the normal range as possible. However, a considerable fraction of affected patients is nonresponsive to pyridoxine treatment. […] Therefore, currently the therapeutic approach for homocystinuria is shifted toward stabilizing and rescuing the protein’s native structural conformations through chemical chaperones and proteasome inhibitors. […] Various treatment approaches, such as chemical chaperones, CBS enzyme replacement therapy, and gene therapy could be promising alternative treatments for homocystinuria patients.

• #10

  https://journals.lww.com/ijo/fulltext/2022/07000/homocystinuria_and_ocular_complications___a_review.13.aspx

  Homocystinuria is a rare metabolic inborn disorder caused due to dysfunctional cystathionine -synthase (CBS) enzyme activity, thus resulting in elevated levels of methionine and homocysteine in the blood and urine. […] The CBS gene is located on the long arm of chromosome 21. More than 191 CBS mutations have been documented to date. Out of these, approximately 87% are missense mutations. However, they do not affect the CBS catalytic site. Instead, they result in an unstable misfolded protein with abnormal biological function. […] To date, more than 191 CBS mutations have been identified. This eventually leads to impairment of conversion of homocysteine to cystathionine, resulting in elevation of both Met and homocysteine levels in blood and urine, leading to hyperhomocystinemia, homocystinuria, hypermethioninemia, and homocysteinemia. The two most frequently reported mutations worldwide are p.G307S (31%) and p.I278T (24%). The p.G307S mutation produces severe effects in the homozygous individuals, and it is also found to be minimally responsive to nonresponsive to pyridoxine treatment. On the other hand, the p. 1278T mutation is pyridoxine responsive with mild clinical manifestations.

• #11 Pathogenic Homocystinuria-Associated T236N Mutation Dramatically Alters the Biochemical Properties of Cystathionine Beta-Synthase Protein

  https://www.mdpi.com/2227-9059/12/5/929

  The CBS T236N mutant displays significant deviations from the CBS WT enzyme. Specifically, CBS T236N exhibits reduced stability and enzymatic activity when compared to the native enzyme. […] The interaction between heme and the PLP active site is believed to occur through molecular interactions involving amino acid residues 258–272 situated at both ends of an α-helix. […] The functional diversity of CBS mutations located within the catalytic domain has been studied, revealing that different mutations target various residues with distinct consequences. […] Our findings demonstrate that the p.T236N mutation markedly disrupts the stability of the human CBS protein, resulting in a significant reduction in specific enzyme activity, which correlates with the severe phenotype observed in homozygous patients.

• #12 Homocystinuria/Homocysteinemia: Overview, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/1115062-overview

  Several mechanisms have been suggested as the possible cause of accelerated vascular disease, including the following: Endothelial cell damage, Smooth muscle cell proliferation, Lipid peroxidation, Upregulation of prothrombotic factors (XII and V), Downregulation of antithrombotic factors or endothelial-derived nitric oxide.

• #13

  https://omim.org/entry/236200

  Thrombotic lesions of arteries and veins are major features of homocystinuria. […] The observations of Ratnoff (1968) may have a bearing on the mechanism of the thrombotic accidents. […] Reviewing the nature of the ocular zonule, Streeten (1982) pointed out that the zonular fibers are composed of glycoprotein with a high concentration of cysteine, which undoubtedly explains their susceptibility to abnormal formation in diseases of sulfur metabolism. […] Di Minno et al. (1993) found evidence for enhanced thromboxane biosynthesis in homocystinuria and concluded from the response to administration of the antioxidant drug probucol that the enhanced thromboxane biosynthesis was dependent in part on probucol-sensitive mechanisms. High urinary excretion of 11-dehydro-TXB2, a major enzymatic derivative of TXA2, was observed in all 11 homocystinuric patients studied. The elevated thromboxane biosynthesis was thought to reflect, at least in part, in vivo platelet activation.

• #14

  https://www.omim.org/entry/236200

  Thrombotic lesions of arteries and veins are major features of homocystinuria. […] Di Minno et al. (1993) found evidence for enhanced thromboxane biosynthesis in homocystinuria and concluded from the response to administration of the antioxidant drug probucol that the enhanced thromboxane biosynthesis was dependent in part on probucol-sensitive mechanisms. High urinary excretion of 11-dehydro-TXB2, a major enzymatic derivative of TXA2, was observed in all 11 homocystinuric patients studied. The elevated thromboxane biosynthesis was thought to reflect, at least in part, in vivo platelet activation. […] McKusick (1966) suggested that excess homocysteine may interfere with the normal synthesis of collagen crosslinks, thus accounting for the development of osteoporosis. […] In cultured human hepatocytes and vascular endothelial and aortic smooth muscle cells, Werstuck et al. (2001) found that homocysteine-induced endoplasmic reticulum (ER) stress activated both the unfolded protein response and sterol regulatory element-binding proteins (SREBPs). Activation of the SREBPs was associated with increased expression of genes responsible for cholesterol/triglyceride biosynthesis and uptake, and with intracellular accumulation of cholesterol.

• #15

  https://www.jci.org/articles/view/116715

  Homocystinuria due to homozygous cystathionine beta-synthase deficiency is an inborn error of metabolism characterized by a high incidence of thrombosis and premature atherosclerosis. […] These results provide evidence for enhanced thromboxane biosynthesis in homocystinuria and for its partial dependence on probucol-sensitive mechanisms. […] Furthermore, the elevated TXA2 formation in homocystinuria is likely to reflect, at least in part, in vivo platelet activation.

• #16

  https://www.omim.org/entry/236200

  Jakubowski et al. (2008) found that patients with homocysteinemia due to MTHFR deficiency (236250) or CBS deficiency had increased plasma levels of N-homocysteine (Hcy)-linked proteins, including the prothrombotic N-Hcy-fibrinogen (134820). N-Hcy-proteins are detrimental by contributing to both thrombogenesis and immune activation. The authors suggested that increased levels of N-Hcy-fibrinogen may explain the increased susceptibility to thrombogenesis in these individuals.

• #17 Homocystinuria due to cystathionine beta-synthase deficiency | MedLink Neurology

  https://www.medlink.com/articles/homocystinuria-due-to-cystathionine-beta-synthase-deficiency

  Investigations on the potential of homocysteine to modify structural and functional properties of recombinant human fibrillin-1 fragments strongly suggest that structural and functional modifications as well as degradation processes of fibrillin-1 in the connective tissues of patients with homocystinuria play a major role in the pathogenesis of this disorder. […] It has not yet been elucidated how cystathionine beta-synthase deficiency impairs cognitive capabilities. […] Increased homocysteine is considered a risk factor for vascular dementia and stroke. […] Research results in murine models suggest that homocysteine causes arterial remodeling, at least in part, by increasing the collagen/elastin ratio. […] Other studies have attempted to clarify the mechanisms involved in the complex neuropathological features associated with abnormal homocysteine metabolism.

• #18

  https://omim.org/entry/236200

  Lubec et al. (1996) studied collagen synthesis and crosslinking by noninvasive tests in 10 patients with homocystinuria. Synthesis of collagen type I and type III was not different from age-matched healthy controls as reflected by comparable plasma levels of C-terminal propeptide of type I procollagen and of plasma levels of N-terminal propeptide of procollagen type III. Collagen type I crosslinks expressed by serum C-terminal telopeptide of collagen type I in the patient group were, however, only about one-third of the values found in the control group. This significant reduction of crosslinks in the patients with homocystinuria did not correlate with serum homocysteine or homocystic acid concentrations. The data supported the disturbed crosslinking hypothesis and indicated that the bone manifestations of homocystinuria are not due to deficient collagen synthesis.

• #19

  https://www.jci.org/articles/view/107449

  The biochemical mechanism accounting for the connective tissue abnormalities in homocystinuria was explored by examining the effects of various amino acids known to accumulate in the plasma of patients with this disease on cross-link formation in collagen. […] It is concluded that homocysteine interferes with the formation of intermolecular cross-links that help stabilize the collagen macromolecular network via its reversible binding to the aldehydic functional groups. […] Although the concentration of homocysteine used in this study to demonstrate these effects in vitro is clearly higher than that which is observed in homocystinuric’s plasma, the data do suggest a possible pathogenetic mechanism of connective tissue defect in homocystinuria.

• #20 Homocystinuria – EyeWiki

  https://eyewiki.org/Homocystinuria

  Raised homocysteine concentrations interfere with the cross-linking of sulfonhydryl groups in proteins such as those in elastin. Increased S-adenosylhomocysteine (SAH), a precursor to homocysteine, impairs methylation reactions; and decreased concentrations of cystathionine and cysteine are associated with apoptosis, oxidative stress, and alterations of structural proteins like fibrillin. The alterations to fibrillin and cross-linking modification in elastin may contribute to connective tissue abnormalities and vascular endothelial dysfunction. This cross-linking interference is thought to contribute to ectopia lentis and the skeletal abnormalities seen in homocystinuria. The interference between elastin proteins may also cause alterations of the scleral connective tissue. Additionally, the lens zonules of the eye have high cysteine content and are possibly weakened by the reduced level of cysteine.

• #21 Homocystinuria

  https://webeye.ophth.uiowa.edu/eyeforum/cases/269-Homocystinuria.htm

  There have been few studies that offer theories for the pathophysiologic mechanisms underlying the ocular sequelae of homocystinuria. Poloschek et al. investigated ERG findings in those with methionine synthase deficiency and proposed that increased homocysteine levels decrease the transport of folates to photoreceptors, which in turn decrease intracellular anabolic processes, impacting cone photoreceptor function. […] They also commented that hyperhomocysteinemia may lead to microvascular damage in the retina, leading to reduced oscillatory potentials. It may also have toxic effects on the neurons of the ganglion cell layer, leading to deformed flash visual evoked potential (VEP) responses.

• #22 Homocystinuria due to cystathionine beta-synthase deficiency | MedLink Neurology

  https://www.medlink.com/articles/homocystinuria-due-to-cystathionine-beta-synthase-deficiency

  Investigations on the effect of elevated homocysteine on the blood-brain barrier suggest an important toxic effect of elevated homocysteine on brain microvessels and implicate homocysteine in the disruption of the blood-brain barrier. […] Investigations on the regional and cellular distribution of cystathionine beta-synthase in the adult and developing mouse brain suggest that the enzyme plays a crucial role in the development and maintenance of the CNS and that enzyme deficiency might cause radial glia or astrocyte dysfunction.

• #23 Pathology of Homocystinuria | SpringerLink

  https://link.springer.com/chapter/10.1007/978-1-4615-5771-5_34

  The accelerated growth observed in some children with homocystinuria is attributed to the growth hormone-like and the insulin-like growth factor activities of homocysteine and homocysteic acid. […] In addition, homocysteine interferes with intramolecular cross-linkages of collagen, probably by reaction with lysyl aldehyde, causing abnormalities of skin, synovium, bone, and other connective tissues. […] Hyperhomocysteinemia produces fibrous arteriosclerotic plaques by a direct effect on the cells and tissues of arteries and arterioles in homocystinuria caused by the three principal types of enzyme deficiency. […] The discovery of the atherogenic effect of homocysteine on arteries in homocystinuria led to development of the homocysteine theory of arteriosclerosis. […] Homocysteine thiolactone causes aggregation of low-density lipoprotein and converts thioretinaco to thioco, inhibiting oxidative metabolism, which may explain increased hepatic cholesterol and triglyceride synthesis.

• #24

  https://omim.org/entry/236200

  In cultured human hepatocytes and vascular endothelial and aortic smooth muscle cells, Werstuck et al. (2001) found that homocysteine-induced endoplasmic reticulum (ER) stress activated both the unfolded protein response and sterol regulatory element-binding proteins (SREBPs). Activation of the SREBPs was associated with increased expression of genes responsible for cholesterol/triglyceride biosynthesis and uptake, and with intracellular accumulation of cholesterol. […] Mice with diet-induced hyperhomocysteinemia had significantly increased cholesterol and triglycerides in liver, but not plasma, due to increased lipid biosynthesis, not impaired hepatic export of lipids. The findings suggested a mechanism by which homocysteine-induced ER stress causes dysregulation of the endogenous sterol response pathway, leading to increased hepatic biosynthesis and uptake of cholesterol and triglycerides, which contribute to hepatic steatosis and possibly atherosclerotic lesions observed in hyperhomocysteinemia.

• #25 Orphanet: Homocystinuria due to cystathionine beta-synthase deficiency

  https://www.orpha.net/en/disease/detail/394

  A rare metabolic disease of methionine catabolism characterized by accumulation of methionine and homocysteine with clinical involvement of the eye, skeletal system, vascular system and central nervous system (CNS). […] The disease is caused by mutations in the CBS gene (21q22.3) leading to the accumulation of homocysteine and methionine, which are toxic for the endothelium, and causes neurocognitive impairment. Cysteine deficiency probably plays a role in connective tissue abnormalities, including lens dislocation.

• #26 Studies of the Mechanism of Pyridoxine-Responsive Homocystinuria | Pediatric Research

  https://www.nature.com/articles/pr197225

  Pharmacologie doses of pyridoxine corrected plasma amino acid abnormalities in two boys (JK and EY) with homocystinuria caused by cystathionine synthase deficiency. […] Cystathionine synthase assays on extracts of cultured skin fibroblasts were carried out to explore this apparent clinical difference. Under basal conditions, synthase activity in extracts from both patients was less than 5% of normal. Addition of saturating concentrations of pyridoxal phosphate to the assay mixture stimulated synthase activity fourfold in extracts from JK’s cells. No detectable increase in enzyme activity was noted in extracts of EY’s cells under identical conditions. These in vivo and in vitro differences suggest that JK’s pyridoxine responsiveness is mediated by partial correction of his underlying synthase deficiency and that EY’s response to pyridoxine may be produced by another mechanism, perhaps stimulation of alternate pathways of sulfur-amino acid metabolism. […] Our results suggest a negative answer to this question and emphasize the need for further clinical and biochemical investigation of such patients.

• #27 Homocystinuria – Wikipedia

  https://en.wikipedia.org/wiki/Homocystinuria

  Homocystinuria (HCU) is an inherited disorder of the metabolism of the amino acid methionine due to a deficiency of cystathionine beta synthase or methionine synthase. […] It is usually caused by the deficiency of the enzyme cystathionine beta synthase, mutations of other related enzymes such as methionine synthase, or the deficiency of folic acid, vitamin B12 and/or pyridoxine (vitamin B6). […] The term homocystinuria describes an increased excretion of the thiol amino acid homocysteine in urine (and incidentally, also an increased concentration in plasma). The source of this increase may be one of many metabolic factors, only one of which is CBS deficiency. Others include the re-methylation defects (cobalamin defects, methionine synthase deficiency, MTHFR) and vitamin deficiencies including riboflavin (vitamin B2), pyridoxal phosphate (vitamin B6), folate (vitamin B9), and cobalamin (vitamin B12).

• #28 SciELO Brazil – Three Main Causes of Homocystinuria: CBS, cblC and MTHFR Deficiency. What do they Have in Common? Three Main Causes of Homocystinuria: CBS, cblC and MTHFR Deficiency. What do they Have in Common?

  https://www.scielo.br/j/jiems/a/5KjZr63wC5Md7t3ZW5SpBhn/

  In remethylation, Hcy receives a methyl group from 5-methyltetrahydrofolate (5MTHF), which is formed from 5,10-methylenetetrahydrofolate by MTHFR. […] MTHFR deficiency blocks the production of methyl-THF, which is the circulation form of folate. […] In CBS deficiency, folate is often deficient at diagnosis probably due to the inhibition of MTHFR by the increased concentration of SAM. […] In cblC deficiency, a different mechanism kicks in: a dysfunctional MTR results in the accumulation of all folates as methyl-THF, which cannot be converted back to methylene-THF because MTHFR is physiologically none-reversible. […] These result in a functional folate deficiency despite that plasma folate may be normal or even increased because of the leakage of methyl-THF out of the cell. […] In particular, the synthesis of thymidylate and purine will be compromised, which will hamper essential cellular functions, especially in cells that rapidly divide, such as those in bone marrow. […] This functional folate deficiency occurs in any cell, which may explain why so many different organ systems can be affected in cblC patients, particularly when compared to the other remethylation defect of MTHFR deficiency, which mainly affects the CNS.

• #29 Homocystinuria – Wikipedia

  https://en.wikipedia.org/wiki/Homocystinuria

  CBS deficiency may be diagnosed by routine metabolic biochemistry. Genetic testing may be used to screen for known SNPs (mutations). In the first instance, plasma or urine amino acid analysis will frequently show an elevation of methionine and the presence of homocysteine. […] The laboratory analysis of homocysteine itself is complicated because most homocysteine (possibly above 85%) is bound to other thiol amino acids and proteins in the form of disulphides (e.g., cysteine in cystine-homocysteine, homocysteine in homocysteine-homocysteine) via disulfide bonds.

• #30 Classical homocystinuria – Genomics Education Programme

  http://www.genomicseducation.hee.nhs.uk/documents/classical-homocystinuria/

  Classical homocystinuria (HCU) is an autosomal recessive disorder caused by a deficiency in cystathionine -synthase (CBS) that results in a defect in the catabolic pathway of the amino acid methionine. […] CBS is a pyridoxine (vitamin-B6) dependent enzyme that is responsible for the conversion of homocysteine to cystathionine. Deficiency therefore leads to the accumulation of homocysteine. […] Diagnosis is characterised biochemically by markedly raised concentrations of plasma total homocysteine and methionine (as determined by plasma amino acid analysis). […] Management of HCU aims to correct biochemical abnormalities, primarily to control the elevated plasma total homocysteine concentrations.

• #31 WV DHHR – OMCFH – Newborn Metabolic Screening – Homocystinuria

  https://www.wvdhhr.org/nbms/diseases/Homocystinuria.asp

  The term „homocystinuria” designates a biochemical abnormality, not a specific disease entity. There are many causes of homocystinuria. All affect one of the transsulfation pathways that convert the sulfur atom of methionine into the sulfur atom of cysteine. This pathway is the chief route of disposal of methionine. The most common defect, cystathionine -synthase (CBS) deficiency (OMIM database No. 236200), results in high concentrations of serum methionine. […] Two mechanisms probably explain most of the clinical symptoms seen: (1) abnormal (hyper) coagulation because of „sticky” platelets; and (2) direct toxicity of homocystine and its metabolites, causing endothelial cell damage. […] Treatment depends on the underlying cause of homocystinuria. As a first step, pyridoxine (vitamin B6) responsiveness should be ascertained, because approximately 50% of patients respond to large doses of this vitamin. Nonresponsive patients with CBS deficiency should be treated with a methionine-restricted, cystine-supplemented diet. […] Clinical variability remains despite therapy. Not all affected individuals have increased methionine concentrations. The relationship between variability and the underlying metabolic processes or compliance has not yet been completely ascertained.

• #32 Homocystinuria due to cystathionine beta synthase deficiency – Indian Journal of Dermatology, Venereology and Leprology

  https://ijdvl.com/homocystinuria-due-to-cystathionine-beta-synthase-deficiency/

  The principles of treatment are to correct the biochemical abnormalities, especially to control the elevated plasma homocystine concentration as much as possible and to prevent or at least reduce, the complications of homocysteinuria and to prevent further complications such as thrombosis. […] Treatment with betaine provides an alternate remethylation pathway to convert excess homocysteine into methionine and may help to prevent complications, particularly thrombosis. […] Folate and vitamin B12 optimize the conversion of homocysteine to methionine by methionine synthase, thus helping to decrease the plasma homocystine concentration. […] As homocystinuria is a genetic disorder, frequent monitoring of blood homocysteine levels should be done and the duration of treatment should be life long.

• #33 Current and Novel Therapeutical Approaches of Classical Homocystinuria in Childhood With Special Focus on Enzyme Replacement Therapy, Liver-Directed Therapy and Gene Therapy | Bittmann | Journal of Clinical Medicine Research

  https://www.jocmr.org/index.php/JOCMR/article/view/4843/25893677

  The most prominent cause of morbidity and mortality is thromboembolism of the great and small arteries and veins. […] Current treatment options for classical HCU are very limited and often inefficient, partially due to a low patient compliance with very strict dietary regimen, especially in children. New therapeutical approaches are initiated and are in study to deal with the immense accumulation of homocysteine and to develop a healthy metabolic balance. […] Treatment with proteasome inhibitors and chaperones could play also an additive role in therapeutical potential due to their potential to bind and stabilize cystathionine beta synthase, resulting in increased total cellular levels after delivery to the lysosomes. […] Gene therapy could play an important role in the future to treat HCU in a curable aspect. But at all, gene therapeutical aspects are still in childhood shoes and should urgently further evaluated in detail.

• #34 Synlogic Announces SYNB1353 Achieves Proof of Mechanism for Treatment of Homocystinuria and Provides Business Update – BioSpace

  https://www.biospace.com/synlogic-announces-synb1353-achieves-proof-of-mechanism-for-treatment-of-homocystinuria-and-provides-business-update

  SYNB1353 is an orally administered, non-systemically absorbed drug candidate designed to consume methionine in the GI tract for the potential treatment of homocystinuria (HCU). […] The goal in treating HCU is to reduce and control severely elevated levels of total homocysteine (tHcy), thereby reducing risk of acute, potentially life-threatening blood clots and chronic, multisystem complications. A diet low in methionine, a precursor to homocysteine, is standard in HCU; SYNB1353 is engineered to metabolize methionine in the GI tract to prevent its absorption and conversion into homocysteine. […] HCU is a rare metabolic disease and inborn error of metabolism characterized by extreme levels of homocysteine and caused by an inherited deficiency in an enzyme known as cystathionine beta-synthase (CBS). When CBS is absent, homocysteine builds up in the blood and urine, putting patients at risk of multisystem complications, including acute thromboembolic events, optical damage from lens dislocation, skeletal deficiencies, and neurocognitive impairments. SYNB1353 is a novel, orally administered, non-systemically absorbed drug candidate designed to lower homocysteine levels in patients with HCU by consuming methionine, a precursor to homocysteine, in the gastrointestinal tract.

• #35 Homocystinuria (HCU): Symptoms, Causes & Treatment

  https://my.clevelandclinic.org/health/diseases/25160-homocystinuria

  Mutations in any of these genes prevent their corresponding enzymes from working properly, which can lead to a buildup of homocysteine. Researchers dont know why excess homocysteine causes the symptoms associated with homocystinuria. […] Homocystinuria treatment involves managing your symptoms by controlling the homocysteine levels in your blood. Treatment usually includes taking a vitamin B6 supplement. If you have vitamin B6-responsive classical homocystinuria, vitamin B6 supplementation may be enough to reduce and control your homocysteine levels.

• #36 Homocystinuria – UF Health

  https://ufhealth.org/conditions-and-treatments/homocystinuria

  Homocystinuria is a genetic disorder that affects the metabolism of the amino acid methionine. […] Homocystinuria is inherited in families as an autosomal recessive trait. This means that the child must inherit a non-working copy of the gene from each parent to be seriously affected. […] There is no cure for homocystinuria. About half of people with the disease respond to vitamin B6 (also known as pyridoxine). […] Neither a low-methionine diet nor medicine will improve existing intellectual disability. […] Although no cure exists for homocystinuria, vitamin B therapy can help about half of people affected by the condition. […] People whose blood homocysteine levels continue to rise are at increased risk for blood clots. Clots can cause serious medical problems and shorten lifespan.

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