-
Journal of Inherited Metabolic Disease Jan 2017Cystathionine beta-synthase (CBS) deficiency is a rare inherited disorder in the methionine catabolic pathway, in which the impaired synthesis of cystathionine leads to... (Review)
Review
Cystathionine beta-synthase (CBS) deficiency is a rare inherited disorder in the methionine catabolic pathway, in which the impaired synthesis of cystathionine leads to accumulation of homocysteine. Patients can present to many different specialists and diagnosis is often delayed. Severely affected patients usually present in childhood with ectopia lentis, learning difficulties and skeletal abnormalities. These patients generally require treatment with a low-methionine diet and/or betaine. In contrast, mildly affected patients are likely to present as adults with thromboembolism and to respond to treatment with pyridoxine. In this article, we present recommendations for the diagnosis and management of CBS deficiency, based on a systematic review of the literature. Unfortunately, the quality of the evidence is poor, as it often is for rare diseases. We strongly recommend measuring the plasma total homocysteine concentrations in any patient whose clinical features suggest the diagnosis. Our recommendations may help to standardise testing for pyridoxine responsiveness. Current evidence suggests that patients are unlikely to develop complications if the plasma total homocysteine concentration is maintained below 120 μmol/L. Nevertheless, we recommend keeping the concentration below 100 μmol/L because levels fluctuate and the complications associated with high levels are so serious.
Topics: Betaine; Cystathionine beta-Synthase; Homocysteine; Homocystinuria; Humans; Methionine; Pyridoxine
PubMed: 27778219
DOI: 10.1007/s10545-016-9979-0 -
Indian Journal of Ophthalmology Jul 2022Homocystinuria is a rare metabolic inborn disorder caused due to dysfunctional cystathionine β-synthase (CBS) enzyme activity, thus resulting in elevated levels of... (Review)
Review
Homocystinuria is a rare metabolic inborn disorder caused due to dysfunctional cystathionine β-synthase (CBS) enzyme activity, thus resulting in elevated levels of methionine and homocysteine in the blood and urine. The timely recognition of this rare metabolic disorder and prompt methionine-restricted diet are crucial in lessening the systemic consequences. The recalcitrant cases have a higher risk for cardiovascular diseases, neurodegenerative diseases, neural tube defects, and other severe clinical complications. This review aims to present the ophthalmic spectrum of homocystinuria and its molecular basis, the disease management, as well as the current and potential treatment approaches with a greater emphasis on preventive strategies.
Topics: Cystathionine beta-Synthase; Homocystinuria; Humans; Methionine
PubMed: 35791106
DOI: 10.4103/ijo.IJO_309_22 -
International Journal of Neonatal... Jan 2022Japan's Newborn Mass Screening (NBS) was started in 1977 for amino acid metabolism disorders (phenylketonuria (PKU), homocystinuria, maple syrup urine, histidineemia...
Japan's Newborn Mass Screening (NBS) was started in 1977 for amino acid metabolism disorders (phenylketonuria (PKU), homocystinuria, maple syrup urine, histidineemia (discontinued in 1993)) and galactosemia at the national level as a national project [...].
PubMed: 35076455
DOI: 10.3390/ijns8010003 -
The Cochrane Database of Systematic... Oct 2015Homocystinuria is a rare inherited disorder due to a deficiency in cystathionine beta synthase. Individuals with this condition appear normal at birth but develop... (Review)
Review
BACKGROUND
Homocystinuria is a rare inherited disorder due to a deficiency in cystathionine beta synthase. Individuals with this condition appear normal at birth but develop serious complications in childhood. Diagnosis and treatment started sufficiently early in life can effectively prevent or reduce the severity of these complications. This is an update of a previously published review.
OBJECTIVES
To determine if newborn population screening for the diagnosis of homocystinuria due to cystathionine beta synthase deficiency leads to clinical benefit compared to later clinical diagnosis.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register.Date of the most recent search of the Inborn Errors of Metabolism Register: 08 June 2015.
SELECTION CRITERIA
Randomised controlled trials and controlled clinical trials assessing the use of any neonatal screening test to diagnose infants with homocystinuria before the condition becomes clinically evident. Eligible studies compare a screened population versus a non-screened population.
DATA COLLECTION AND ANALYSIS
No studies were identified for inclusion in the review.
MAIN RESULTS
No studies were identified for inclusion in the review.
AUTHORS' CONCLUSIONS
We were unable to identify eligible studies for inclusion in this review and hence it is not possible to draw any conclusions based on controlled studies; however, we are aware of uncontrolled case-series which support the efficacy of newborn screening for homocystinuria and its early treatment. Any future randomised controlled trial would need to be both multicentre and long term in order to provide robust evidence for or against screening and to allow a cost effectiveness analysis to be undertaken.
Topics: Cystathionine beta-Synthase; Early Diagnosis; Homocystinuria; Humans; Infant, Newborn; Neonatal Screening
PubMed: 26423208
DOI: 10.1002/14651858.CD008840.pub4 -
Nature Communications Jan 2022Combined methylmalonic acidemia and homocystinuria (cblC) is the most common inborn error of intracellular cobalamin metabolism and due to mutations in Methylmalonic...
Combined methylmalonic acidemia and homocystinuria (cblC) is the most common inborn error of intracellular cobalamin metabolism and due to mutations in Methylmalonic Aciduria type C and Homocystinuria (MMACHC). Recently, mutations in the transcriptional regulators HCFC1 and RONIN (THAP11) were shown to result in cellular phenocopies of cblC. Since HCFC1/RONIN jointly regulate MMACHC, patients with mutations in these factors suffer from reduced MMACHC expression and exhibit a cblC-like disease. However, additional de-regulated genes and the resulting pathophysiology is unknown. Therefore, we have generated mouse models of this disease. In addition to exhibiting loss of Mmachc, metabolic perturbations, and developmental defects previously observed in cblC, we uncovered reduced expression of target genes that encode ribosome protein subunits. We also identified specific phenotypes that we ascribe to deregulation of ribosome biogenesis impacting normal translation during development. These findings identify HCFC1/RONIN as transcriptional regulators of ribosome biogenesis during development and their mutation results in complex syndromes exhibiting aspects of both cblC and ribosomopathies.
Topics: Amino Acid Metabolism, Inborn Errors; Animals; Disease Models, Animal; Embryo, Mammalian; Female; Gene Expression Regulation, Developmental; Homocystinuria; Host Cell Factor C1; Humans; Male; Mice; Mice, Knockout; Mutation; Organelle Biogenesis; Oxidoreductases; Protein Biosynthesis; Protein Subunits; Repressor Proteins; Ribosomal Proteins; Ribosomes; Vitamin B 12; Vitamin B 12 Deficiency
PubMed: 35013307
DOI: 10.1038/s41467-021-27759-7 -
British Journal of Pharmacology Feb 2023Cystathionine beta-synthase (CBS)-deficient homocystinuria (HCU) is the most common inborn error of sulfur amino acid metabolism. The pyridoxine non-responsive form of... (Review)
Review
Cystathionine beta-synthase (CBS)-deficient homocystinuria (HCU) is the most common inborn error of sulfur amino acid metabolism. The pyridoxine non-responsive form of the disease manifests itself by massively increasing plasma and tissue concentrations of homocysteine, a toxic intermediate of methionine metabolism that is thought to be the major cause of clinical complications including skeletal deformities, connective tissue defects, thromboembolism and cognitive impairment. The current standard of care involves significant dietary interventions that, despite being effective, often adversely affect quality of life of HCU patients, leading to poor adherence to therapy and inadequate biochemical control with clinical complications. In recent years, the unmet need for better therapeutic options has resulted in development of novel enzyme and gene therapies and exploration of pharmacological approaches to rescue CBS folding defects caused by missense pathogenic mutations. Here, we review scientific evidence and current state of affairs in development of recent approaches to treat HCU.
Topics: Humans; Homocystinuria; Cystathionine beta-Synthase; Quality of Life; Thromboembolism; Mutation, Missense
PubMed: 36417581
DOI: 10.1111/bph.15991 -
Proceedings of the Royal Society of... Nov 1963
Topics: Amino Acid Metabolism, Inborn Errors; Child; Homocystinuria; Humans; Intellectual Disability; Kidney; Renal Aminoacidurias; Urologic Diseases
PubMed: 14084422
DOI: No ID Found -
Genes Mar 2020Homocystinuria is an inborn error of metabolism due to the deficiency in cystathionine beta-synthase (CBS) enzyme activity. It leads to the elevation of both... (Review)
Review
Homocystinuria is an inborn error of metabolism due to the deficiency in cystathionine beta-synthase (CBS) enzyme activity. It leads to the elevation of both homocysteine and methionine levels in the blood and urine. Consequently, this build-up could lead to several complications such as nearsightedness, dislocated eye lenses, a variety of psychiatric and behavioral disorders, as well as vascular system complications. The prevalence of homocystinuria is around 1/200,000 births worldwide. However, its prevalence in the Gulf region, notably Qatar, is exceptionally high and reached 1:1800. To date, more than 191 pathogenic mutations have been documented. The majority of these mutations were identified in Caucasians of European ancestry, whereas only a few mutations from African-Americans or Asians were reported. Approximately 87% of all 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 early detection of homocystinuria along with low protein and methionine-restricted diet is the best treatment approach for all types of homocystinuria patients. Yet, less than 50% of affected individuals show a significant reduction in plasma homocysteine levels after treatment. Patients who fail to lower the elevated homocysteine levels, through high protein-restricted diet or by B6 and folic acid supplements, are at higher risk for cardiovascular diseases, neurodegenerative diseases, neural tube defects, and other severe clinical complications. This review aims to examine the mutations spectrum of the gene, the disease management, as well as the current and potential treatment approaches with a greater emphasis on studies reported in the Middle East and North Africa (MENA) region.
Topics: Cystathionine beta-Synthase; Genetic Testing; Homocystinuria; Humans; Mutation
PubMed: 32245022
DOI: 10.3390/genes11030330