Última actualización:
10/2/2024
Años publicados: 1987, 1988, 1990, 1994, 1995, 1996, 1997, 1998, 1999, 2000, 2009, 2012, 2015, 2018, 2021
NORD gratefully acknowledges Kimberly Chapman, MD, PhD, Medical Geneticist, Children’s National Medical Center and Jan P. Kraus, PhD (deceased), Professor of Pediatrics, University of Colorado School of Medicine, for assistance in the preparation of this report.
Cystathionine Beta-Synthase (CBS) deficiency, more commonly referred to as homocystinuria is a rare metabolic condition characterized by an excess of the compound homocysteine in the urine and blood. CBS deficiency is one of the conditions which often result from deficiency of any one of several enzymes involved in the conversion of the essential amino acid methionine to another amino acid (cysteine)–or, less commonly, impaired conversion of the compound homocysteine to methionine. Enzymes are proteins that accelerate the rate of chemical reactions in the body. Certain amino acids, which are the chemical building blocks of proteins, are essential for proper growth and development. In most cases, homocystinuria is caused by reduced activity of an enzyme known as cystathionine beta-synthase and this results in CBS deficiency. Infants who develop homocystinuria due to CBS deficiency (which is also known as classical homocystinuria) may fail to grow, or grow longer too fast, often have difficulty with gain weight at the expected rate (failure to thrive) and have developmental delays.
By approximately age three, additional, more specific symptoms and findings may become apparent. These may include partial dislocation (subluxation) of the lens of the eyes (ectopia lentis), associated «quivering» (iridodonesis) of the colored region of the eyes (iris), severe nearsightedness (myopia), and other eye (ocular) abnormalities. Although intelligence may be normal in some cases, many children may be affected by progressive intellectual disability. In addition, some may develop psychiatric disturbances and/or episodes of uncontrolled electrical activity in the brain (seizures). Affected individuals also tend to be thin with unusually tall stature for their family; long, slender fingers and toes (arachnodactyly); and elongated arms and legs («marfanoid» features). In addition, affected individuals may be at risk for the development of blood clots that can become lodged within certain large and small blood vessels (thromboembolisms), potentially leading to life-threatening complications.
Homocystinuria due to deficiency of CBS deficiency is inherited in an autosomal recessive pattern. The disorder is caused by changes (mutations) of a gene that regulates the production of the CBS enzyme. The CBS enzyme requires the vitamin pyridoxine (also known as vitamin B6) and in some people this vitamin in their diet of supplements may delay diagnosis by making it harder to identify clinically and thus test for it.
The symptoms associated with homocystinuria due to CBS deficiency are highly variable. Some affected individuals may have only very mild signs of the disorder; others may have many different symptoms including some potentially life-threatening complications. Individuals can be separated into two distinct groups: those who respond to therapy with pyridoxine (vitamin B6) and those who do not. Generally, individuals who respond to pyridoxine therapy have a milder form of the disorder, most likely because of residual activity of the CBS enzyme, but this does not mean that they will not have life-threatening complications. In addition, the presence and specific location of blood clots also determines the severity of associated symptoms in each individual.
Infants with homocystinuria due to CBS deficiency are normal at birth, but, if left untreated, will slowly develop the various symptoms associated with the disorder. Prompt detection and treatment of homocystinuria due to CBS deficiency is important in preventing or reducing the symptoms associated with the disorder.
Homocystinuria due to CBS deficiency can potentially affect many different organ systems of the body. The four organ systems most commonly involved are the eyes, central nervous system, skeleton and the network of vessels that carry blood and other fluids throughout the body (vascular [circulatory] system).
In some cases, the abnormalities affecting the eyes may be the first noticed outward sign of homocystinuria due to CBS-deficiency. Many individuals develop displacement of the lenses of the eyes (ectopia lentis) away from the center of the eyeball. Affected individuals also usually develop severe nearsightedness (myopia) and quivering of the colored portion of the eye (iridodonesis). Ectopia lentis and myopia usually develop after the first year of life, often by 10 years of age.
Additional abnormalities of the eyes have been reported in individuals with homocystinuria due to CBS deficiency. These abnormalities occur less frequently than ectopia lentis and myopia. Such abnormalities include clouding of the lenses of the eyes (cataracts), degeneration of the nerve (optic nerve) that relays signals from the eye to the brain (optic atrophy), and glaucoma, a condition in which increased pressure within the eye causes characteristic damage to the optic nerve. Some individuals may have separation of the thin layer of nerve cells (retina) that lines the back of the eyes from its underlying support tissue (retinal detachment). The retina normally senses light and converts it into nerve signals, which are then relayed to the brain through the optic nerve. Retinal detachment may cause blurred vision or the appearance of “floaters” in the field of vision.
In some patients, delays in attaining developmental milestones (developmental delays) may be the first noticeable symptom in children with homocystinuria due to CBS deficiency. Affected children may be slow in sitting, standing, walking and speaking or other milestones. Some children have normal intelligence; others develop varying degrees of intellectual disability. Treatment early (in the first few months and at least by 3 years) can help preserve intellect. Approximately 20 percent of children with homocystinuria due to CBS deficiency develop seizures. Some affected children also exhibit psychiatric issues including depression, anxiety, obsessive-compulsive disorder, and other behavioral or personality disorders. These complications may be more common in adults with homocystinuria.
Individuals with homocystinuria due to CBS deficiency also develop a variety of skeletal abnormalities. Skeletal abnormalities are usually not present at birth and may not become detectable until later during childhood. Common findings include thinning and lengthening of the long bones (dolichostenomelia), knees that are bent inward so that they touch when the legs are straight (“knock knees” or genu valgum), a highly arched foot (pes cavus), abnormal sideways curvature of the spine (scoliosis), or an abnormally protruding chest (pectus carinatum) or an abnormally sunken chest (pectus excavatum). Many individuals with homocystinuria due to CBS deficiency are at a greater risk than the general population of developing osteoporosis. Osteoporosis is condition characterized by a general loss of bone density that can lead to an increased risk of fractures.
A serious complication associated with homocystinuria due to CBS deficiency is an increased risk of developing clots (thrombi) in blood vessels that can break off and become lodged in another vessel (thromboembolism). Blood clots can occur at any age. Specific symptoms associated with a thromboembolic event depend on the exact site of the clot and the specific blood vessels and organs that are affected. Thromboemboli can cause serious, life-threatening complications including strokes and blood clots in the lungs (pulmonary embolisms).
Although less common, several additional findings have been reported in individuals with homocystinuria due to CBS deficiency including extremely fine, fragile skin, discoloration of the skin (hypopigmentation), rashes on the cheeks (malar flushing) and abnormally thin skin. Some individuals may develop fatty changes in the liver, protrusion of part of the intestines through a tear in the abdominal wall (inguinal hernia) or inflammation of the pancreas (pancreatitis), a small organ located behind the stomach that secretes enzymes that travel to the intestines and aid in digestion. Abnormal front-to-back curvature of the spine (kyphosis) and a collapsed lung (spontaneous pneumothorax) have also been reported in individuals with homocystinuria due to CBS deficiency.
Homocystinuria due to CBS deficiency is caused by changes (mutations) of a gene that regulates the production of the enzyme cystathionine beta-synthase. Mutations of the CBS gene may result in reduced activity of the cystathionine beta-synthase enzyme, which is involved in the conversion of the essential amino acid methionine to another amino acid (cysteine). Deficiency of the enzyme leads to increased levels of methionine and the compound homocysteine in bodily fluids, reduced concentrations of cysteine, and the characteristic symptoms and physical findings seen in those with homocystinuria due to CBS deficiency. More than 160 different mutations of the CBS gene have been identified in individuals with the disorder, with many affecting only one or a small number of affected families (kindreds).
This mutation is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Homocystinuria due to CBS deficiency is a rare disorder that affects males and females in equal numbers. Population studies suggest that the worldwide frequency of homocystinuria in the general population is one in 344,000. In individual countries, the prevalence may be higher. In Ireland the prevalence has been estimated to be 1 in 65,000. In Germany, the prevalence has been estimated at 1 in 17,500. Several studies in four European countries, suggested that the prevalence of homocystinuria due to CBS deficiency is as high as 1 in 6,400 to 1 in 20,000.
Homocystinuria was first described in the medical literature as a distinct disorder in 1962.
A diagnosis of homocystinuria due to CBS deficiency may be suspected based upon identification of characteristic findings. A diagnosis may be confirmed by a thorough clinical evaluation, a detailed patient history and a variety of specialized tests. Tests that can detect elevated levels of homocysteine, methionine, or homocysteine in the plasma or urine may be used to help confirm a diagnosis of homocystinuria. Usually individuals will undergo genetic testing looking for changes in both copies of the CBS gene to confirm their diagnosis. Historically and occasionally now, tests can be performed to determine the level of enzyme function in certain cells of the body to confirm CBS deficiency.
Homocystinuria due to CBS deficiency may also be diagnosed through newborn screening programs. Most states have newborn screening programs that test newborns for various metabolic disorders. However, most states do not test for all the disorders that can be detected through screening and specific states may not test for homocystinuria. Newborn screening for homocystinuria due to CBS deficiency typically measures methionine levels and sometimes these are not elevated enough to be determined to be abnormal immediately after birth even if the infant is CBS deficient. Most children diagnosed through newborn screening have the pyridoxine-unresponsive form of homocystinuria due to CBS deficiency. Researchers believe that newborn screening fails to detect many of the infants with the pyridoxine-responsive form of the disorder because these infants do not have elevated levels of methionine when the newborn screening sample is taken shortly after birth.
Treatment
The treatment of homocystinuria due to CBS deficiency is directed toward preventing or reducing the symptoms commonly associated with the disorder by controlling the levels of homocysteine in the fluid portion of the blood (plasma). Treatment may include therapy with pyridoxine (vitamin B6), a diet that restricts the intake of protein and methionine, betaine therapy, and supplementation with folate (vitamin B9) or cobalamin (vitamin B12).
Affected individuals may first undergo a pyridoxine response assessment. In approximately 50 percent of individuals, pyridoxine therapy is effective in reducing the levels of homocysteine and methionine in the body. In order to determine whether an individual is responsive to pyridoxine therapy, folate levels must be normal and some individuals may require folate supplementation.
The medical community has identified some individuals who do not respond to pyridoxine therapy completely with normalization of measures for homocystinuria. The extent to which these individuals respond to pyridoxine, will dictate whether they can be treated with pyridoxine and perhaps betaine (a medication, see below) or whether they will also need a diet low in protein and methionine as well.
Individuals who are not diagnosed with homocystinuria due to CBS deficiency until childhood, adolescence or adulthood and do not respond to therapy with pyridoxine still may require a restricted diet that is low in protein and methionine although this can be hard to maintain due to differences in taste. Individuals on this diet require methionine-free supplemental metabolic foods usually in the form of a formula to provide them with other essential amino acids. A low protein, low methionine diet when started during infancy before any complications have developed has been effective in preventing or delaying the onset of symptoms.
A low protein, low methionine diet may be combined with cysteine supplementation. Cysteine is an amino acid that is often low in individuals with homocystinuria due to CBS deficiency. When methionine is broken down (metabolized) it produces cystine. Since individuals with homocystinuria cannot properly breakdown methionine, this may cause low levels of cysteine in some individuals, however good control of homocysteine levels and use of metabolic foods (i.e. formulas) often attenuates the need for supplementation.
When individuals who are not responsive to pyridoxine therapy are diagnosed later during childhood or adolescence, maintaining the dietary restrictions often proves difficult. The diet is usually not well-tolerated when it is begun in individuals diagnosed in childhood or adolescence.
Individuals with homocystinuria due to CBS deficiency, especially those who do not respond to pyridoxine therapy may be treated with betaine, which can be used to lower the levels of homocysteine in the body. Betaine is often used an adjunct to individuals on a low protein, low methionine treatment. Betaine for oral solution (Cystadane) is approved by the U.S. Food and Drug Administration (FDA) as a treatment for homocystinuria due to CBS deficiency.
Specific symptoms of homocystinuria due to CBS deficiency are treated as appropriate. For example, dislocation of the lenses of the eyes (ectopia lentis) or certain skeletal malformations may be treated surgically. However, affected individuals who undergo any surgery should receive particular care because homocystinuria due to CBS deficiency may increase the risk of post-surgical thromboembolic complications.
Genetic counseling is recommended for affected individuals and their families.
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For information about clinical trials sponsored by private sources, contact:
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For information about clinical trials conducted in Europe, contact:
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JOURNAL ARTICLES
Morris AAM, Kožich V et al Guidelines for diagnosis and management of cystathionine beta-synthase deficiency. J Inherit Metab Dis. 2017; 40(1):49-74.
Lee PJ, Briddon A. A rationale for cystine supplementation in severe homocystinuria. J Inherit J Metab. 2007;30:35-38.
Lawson-Yuen A, Levy HL. The use of betaine in the treatment of elevated homocysteine. Mol Genet Metab. 2006;88:201-207.
Yap S. Classical homocystinuria: vascular risk and its prevention. J Inherit Metab Dis. 2003;26:259-65.
Yap S, Boers GH, Wilcken B, et al. Vascular outcome in patients with homocystinuria due to cystathionine beta-synthase deficiency treated chronically: a multicenter observational study. Arter Throm Vas Bio. 2001;21:2080-2085.
Mudd SH, Finkelstein JD, Refsum H, et al. Homocysteine and its disulfide derivatives: a suggested consensus terminology. Arterioscler Thromb Vasc Biol. 2000;20:1704, 1706.
Abbott MH, Folstein SE, Abbey H, Pyeritz RE. Psychiatric manifestations of homocystinuria due to cystathionine beta-synthase deficiency: prevalence, natural history, and relationship to neurologic impairment and vitamin B6-responsiveness. Am J Med Genet. 1987;26:956-969.
Mudd SH, Skovby F, Levy HL, et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet. 1985;37:1, 31.
INTERNET
European Network and Registry for Homocystinurias and Methylation Defects (E-hod) https://e-hod.org/patients-and-families/information-materials/ Accessed March 30, 2021.
Sacharow SJ, Picker JD, Levy HL. Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency. 2004 Jan 15 [Updated 2017 May 18]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1524/ Accessed March 30, 2021.
Baloghova J, Schwartz RA, Baranova Z. Dermatologic Manifestations of Homocystinuria. Medscape. Updated: Jun 21, 2018.
https://emedicine.medscape.com/article/1115062-overview Accessed March 30, 2021.
Kraus JP, Kozich V, Janosik, M. CBS Main Page. Last update on 3/6/2012. https://cbs.lf1.cuni.cz/cbsdata/cbsmain.htm Accessed March 30, 2021.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Homocystinuria Due to Cystathionine Beta-Synthase Deficiency. Entry No: 236200. Last Edited 08/03/2016. Available at: https://omim.org/entry/236200 Accessed March 30, 2021.
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The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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