NORD gratefully acknowledges Jan P. Kraus, PhD, Professor of Pediatrics, University of Colorado School of Medicine, for assistance in the preparation of this report.
Homocystinuria is a rare metabolic condition characterized by an excess of the compound homocystine in the urine. The condition may result from deficiency of any 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 (CBS). Infants who develop homocystinuria due to CBS deficiency (which is also known as classical homocystinuria) may fail to grow and 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; 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 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) therapy 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. 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 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. 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.
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.
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 homocystine in bodily fluids, reduced concentrations of cysteine, and the characteristic symptoms and physical findings seen in those with homocystinuria due to CBS deficiency. According to investigators, 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 homocystine, methionine, or homocysteine in the plasma or urine may be used to help confirm a diagnosis of homocystinuria. Tests are performed to determine the levels of the enzyme cystathionine beta-synthase in certain cells or tissues of the body.
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 specifically tests for methionine levels. 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 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.
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 homocystine 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 homocystine 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.
There is debate within the medical community as whether individuals who respond to pyridoxine therapy require additional treatment. Some physicians believe such individuals should also be placed on a diet low in protein and methionine or receive supplementary treatment with betaine (see below).
Individuals who are not diagnosed with homocystinuria due to CBS deficiency until childhood or adolescence or individuals who do not respond to therapy with pyridoxine require a restricted diet that is low in protein and methionine. Individuals on this diet require a methionine-free supplemental 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.
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 homocystine in the body. Betaine is often used an adjunct to individuals on a low protein, low methionine treatment. Betaine for oral solution (Cystadane®) has received marketing approval from the Food and Drug Administration (FDA) as a treatment for homocystinuria due to CBS deficiency and is manufactured by Rare Disease Therapeutics.
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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