The term homocystinuria is actually a description of a biochemical abnormality, as opposed to the name of a particular disease, although many refer to homocystinuria as a disease. Homocystinuria refers to elevated levels of homocysteine in the urine. This can be caused by different biochemical abnormalities and in fact there are at least eight different gene changes that are known to cause excretion of too much homocysteine in the urine. The best known and most common cause of homocystinuria is the lack of cystathionine b-synthase. For the purpose of this entry we will be referring to "classical homocystinuria" that is caused by cystathionine b-synthase deficiency (CBS deficiency).
Description
In Northern Ireland in the early 1960s, homocystinuria was described in individuals who were mentally retarded. Soon after that, it was shown that the cause of the homocystinuria was a deficiency of the enzyme cystathionine b-synthase. This condition is an inborn error of metabolism, meaning that the cause for this condition is present from birth and it affects metabolism.
Metabolism is the sum of all of the chemical processes that take place in the body. Metabolism includes both construction (anabolism) and break down (catabolism) of important components. For example, amino acids are the building blocks for proteins and are converted to proteins through many steps in the process of anabolism. In contrast, proteins can also be broken down into amino acids through many steps in the process of catabolism. These processes require multiple steps that involve different substances called enzymes. These enzymes are proteins that temporarily combine with reactants and in the process, allow these chemical processes to occur quickly. Since practically all of the reactions in the body use enzymes, they are essential for life. At any point along the way, if an enzyme is missing, the particular process that requires that enzyme would not be able to be completed as usual. Such a situation can lead to disease.
Homocysteine is involved with the catabolism of methionine. Methionine is an essential amino acid. Amino acids are the building blocks of proteins. Over 100 amino acids are found in nature, but only 22 are found in humans. Of these 22 amino acids, eight are essential for human life, including methionine. Methionine comes from dietary protein. Generally, the amount of methionine that is consumed is more than the body needs. Excess methionine is converted to homocysteine, which is then metabolized into cystathionine; cystathionine is then converted to cysteine. The cysteine is excreted in the urine. Each step along this pathway is carried out by a specific enzyme and that enzyme may even require help from vitamin co-factors to be able to complete the job. For example, the conversion of homocysteine to cystathionine by cystathionine b-synthase requires vitamin B6 (pyridoxine). If cystathionine b-synthase is missing, then homocysteine cannot be broken down into cystathionine and cysteine, and instead, homocysteine accumulates and the elevated levels of homocysteine and methionine can be found in the blood. Also, decreased levels of cysteine can be found in the blood. Elevated levels of homocysteine lead to a disease state that, if untreated, affects multiple systems, including the central nervous system, the eyes, the skeleton, and the vascular system.
Genetic profile
Classical homocystinuria or cystathionine b-synthase (CBS) deficiency is an autosomal recessive condition. This means that in order to have the condition, an individual must inherit one copy of the gene for CBS deficiency from each parent. An individual who has only one copy of the gene is called a carrier for the condition. In most cases of autosomal recessive inheritance a carrier for a condition does not have any signs, symptoms, or effects of the condition. This is not necessarily the case with CBS deficiency. Individuals who are carriers for CBS deficiency may have levels of homocysteine that are elevated enough to increase the risk for thromboembolic events. So, although carriers may not exhibit obvious physical signs or symptoms of the condition, they may have clinical effects of elevated levels of homocysteine, such as vascular or cardiovascular disease. A carrier for CBS deficiency can have vascular complications, especially if they are also carriers for other clotting disorders such as factor V Leiden thrombophilia.
When two parents are carriers for CBS deficiency, there is a one in four or 25% chance, with each pregnancy, for having a child with CBS deficiency. They have a one in two or 50% chance for having a child who is a carrier for the condition and a one in four or 25% chance for having a child who is neither affected nor a carrier for CBS deficiency.
The gene for CBS has been mapped to the long arm of chromosome 21, specifically at 21q22.3. Approximately 100 different disease-associated gene changes or alterations of the CBS gene have been identified. The two most frequently encountered gene changes are 1278T and G307S. G307S is the most common cause of CBS deficiency in Irish patients and the 1278T gene is the most common cause of CBS deficiency in Italian patients.
Demographics
The worldwide frequency of individuals with CBS deficiency who are identified through newborn screening and clinical detection is approximately one in 350,000; however, newborn screening may be missing half of affected patients and thus the worldwide incidence may be as high as one in 180,000. One study showed that by lowering the cutoff level of methionine from 2 mg per deciliter to 1 mg per deciliter in newborn screening, detection of the deficiency increased from 1 in 275,000 to 1 in 157,000. The incidence of CBS deficiency in the United States population is 1 in 58,000; in the Irish population it is estimated to be 1 in 65,000; in the Italian population it is 1 in 55,000 and in the Japanese population it is 1 in 889,000. CBS deficiency has been seen in persons of many different ethnic origins living in the United States.
Signs and symptoms
Individuals who have CBS deficiency tend to be tall and thin with thinning and lengthening of the bones. They tend to have a long, narrow face and high arched palate (roof of the mouth). The thinning and lengthening of the long bones causes individuals to be tall and thin by the time they reach late childhood. Their fingers tend to be long and thin as well (referred to as arachnodactyly). They can have curvature of the spine, called scoliosis. Their chest can be sunken in (pectus excavatum) or it may protrude out (pectus carinatum). Osteoporosis may occur. Also, they tend to have stiff joints. CBS deficiency affects the eyes, causing dislocated lenses and nearsightedness (myopia). Untreated individuals or those individuals who do not respond to treatment develop mental retardation or learning disabilities. Affected individuals may also develop psychiatric problems. These psychiatric problems may include depression, chronic behavior problems, chronic obsessive-compulsive disorder, and personality disorders. The most frequent cause of death associated with CBS deficiency is blood clots that form in veins and arteries. These are known as thromboembolisms, and include deep vein thrombosis (blood clots that form in the deep veins of the legs, etc.), pulmonary embolus (blood clots that form in the lungs), and strokes. Thromboembolism can occur even in childhood. When thromboembolism does occur in childhood, CBS deficiency should always be considered as a cause for the thromboembolic events. These thromboembolic events can occur in any part of the body. Lastly, another complication of CBS deficiency is severe premature arteriosclerosis (hardening of the arteries).
Diagnosis
Approximately 50% of individuals who have CBS deficiency are diagnosed by newborn screening because they have an elevated level of methionine in their blood. The reason for performing newborn screening is so that infants affected with genetic disorders can be identified early enough to be treated. The screening is done by collecting blood from a pin-prick on the baby's heel prior to leaving the hospital, but at least 24 hours after birth. For CBS deficiency, the screening test checks for elevated levels of methionine. If the levels are elevated then follow-up testing to verify the diagnosis is performed. There are other disorders of methionine metabolism, and follow-up testing determines the underlying cause of the positive newborn screen.
If not identified at newborn screening, diagnosis is made by identifying low levels of cysteine in blood and urine. Measurements of the amount of methionine and homocysteine produced by cultured blood cells (lymphoblasts) or cultured skin cells (fibroblasts) also can confirm the diagnosis of CBS deficiency.
DNA testing is available for families in which a gene alteration is identified. Potentially, this makes prenatal diagnosis by chorionic villus sampling (CVS) and amniocentesis available for families who have had a previously affected child and in which two identifiable gene alterations for CBS deficiency have been detected. Prenatal diagnosis is also possible by measuring the amount of enzyme activity in cultured cells grown from amniotic fluid.
CBS deficiency has several features in common with Marfan syndrome, including the tall, thin build with long limbs and long, thin fingers (arachnodactyly), a sunken-in chest (pectus excavatum), and dislocated lenses. The dislocated lens in Marfan syndrome tends to be dislocated upward; the tendency for the lens dislocation is to be downward in CBS deficiency. Also, individuals who have Marfan syndrome tend to have lens dislocation from birth (congenital) whereas individuals who have CBS deficiency have not been identified to have lens dislocation before 2 years of age.
Treatment and management
The first choice of therapy for patients with CBS deficiency is administration of pyridoxine (vitamin B6). Vitamin B6 is the cofactor for the cystathionine b-synthase reaction. Potentially, some individuals who have CBS deficiency are not missing the enzyme, but rather have an enzyme that is unable to perform its job. The addition of pyridoxine can help to push the reaction along and thus help to reduce the levels of homocysteine and methionine in the blood. Information suggests that approximately 50% of patients with CBS deficiency respond to high doses of pyridoxine (pyridoxine responsive) and show a significant reduction in levels of homocysteine in the blood. Patients who do not respond to pyridoxine treatment (pyridoxine non-responsive) tend to be more severely affected than the patients who do respond. Those non-responding patients are treated with combinations of folic acid, hydroxycobalamin, and betaine, which stimulate the conversion of homocysteine back to methionine. The reason that the addition of folic acid can help is because within the methylene H4-folate (MTHFR) molecule, there is a molecule known as flavin adenine dinucleotide, or FAD. The FAD molecule binds to the MTHFR molecule and helps with the conversion of homocysteine to methionine. Increased levels of folates help bind FAD more tightly to MTHFR, protect the enzyme against heat inactivation, and allow the homocysteine to methionine conversion pathway to proceed. Betaine and cobalamin also help in the conversion of homocysteine to methionine by acting as cofactors. The rationale behind this method of treatment is that although the methionine levels are raised, the net drop in homocysteine is beneficial as it appears that the elevated levels of homocysteine are what cause ectopia lentis, osteoporosis, mental deficiency, and thromboembolic events.
It appears that the addition of dietary betaine in B6-responsive patients is also beneficial. Homocysteine that is not metabolized to cysteine is converted back to methionine in a reaction that uses betaine, so the addition of betaine may help to make this reaction occur and thus reduce the levels of homocysteine.
Other treatments include protein restriction, specifically a low methionine diet with the addition of extra cysteine. Dietary treatment includes avoidance of all high protein foods throughout life, with the use of a nutritional supplement. Special formulas for infants are available. The reasoning behind this is to reduce the methionine and homocysteine levels that accumulate and supplement the low levels of cysteine.
The occurrence of clinically apparent thromboembolism depends upon the age of the affected individual and whether or not he/she responds to pyridoxine treatment. In one study, untreated pyridoxine-responsive patients were at little risk for a thromboembolic event until age 12. After age 12, the risk for thromboembolism increased. By age 20, patients who would have been responsive to pyridoxine had a 25% cumulative risk for a thromboembolic event. In comparison, individuals with CBS deficiency who were untreated and not responsive to pyridoxine treatment had a similar cumulative risk for a thromboembolic event by age 15.
In reference to the two common CBS gene alterations, CBS deficiency caused by the 1278T gene change is pyridoxine responsive. CBS deficiency caused by the G307S gene tends to be pyridoxine non-responsive; however this is not always the case as some individuals with the G307S gene change are pyridoxine responsive.
Very little is known about the risks to an unborn child of a mother with pyridoxine non-responsive CBS deficiency. There have been numerous reports of healthy children born to women and men who have pyridoxine responsive CBS deficiency, however only two reports of children born to pyridoxine non-responsive women have been reported and one had multiple birth defects that may have been related to the mother's condition. Potentially, the mother's elevated levels of homocysteine can cause problems for a developing baby. This could be similar to the process by which infants of mothers who have phenylketonuria are affected by the elevated levels of phenylalanine if their mothers are not being treated with dietary restriction during pregnancy.
Prognosis
Untreated CBS deficiency leads to mental retardation, lens dislocation, and a decreased life expectancy because of complications associated with blood clots. If untreated from early infancy, approximately 20% of affected patients will have seizures. If treated from birth, prevention or long term delay of the complications of CBS deficiency can be expected.
BOOKS
Scriver, C.R., A.L. Beaudet, W.S. Sly, and D. Valle, eds. The Metabolic Basis of Inherited Disease. 6th ed. New York: McGraw-Hill Medical Publishing Division, 1989.
ORGANIZATIONS
National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.
