Homocystinuria (Homocystinuria) - Genes CBS, MTHFR, MTR, MTRR and MMADHC
Homocystinuria is an inherited disease in which the body can not process amino acids properly. There are multiple forms of homocystinuria, which are distinguished by their signs and symptoms, as well as its genetic cause. The most common form of homocystinuria is characterized by myopia lens dislocation, increased risk of abnormal blood clots and osteoporosis or other skeletal abnormalities. Some affected individuals also have developmental delays and learning disabilities. Less common forms of homocystinuria can cause mental retardation, growth retardation, seizures, problems with movement and megaloblastic anemia.
In general, the signs and symptoms of the disease develop in the first year of life, although some people with a mild form of the disease may not show signs or symptoms until later in childhood or adulthood.
This process is due to mutations in CBS (cystathionine-beta-synthase), MTHFR (methylenetetrahydrofolate reductase -NAD-PH) genes -, MTR (5-methyltetrahydrofolate-homocysteine methyltransferase), MTRR (5-methyltetrahydrofolate-homocysteine methyltransferase reductase)) and MMADHC (methylmalonic aciduria and homocystinuria, cblD type).
CBS (cystathionine-beta-synthase) gene, located on the long arm of chromosome 21 (21q22.3), encodes an enzyme called cystathionine beta synthase. This enzyme acts in a chemical pathway that is responsible, through the use of vitamin B6, to convert homocysteine and serine amino acids to a molecule called cystathionine. Subsequently, another enzyme converts cystathionine to the amino acid cysteine, which is used to form proteins or decomposed and excreted in urine. In addition, other amino acids, including methionine, are produced in this way. They have identified more than 150 mutations in the CBS gene in people with homocystinuria. Mutations in the CBS gene lead to the most common form of homocystinuria. Most of these mutations change individual amino acids in the beta-synthase cystathionine. The most frequent mutation replaces the amino acid threonine by isoleucine at amino acid position 278 of the enzyme (Ile278Thr or I278T). Another frequent mutation is the most common cause of homocystinuria in the Irish population, replacing the amino acid glycine by serine at amino acid position 307 (Gly307Ser or G307S). These mutations alter the normal function of cystathionine beta synthase. Consequently, homocysteine and other potentially toxic compounds accumulate in the blood, and homocysteine excreted in urine. It is unclear how excess homocysteine leads to the signs and symptoms of homocystinuria.
MTHFR (methylenetetrahydrofolate reductase -NAD-PH) gene -), located on the short arm of chromosome 1 (1p36.3), methylenetetrahydrofolate reductase enzyme encoded. This enzyme plays a role in processing of amino acids, and is important for a chemical reaction involving forms of folic acid (vitamin B9) vitamin. Specifically, this enzyme converts 5,10-methylenetetrahydrofolate molecule in a molecule of 5- methyltetrahydrofolate. This reaction is required for multi - step process that converts the amino acid homocysteine to methionine. The body uses methionine to synthesize proteins and other important compounds. They have identified at least 40 mutations in the MTHFR gene in people with homocystinuria. Most of these mutations change individual amino acids in methylenetetrahydrofolate reductase. These changes alter the function of the enzyme and some, cause the enzyme is inactive. Other mutations lead to the codification of an abnormally small version of the enzyme nonfunctional. Without methylenetetrahydrofolate reductase functional, homocysteine can not be converted to methionine. Consequently, homocysteine accumulates in the bloodstream, and the amount of methionine is reduced. Some excesses of homocysteine are excreted in the urine. It is unclear how altered levels of homocysteine and methionine lead to health problems associated with homocystinuria.
MTR (5-methyltetrahydrofolate-homocysteine methyltransferase) gene, located on the long arm of chromosome 1 (1q43), encoding methionine synthase enzyme. This enzyme plays a role in processing amino acids. Specifically, the methionine synthase performs chemical reaction that converts the amino acid homocysteine to methionine. To function properly, the methionine synthase requires methylcobalamin (B12) and methionine synthase reductase enzyme, which is encoded from MTRR gene. They have identified more than 20 mutations in the MTR gene in people with homocystinuria. Many of these mutations result in coding an abnormally small version, non - functional methionine synthase. Other mutations change individual amino acids in the enzyme. One of the most frequent mutations replaces the amino acid proline in the amino acid leucine position 1173 (Pro1173Leu or P1173L), resulting in an enzyme with reduced function. Methionine synthase functional, homocysteine can not be converted to methionine. Consequently, homocysteine accumulates in the bloodstream, and the amount of methionine is reduced. Some excesses of homocysteine are excreted in the urine. It is unclear how altered levels of homocysteine and methionine lead to problems associated with homocystinuria.
MTRR (5-methyltetrahydrofolate-homocysteine methyltransferase reductase) gene, located on the short arm of chromosome 5 (5p15.31), encodes the enzyme methionine synthase reductase. This enzyme is necessary for the proper functioning of methionine synthase enzyme. The methionine synthase converts the amino acid homocysteine to methionine. After a period of being active, methionine synthase is deactivated. Methionine synthase reductase methionine synthase reaction so that the enzyme can continue producendo methionine. They have identified at least 20 mutations in the MTRR gene in people with homocystinuria. Some of these mutations change the individual amino acids methionine synthase reductase in. Other mutations result in an abnormally small version of the enzyme nonfunctional. All these mutations prevent the enzyme to function normally. Methionine synthase reductase, methionine synthase can not convert homocysteine to methionine. Consequently, homocysteine accumulates in the bloodstream, and the amount of methionine is reduced. Some excesses of homocysteine are excreted in the urine. It is unclear how altered levels of homocysteine and methionine lead to problems associated with homocystinuria.
The MMADHC gene (methylmalonic aciduria and homocystinuria, cblD type), located on the long arm of chromosome 2 (2q23.2), encoding a protein that helps convert vitamin B12 (cobalamin) in one of two molecules, adenosylcobalamin (AdoCbl) or methylcobalamin (MeCbl). On the one hand, AdoCbl is necessary for the normal function of methylmalonyl-CoA mutase enzyme. This helps break down certain amino acids, lipids and cholesterol. AdoCbl is a cofactor that helps methylmalonyl-CoA mutase to carry out its function. Furthermore, MeCbl is also a cofactor for methionine synthase enzyme. This enzyme converts the amino acid homocysteine in the amino acid methionine. The body uses methionine to produce proteins and other important compounds. MMADHC is likely that the protein plays a role in one of the final steps in the formation of AdoCbl and MeCbl, transport of vitamin B12 in the mitochondria. Subsequently, other chemical reactions convert vitamin B12 in AdoCbl or MeCbl. They have identified at least seven mutations in the gene MMADHC result homocystinuria. These mutations result in the synthesis of a protein can not produce MeCbl. No MeCbl, methionine synthase can not convert homocysteine to methionine. Consequently, homocysteine accumulates in the bloodstream and the amount of methionine is reduced. Some excesses of homocysteine are excreted in the urine. It is unclear how altered levels of homocysteine and methionine lead to problems associated with homocystinuria.
This disease is inherited in an autosomal recessive pattern, that is, both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.
Tests in IVAMI: in IVAMI perform detection of mutations associated with homocystinuria, by complete PCR amplification of exons delos CBS, MTHFR, MTR, MTRR and MMADHC genes, respectively, and subsequent sequencing.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).