Homocystinuria

Introduction to homocystinuria Homocystinuria, also known as homocystinuria, is a disease caused by dysfunction of methionine during metabolic metabolism of methionine. It is a congenital metabolic disorder with sulfur-containing amino acids and is a syndrome involving the eye, cardiovascular, bone, and nervous system. The main clinical manifestations are multiple thrombosis, insufficiency, crystal ectopic and excessive finger (toe). basic knowledge The proportion of illness: 0.0008% Susceptible people: no specific population Mode of infection: non-infectious Complications: glaucoma retinal detachment scoliosis cerebral infarction

Idiopathic cystineuria

(1) Causes of the disease

Homocytosis is an autosomal inherited metabolic disease. The mutant gene may be located on the short arm of chromosome 2, which is caused by the degradation of metabolic impurities caused by sulfur-containing amino acids (methionine, cystine).

(two) pathogenesis

Methionine is an essential amino acid whose main conversion pathway is to transfer sulfur in the molecule to L-homocysteine and further to cystine (Lalonge et al., 1994) SLC3A1, gene in patients with this disease. A cysteine was detected, and a mutation of 467 to threonine induced the amino acid transport activity to almost completely disappear.

It has been found that in this transformation process, defects in various enzymes can cause certain amino acids to be deposited in cells, accompanied by an increase in the concentration of other amino acids in the serum. Similarly, this enzyme deficiency can also affect homocysteines. Re-methylation of tyrosine to methionine, the first step in the conversion of methionine to homocysteine is the formation of S-adenosylmethionine, which is catalyzed by methionine adenyltransferase, normally, ATP molecule The adenylyl group is transferred to methionine to form adenosylmethionine, which can later participate in several transmethylation reactions. In normal human cells, S-adenosylmethionine is converted to methyl group to form S-adenosyl homotype. Cysteine, which can be hydrolyzed quickly, and can synthesize cystathionine with serine. It can be remethylated by one-step sulfur transfer to form methionine or oxidized to homocysteine. Methionine metabolism begins two-step reaction. Blocking can cause homocysteine to deposit in tissues, while the concentration in urine and serum is also increased. Methionine accounts for about 2.5% of the amino acids in dietary protein, and a part of the tissue protein is synthesized in the body. It is cystine, homocysteine and other derivatives.

Type:

Cystathionine synthase deficiency

Referred to as the synthetase type, this type is most common, due to the blockage of the metabolic pathway from homocysteine to cystathionine, the concentration of homocysteine and methionine in blood and urine is increased, and methionine is intermediate metabolite S. - adenosylmethionine and S-adenosyl homocysteine are converted to homocysteine, which can be oxidized to homocysteine or serine and combined to form cystathionine, the reaction to form cystathionine Cystathionine synthase catalyzes the enzyme, which requires vitamin B6 as a coenzyme. Therefore, some cases are effective with large doses of vitamin B6.

2. Methyltetrahydrofolate-homocysteine methyltransferase deficiency

Referred to as methyltransferase type, the activity of the methyltransferase protein itself in this type of patient is not reduced, but there is a deficiency of coenzyme (vitamin B12). Normally, homocysteine can form methionine by methylation. The transformation is carried out under the catalysis of methyltransferase. The required coenzyme is the activated form of vitamin B12, namely methyl vitamin B12. This type is due to the abnormal metabolism of vitamin B12 in the body, and can not transform the vitamin B12 absorbed in the body. It is caused by vitamin B12 which is active in the coenzyme function.

3. N5,10-Methylenetetrahydrofolate reductase deficiency

Reductive enzyme type, the function of this type is to catalyze the reduction of N5,10-methylenetetrahydrofolate to N5-methyltetrahydrofolate, which can be provided in the reaction of homocysteine methylation to methionine. Methyl, when the enzyme is deficient, can not form enough N5-methyltetrahydrofolate, so it can cause the same type of cystine methylation is insufficient to deposit in the body, and homocystrineuria occurs at the same time.

Normally, cystathionine synthase is present in liver and brain tissues. When this enzyme is lacking, the enzyme activity is only 1% to 2% of normal. Since homocysteine cannot form cystathionine, homocystein in blood Both arginine and methionine are increased, and a large amount of homocysteine and a certain amount of methionine can also be excreted in the urine.

The homocysteine caused by methyltransferase deficiency, the decrease of methyl B12 in plasma, the increase of homocysteine and methylmalonic acid in blood and urine, the increase of methionine in blood, and even reduction, which is also The main difference from the cystathionine synthase deficiency type, increased cysteine in blood and urine, and increased blood folic acid.

Pathological changes: blood vessels (arteries and veins) in various organs are characterized by intimal fibrosis, hyperplasia, elastic fiber destruction and stenosis or occlusion, aortic valve closure due to narrowing or dilatation of the aorta Incomplete, large blood vessels in the middle layer, thrombosis in arteries and veins, multifocal demyelinating changes in the white matter, vascular damage, multiple embolism to form brain softening and cavernous degeneration, thrombosis in the dural sinus In the brain parenchyma, neuronal loss can also be seen. The metabolic disorder and thrombosis of this disease may be related to the high concentration of homocysteine to activate coagulation factors or alter the structure of proteoglycans. Fatty degeneration can be seen in the liver, accompanied by coarse Mitochondria and multivesicular bodies, epithelial cell swelling can be seen in the kidney, striated muscle shows focal fragmentation "Z" band destruction and myofilament structure disorder, the most common change in intraocular tissue is small band abnormality, The bone changes to osteoporosis with poor bone formation.

Homocysteine prevention

1. The disease is often recessively inherited by the chromosomes. Most patients are married to close relatives of their parents. According to this situation, the incidence of the disease can be reduced from the perspective of strengthening the marriage law prohibiting marriage by close relatives, effectively improving the body of our people. Quality.

2, the prognosis of this disease depends on the formation of vascular occlusive disease, early and late, is a rare cause of adolescent myocardial infarction, long-term follow-up, ophthalmologists should be highly vigilant for the examination and follow-up work for binocular lens dislocation.

Homocystic urinary complications Complications glaucoma retinal detachment scoliosis cerebral infarction

The disease can also be secondary to glaucoma, retinal detachment, convulsions, hemiplegia and other biblical mental symptoms, patients may have arched feet, scoliosis and kyphosis, hair yellow, rare and brittle, homocysteine Patients with cerebral infarction may have hemiplegia, aphasia and convulsions. Patients with cystathionine synthase deficiency may die of coronary occlusion during puberty.

Symptoms of homocystinuria Common symptoms Spider refers to a special rat smell in the urine. Thoracic deformity is slow, convulsions, scoliosis, sacral splenomegaly, hepatosplenomegaly, coronary artery embolism, osteoporosis

Typical symptoms are found in cases of cystathionine synthase deficient. The child is normal at birth and starts from 5 to 9 months. The main symptoms are abnormal bones, crystal dislocation, thrombosis, mental retardation, and convulsions.

Skeletal deformities have limbs and finger-toe slender (spider finger toes), which is easily mistaken for Marfan syndrome. X-ray examination showed osteoporosis, a biconcave shape on the dorsal side of the vertebral body, and scoliosis. There are many dislocations of the eye symptoms, mostly in the 3 to 10 years old, often accompanied by glaucoma, retinal detachment. Thrombosis can occur in any organ, and one or more thromboembolic episodes occur in about 50% of cases. Thrombosis can occur in intracranial vessels, coronary arteries, renal arteries, pulmonary vessels, skin blood vessels, etc., and corresponding symptoms appear. . Symptoms of the nervous system are more obvious, and there may be mental retardation and seizures. Multiple cerebrovascular accidents can cause hemiplegia, pseudobulbar paralysis, and mental symptoms. Other symptoms can also be seen, such as flushing of the ankle, marble skin, thin skin, thin and easy to fold, prothrombin reduction, myopathy and so on.

The "methyltransferase-deficient" symptoms of this disease are mild, may have skeletal deformities, physical and mental retardation, but rare crystal ectopic and thrombosis. This type can also be combined with a malonate.

The "reductase-deficient type" of this disease is mainly characterized by the nervous system, such as convulsions, mental retardation, schizophrenia symptoms, and myopathy. There are no bone deformities, crystal ectopic, and no vascular symptoms.

Examination of homocystinuria

1. Determination of urinary homocysteine: screening method, ie sodium nitroprusside test: 1ml of urine is added to 5% aqueous solution of sodium cyanide, placed for 5 minutes, a drop of 5% sodium nitroprusside solution is added, red or purple is red Positive, indicating an excess of sulfur-containing amino acids in the urine.

2. Determination of enzyme activity: The activity of the enzyme can be measured by skin fibroblasts, and heterozygotes can also be detected by this method.

3. Prenatal diagnosis: The enzyme activity of amniotic fluid cells can be measured.

4. X-ray examination: osteoporosis can be seen, the dorsal side of the vertebral body is biconcave, and scoliosis, etc., and there are many dislocations of the eye, which occur mostly in the 3 to 10 years old, often accompanied by glaucoma and retinal detachment.

5. Vascular calcification, angiographic endometrial stripe wavy appearance, systemic circulation and pulmonary vascular occlusion (thrombosis and embolism).

Diagnosis and identification of homocystinuria

diagnosis

According to clinical manifestations and experimental examinations. 1 urine homocysteine determination, can be used screening method, that is, sodium nitroprusside test: 1ml of urine is added to 5% sodium cyanide aqueous solution, placed for 5 minutes, add a drop of 5% sodium nitroprusside solution, red or purple red is positive , indicating that there is an excess of sulfur-containing amino acids in the urine. 2 The diagnosis depends on the enzyme activity. The activity of the enzyme can be measured by skin fibroblasts. Heterozygotes can also be detected by this method. 3 prenatal diagnosis can measure the enzyme activity of amniocytes.

Differential diagnosis

1, should first rule out the horse square syndrome.

The commonality of the two is crystal ectopic, spider toe, cardiovascular symptoms, but the genetic pattern and disease development are different, the disease is recessive, Marfan syndrome is autosomal dominant, and the toe is slender. It can be seen at birth; while homocystinuria is normal in primary life, bone growth is disproportionate after several years, and limbs are lengthened, in addition to thromboembolic symptoms, osteoporosis, bifurcation of vertebrae, etc. The Marfan syndrome does not have the biochemical metabolic abnormalities of this disease.

Clinically, angiography, CD I, MR I and medical history, physical examination, and laboratory tests are different. Urinary homocysteine qualitative test is the main basis for identification.

2, clinically, it needs to be distinguished from the visceral storage disease that causes nerve and skeletal abnormalities. It is easy to distinguish through laboratory tests and X-ray findings.

3, the three types of biochemical defects of this disease are different, the treatment methods are not the same, so the three types must be distinguished, the three clinical classification of the disease.

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