Introduction
Propionic acidemiaIt is a genetic defect in the process of catabolism of propionic acid, which is caused by the lack of propionyl CoA carboxylase and is autosomal recessive. It is characterized by recurrent metabolic ketoacidosis, protein intolerance and a significant increase in plasma glycine levels. The disease is often caused by the intake of protein, especially a diet rich in branched chain amino acids, methionine and threonine. The patient has a large amount of propionic acid accumulation in the blood, maltolactone dysfunction in leukocytes, and carboxylase deficiency in fibroblasts.
Cause
(1) Causes of the disease
The disease is autosomal recessive. The disease is caused by the genetic defect of propionylamino-CoA carboxylase or the metabolic disorder of biotin coenzyme, which causes propionic acid to be unable to be converted into D-methylmalonic acid and accumulated in the blood.
(two) pathogenesis
This disease is an abnormality in the catabolism of branched-chain amino acids. Although the patient had significant hyperglycemia, there was no significant abnormality in glycine production and utilization. The plasma levels of proline, isoleucine and leucine were increased in patients, and the onset of ketoacidosis was secondary to eating a branched-chain amino acid diet. The concentration of propionic acid in infants with propionic acidemia can be as high as 40 mg/dl (5.4 mmol/L), which is more than 100 times higher than that of normal infants. The patient's urine propionic acid and its derivatives were also significantly increased, including methyl decanoic acid, propionyl glycine, β-hydroxypropionic acid and α-methyl crotonic acid. Other abnormalities unrelated to the propionate metabolic pathway are hyperglycemia, hyperglycemia, and hyperammonemia. The propionyl-CoA carboxylase activity in the patient cell extract was significantly reduced from 1% to 5% of normal. Carboxylase molecules have two subunits, α and β. Enzyme defects are caused by two mutations, pccA and pccBC, affecting two subunits, respectively, but the β subunits often have partial residues.
Multiple carboxylase deficiency is a biotin-derived defect in biotin metabolism. It is known as biotin-producing propionateemia. The common product of propionyl-CoA deficiency and β-methylcrotonyl-CoA carboxylase deficiency can be detected in urine. .
symptom
The incidence of propionic acidemia is mostly early. It is characterized by recurrent ketoacidosis, developmental delay, EEG abnormalities, and osteoporosis after a high-protein diet. In the neonatal period, severe acidosis occurs, which is characterized by refusal to eat, vomiting, lethargy, and low muscle tone. Dehydration, convulsions, and hepatomegaly are also common. Some cases have a late onset, manifested as acute encephalopathy, or paroxysmal ketoacidosis, although severe acidosis, but slow response to alkali replacement therapy. There may be transient neutropenia and thrombocytopenia. The neurological symptoms of this disease are characterized by stunting, convulsions, brain atrophy and EEG abnormalities. Others include abnormal muscle tone, severe chorea and cone system symptoms, especially in patients with longer survival. Late-onset people can have chorea and dementia as the first symptom.
diagnosis
Defects of propionate carboxylation should be considered in the development of ketosis or acidosis in the neonatal period. Diagnosis requires determination of the concentration of propionic acid and its metabolites in blood or urine, and the activity of propionyl-CoA carboxylase in leukocytes or fibroblasts. The enzyme activity can be determined. The determination of enzyme activity in cord blood can be diagnosed in high-risk newborns.
Identification
Different from other branched amino acid metabolic defects, it must be confirmed by laboratory tests.
complication
Severe acidosis, dehydration, convulsions, hepatomegaly, acute encephalopathy, developmental delay, severe chorea and cone system symptoms, dementia, secondary infections, etc.
treatment
Western medicine treatment
A low protein 0.5-1.5 g/(kg·d) or low propionic acid precursor diet is currently the best treatment to reduce the number of episodes of ketoacidosis. Since the fasting will increase the excretion of propionic acid metabolites, the number of feedings should be increased. All protein-containing diets should be stopped immediately upon the onset of ketoacidosis and glucose should be given to avoid catabolism. Peripheral dialysis can be considered in patients with acute attacks, especially those with hyperammonemia. Biotin is a propionyl-CoA carboxylase coenzyme, which is effective in treating a variety of carboxylase deficiency, sensitive to biotin 10 mg/d, and has a rapid and long-lasting effect. L-carnitine oral (100m / kg) has a certain clinical effect. Intestinal bacteria produce a certain amount of propionic acid, and oral antibiotics may reduce the concentration of propionic acid in serum and tissues.
The above content is for reference only, please consult the relevant physician or relevant medical institution if necessary.
prevention
Most of the hereditary metabolic diseases have no effective treatment, so prevention is more important. Antenatal diagnosis of hereditary metabolic disease is one of the effective measures to prevent the occurrence of genetic diseases. By measuring the enzyme activity of cultured amniocytes or chorionic villus, or the level of methyl citrate in amniotic fluid. Conduct prenatal diagnosis.
Since the early 1960s, the prenatal diagnosis has been developed with transabdominal amniocentesis. Prenatal diagnosis techniques have developed rapidly. Following the fetal microscopy of fetal blood specimens and the transcervical and transabdominal wall, it has been developed in recent years. Non-invasive prenatal diagnostic techniques. Enrichment and isolation of fetal nucleated red blood cells from the peripheral blood of pregnant women, the cells derived from the fetus can be subjected to interphase nuclear fluorescence in situ hybridization (FISH) for abnormal chromosome number detection, or DNA extracted for PCR amplification and then subjected to linkage analysis or Direct detection of mutations for prenatal genetic diagnosis.
Amniocentesis can be performed through the abdominal wall 17 to 20 weeks of pregnancy. Amniocytes are epithelial cells that are shed by the fetus and can be used for enzyme activity assay or genetic analysis after culture. The fetal loss rate caused by this method is 0.5%. It is still an important means of prenatal diagnosis.
The villi are from the embryonic trophoblast and can be taken through the abdominal wall 10 to 12 weeks of gestation. Can be used for enzyme activity determination or genetic analysis. The advantage is that the amniocentesis is 2 months earlier than the amniocentesis, and it is not necessary to culture, and the prenatal diagnosis result can be obtained earlier. Once the fetus is sick, the pregnant woman can choose artificial abortion in time, the subsequent operation is easier to carry out, and the psychological burden of the pregnant woman can be relieved as soon as possible.
According to the detection method, it can be divided into metabolite measurement, enzyme activity measurement and gene analysis.
1. Determination of metabolites can be analyzed with amniotic fluid.
2. Determination of enzyme activity Most of the genetic metabolic diseases are caused by enzyme defects. Therefore, prenatal diagnosis can be performed by using cultured amniotic cells or fluff using enzyme activity assays. First, the amniocytes should be harvested and cultured for 1 million hours to re-test enzyme activity, or directly measure the enzyme activity in the villi. However, some enzymes are not expressed in amniotic fluid cells or villi. A prenatal diagnosis should have a normal specimen (amniotic fluid or villi) as a control. It is better to have a positive specimen that has been retained in the past as a positive control. A disease in which the gene has been isolated or localized can be used for prenatal genetic diagnosis.
3. Gene diagnosis can be directly detected, polymorphic linkage analysis.
A prerequisite for prenatal diagnosis is to make an accurate diagnosis of the proband. It is only possible for the mother to check for an enzyme or a genetic test at the time of prenatal diagnosis. Due to the serious condition of lysosomal storage disease, most diseases have no effective treatment and the prognosis is poor. The birth of a child brings a heavy economic and spiritual burden to society and the family. There is no effective treatment for this disease, but most of them can clearly determine whether the fetus is sick before delivery, and some can also make prenatal diagnosis in the early pregnancy, which has the meaning of "prevention" in eugenics. Because it can prevent the birth of a baby based on a clear prenatal diagnosis, it is not only the only viable eugenics, but also reduces the burden on families and society and improves the quality of the population.
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