Propionic acidemia in children

Introduction to pediatric propionateemia Propionic acidemia is a genetic defect in the catabolism of propionic acid, which is caused by the deficiency of propionylCoAcarboxylase. It is autosomal recessive, with recurrent metabolic ketones. It is characterized by acidosis, protein intolerance and a significant increase in plasma glycine levels. The disease is often caused by ingestion of protein, especially a mixture of 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. basic knowledge The proportion of illness: 0.021% Susceptible people: infants and young children Mode of infection: non-infectious Complications: dehydration, convulsions in children, hepatomegaly, dementia

Causes of pediatric propionateemia

(1) Causes of the disease

The disease is autosomal recessive, caused by a genetic defect of propionylamino-CoA carboxylase or a metabolic disorder of biotin coenzyme, which causes propionic acid to be converted into D-methylmalonic acid and accumulated in the blood.

(two) pathogenesis

This disease is a dysfunction of branched-chain amino acid catabolism. Although patients have significant hyperglycemia, there is no abnormality in glycine production and utilization. The plasma levels of valine, isoleucine and leucine are increased in patients, while ketoacid The episodes of poisoning are secondary to eating a branched-chain amino acid diet. The serum propionic acid concentration of infants with propionateemia can be as high as 40 mg/dl (5.4 mmol/L), more than 100 times higher than that of normal infants, and the patient's urine propionic acid and its derivatives. Also significantly increased, including methyl decanoic acid, propionyl glycine, -hydroxypropionic acid and -methyl crotonic acid, other abnormalities unrelated to the propionic acid metabolic pathway, high glycineemia, high glycineuria and high ammonia In the blood, the activity of propionyl-CoA carboxylase in the cell extract of the patient is significantly reduced, which is 1% to 5% of normal. The carboxylase molecule has two subunits of and , and the enzyme is caused by two mutations of pccA and pccBC. Defects affect two subunits separately, but beta subunits often have partial residues.

Multiple carboxylase deficiency is a biotin-derived defect in biotin metabolism. It is known as biotin-effective propionateemia. The common product of propionyl-CoA deficiency and -methylcrotonyl-CoA carboxylase deficiency can be detected in urine. .

Pediatric propionate prevention

Most of the hereditary metabolic diseases have no effective treatment, so prevention is more important. The antenatal diagnosis of hereditary metabolic disease is one of the effective measures to prevent the occurrence of genetic diseases. Cultured amniotic fluid cells or chorionic villus tissue activity, or methyl citrate levels in amniotic fluid for prenatal diagnosis.

Since the early 1960s, the prenatal diagnosis of the transabdominal amniocentesis has been developed rapidly. The fetal blood sample and the cervix have been taken by the fetal lens, and the villus is taken through the abdominal wall. Non-invasive prenatal diagnostic technique, which is enriched from the peripheral blood of pregnant women, and separates fetal nucleated red blood cells. The cells derived from the fetus can be subjected to interphase nuclear fluorescence in situ hybridization (FISH) for abnormal chromosome number detection or DNA extraction. Prenatal genetic diagnosis is performed by PCR analysis or direct detection of mutation after PCR amplification.

Amniocentesis can be performed through the abdominal wall 17 to 20 weeks of pregnancy. The amniotic fluid cells are epithelial cells that are shed by the fetus. After culture, enzyme activity or genetic analysis can be performed. 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. They can be taken from the abdominal wall by 10 to 12 weeks of gestation. They can be used for enzyme activity determination or genetic analysis. The advantage is that the amniocentesis is 2 months earlier than the amniocentesis. It is not necessary to culture, and the prenatal diagnosis can be obtained earlier. As a result, once the fetus is sick, the pregnant woman can choose artificial abortion in time, the subsequent operation is relatively easy, 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 the measurement of metabolites, enzyme activity measurement and gene analysis.

1. Determination of metabolites

Amniotic fluid can be used for analysis.

2. Determination of enzyme activity

Most of the genetic metabolic diseases are caused by enzyme defects. Therefore, the prenatal diagnosis can be made by the method of measuring the enzyme activity of cultured amniotic cells or fluff. First, the amniotic cells should be harvested and cultured for 1 million hours to re-test enzyme activity. Or directly measure the enzyme activity in the villus, but some enzymes are not expressed in amniotic fluid cells or villi. Prenatal diagnosis should have a normal specimen (amniotic fluid or villus) as a control. If there is a positive specimen retained in the past, it is better to be a positive control. A disease in which the gene has been isolated or localized can be used for prenatal genetic diagnosis.

3. Genetic diagnosis

Direct detection method, polymorphism linkage analysis can be used.

The 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 certain genetic test in the prenatal diagnosis when the mother is pregnant again. The lysosomal storage disease is seriously ill. Most diseases have no effective treatment, and the prognosis is poor. The birth of the child brings a heavy economic and mental burden to the 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 giving birth. Some can also make prenatal diagnosis in the first trimester of pregnancy, and have the meaning of "prevention" in eugenics. Because it can prevent fetal birth based on clear prenatal diagnosis results, it is not only the only feasible eugenics, but also Reduce the burden on families and society and improve the quality of the population.

Pediatric propionate complications Complications dehydration children convulsions hepatic dementia

Severe acidosis, dehydration, convulsions, hepatomegaly, acute encephalopathy, developmental delay, severe chorea and cone system symptoms, dementia, secondary infections, etc.

Symptoms of propionic acidosis in children Common symptoms Thrombocytopenic ketoacidosis, refusal of convulsions, leukopenia, dementia, osteoporosis, sleepiness

Most of the causes of propionic acidemia are early, with recurrent ketoacidosis, stunting, EEG abnormalities and osteoporosis after high protein diet, severe acidosis in the neonatal period, manifested as refusal to eat, vomiting, Drowsiness and low muscle tone, dehydration, convulsions, and liver enlargement are more common. Some cases have a late onset, which is characterized by acute encephalopathy, or paroxysmal ketoacidosis. Although there is severe acidosis, it has a slow response to alkali replacement therapy. Over-neutral neutropenia and thrombocytopenia, the neurological symptoms of this disease are characterized by developmental delay, convulsions, brain atrophy and EEG abnormalities. Others include abnormal muscle tone, severe chorea and cone system symptoms, especially in survival. Long patients, late-onset people can have chorea and dementia as the first symptom.

Examination of pediatric propionateemia

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. Since propionic acid accumulation can also be seen in patients with metabolic problems of methylmalonic acid metabolism, the enzyme activity can be measured. The final diagnosis, the high-risk neonatal determination of cord blood enzyme activity can be immediately diagnosed, by measuring the culture of amniotic fluid cells or chorionic villus tissue activity, or amyloid levels in amniotic fluid for prenatal diagnosis, cultured into fibroblasts Propionyl-CoA carboxylase is deficient or almost completely absent.

EEG, brain CT examination, abnormal brain waves, brain atrophy, abdominal hyperabsorption of liver enlargement, X-ray examination showed osteoporosis.

Diagnosis and differential diagnosis of pediatric propionate

diagnosis

In the neonatal period, ketosis or acidosis should take into account the defect of propionate carboxylation. The diagnosis needs to determine 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 finally diagnosed, and the enzyme activity in cord blood can be diagnosed in high-risk newborns.

Differential diagnosis

Different from other branched amino acid metabolic defects, it must be confirmed by laboratory tests.

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