Pediatric Methylmalonic Acidemia

Introduction to pediatric methylmalonic acidemia Methylmalonic acidemia (methylmalonic acidemia) is also called methylmalonic aciduria, which is autosomal recessive. The main clinical manifestations are early onset, severe intermittent ketoacidosis, blood and urine. Increased amount of malonate, often accompanied by central nervous system symptoms. basic knowledge The proportion of illness: 0.002% Susceptible people: children Mode of infection: non-infectious Complications: dementia, liver enlargement, hypoglycemia

Causes of pediatric methylmalonic acidemia

(1) Causes of the disease

The disease is autosomal recessive, due to methylmalonyl-CoA mutase (vitamin B12 non-reactive) or coenzyme adenosine cobalt ammonium deficiency (vitamin B12 reactive), L-methylmalonic acid can not It is caused by the accumulation of succinic acid and accumulation in the blood.

(two) pathogenesis

Hereditary methylmalonic acidemia has a variety of biochemical defects, including complete mutase deficiency (mut0) and partial deficiency (partial deficiency) caused by defects in two mutase apoenzymes. Mut-); two adenosine cobamine reductase (cblA) deficiency and mitochondrial cobalamin adenosyltransferase (cblB) deficiency; And three kinds of defects in the synthesis of adenosylcobalamin and methylcobalamin (MeCbl) due to abnormal cytosolic and lysosomal cobalamin metabolism (cblC, cblD, cblF), patients with genetic defects mut0, mut-, CblA and cblB only had methylmalonic acidemia, and the clinical manifestations were similar. The defects were cblC, cblD, and cblF, which produced methylmalonic acidemia and homocystinuria.

Prevention of methylmalonic acidemia in children

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. The practical application of genetics knowledge is an important measure for eugenics. The prenatal diagnosis of hereditary metabolic diseases is a combination of biochemical inheritance, molecular genetics and clinical practice, and has strong practical application value.

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: Analysis can be performed with amniotic fluid, such as phosphocreatine kinase (CK), alpha-fetoprotein (AFP), and mucopolysaccharide in amniotic fluid can be used to diagnose mucopolysaccharidosis, including dermatan sulfate (DS). Heparin sulfate (HS), keratan sulfate (KS), chondroitin sulfate (CS), using one-way or two-way cellulose acetate membrane electrophoresis, dimethylmethan-Tris method, etc., in organic acidemia Methylmalonic aciduria can be used to determine methylmalonic acid in amniotic fluid by gas chromatography-mass spectrometry (GS/MS).

This disease can be used in amniotic fluid or mid-pregnancy gestational urinary methylmalonic acid concentration or enzyme activity in cultured amniotic fluid cells for prenatal diagnosis and termination of pregnancy if necessary.

2. Determination of enzyme activity: Most of the metabolic diseases are caused by enzyme defects. Therefore, the cultured amniotic fluid cells or villous hair can be used for the prenatal diagnosis by the method of enzyme activity measurement. First, the amniocytes should be cultured for 1 million hours. Harvest re-test enzyme activity, or directly measure the enzyme activity in the villus, but some enzymes are not expressed in amniotic cells or villi, such as phenylalanine hydroxylase expressed only in liver cells, prenatal diagnosis of phenylketonuria can only For DNA analysis, lysosomal storage disease is the group with the most prenatal diagnosis by enzyme activity measurement. Prenatal diagnosis should have a normal specimen (amniotic fluid or villus) as a control, if there is a positive retention in the past. Specimens are better for positive controls, and diseases with isolated or localized genes can be used for prenatal genetic diagnosis.

3. Genetic diagnosis: Different types of mutations have different diagnostic pathways, such as direct detection, polymorphism linkage analysis.

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.

Complications of pediatric methylmalonic acidemia Complications, dementia, liver hypoglycemia

Growth dysplasia, vomiting can cause dehydration acidosis, respiratory distress and mental retardation or dementia, myelopathy, liver enlargement and coma, hyperammonemia, hypoglycemia, sputum and tonic sputum, abnormal blood system such as giant red blood cells Anemia and platelets, leukopenia, etc.

Symptoms of methylmalonic acidemia in children Common symptoms Mental retardation Leukopenia Slow growth Thrombocytopenia Muscle tone reduction Sleepiness ketoneuria Hypoglycemia Metabolic acidosis Facial malformation

Methylmalonic acidemia has a variety of biochemical defects, but the clinical manifestations are similar, early onset, usually in neonatal or early infancy, common sleepiness, poor growth, recurrent vomiting, dehydration, respiratory distress and Low muscle tone, some have intelligence backwardness, liver enlargement and coma, symptoms of mut0 are early, 80% in the first week after birth, serum cobalamin concentration is normal, metabolic acidosis, 80% have ketone blood or ketone Urine, 70% have hyperammonemia, half of patients have leukopenia, thrombocytopenia and anemia, some cases have hypoglycemia, patients with urine or blood with a lot of methylmalonic acid, mild, late-onset or so-called In "benign" cases, the level of methylmalonic acid is low. Ingestion of propionic acid and methylmalonic acid precursor proteins or amino acids may increase the accumulation of methylmalonic acid or even cause ketosis or acidosis.

Hereditary methylmalonic acidemia with homocystrineuria, the defects of cblC, cblD, cblF, cblC defects in clinical manifestations of large variations, but mainly neurological symptoms, early cases in the postnatal 2 Symptoms appear in the month, manifested as growth dysplasia, feeding difficulties or lethargy, late cases can appear symptoms in 4 to 14 years old, may have burnout, phlegm and tonic, or dementia, myelopathy, etc., most cases have blood system Abnormalities, such as giant red blood cells and giant red blood cell anemia, polymorphonuclear leukocyte nuclear lobulation and thrombocytopenia, serum cobalamin and folic acid concentrations are normal, cblD defects generally late onset, manifested as behavioral abnormalities, intelligent backward And neuromuscular lesions, no abnormalities in the blood system, cblF deficiency occurred stomatitis 2 weeks after birth, low muscle tone and facial deformity, some have abnormal blood cell morphology, some cases have hypomethioninemia and cysteine Cystathioninuria.

Examination of pediatric methylmalonic acidemia

1. Blood routine examination: Leukopenia, thrombocytopenia and anemia, megaloblastic and giant red blood cell anemia, polymorphonuclear leukocyte nuclear lobulation and thrombocytopenia.

2. Blood and urine examination: The serum cobalamin and folic acid concentrations are normal, metabolic acidosis, ketone blood or ketonuria, hyperammonemia and hypoglycemia.

3. There is a large amount of methylmalonic acid in the urine or blood of patients: In mild cases, the level of methylmalonic acid is low, and the intake of propionic acid and methylmalonic acid precursor protein or amino acid increases the accumulation of methylmalonic acid. Or even cause ketosis or acidosis, some cases have hypomethionemia and cystathione.

Prenatal diagnosis can be performed in amniotic fluid or mid-pregnancy gestational urinary methylmalonic acid concentration or enzyme activity in cultured amniotic fluid cells.

B-ultrasound can be found in liver enlargement, abnormal brainwaves in EEG, and mental retardation in mental tests.

Diagnosis and differential diagnosis of methylmalonate in children

Blood and urine organic acid analysis can be used to diagnose this disease by GC-MS. The determination of various genetic defects depends on the enzymatic analysis of culture cells.

Care should be taken to rule out ketoacidosis, cobalamin deficiency, and simple homocystinuria caused by other causes during the neonatal period.

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