Introduction
Methylmalonic acidemia(methylmaloni cacidemia) also known as methylmalonic aciduria, is an autosomal recessive inheritance. The main clinical manifestations are early onset, severe intermittent ketoacidosis, increased methyl and malonate in blood and urine, often accompanied by central nervous system symptoms.
Cause
(1) Causes of the disease
The disease is autosomal recessive. MethylmalonylCoenzyme AThe mutase (vitamin B12 non-reactive type) or the coenzyme adenosine cobalt ammonium deficiency (vitamin B12 reactive type) causes L-methylmalonic acid to be converted into succinic acid and accumulated in the blood.
(two) pathogenesis
Hereditary methylmalonic acidemia has a variety of biochemical defects. Complete mutase deficiency (mut0) and partial deficiency (mut-) due to defects in two mutase apoenzymes; synthesis of two adenosine cobalamin (AdoCbl) Defects, namely mitochondrial cobamide reductase (cblA) deficiency and mitochondrial cobalamin adenosyltransferase (cblB) deficiency; and 3 abnormalities due to cytosolic and lysosomal cobalamin metabolism Defects in the synthesis of adenosine cobalamin and methylcobalamin (MeCbl) (cblC, cblD, cblF). The patients had only methylmalonic acidemia with genetic defects mut0, mut-, cblA and cblB, and the clinical manifestations were similar. Defects such as cblC, cblD, and cblF produce methylmalonic acidemia and homocystinuria.
symptom
Although methylmalonate has many biochemical defects, its clinical manifestations are similar. It is early onset and usually occurs in neonates or early infancy. Common sleepiness, growth dysplasia, recurrent vomiting, dehydration, respiratory distress and low muscle tone. Some have intelligence behind, liver and coma. Symptoms of mut0 were early, and 80% were in the first week after birth. Serum cobalamin concentration is normal, metabolic acidosis, 80% have ketone blood or ketonuria, 70% have hyperammonemia. Half of the patients had leukopenia, thrombocytopenia, and anemia. Some cases have hypoglycemia. There is a large amount of methylmalonic acid in the urine or blood of the patient. Mild, late-onset or so-called "benign" cases have lower levels of methylmalonic acid. Ingestion of propionic acid and methylmalonic acid precursor proteins or amino acids can increase the accumulation of methylmalonic acid, or even cause ketosis or acidosis.
Hereditary methylmalonic acidemia with homocystinuria, defects are cblC, cblD, cblF. The clinical manifestations of cblC deficiency were highly variable, but all of them were mainly neurological symptoms. Early onset symptoms appear 2 months after birth, manifested as poor growth, feeding difficulties or lethargy. Late onset symptoms can occur in 4 to 14 years of age, including burnout, cramps and tonic, or dementia, myelopathy. Most cases have abnormal blood system, such as giant red blood cells and giant red blood cell anemia, polymorphonuclear leukocyte nuclear lobulation and thrombocytopenia. Serum cobalamin and folic acid concentrations were normal. The defects of cblD generally occur later, manifested as behavioral abnormalities, intelligent backwardness and neuromuscular lesions, and no abnormalities in the blood system. Patients with cblF deficiency developed stomatitis, hypotonia and facial deformities 2 weeks after birth, and some had abnormal blood cell morphology. Some cases have hypomethioninemia and cystathioninuria.
diagnosis
Diagnosis The application of GC-MS for blood and urine organic acid analysis can diagnose this disease. The determination of various genetic defects depends on the enzymatic analysis of cultured cells.
Identification should be noted to rule out ketoacidosis, cobalamin deficiency, and homocysteine in other causes of neonatal period.
complication
Growth dysplasia, vomiting can cause dehydration acidosis, respiratory distress and mental retardation or dementia, myelopathy. Liver and coma. Hyperammonemia, hypoglycemia, paralysis and tonicity can occur. Abnormal blood system such as megaloblastic anemia and platelets, leukopenia, etc.
treatment
Western medicine treatment
Dietary therapy is effective. Limit protein intake and reduce amino acid intake of methylmalonate precursors as soon as possible. L-carnitine and oral antibiotics may be effective. Some cases are effective for supplementing large doses of vitamin B12, that is, B12-dependent methylmalonic acidemia, which can be given first to B1 1 to 5 mg/d for 1 week. If the effect is effective, the maintenance dose can be given for a long time. The dose is generally 1 mg per week, adjusted according to clinical and biochemical reactions.
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. It is the practical application of human genetics knowledge and an important measure for eugenics. The prenatal diagnosis of hereditary metabolic diseases is a combination of biochemical genetics, molecular genetics and clinical practice, and has a strong practical application value.
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 by amniotic fluid, such as phosphocreatine kinase (CK), alpha-fetoprotein (AFP), mucopolysaccharide in amniotic fluid can be used to diagnose mucopolysaccharidosis, including dermatan sulfate (DS), sulfuric acid Heparin (HS), keratan sulfate (KS), chondroitin sulfate (CS). The methods used are one-way or two-dimensional cellulose acetate membrane electrophoresis, dimethyl methylene blue-Tris method and the like. Methylmalonic aciduria in organic acidemia can be measured by gas chromatography-mass spectrometry (GS/MS) for methylmalonic acid in amniotic fluid.
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 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. For example, phenylalanine hydroxylase is only expressed in liver cells, and prenatal diagnosis of phenylketonuria can only be performed by DNA analysis. Lysosomal storage disease is a group of diseases that have the most prenatal diagnosis by enzyme activity assay. A prenatal diagnosis should have a normal specimen (amniotic fluid or villus) as a control. It would be better to have a positive specimen that was 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. Genetic diagnosis Different types of mutations have different diagnostic pathways, such as direct detection, polymorphism 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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