What Are the Different Types of Congenital Defects?

Congenital metabolic defects are structural abnormalities of the enzyme protein caused by mutations in the structural gene encoding the enzyme protein; or changes in the amount of the enzyme protein caused by abnormalities in the regulatory system of the gene, resulting in congenital metabolic disorders. The inheritance is generally autosomal recessive. AE Garrod, a British medical scientist, conducted a detailed study of patients with melanuric aciduria, cystineuria, albinism, and pentoseuria from 1902 to 1908, pointing out that these diseases are caused by a metabolic pathway Caused by a genetic disorder in one of the enzymatic reactions, which led to the concept of congenital metabolic defects.

Congenital metabolic defect

Overview of Congenital Metabolic Defects

Inborn errors of metabo-lism, also known as hereditary enzyme diseases, mainly refer to diseases caused by enzyme defects during metabolism. They are structural abnormalities of enzyme proteins caused by mutations in the structural genes encoding enzyme proteins ; Or the changes in the amount of enzyme protein due to the abnormality of the gene's regulatory system, resulting in congenital metabolic disorders. The inheritance is generally autosomal recessive. Congenital metabolic defects can occur in any organism other than viruses and phages. Various types of auxotrophs are the result of congenital metabolic defects that occur during the metabolism of amino acids, nucleotides, or vitamins. Dystrophy is an important tool for genetic research, especially for microbial genetics.

A brief history of congenital metabolic defects

British medical scientist A. E. Garrodt conducted a detailed study of patients with melanuric aciduria, cystineuria, albinism, and pentoseuria from 1902 to 1908, pointing out that these diseases are caused by A genetic disorder caused by an enzymatic reaction in the metabolic pathway has led to the concept of congenital metabolic defects. Garrod's hypothesis was only confirmed after half a century.

In 1952, American scholar G · T · Cory discovered that glycogen accumulation disease type I was caused by the lack of glucose-6-phosphatase in the liver of patients.

In 1955, a Japanese scholar Kukita and others confirmed that melanocytes in the hair follicle matrix of patients with albinism lack tyrosinase.

In 1958, French scholar B.N. Ladi and others confirmed the lack of melanate oxidase in the liver of patients with melanuric aciduria.

In 1970, Y · M · Wang et al. Confirmed that patients with pentaturia lacked xylitol dehydrogenase in red blood cells. The above diseases are the result of disorders of intermediate metabolism.

Congenital metabolic defect mechanism

Enzyme proteins are all encoded by genes. If a mutation in the gene encoding an enzyme protein changes the active center of the encoded protein, the activity of this enzyme is often reduced or even completely lost, and the corresponding biochemical reaction cannot proceed smoothly. This reaction can result in the accumulation of substrates or precursors, or the deficiency of normal products or the appearance of abnormal products. If the precursor is toxic or a normal product is required, it can cause congenital metabolic disorders.

Phenylalanine is catalyzed by phenylalanine hydroxylase to tyrosine (Reaction 1). If the gene encoding this enzyme is mutated and the reaction cannot proceed smoothly, phenylalanine is accumulated in the body and phenylalanine oxidation products, phenylpyruvate, phenyllactic acid, phenylacetic acid, and o-hydroxyl, appear in the urine. Phenylpyruvic acid and other abnormal products, leading to phenylketonuria; patients with impaired brain development, most of them mentally retarded. Because the normal product tyrosine is also a precursor of melanin, the deficiency of tyrosine makes patients with lighter hair and complexion.

Tyrosine undergoes many biochemical reactions to produce melanin on the one hand (Reaction 2), and on the other hand, it turns into melaninic acid through two biochemical reactions (Reaction 3), which is further decomposed into fumaric acid and acetoacetic acid or converted into Brownish yellow substance (Reaction 4). If the gene mutation inactivates tyrosine transaminase, then reaction 2 cannot proceed smoothly, so hypertyrosinemia (or tyrosinemia ) occurs, and the patient's blood has increased tyrosine and has low intelligence. If p-hydroxyphenylpyruvate oxidase is inactivated, reaction 3 cannot proceed smoothly, hereditary tyrosinemia (or tyrosinemia I) occurs, and the patient has enlarged liver and impaired renal function. If the uric acid oxidase is inactivated, reaction 4 cannot proceed smoothly, and uric aciduria occurs. The patient's urine becomes black after contact with air. In old age, it is easy to cause joints due to the deposition of brown-yellow substances in cartilage tissue. inflammation. If tyrosinase is inactivated, reaction 5 cannot proceed smoothly, and melanin cannot be formed, thus causing albinism.

Congenital Metabolic Defect Type

At present, there are more than 1,000 kinds of diseases caused by congenital metabolic defects, which can be divided into multiple types from different perspectives:

According to the biochemical properties of metabolites, they can be divided into carbohydrates, amino acids, lipids (including sphingomyelin, glycosphingolipids, glycocerebrosides, gangliosides, mucolipids), mucopolysaccharides, steroid hormones, and nucleic acids (including Purine and pyrimidine), metal ions, vitamins and other metabolic defects.

According to the pathogenesis of the disease, it can be divided into active transport disorders (such as defects caused by renal diabetes, diabetes insipidus), excessive accumulation or accumulation of metabolites (such as defects caused by glycogen accumulation disease, mucopolysaccharidosis) , Intermediate metabolic disorders (such as urea cycle disorders, leaf gonorrhea), and synthetic disorders (such as hyperlipoproteinemia, defects caused by adrenal corticosteroid synthesis).

According to the genetic method, it can be divided into two types of single genes and multiple genes. Single genes can be divided into autosomal recessive, autosomal dominant, X-linked recessive and X-linked dominant.

Congenital metabolic defects can be asymptomatic clinically, such as pentaturia; symptoms can be induced by certain external factors, such as glucose-6-phosphate deaminase (G6PD) deficiency (see Pharmacogenetics) It can also show persistent symptoms without being induced. Mild ones can survive long-term and even reach normal survival age. Serious ones often lead to death. For example, children with lipid accumulation disease usually die in infancy.

Prevention of congenital metabolic defects

The measures to genetically reduce the incidence of congenital metabolic defects in the population are:

Avoid marriage with close relatives.

Genetic counseling. According to the distribution of patients in the family and the genetic manner of the disease, the probability of having a sick child can be calculated, and whether or not to have children or continue pregnancy can be determined.

The heterozygous heterozygosity is normal in appearance, but the activity of the corresponding enzyme is usually between normal and recessive homozygous patients. Therefore, hybrids can be detected through the measurement of enzyme activity, but if the measurement results overlap with normal values, other methods must be used, for example, phenylketonuria hybrids can be detected using a phenylalanine tolerance test. Detection of heterozygosity in populations with high incidence can effectively prevent the occurrence of congenital metabolic defects.

Prenatal diagnosis. Certain congenital metabolic defects can be detected by measuring the enzyme activity of fetal desquamative cells in cultured amniotic fluid. As of 1979, 75 congenital metabolic defects have been detected by this method. Certain metabolic defects, such as Duchenne muscular dystrophy or pseudohypertrophic dystrophy, can be detected through fetal blood samples taken from the fetus. Since the 1980s, recombinant DNA technology has been used for prenatal diagnosis of congenital metabolic defects, which has entered the level of genetic diagnosis. This is of great help in guiding abortion, especially for pregnant women who have had children with congenital metabolic defects.

Treatment of congenital metabolic defects

The treatment of congenital metabolic defects mainly uses enzyme therapy. Since the 1970s, microcapsules (artificial cells) have been made from enzymes that can be degraded in the body by nylon film packaging. Periodically injecting such artificial cells into patients is a promising way to treat enzyme defects. Supplement the lack of metabolism (products), avoid contact with inducing substances, induce metabolism to reduce the accumulation of substances in the body, use inhibitors, use coenzymes, limit the intake of defective enzyme substrates and supplement the lack of substances, etc. Therapy.

Detection of congenital metabolic defects

Congenital Metabolic Defective Neonatal Examination

Newborn genetic metabolic disease testing is a simple, fast, and inexpensive blood spot test. Through this screening, you can find out whether your child has a congenital genetic disease early and take timely treatment to make it grow up healthily.

In recent years, genetic metabolic diseases have gradually become the main cause of death and disability in newborns, and especially today when family planning is implemented, efforts should be made to reduce the harm of such diseases. Liquid-phase tandem mass spectrometry (LC-MS / MS) technology, which represents the world's highest level of clinical laboratory technology development, can use a drop of blood sample to analyze nearly a hundred metabolites at once in a few minutes and detect 35 genetic metabolic diseases. Said to be the most advanced, most cost-effective and most efficient screening method in the world. This technology is commonly used in developed countries around the world to screen newborns. China has introduced this patented technology, and a Concord Laboratory Medical R & D Center certified by the United States Centers for Disease Control (CDC) provides services nationwide. Therefore, China has technically developed 35 genetic and metabolic disease tests that have evolved from the current first-generation newborn screening to the second generation, reaching the level of developed countries.

Status of congenital metabolic defects

At present, of the more than 20 million births in China each year, about 400,000 to 500,000 children suffer from genetic metabolic diseases. It has caused great harm to the family and society of children.

For patients with genetic metabolic disease, the sooner they are found and the sooner they are treated, the better it will be for children. Professor Li Changming, former director of the Department of Primary Health and Maternal and Child Health of the Ministry of Health, believes that screening for neonatal diseases is a third-level prevention measure to improve the quality of the birth population and reduce birth defects, and is the first "security check" for infants to enter a healthy life. The National "Mother and Child Health Law" and its implementation measures have clearly stipulated that medical and health care institutions should gradually carry out screening for newborn diseases and include it in maternal and child health technical service projects. Professor Li emphasized: "Genetic metabolic diseases are a large group of diseases that are mainly screened in newborn disease screening. Screening with more diseases and higher coverage is of great significance for reducing birth defects and improving the quality of the population."

It is understood that in 1981, Shanghai started screening phenylketonuria, congenital hypothyroidism and galactosemia in newborns in China. Since 1989, Beijing, Shanghai, Guangzhou, Tianjin and other provinces and cities have gradually carried out routine screening for phenylketonuria and congenital hypothyroidism. In 1994, the State promulgated the "Mother and Child Health Law", which legally established the status of newborn screening in disease prevention. However, in general, the screening of newborns in China is still relatively backward. There are 21 million live births in the country each year, and only more than 500,000 are screened, with a coverage rate of less than 3%. In addition, there are few screening diseases, and genetic metabolic diseases are generally only checked for two. Many children fail to be diagnosed and treated in time, resulting in severe intellectual disability, which seriously affects the improvement of the quality of the birth population.

Effective control of congenital metabolic defects

New technology for effective control

In terms of newborn screening, developed countries are ahead of us. According to He Jian, a professor at the Chinese Academy of Medical Sciences and the Center for Laboratory Medicine Research and Development of the Union Medical College of Medical Sciences, the current international screening for neonatal diseases mainly uses "liquid phase tandem mass spectrometry interpretation technology. Generally, professional nurses are born 24 hours after birth Take one or two drops of heel blood from a newborn, and you can detect more than 30 genetic metabolic diseases in a few minutes.

Relevant data show that 88% of the United States in 2007 used liquid tandem mass spectrometry to perform newborn screening; Germany 1991 to 2001 used liquid tandem mass spectrometry to screen 98% of births; Australia Since 2004, screening of newborns with genetic and metabolic diseases using liquid-phase tandem mass spectrometry has been implemented; newborn screenings in Japan and South Korea have been changed from voluntary screening by parents to items that must be performed in accordance with national legislation. "The use of liquid tandem mass spectrometry in China for newborn screening has just begun and has a long way to go!" He Jian said.

Prevention of congenital metabolic defects

On July 12 this year, the launching ceremony of the "Oasis in Life", a nationwide universal campaign for the detection of genetic and metabolic diseases, sponsored by the China Eugenics Association, the Chinese Academy of Medical Sciences, and the Laboratory Medical Research and Development Center of the Chinese Academy of Medical Sciences was held in Beijing. Professor Xia Xuehong, Secretary-General of the China Eugenics Association, said that the purpose of the event was to improve the quality of the birth population, reduce birth defects, and promote the development of maternal and child health and the science of eugenics. The event brought together nationally renowned experts in eugenics, genetic diagnosis and treatment, and established a National Steering Committee with Qian Xinzhong, the senior leader of the Ministry of Health, and Lin Jiayu as honorary directors. The "Oasis of Life" will take about 3 years to widely publicize the concept of newborn screening through the organization of forums, professional training, science popularization classes, etc., popularize the knowledge of genetic metabolic disease detection and diagnosis and treatment, and promote the next generation of genetic metabolic disease The detection technology establishes the concept of "the first physical examination in life" and enhances the disease prevention awareness of families of childbearing age.

Expected effects of congenital metabolic defects

"Genetic metabolic diseases are treatable and controllable." Researcher Yang Yanling, deputy director of the National Steering Committee of the "Oasis in Action" and expert in genetic metabolic diagnosis and treatment, said that children with positive screening results need to be further diagnosed, and the metabolic abnormalities of the genetic metabolic disease are confirmed Mainly rely on the determination of metabolites and enzyme activity. The general principles of treatment are to reduce the accumulation of toxic substances caused by metabolic defects, to supplement normally needed substances, enzymes or to perform genetic medicine. Most genetic metabolic diseases are mainly treated with diet, and some diseases can be treated with vitamins and coenzymes. Many diseases can be effectively controlled through symptomatic treatment, and they can live, study and work normally.