Mucolipidosis type Ⅳ

Introduction to type IV of viscous storage disease Kohn (1975) studied five Jewish patients and found a variant of mucoidosis. In the same year, Merin identified this variant as a type IV of viscera storage disease characterized by corneal opacity, mental retardation, and mental abnormalities, but no bone changes and a rough face. basic knowledge The proportion of illness: 0.001% Susceptible people: no special people Mode of infection: non-infectious complication:

Visceral storage disease type IV etiology

(1) Causes of the disease

The cause of viscous storage disease is autosomal recessive inheritance.

(two) pathogenesis

The basic biochemical defect of this type of viscous storage disease is ganglioside sialidase deficiency, which can lead to abnormal distribution of gangliosides of GM3 and GD3. These two gangliosides can affect the function of tissue cells. And through a certain unclear mechanism, these two lipids are the main components of the inclusion of lipid-like substances in the body.

Pathology: Liver biopsy showed inclusion bodies in hepatocytes and Kupffer cells. Kupffer cells were foamy, some vacuoles contained fibrous particulate matter, and other vacuoles contained membranous layered inclusions, electron microscopy. Shows vacuoles containing membranes, some of which contain transparent contents, while some vacuoles contain membranous bodies composed of concentric or equal layered structures, and conjunctival biopsies are shown in epithelial cells and Fibroblasts have large lysosomes and contain a large number of layered structures, and the substances in the small bodies are mostly hydrophilic.

Viscous storage disease type IV prevention

Primary prevention

Prevention of genetic diseases, in addition to the epidemiological investigation from the perspective of the entire population, carriers are detected, genetic monitoring and environmental monitoring of the population, marriage and birth guidance, efforts to reduce the incidence of genetic diseases in the population, improve the quality of the population In addition, for individuals, effective preventive measures must be taken to avoid the birth of genetically ill offspring (ie, eugenics) and genetic variation. The usual measures include: premarital examination, genetic counseling, prenatal care, and early treatment of genetic diseases. .

(1) Pre-marital examination: pre-marital examination (ie marriage health care), it is an important link to ensure the happiness of both men and women after marriage, the health of future generations, the focus of pre-marital examination is:

1 Investigation of genetic diseases, including detailed inquiry about the health status of men and women and their family members, past medical history and treatment, especially the presence or absence of congenital malformations, genetic history and close relatives marriage history, if necessary, family surveys, blood group examinations, Chromosome examination or genetic diagnosis to detect carriers;

2 comprehensive physical examination, mainly for acute infectious diseases, tuberculosis, or severe heart, liver, kidney disease, chronic inflammation of the urinary tract and other diseases that can seriously threaten the health of individuals or spouses, as well as severe anemia of the woman, diabetes, etc. The detection of the disease caused by the fetus, and mobilization after the cure can be married;

3 Check the male and female reproductive organs, detect sexual organ malformations, gender deformity and other diseases, so as to take early measures.

(2) Genetic counseling: genetic counseling is a positive answer by clinicians and genetics, and the causes, hereditary methods, diagnosis, treatment and prognosis of hereditary diseases raised by patients with genetic diseases and their relatives. Estimate the probability that a child's child will suffer from a disease, and provide advice and guidance for the patient and his relatives to refer to. The significance of genetic counseling is:

1 to alleviate the physical and mental pain of patients, reduce the psychological pressure of patients and their relatives, help them treat genetic diseases correctly, understand the probability of morbidity, take correct prevention and treatment measures;

2 reduce the incidence of genetic diseases in the population, reduce the frequency of harmful genes, and reduce transmission opportunities.

2. The general principle in the treatment of genetic diseases is to ban their avoidance, to remove the rest, to adjust their metabolic balance, to prevent the appearance of symptoms.

(1) Correcting metabolic disorders: This is the most important method for the treatment of hereditary metabolic diseases. With the deepening of the understanding of the pathogenesis and intermediate processes of hereditary metabolic diseases, the scope of application of this method is also expanding.

1 diet control (forbidden): When the metabolic abnormalities cause the lack of certain essential substances in the body, they are supplemented by diet; when the metabolic substances are stored, the intake of the metabolites or their precursors is restricted. Maintaining a balance, a low phenylalanine diet in patients with phenylketonuria is a good example. In addition, it can also reduce intake by limiting the absorption of specific substances, such as phenylalanine aminohydrolase in patients with phenylketonuria. Capsules, which convert phenylalanine in food to phenylacrylic acid, are eliminated.

2 reduce the substrate (to the rest): when the disease caused by the metabolism of harmful substances, you can control or improve the disease by reducing harmful substances and reducing the concentration of its precursors and metabolic derivatives, removing or reducing its toxic effects Symptoms, the main methods are: A. chelation or promote excretion; B. plasma exchange and affinity binding; C. change metabolic pathway; D. surgical bypass surgery; E. metabolic inhibition.

3 product substitution (to make up for it): When the important enzymatic reaction product is insufficient and cause disease, it can directly supplement the corresponding essential end products, such as giving growth hormone to pituitary dwarf patients, and resisting hemophilia patients. Hemophilia protein (coagulation factor), which is a corresponding immunoglobulin for patients with hereditary immunodeficiency.

(2) Correcting abnormal enzyme activity:

1 Coenzyme supplement: Some genetic diseases, abnormal enzyme activity may involve:

A. A binding site for a specific coenzyme or vitamin.

B. Active coenzyme transport or biosynthesis process, leading to abnormality, many coenzymes are necessary for the normal activity of the whole enzyme, so supplementing the coenzyme component is also an effective method to induce the increase of enzyme activity, which can make the whole enzyme degrade in cells. Slower speed, increase the half-life of the enzyme, and reduce the Michaelis constant (Km) of the enzymatic reaction. Currently, more than 25 genetic diseases have been treated with this method, such as cobalamin (B12) for the treatment of various anemias and nails. Base malonateuria and the like.

2 enzyme induction or feedback inhibition: another treatment for the level of enzyme deficiency is to use drugs to increase residual enzyme activity to improve metabolic levels, such as phenobarbital and related drugs can significantly stimulate the formation of smooth endoplasmic reticulum, and can Accelerating specific enzyme synthesis in the endoplasmic reticulum, including liver UDP glucuronyltransferase, provides a theoretical basis for the treatment of Gibert syndrome and Crigler-Najjar syndrome with phenobarbital.

Feedback inhibition is an important form of many metabolic regulation. For the accumulation of substrates or their precursors caused by certain enzyme defects, feedback inhibition by other bypass metabolism can improve enzyme activity and reduce accumulated substrate. Inhibition has been used as a method of treating acute porphyria.

3 Allogeneic transplantation: by implanting the same kind of cells, tissues or organs containing normal genes into genetically ill individuals, in order to produce corresponding active enzymes and other gene products in the receptor for therapeutic purposes, the grafts are at the receptor. There are two mechanisms that work:

A. Producing an active enzyme that is metabolized in situ to remove the original storage substrate.

B. release of active enzymes, coenzymes or immunologically active factors into the blood, distributed to other tissues of the body to play a role, so far have carried out such allografts of the organs and organs are: kidney, liver, adrenal gland, bone marrow, thymus, spleen, pancreas Etc. Some have achieved significant results.

4 enzyme replacement therapy: directly provide the corresponding normal enzymes to patients with enzyme deficiency. With the development of enzymatic technology and cell engineering, genetic engineering technology, it is possible to provide sufficient, high-purity enzyme preparations. It has long half-life, low antigenicity, good orientation, etc. The methods commonly used for this are:

A. The enzyme preparation is packaged by using a carrier such as a microcapsule, a liposome or a red blood cell shadow to reduce the immunogenicity and prolong the half life.

B. Application of receptor-mediated molecular recognition to improve directivity.

C. For some lysosomal storage diseases, because the sediment can be diffused into the blood and maintain dynamic balance, it can be treated by the "balance-removal" method.

(3) Gene therapy: Gene therapy refers to a new treatment method that uses genetic transfer technology to directly introduce genetic material into germ cells or somatic cells to treat genetic diseases and other diseases. Gene therapy for genetic diseases is expected to be Fundamentally correct the phenotypic abnormalities of genetic diseases.

1 Basic strategy of gene therapy: In the past 10 years, gene therapy research has been flourishing, and many new ideas and new ideas have been proposed. At present, the main strategies are:

A. In situ correction and in situ replacement of the gene, the purpose of this strategy is to repair the mutated gene in situ without affecting the structure and function of other genes surrounding it, with in situ correction For point mutations or small-scale mutations of genes, it is proposed to fix them by specific methods. In situ replacement, it is ideal to remove genes with a large range of mutations and replace them with normal genes. The most direct method to cure genetic variation, the current research on a number of mammalian intracellular site-directed integration (homologous recombination), provides theoretical and experimental evidence for this strategy, but has not been used in human trials.

B. Gene augmentation or gene complementation, transfer the exogenous functional gene into the diseased cell or individual genome without changing the defective gene itself, and express it to compensate for the loss of the diseased gene. This strategy is currently the most studied and the most mature method.

C. Introducing an antisense gene or other gene that targets an abnormal gene expression product into a cell, and suppressing it, or gene inhibition therapy or intercellular immunity.

2 The technical points of gene therapy are the most studied in many strategies of gene therapy. The most mature and applied to clinical trials is the strategy of gene enhancement. The whole research process usually includes preclinical studies and clinical studies (Table 1).

A. Choice of disease: At present, the first choice for gene therapy is single-gene deficient disease. The basic conditions for selection often include:

a. The genetic basis is relatively clear, and the target gene can be cloned in vitro.

b. Gene expression does not need to be finely regulated, and is often open, and the physiological level of the product is not high.

c. It has a certain incidence rate, which is harmful, and there are still other effective treatment measures.

China is one of the countries that carried out research on gene therapy earlier. Xue Jinglun of Fudan University and other countries chose hemophilia as the research object according to these conditions. It has achieved good results and reached the world advanced level. Of course, these conditions are limited. The current level of research is presented.

B. Selection of target cells: Target cells for gene therapy can be divided into two major categories: germ cells and somatic cells, which lead to the classification of germ cell gene therapy and somatic gene therapy, if it can be on germ cells or early embryonic cells. Gene repair or replacement, genetic defects can be corrected, genetic diseases can not only be treated in the contemporary era, but also can pass new genes to the next generation, and also reduce a harmful gene for the population. It is an ideal cure for genetic diseases, however, Due to modern biotechnology, theoretical limitations, and genetic manipulation of germ cells involving many factors such as ethics, morality, and law in human society, animal testing can only be carried out for a long period of time. In 1985, the US government had stipulated that Human trials of gene therapy are restricted to somatic cells, and have been used as target cells: hematopoietic stem cells, hepatocytes, fibroblasts, endothelial cells, lymphocytes, and the like.

C. Vector transfer and transfer methods: construction of appropriate transfer and expression vectors and selection of efficient gene transfer methods are the key to gene therapy. Commonly used vectors are: retroviral vector, plasmid vector and adenoviral vector, adeno-associated virus Vectors, in addition to liposome vectors, there are four main types of gene transfer methods:

a. Chemical method: mainly calcium phosphate precipitation method.

b. Physical method: commonly used conductance and microinjection.

c. Membrane fusion method: better by liposome encapsulation method.

d. Viral method: mainly refers to retrovirus and adenovirus-mediated gene transfer.

3 Prospects of gene therapy: The concept of gene therapy has been proposed for decades. It has only been nearly ten years. With the development of modern molecular biology techniques (especially DNA recombination technology), this concept has gained a powerful theory. Fundamental and technical methods were supported and put into practice. In 1990, two patients with severe immunodeficiency caused by adenosine deaminase (ADA) deficiency were successfully treated with gene therapy, which marked the beginning of a new study in gene therapy. At this stage, biomedical scientists from all over the world, with the support of various government departments and various social forces, have launched a comprehensive research on gene therapy, from a single genetic disease to a tumor, infectious disease and other diseases. New concepts such as gene regulation therapy and gene suppression therapy have been proposed. By the first half of 1994, more than 100 clinical trial programs have been approved, and some have achieved good results. Of course, the history of gene therapy development Not long, it needs a lot of research and exploration to be widely used in clinical practice, especially the following aspects:

A. A deeper understanding of the molecular basis of more genetic diseases and the regulation mechanisms of gene expression, which is the basis of gene therapy.

B. Construct vectors that are expressed and transferred more efficiently and safely.

C. Establishment of a simpler and more efficient gene transfer method.

D. Fixed point integration, in-situ repair system and other technologies.

E. More close to the actual animal model (especially the transgenic animal model), which is the only way to preclinical testing of gene therapy.

F. Discussion on ethics of somatic cell gene therapy, germ cell gene therapy, and related scientific and technological management legislation.

G. It is also necessary to fully consider the possible harms of gene therapy, such as the serious consequences caused by the insertion of mutations, the recovery of the defective virus vector after reconstitution, and the potential harm of foreign genes into the body. In short, we believe that Gene therapy, as the only one that starts from the genetic defect itself, is expected to completely cure the new therapeutic approach of genetic diseases. It has a very attractive future, but it still needs extensive and extensive research and exploration from basic theory, technical methods and ethics. In order to adapt to the modern medical model, it has been accepted by people and has become an effective means for human disease prevention and treatment.

Viscous storage disease type IV complications Complication

The disease can be complicated by sputum reflexes and sputum.

Viscous storage disease type IV symptoms common symptoms reflex hyperthyroidism reduce corneal opacity

It develops normally within 6 to 12 months after birth, and then has mild exercise retardation. The earliest signs of this type of patient are corneal opacity, corneal epithelial layer and stroma may be involved, and muscle tension may be low in the limbs. And the sputum, no face rough, no hepatosplenomegaly or mild swelling, like other types of mucolipid storage, no mucopolysaccharide urine.

Viscous storage disease type IV examination

The fibroblasts cultured in the skin are filled with lipid-containing inclusion bodies, and the size thereof is 1 to 3 m. The contents of the inclusion bodies are polymorphic, electron microscopic examination reveals electron translucent vacuoles, and some vacuoles contain Compared with dense amorphous materials, some vacuoles are composed of a membranous layered structure. Histochemical staining proves that the vacuoles contain neutral glycoproteins, lipids and a small amount of acidic mucopolysaccharides.

X-ray examination did not have any bone changes.

Visceral storage disease type IV diagnosis and identification

According to clinical features, corneal biopsy shows special inclusion bodies, cultured fibroblasts are filled with lipid inclusion bodies, and electron microscopy findings and histochemical staining results can be used to diagnose type IV of viscera storage disease.

This type of viscous storage disease has no skeletal abnormalities and can be distinguished from other types of viscous storage diseases.

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