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Introduction Gauchers disease (GD) is the most common type of lysosomal storage disease (LSD). It is an autosomal recessive disorder that causes abnormal glucocerebroside in the reticular form. Accumulation in endothelial cells. French Pitt doctor Phillipe Gaucher first reported in 1882 that 50 years later Aghion reported that Gaucher disease is due to accumulation of glucocerebroside (GC) in mononuclear-macrophages of the liver, spleen, bone and central nervous system. Caused. Brady et al. discovered in 1964 that the accumulation of glucocerebroside was caused by the deficiency of β-glucosidase-gluce brosidase (GBA), which is the diagnosis and treatment of Gaucher disease. Provide a theoretical basis. Causes (1) Causes of disease GD is an autosomal recessive hereditary disease. It is due to the deficiency of β-glucosidase-glucocerebrosidase-induced accumulation of glucocerebroside in mononuclear macrophages of the liver, spleen, bone and central nervous system. The fundamental drawback of this disease is the lack of glucocerebrosidase activity, which breaks down glucosinolates into glucose and ceramides. Often in childhood, but many also occur in infancy and adulthood. Typical pathological features are extensive reticulocyte proliferation, cells filled with glucocerebroside and fibroblasts, cell deformation, one or several The nucleus deviates from the center of the cell, which can be found in the liver, spleen, lymph nodes and bone marrow. (B) the pathogenesis lysosome (lysosome) is an organelle, that is, the ultrastructure of the cells, a single layer of coated vesicles, outside a layer of lipoprotein membrane. It is a cell processing and recycling system. The internal liquid is acidic and contains more than 60 kinds of acidic hydrolase, which can degrade various biological macromolecules such as nucleic acids, proteins, lipids, mucopolysaccharides and glycogen. The various biomacromolecules that make up the cells are in dynamic equilibrium, constantly decomposed and continuously re-synthesized. Biomacromolecules that are ingested by endocytosis also need to be broken down into different components before they can be utilized. The decomposition of these macromolecules is carried out in lysosomes. Each of the enzymes in the lysosome has its own coding gene. Defects in each enzyme directly cause a particular biomacromolecule to fail to degrade normally and accumulate in the lysosome. The common result is that the lysosomes are swollen, the cells become bloated, the cell function is seriously affected, and eventually the disease is called lysosomal storage disease (LSD). Glucocerebrosidase is a soluble glycolipid and is one of the components of cells and is widely present in the body. Normal people per gram of spleen tissue (wet weight) contain GC 60 ~ 280μg, and GD patients can be as high as 3 ~ 40.5mg. Under physiological conditions, glucosinolates derived from tissue cells of aging and death are phagocytosed by mononuclear macrophages, and then hydrolyzed by plasmin in the lysosome to form glucose and ceramide. The reaction formula is as follows: : GC H20ceramide glucose The accumulation of GC in brain tissue is mainly derived from ganglioside, and it can also be derived from various tissues such as liver, kidney and muscle. Due to GBA gene mutation, GBA in the absence of GBA production or production in vivo is inactive, resulting in GC can not be effectively hydrolyzed in mononuclear macrophages, a large number of GC in the liver, spleen, bone, bone marrow, lung and brain tissue mononuclear macrophages The cells accumulate and form typical Gaucher cells. The disease gene for Gaucher disease is located on chromosome 1. It has now been found that many different GBA point mutations are associated with pathogenesis. The gene encoding GC is located on autosome 1q21, and the gene is 7 kb in length and contains 8 exons. There is a highly homologous pseudogene at 16 kb downstream of this gene. GD patients can be found in missense mutations, splicing mutations, metastatic mutations, gene deletions, gene and pseudogene fusion. The most common mutations are missed, resulting in a decrease in the catalytic function and stability of the GC. Different human genotypes vary in variation. For example, N370S is the most common in the Ashkenzi Jewish population. It is only found in type I patients, and homozygous is mild. There is no such variant in the Asian population. L444P can be found to be homozygous in patients with type I, II and III, often with neurological symptoms. There are more than 100 genetic mutations identified in GD patients. Ten genotypes of Chinese GD have been reported, of which 5 are type I G46E/L444P, F37V/L444P, N188S/L444P, Y205S/L444P and R48W/R120W; 2 cases of type II were F213I/L444P; 3 cases of type III were N409H/N409H, G202R/N409H and L444P/L444P, of which L444P genotype was the most common, occupying 40% of alleles and appearing in each type of GD in. F37V and Y205C are unique new mutations in Chinese. Symptoms Any age can occur from birth to age 80, but it is more common in children and children, and more than 7 years old. Can be divided into three types: 1. Adult type (type I) is the most common type of disease, and is also common in lipid storage diseases. More common in the Jews (Ashkenazi-Jewish nation), but among all ethnic groups. In the United States, it is estimated that there are fewer than 5,000 children per year. You can get sick at any age, often go to the spleen for medical treatment. Progress can be fast or slow, slow progress, especially spleen, sometimes spleen infarction or spleen rupture and acute abdomen symptoms. The liver is progressively enlarged, but not as swollen as the spleen. For a long time, the skin and mucous membranes are tea yellow, often misdiagnosed as jaundice, and the exposed parts such as the neck, hands and calves are the most obvious, brownish yellow. There are often cleft palate cracks on the conjunctiva of the eyeball. The bottom is at the edge of the cornea. The tip points to the inner and outer ridges. It is yellowish white at first and then turns brownish yellow. Pulmonary fatigue can affect the gas exchange and cause symptoms. Patients with advanced limbs may have bone pain, even pathological fractures. The lower end of the femur is the most common, and may also involve the femoral neck and spinal bone. When there is hypersplenism, there may be bleeding tendency due to thrombocytopenia. Pediatric patients are often affected by height and weight. 2. Infant type (type II) The child can have large liver and spleen after birth. It is obvious after 3 to 6 months. It has difficulty in sucking, swallowing, and poor growth and development. The symptoms of the nervous system are prominent, the neck is straight, the head is reclined, the muscle tension is increased, the horn arch is reversed, the tendon reflex is hyperthyroidism, and finally it becomes soft palate, and there is no reaction. When the cranial nerve is involved, there may be symptoms such as internal oblique and facial paralysis. Easy to concomitant infection. Due to the short course of the disease, more deaths than infancy, the liver and spleen enlargement is not as obvious as the adult type, no skin pigmentation, and bone changes are not significant. 3. Juvenile type (type III) is often caused by the onset of 2 years to adolescence. The splenomegaly is often found during physical examination and is generally moderately enlarged. The disease progresses slowly, and the central nervous system symptoms gradually appear, such as: myoclonic convulsions, uncoordinated movements, insanity, and finally bedridden. The liver is often slightly enlarged, but it can also be progressively enlarged and severely impaired liver function. According to the liver, splenomegaly or central nervous system symptoms, bone marrow examination, typical Goce cells, serum acid phosphatase increased can make a preliminary diagnosis. Further diagnosis should be done to determine the GC activity of leukocytes or skin fibroblasts. It is worth noting that sometimes a pseudo gaucher's cell, which is similar to Gaucher cells, is seen in the bone marrow. It can occur in chronic myeloid leukemia, thalassemia, multiple myeloma, Hodgkin. Lymphoma, plasmacytoid lymphoma and chronic myelogenous leukemia. It differs from the Gaucher cells in that there is no typical tube-like structure in the cytoplasm. GC enzyme activity can be determined in differential diagnosis. Electroencephalography can detect early infiltration of the nervous system, and there are a wide range of abnormal waveforms before the onset of neurological symptoms. Type III patients are difficult to differentiate from type I before neurological symptoms appear. EEG examination can predict whether patients may have neurological symptoms in the future. Prenatal diagnosis: The mother of the patient may take the prenatal diagnosis of the villus or amniotic fluid cells after the pregnancy, and if the genotype of the patient has been determined, the prenatal genetic diagnosis may also be performed. Typical cells can be found in specimens of bone marrow, spleen puncture or liver biopsy. Cell culture without cerebroside esterase activity can be clearly diagnosed. Gaucher disease can be prenatally diagnosed by amniocentesis or villus sampling. DNA technology can diagnose specific Gaucher disease alleles, genes encoding glucuronide Located at the Iq21 position of the human chromosome. Diagnosis of this disease should be identified with the following diseases. 1. Niemann-Pick disease (sphingomyelin storage disease) is found in infants, and the liver and spleen are also swollen, but the liver is larger than the spleen; the central nervous system symptoms are not as significant as Gaucher disease. The main identification point is the cherry red spot on the macula. The special cells seen in the bone marrow are significantly different from Gaucher disease, and the acid phosphatase reaction is negative, which can be identified by combining other histochemical staining. 2. Some metabolic diseases such as GM1 ganglioside storage disease in lipid storage disease, fucosidosis storage disease and mucopolysaccharidosis type IH (Hurler syndrome), have hepatomegaly and spleen Large and nervous system performance, but GM1 ganglioside storage disease is 50%, there are red spots on the macula, and there are foam cells in the bone marrow. All three have ugly face, large tongue, and hypertrophy of the heart. Sexual bone dysplasia changes, fucoside storage disease still has skin thickening and difficulty breathing. 3. Diseases with hepatosplenomegaly such as leukemia, Hodgkin's disease, Hand-Schüller-Christian disease, and severe globin-producing anemia in blood diseases are generally not difficult to identify. Han-Xu-Ke disease has bone defects and/or exophthalmos and/or diabetes insipidus in addition to liver and splenomegaly. In addition, it should be differentiated from kala-azar and schistosomiasis. 4. Disease with Gaucher cells Gaucher cells can be found in chronic myeloid leukemia, severe globin-producing anemia, chronic lymphocytic leukemia, in which β-glucocerebrosidase is normal, but due to too many white blood cells For example, in chronic myeloid leukemia, the daily conversion rate of sphingolipids is 5 to 10 times normal; when heavy globin-producing anemia occurs, the sphingolipid conversion rate of red blood cells also increases, surpassing the catabolic ability of tissue macrophage system. And the deposition of glucocerebroside occurs to form Goscher cells. Gossip cells can also be present in AIDS and mycobacterial infections and Hodgkin's disease. Identification depends on clinical, auxiliary examination and determination of β-glucocerebrosidase. 5. Spleen lymphoma/leukemia: Microscopically consistent lymphoma cells/leukemia cell infiltration in the spleen, immunophenotype showed clonal growth of heterotypic cells. For unexplained hepatosplenomegaly and mild anemia or with progressive developmental retardation, mental retardation, pathological fractures should be thought of the possibility of the disease, bone marrow puncture smear, resection of the pathological section of the specimen to find Gaucher cells, help The diagnosis of the disease depends on the culture of white blood cells and skin fibroblasts. The isotope-labeled glucosides are used as substrates, and the β-glucosidase activity is measured. The glucosidase activity is <20% (the carrier is 60% or less). ), while serum acid phosphatase activity is high. Complications 1. The main complication is spleen infarction or spleen rupture and life-threatening. The normal structure of the spleen is destroyed and fibrosis; the liver has varying degrees of fibrosis. Read more...

Introduction Incontinentia pigmenti is also known as Bloch-sulzberger disease or Blohh-si-ments syndrome. It is a hereditary disease. After erythema, blisters, warts or inflammation changes, pigmented skin lesions may be present, which may be associated with defects in the eyes, bones, and central nervous system. Etiology (1) The cause of the disease is a sexually linked X-linked dominant genetic disease, more women than men. (2) The abnormal gene of the pathogenesis-linked X-linked dominant inheritance is only located in one of the two X chromosomes, and the pathogenic gene can be protected by another normal X gene, so the lesion is not serious and the survival rate is high. There is only one X gene in men. If it is a disease-causing gene, the lesion is heavier and often dies in the uterus. There are often close relatives married and family genetic history. Symptoms occur shortly after birth and rarely occur after 2 months. The damage is divided into three phases: erythema and bullae; papules and sickle lesions; pigmentation. They occur irregularly, overlap each other, and are diversified. The lesions are characterized by taupe and black-gray spots, which are irregular in shape such as lines, drops, threads, and marbles. They are arranged in an orderly manner and are often distributed in the trunk, upper arms, and thighs (Fig. 1). Before the appearance of pigmented spots, there are often bullae, Nissl's sign is negative, one after another, after the blisters disappear, red smooth nodules and plaques can be seen. Blue to brown splatter-like pigmentation spots can appear in the skin lesions. Color spots can gradually fade after several years, until 20 to 30 years old, and some are accompanied by atrophy and hardening. Children with pseudo-alopecia areata, nail dysplasia, nail defect, nail deformity, eye damage accounted for about 30%, showing cataract, strabismus, optic atrophy, blue sclera, exudative choroiditis, etc.; bone abnormalities are rare Such as and refers to (toe), multi-ribs, osteoma, partial atrophy and tooth defects; delayed or partially toothless. The central nervous system can also be affected, showing mental retardation, microcephaly, epilepsy, paralyzed limb paralysis, short arms, short legs and so on. According to the clinical manifestations, the characteristics of skin lesions and histopathological features can be diagnosed. Diagnosis 1. Franceschetti-Jadassohn syndrome Some people think that the disease is a heterogeneous pigment incontinence, the color is reticular, no water droplets, early no blister, sickle damage. There are also no tooth and eye damage. 2. Depigmentation pigment incontinence is more common in girls, colorless and opaque, only color spots, no blister in the early stage, no inflammation, no family history. 3. Pigmented urticaria Also known as mastocytosis, the pigmented spots of the disease are not in the form of water droplets, stimulating pigment spots can appear wheal, skin scratch marks positive, histopathology shows that a large number of mast cells can be seen in the dermis. Complications are currently not described in the relevant content. Treatment (a) treatment of pigmented spots can be self-retardant, generally no treatment. Corticosteroids can be applied to the early period of vesicular inflammation. TCM treatment: the inflammatory phase should be detoxification and cooling blood, and the detoxification and cooling blood soup should be added or subtracted. In the later period, the method should be spleen and dehumidification, and the spleen and dehumidification soup should be added or subtracted. (B) prognosis color spots can continue to fade after several years, until 20 to 30 years old, it is observed, and some are accompanied by atrophy and hardening.

Introduction This disease is a chronic progressive, bilateral retinal degeneration of the carpet. It is often difficult to determine the type of inheritance. Most cases are autosomal recessive, but they can also be autosomal dominant or X-linked, while the latter are not common. The disease may also be part of certain syndromes (eg, Bassen-Kornzweig syndrome, Laurence-Moon-Biedl syndrome). The cause is a hereditary disease. Its genetic pattern is autocrine recessive, dominant and sexually linked recessive. The autosomal recessive inheritance is the most; the dominant is second; the sexual linkage recessive inheritance is the smallest. At present, the autosomal dominant inheritance is considered to have at least two gene loci, located on the short arm of the first chromosome and the long arm of the third chromosome. The sex-linked genetics are located in the short-wall region of the X chromosome and in the second region. Regarding the pathogenesis, in the past 20 to 30 years, there have been some clues to the valve. According to the electron microscopy, histochemistry, electrophysiology, fundus fluorescein angiography and other examination data, it is speculated that the occurrence of this disease is mainly due to the phagocytosis and digestive function of the retinal pigment epithelial cells to the extracellular disk membrane, resulting in disc film disintegration. Residues, procedures form a layer of obstacles, hinder the rotation of nutrients from the choroid to the retina, causing progressive malnutrition and progressive degeneration and disappearance of visual cells. This process has been confirmed in a retina of RCS mice with primary retinal pigmentation. As for the cause of phagocytic digestive failure of pigment epithelial cells, it is still unclear. May be associated with genetic abnormalities, the lack of certain or certain enzymes. In immunology, in recent years, studies have found that patients with this disease have abnormal humoral and cellular immunity, activated T cells, B cells and macrophages in the vitreous, and retinal pigment epithelial cells express HLA-DR antigen, but normal people do not. Performance. At the same time, it is also found that patients with this disease have autoimmune phenomena, but there is still no sufficient basis for whether the disease has autoimmune diseases. In terms of biochemistry, it is also found that patients with this disease have autoimmune phenomena, but there is still no sufficient basis for whether the disease has autoimmune diseases. In terms of biochemistry, it was found that the patients had abnormal lipid metabolism and accumulation of lipofuscin in the retina; trace elements such as zinc, copper and selenium and enzyme metabolism were also abnormal. In summary, the disease may have a variety of different pathogenesis. Symptoms Retinal stalks are involved, resulting in night blindness and a symptom that occurs early in childhood. The mid-circumferential dark spots (found through visual field examinations) gradually expanded, resulting in a loss of vision in the final center. The most prominent finding under ophthalmoscopy is the presence of a melanocyte-like appearance of melanin in the equator of the retina. Retinal artery stenosis, the nipple can be yellow wax color. Other clinical manifestations include degenerative vitreous opacity, cataract and myopia, which may be associated with congenital hearing loss. Diagnosis can be by special examination (eg dark adaptation, electroretinogram). Other retinopathy similar to retinitis pigmentosa (such as those with syphilis, rubella, chloroquine poisoning) must be excluded, and the patient's family should be examined to determine their genetic pattern. Diagnosis and differential identification of secondary retinitis pigmentosa after congenital or acquired chorioretinal inflammation. Congenital syphilis and fetal fundus lesions caused by pregnant women in the third month of pregnancy, the fundus findings after birth are almost identical to the disease, ERG, visual field and other visual function test results are also difficult to distinguish. Primary pigmentation can only be diagnosed after determining that the child's parental serum syphilis response is negative and that the mother has no history of rubella in the early pregnancy. If necessary, it will take a long time to follow-up observation. Congenital secondary pigmentary degeneration is already present at birth and the condition is still. Acquired syphilis and certain acute infectious diseases (such as smallpox, measles, scarlet fever, mumps, etc.) can occur in chorioretinitis, and the fundus changes after inflammation subsides, sometimes similar to primary pigmentary degeneration. When the medical history, serological examination and fundus pigmentation are large, the position is deep, irregular (non-osteocyte-like), choroidal retinal atrophy, optic disc atrophy is grayish white (not waxy yellow), and night blindness is lighter. Identification. Polar cataract after complications is a common complication of this disease. It usually occurs in the late stage, the crystal turbidity is star-shaped, and it is located in the inferior cortex of the posterior capsule. The progress is slow, and finally the whole crystal is turbid. About 1% to 3% of cases are complicated by glaucoma, mostly wide angle, and the angle of closure is rare. Some people have studied from a statistical point of view and believe that glaucoma is associated with the disease rather than complications. About 50% of cases are accompanied by myopia. Myopia is more common in patients with autosomal recessive and sex-linked recessive inheritance. It can also be found in other members of the family. Deaf-mute disease and the disease also reached 19.4%. Both the retina and the inner ear Corti are derived from the neuroepithelial, so the progressive degeneration of both may be from the same gene. Pigmentation and deafness can occur not only in the same patient, but also in different members of the same family, but the two do not seem to be derived from different genes, possibly due to the multi-directionality of the same gene. The disease may be associated with other hereditary diseases, the more common one is the Laurence-Moon-Bardt-Biedl syndrome, which is caused by the pituitary region and the retina. Typical individuals have five components: retinitis pigmentosa, genital dysplasia, obesity, multiple fingers (toe) and intelligent defects. The syndrome occurs in the early stages of development and has significant clinical manifestations around the age of 10 (or earlier). The five components are not owned, and are called incomplete. In addition, the disease has a blink of an eye or other organs complicated or associated with diseases, rare. Treatment lacks effective treatment in slowing the course of retinal degeneration. In recent years, the fetal retinal nerve layer has been transplanted into patients, and preliminary reports have confirmed that vision can be improved. In the literature, there are trials of vasodilators, vitamin A and B1, tissue therapy, various hormones, Chinese herbal medicines, acupuncture and other methods, or to avoid rapid deterioration of visual function. 1. The choice of blackout glasses can accelerate the appearance of extracellular nodules, so it is necessary to wear blackout glasses. In theory, the color of the lens should be red and purple in the same color as the red, but it is harmful to the gray for beauty, 0 to 1 for cloudy or indoor use, and 2 to 3 for gray or sunny. Dark black sunglasses are not suitable. Green lenses are disabled. 2, to avoid mental and physical over-stress When excessive stress, catecholamine increases in body fluids, choroidal blood vessels thus contract and in hypoxia, causing denaturation of visual cells. China's traditional Qigong (static power), with its own will, high-speed cerebral cortex and the activities of various organs of the body, such as perseverance, may be beneficial to prevent the rapid deterioration of the visual function of this disease. The above content is for reference only, please consult the relevant physician or relevant medical institution if necessary. Prevention of recessive hereditary patients with early onset, serious illness, rapid development, and extremely poor prognosis. At the age of 30, the visual function has been highly deficient, and it is nearly blind until the age of 50. In patients with dominant inheritance, the opposite is true, and occasionally it develops to a certain extent and then tends to be stationary, so the prognosis is relatively better than the recessive genotype. Therefore, you can wait until you are barely able to attend school and find employment. The insidious inheritance of this disease, its ancestors have a history of close relatives, and the prohibition of close relatives can reduce the incidence of this disease by about 22%. In addition, patients with recessive inheritance should try to avoid marriage with family members of the disease, and can not marry those who also suffer from this disease. In patients with dominant inheritance, the risk of developing this disease in their children is 50%.

Introduction: Parkinson's disease, also known as idiopathic Parkinson's disease (PD), referred to as Parkinson's disease, also known as paralysis agitans (shaking palsy), is a common neurodegenerative disease in the elderly. The most common extrapyramidal disease in the elderly. The main lesions are in the substantia nigra and striatum pathways, and dopamine production is reduced. The prevalence rate of people over 65 years old is 1000/100,000. With age, men are slightly more than women. The main clinical features of the disease: resting tremor, slowness and reduction of movement, increased muscle tone, and instability of posture are the main features. Causes: (1) The cause of idiopathic Parkinson's disease has not been known so far. Some central nervous system degenerative diseases with Parkinson's disease symptoms, mainly degeneration of different parts of the central nervous system, there are other clinical features, it can be called symptomatic Parkinson disease, such as progressive supranuclear palsy (PSP), lines Sexual substantia nigra degeneration (SND), Shy-Drager syndrome (SDS) and olive pons cerebellar atrophy (OPCA). There are also some diseases or factors that can produce clinical symptoms similar to PD, such as infection, drugs (dopamine receptor blockers, etc.), poisons (MPTP, carbon monoxide, manganese, etc.), vascular (multiple cerebral infarction) and brain trauma. Etc., clinically known as Parkinson's syndrome (Palkinsonism). So far, the cause of PD remains unclear. Current research tends to be associated with a combination of ageing, genetic susceptibility, and exposure to environmental toxins. 1) Ageing: Parkinson mainly occurs in middle-aged and elderly people. It is rare to have a disease before the age of 40, suggesting that ageing is related to the disease. Studies have found that from the age of 30, dopaminergic neurons, tyrosine oxidase and dopa decarboxylase activity, striatum dopamine transmitter levels gradually decrease with age. However, only a small number of elderly people suffer from this disease, indicating that physiological dopaminergic neurons are not enough to cause disease, and age aging is only a trigger for the onset of this disease. 2) Environmental factors: Epidemiological survey results show that there is a regional difference in the prevalence of Parkinson's disease, so people suspect that there may be some toxic substances in the environment, which damage the brain's neurons. 3) Genetic susceptibility. In recent years, Alα53THr mutation of a common nuclear gene has been found in patients with familial Parkinson's disease. But it has not been confirmed many times in the future. 4) Family hereditary: In the long-term practice, medical scientists found that Parkinson's disease seems to have a tendency to family aggregation. The family members of patients with Parkinson's disease have a higher incidence than their normal counterparts. It is now widely accepted that Parkinson is not a single factor and multiple factors may be involved. Genetic factors can increase the susceptibility to disease, and only through interaction with environmental factors and aging, through oxidative stress, mitochondrial failure, calcium overload, excitatory amino acid toxicity, apoptosis, immune abnormalities and other mechanisms lead to black A large number of degeneration of dopaminergic neurons are lost and the disease occurs. (B) pathogenesis 1. The pathogenesis is very complicated and may be related to the following factors. (1) Age aging: PD mainly occurs in middle-aged and elderly people. It is rare before 40 years old, suggesting that aging is related to the disease. The study found that from the age of 30, the activity of DA neurons, tyrosine hydroxylase (TH) and dopa decarboxylase (DDC), striatum DA transmitter decreased, DAD1 and D2 receptor density decreased. However, the elderly suffer from PD, after all, is a minority, indicating that physiological DA can degenerate neurons to cause the disease. In fact, only the substantia nigra DA neurons can be reduced by more than 50%, and the striatum DA transmitters are reduced by more than 80%. The symptoms of PD will appear in the clinic, and aging is only the triggering factor of PD. (2) Environmental factors: Epidemiological surveys show that long-term exposure to pesticides, herbicides or certain industrial chemicals may be a risk factor for PD. In the early 1980s, some drug users in California used a neurotoxic substance, the pyridine derivative 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP), which appeared to be like primary. Some pathological changes, biochemical changes, symptoms and drug treatment responses of PD have similar effects on monkeys injected with MPTP. Neurotropic MPTP and certain insecticides and herbicides may inhibit the activity of NADH-CoQ reductase (complex I) in the mitochondrial respiratory chain of the substantia nigra, resulting in decreased ATP production and increased free radical production, leading to degeneration of DA neurons. There is significant lipid peroxidation in PD substantia nigra, and reduced glutathione is significantly decreased, suggesting that antioxidant mechanisms and oxidative stress may be related to PD. (3) Genetic factors: About 10% of patients have a family history, with incompletely explicit autosomal dominant or recessive inheritance, and the rest are sporadic PD. Twin-consistent studies have shown that genetic factors may play an important role in some young (<40 years old) patients. It has been determined that 10 single genes such as PARK 1～10 are related to PD, and it has been confirmed that three gene products are related to familial PD: 1α-synuclein is a mutation of PARK1 gene, and the gene is located on chromosome 4 long arm 4q21～ 23, α-synuclein may increase the sensitivity of DA neurons to neurotoxin; 2 Parkin is a mutation of PARK2 gene, located on chromosome 6 long arm 6q25.2~27; 3 ubiquitin C-terminal hydroxylase- L1 is a mutation in the PARK5 gene and is located on the short arm 4p14 of chromosome 4. The cytochrome P45O2D6 gene and some mitochondrial DNA mutations may be one of the susceptible factors of PD, which may reduce the activity of P450 enzyme, impair the detoxification function of the liver, and easily cause damage to the nigrostriae by toxins such as MPTP. (4) Oxidative stress and free radical formation: Free radicals can cause lipid peroxidation (LPO) of unsaturated fatty acids, which can oxidize damage to proteins and DNA, leading to cell degeneration and death. Due to the increased activity of type B monoamine oxidase (MAO-B), patients with PD can produce excess OH groups and destroy cell membranes. At the same time of oxidation, the DA oxidation product in the substantia nigra cells polymerizes to form neuromelanin, which combines with iron to produce a Fenton reaction to form OH. Under normal circumstances, there are enough antioxidants in the cells, such as glutathione (GSH), glutathione peroxidase (GSH-PX) and superoxide dismutase (SOD) in the brain, DA Oxidation produces free radicals that do not produce oxidative stress and are protected from free radical damage. PD patients have reduced GSH and increased LPO in the substantia nigra, increased iron ion (Fe2) concentration and decreased ferritin content, making the substantia nigra a site susceptible to oxidative stress. (5) Mitochondrial function defects: In recent years, it has been found that mitochondrial function defects play an important role in the pathogenesis of PD. The understanding of mitochondrial dysfunction in PD patients stems from the study of the mechanism of action of MPTP, which causes Parkinson's disease by inhibiting the activity of the mitochondrial respiratory chain complex I. In vitro experiments confirmed that MPTP active ingredient MPP can cause a decrease in mitochondrial membrane potential (ΔΨm) and an increase in oxygen free radical production in MES 23.5 cells. The activity of mitochondrial complex I in the patients with PD can be reduced by 32% to 38%, and the decrease in the activity of the complex alpha increases the sensitivity of the nigral cells to free radical damage. No change in complex I activity was observed in the substantia nigra of patients with multiple system atrophy and progressive supranuclear palsy, suggesting that the decrease in PD substantia nigra I activity may be a relative change in PD. The presence of mitochondrial dysfunction in PD patients may be related to genetic and environmental factors. Studies suggest that mitochondrial DNA mutations exist in PD patients. Complex I is encoded by both nucleus and mitochondria. Any fragment defect in both groups can affect complex I function. . (6) Excitotoxicity: Some authors used microdialysis and HPLC to find that the content of excitatory amino acids (glutamate, aspartic acid) in the striatum of PD monkey model prepared by MPTP was significantly increased. If the extracellular space glutamate concentration is abnormally increased, the receptor will be over-stimulated and it will have a significant toxic effect on the CNS. Animal experiments have found that intracerebral injection of trace glutamate can cause large neuronal necrosis. Glutamate neurotoxicity acts through receptors. NMDA receptor-mediated excitotoxicity is associated with DA neuron degeneration. Glutamic acid can damage nerve cells by activating nitric oxide (NO) by activating NMDA receptors, and releasing more excitatory amino acids, further aggravating neuronal damage. (7) Cytotoxicity of calcium: human aging may be associated with increased concentration of free Ca2 in nerve cells, decreased Ca2/Mg2-ATPase activity, and decreased mitochondrial calcium storage capacity. Changes in intracellular Ca2 concentration affect many important functions of neurons, such as cytoskeletal maintenance, neurotransmitter function, protein synthesis and Ca2-mediated enzyme activity, calcium-binding protein, especially 28KD vitamin D-dependent calcium-binding protein (Calbindin-D28K) May play an important role, related to calcium / magnesium - ATPase activation, with neuroprotective effects. Icopini and Christakos reported that the content of Calbindin-D28K and mRNA in the substantia nigra, hippocampus and dorsal nucleus of PD patients were significantly lower than those in normal subjects, suggesting that the decrease of calbindin gene expression may also lead to cytotoxicity. (8) Immunological abnormalities: Abramsky (1978) proposed that PD is associated with immune abnormalities. Clinical studies have found that PD patients have decreased cellular immune function and decreased IL-1 activity. McRae-Degueurce et al reported the presence of anti-DA neuron antibodies in cerebrospinal fluid (CSF) of PD patients. Cell culture found that PD plasma and CSF inhibited the function and growth of DA neurons in the midbrain of rats. Stereotactic injection of blood IgG into PD patients was observed, and the tyrosine hydroxylase (TH) and DA neurons were significantly reduced, suggesting that it may initiate or participate in immune-mediated nigral cell damage. Tumor necrosis factor-α (TNF-α), IL-6, epidermal growth factor (EGF), transfer growth factor-α (TGF-α) and β2-microglobulin (β2-MG) may be involved in the pathogenesis of PD. (9) Apoptosis: Studies have shown that there are apoptosis, free radicals, neurotoxins and neurotrophic factors in the pathogenesis of PD. Agid (1995) detected the apoptotic morphological and biochemical features of DA neurons in patients with PD, and found that about 5 neurons in the brain of PD patients have characteristic apoptosis and TNF-α receptor (α-TN- FR) and bcl-2 proto-oncogene expression, apoptosis may be a basic step in the degeneration of DA neurons. It is generally believed that PD is not a single factor causing disease and may involve multiple factors. Genetic factors increase the susceptibility to disease, and under the combined action of environmental factors and ageing, the degeneration of DA neurons can be induced by oxidative stress, mitochondrial failure, calcium overload, excitatory amino acid toxicity and apoptosis. Causes the disease. 2. Pathological changes The main pathological changes of PD are degeneration and loss of pigment-containing neurons, and the DA neurons of the substantia nigra pars compacta are most prominent. Microscopically, neuronal cells were reduced, melanocytes in the substantia nigra disappeared, and melanin particles were scattered in tissues and macrophages, with varying degrees of gliosis. Normal human substantia nigra cells decrease with age. When the substantia nigra cells are 80 years old, they are reduced from the original 425,000 to 200,000, and there are less than 100,000 PD patients. When symptoms appear, DA neurons can lose more than 50%, blue spots. Mild changes were also observed in the nucleus of the nucleus, the dorsal nucleus of the vagus nerve, the globus pallidus, the putamen, the caudate nucleus, and the subthalamic nucleus. Lewy corpuscles in the cytoplasm of residual neurons are important pathological features of this disease. Lewy bodies are glass-like masses composed of cytoplasmic proteins with a dense core in the center and a filamentous halo around them. . A cell can sometimes be seen in a number of different sizes of Lewy bodies, found in about 10% of residual cells, black matter is obvious, globus, striatum and blue spots are also visible, α-synuclein and ubiquitin are Lewy small An important component of the body. 3. Neurochemical changes DA and acetylcholine (Ach) act as two important neurotransmitters in the striatum, and their functions are mutually antagonistic. Maintaining the balance between the two plays an important role in regulating the activity of the basal ganglia. The DA transmitter pathway in the brain is mainly a substantia nigra-striate system. The DA neurons of the substantia nigra pars compacta take L-tyrosine from the bloodstream and form levodosine under the action of intracellular tyrosine hydroxylase (TH). L-dopa; further produces dopamine (DA) by dopamine decarboxylase (DDC); through the substantia nigra-striatum bundle, DA acts on the putamen, caudate nucleus, and is decomposed into High vanillic acid (HVA). Due to a decrease in TH and DDC in idiopathic Parkinson's disease, DA production is reduced (L-dopa is reduced by L-tyrosine production, and DA production is decreased). Monoamine oxidase B (MAO-B) inhibitor can reduce DA catabolism in neurons and increase DA content in brain. The catechol-oxygen-methyltransferase (COMT) inhibitor reduces peripheral metabolism of L-dopa and maintains a stable plasma concentration of L-dopa. Degeneration of the substantia nigra DA neurons in PD patients, degeneration of the nigrostriatal striatum DA pathway, and a significant decrease in the striatum DA content (>80%), which makes the Ach system function relatively hyperactive, leading to increased muscle tone and reduced movement. The biochemical basis of the symptoms of exercise. In recent years, the DA content in the midbrain-marginal system and the midbrain-cortex system has also been significantly reduced, which may lead to advanced neurological activity disorders such as mental decline, behavioral abnormalities, and speech disorder. The degree of DA transmitter reduction is consistent with the patient's symptom severity. The early stage of the lesion is increased by the rate of DA renewal (pre-synaptic compensation) and the DA receptor is hyper-sensitive (post-synaptic compensation), and the clinical symptoms are not obvious. Reimbursement), typical PD symptoms (decompensation period) with disease progression. Other basal ganglia or neuropeptides such as norepinephrine (NE), serotonin (5-HT), substance P (SP), enkephalin (ENK), and somatostatin (SS) also vary. Symptoms: Clinical manifestations of PD usually occur between the ages of 40 and 70 years. After 60 years of age, the incidence is increased. Before the age of 30, the incidence is rare. In a group of 380 patients with PD, only 4 cases; slightly more males. Insidious onset, slow development, mainly manifested in resting tremor, increased muscle tone and retarded exercise, etc., the symptoms appear first and then vary from person to person. The first symptom was the most tremor (60% to 70%), followed by walking disorders (12%), myotonia (10%), and bradykinesia (10%). Symptoms often start from one upper limb, gradually affecting the ipsilateral lower limb, contralateral upper limb and lower limb, showing an "N" shape progression (65% to 70%); 25% to 30% of cases can start from one lower limb, two Lateral lower limbs are rare at the same time. In many cases, there are still left and right differences in the symptoms of advanced disease. Read more...

Introduction Epidermolysis bullosa (EB) is divided into hereditary and acquired. Hereditary EB includes at least 23 different types, which can be divided into three categories according to the location of the disease: 1 simple bullous epidermolysis (simplexEB, EBS), blisters in the epidermis 2 borderline bullous epidermolysis (junctionalEB, JEB), blisters occur in the transparent layer; 3 dystrophic dystrophic EB (DEB), blister occurs in the dense lower layer. Pathogenesis [Etiology and pathogenesis] It has been confirmed that EBS is involved in gene mutations encoding keratin 5 and 14; JEB is involved in gene mutations encoding substances such as laminin 5 and xVII collagen; DEB and gene mutations encoding type VII collagen related. Due to mutations in the genes encoding the structural components of the epidermis and the basement membrane, these proteins are structurally or structurally abnormal, resulting in the production of blisters at different anatomical sites. Clinical manifestations A common feature of all types of bullous epidermolysis is the appearance of blisters and blood blisters after a slight friction or collision (Figure 25-4). Occurs in the extremities and the extremities of the limbs. In severe cases, it can involve any part. After the leather bed is combined, a scar or a millet rash can be formed, and the skin lesions with repeated attacks on the extremities can cause the nails to fall off. The simple type only affects the extremities and the extremities of the extremities, does not involve the mucosa, and the lesions are the most superficial, and generally no scars are left after the healing. Malnourished type can affect any part (including mucosa), the condition is more serious, often after birth, skin lesions appear, and the position is deep, leaving obvious scars after healing, repeated blisters and scars on the extremities can make the fingers Between the skin adhesions, the phalanx atrophy forms a claw-shaped hand; the oropharynx mucosa repeatedly collapses, crusting can cause mouth opening, difficulty swallowing, and poor after treatment. Border type is rare, widespread blisters, bullae and erosion surface appear after birth The prognosis is poor, and most of them die within 2 years old. [Histological pathology and immunopathology] Transmission electron microscopy and immunohistochemistry showed that the blister of EBS was located in the epidermis, the blister of DEB was located in the dense lower layer, and the blister of JEB was located in the transparent layer. [Diagnosis and differential diagnosis] According to family history, clinical features, combined with immunohistochemistry and transmission electron microscopy can generally confirm the diagnosis and classification. It should be differentiated from acquired bullous epidermolysis. The clinical manifestations of the latter are similar to those of hereditary bullous epidermolysis. There may be anti-basement membrane autoantibodies in serum. In addition, it should be differentiated from bullous pemphigoid and pemphigus. There is currently no specific treatment for treatment. The skin should be protected from friction and compression. Non-adhesive synthetic dressings, sterile gauze or broad-spectrum antibiotic ointments can be used to prevent infection, and supportive therapy should be strengthened.

Introduction X-linked adrenal leukodystrophy (ALD) is a refractory neurodegenerative disease associated with the accumulation of very long-chain saturated fatty acids (VLCFA) in tissues and body fluids. We have established a Japanese ALD diagnostic center using VLCFA measurement and mutation analysis. ABCD 1 identified 60 mutations in 69 Japanese ALD families, including 38 missense mutations, 6 nonsense mutations, 8 frame translocation mutations, 3 amino acid deletions, 2 exon mutations, and large deletions. 3 types. By reference to the current worldwide ALD mutation database, 24 mutations (40%) were found in Japanese patients. In these 69 families, there was no significant correlation between these mutations and phenotype in 81 male patients. About 12% of ALD patients Drewo performed mutation analysis on male probands and their mothers, providing useful data for genetic counseling. The only effective treatment for brain-type ALD is early hematopoietic stem cell transplantation. Therefore, we conducted extensive family screening of probands and conducted pre-tympanic diagnosis of ALD through genetic counseling, and established long-term for these patients. Follow-up system to prevent progression of brain involvement and to monitor adrenal insufficiency. Further elucidation of the pathology of ALD, especially the mechanism of brain involvement, is worth looking forward to. Introduction X-linked adrenal leukodystrophy is one of the most common peroxisome diseases involved in the oxidation of saturated long-chain fatty acids (β), leading to the accumulation of fatty acids in tissues and plasma. The pathogenic gene of ALD, ABCD 1 has been mapped to Xq 28, a gene of the peroxisome membrane protein homologous to the ATP-binding cassette transporter family, which acts as a VLCF- on the peroxisome membrane. The transporter of CoA. Clinical manifestations include childhood brain type (CCALD), adolescent brain type, adult brain type, adrenal myelinopathy (AMN), Olivo-P-cerebellar type and Addison's disease. 1CCALD is the most common phenotype characterized by progression of intellectual, psychological, visual, and gait disorders between the ages of 3 and 10. The prognosis of CCALD is generally poor, and patients are thought to die within a few years, but good comprehensive care improves the prognosis of these days. Hematopoietic stem cell transplantation (HSCT) is currently the only treatment that can prevent brain-type ALD brain involvement, but HSCT is only effective in patients with early brain symptoms. 2 Therefore, we established a rapid diagnostic system for ALD patients, combined with the detection and mutation analysis of VLCFA in serum, established a rapid diagnosis system for ALD patients. ABCD 1 gene. Even so, even now, only about one-third of CCALD patients have received HSCT in Japan (data not shown), so pre-tympanic diagnosis and early intervention are important to overcome this thorny disease. Diagnostic System and Mutation Range of ALD Patients in Japan This paper analyzed the VLCFA in serum or plasma of suspected ALD patients with clinical and brain magnetic resonance imaging (MRI) by gas chromatography/mass spectrometry. 3 These patients were diagnosed with an increase in VLCFA, and then we performed molecular analysis. ABCD 1 gene. The ratio of C24:0/C22:0, C25:0/C22:0 and C26:0/C22:0 in male ALD patients was significantly higher than that in the control group, but some female carriers had C24:0/C22:0, C25 The ratio of :0/C22:0 and C26:0/C22:0 overlaps with the control value (Figure 1). Moser et al. 4 also reported that 85% of obligate heterozygotes have abnormally high VLCFA levels, but normal results do not preclude carrying status. Therefore, male ALD patients can only be diagnosed by an increase in VLCFA, but female carriers should conduct molecular analysis. ABCD 1 in order to get an accurate diagnosis. In addition, our data showed that mutations in male probands and their mothers were analyzed in 33 families, 4 of whom found no mutations in the proband, which means approximately 12% of ALD patients There may be mutations. Drevo mutation. In the ALD database, approximately 93% of index cases are mutations that are inherited from one of the parents. Both data indicate that a significant number of male probands may not inherit mutations that cause disease from their mothers, and accurate carrier testing is necessary not only for further family analysis, but also for genetic counseling. . We analyzed the phenotypes of 142 patients in 69 families, including 52 children with brain type, 5 with adolescent brain type, 2 with adult brain type, and 7 with adult brain type, and 3 cases with adolescent or adult brain type. Amn>Adoc or amn>ac), 1 case of cerebellum, 11 cases of tympanic membrane, 60 cases of female carrier. figure 2). There was no significant correlation between these mutations and phenotype in Japanese ALD patients, which was not reported in previous reports. 1 Even in the same family, there is the same mutation ABCD 1, and there is variation in phenotype. At present, we cannot predict the further clinical course of tympanic ALD patients by analyzing family, genotype, VLCFA values, and even their expression. ABCD 1 gene and ALDP protein. HSCT and ALD pre-pulmonary diagnosis HSCT is the only treatment to prevent brain-type ALD brain involvement, but it is only effective in patients with early brain symptoms. 2 Although we have established a rapid diagnostic system for ALD in Japan, only one-third of patients with CCALD are able to receive HSCT after onset (data not shown) for the following reasons. First, for a significant number of CCALD patients, there was a gap between onset and brain MRI/VLCFA detection because they were initially diagnosed with attention deficit/hyperactivity disorder, learning disability, hearing impairment, exotropia, and vision loss. In addition, HSCT preparation will take a considerable amount of time, including finding matching donors, while HSCT surgery in advanced brain patients can accelerate neurological decline. Therefore, familial screening of probands has important clinical implications for early intervention and prevention of advanced brain symptoms. In addition, at least 70% of patients with CCALD and AMN have clinical and biochemical evidence of primary adrenal insufficiency (http://www.x-ald.nl). Therefore, pre-tympanic diagnosis is also useful for preparing adrenal hormone therapy. This is necessary to save the lives of all patients with ALD who have adrenal insufficiency. The vector is detected by genetic counseling, which can be achieved by paying attention to the increase in VLCFA in plasma and mutation analysis. The ABCD 1 gene is an important gene for identifying pre-tympanic patients and other female carriers. Elevated VLCFA levels confirm the diagnosis of carriers, but there may be C24 between 0:0/C22:0, C25:0/C22:0, and C26:0/C22:0 between healthy controls and at least 10% of carriers. The overlap between them. In addition, our data and other data indicate that approximately 10% of the probands are identified by the ABCD 1 gene, which means that the mother of these patients should not be carriers. For these reasons, the ABCD 1 gene is not only necessary for vector detection, but also a necessary condition for confirming spontaneous mutation. In summary, 32%-48% of female carriers over the age of 20 have some symptoms, mainly due to abnormalities in the spinal cord and leg nerves, similar to AMN. It seems that as you get older, the frequency of carriers with symptoms increases. Http://www.x-ald.nl). Proper medications are often recommended for these carriers to reduce leg cramps and pain in the lower back and hips. Neonatal screening may be a potential method for the widespread discovery of pre-tympanic male patients and female carriers. Hubbard et al.6 used liquid chromatography-tandem mass spectrometry to conduct a preliminary study on the quality screening of 1-hexacosanoyl-2-lyso-sn-3-glycerophosphorylcholine (26:0-lyso-PC). Early intervention and long-term follow-up of anterior tympanic patients The anterior tympanic male patients can develop into multiple phenotypes between the ages of 3 and 50, and their phenotype may differ from those of the proband. Therefore, it is very important to provide information to patients and their families through genetic counseling. For HSCT diagnosis of anterior tympanic ALD patients under 3 years of age, follow-up every 6 months for subtle neuropsychological signs, brain MRI and electrophysiological examination is beneficial to such boys. When any abnormalities are found, the HSCT should be performed as soon as possible. Lorenzo's oil is one of the choices for these pretympanic patients, because Moser et al. reported that Lorenzo oil therapy for asymptomatic ALD boys reduced the risk of MRI abnormalities in the normal MRI of the brain. 7 However, further research confirms that this validity has not been reported. In addition, it is reported that approximately 80% of asymptomatic ALD boys have impaired adrenal function, 8 therefore, all male patients should be monitored for adrenal insufficiency. Adrenal hormone replacement therapy is necessary and effective in patients with morbid adrenal insufficiency. Recently, HSC gene therapy with lentiviral vectors successfully prevented the progression of CCALD in two patients at an early stage. 11 However, the therapeutic mechanism of this therapy remains unclear, probably because of the replacement of ABCD 1 gene, normal stem cells or other factor. Further research on VLCFA regulation or prevention of brain damage in patients and their families should be expedited, and predictors of brain damage should be identified as the key to solving the problem.