11 单基因遗传病.ppt

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　　标题： 11 单基因遗传病(B)Single Gene Disorder (B)

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　　标题： 2. Inborn Errors of Metabolism

　　正文： Inborn errors of metabolism are rare genetic disorders in which the body cannot turn food into energy (metabolize food) normally. The disorders are usually caused by defects in the enzymes involved in the biochemical pathways that break down food components.

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　　正文： In 1904 the doctor Archibald E. Garrod described alkaptonuria, a disease he classified as a lifelong congenital chemical alteration. Later on, in 1909, he described other diseases: albinism, cystinuria, porphyria and pentosuria, which he named "Inborn Errors of Metabolism". Garrod's conclusions were completely correct in relation to the genetic basis of metabolic disorders and the gene-enzyme concept.

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　　正文： The gene defect can cause a particular enzyme to be defective or missing. And because the enzyme isn't doing what it is supposed to do for the body, poor health may result.

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　　正文： Simply put, enzymes help the body by stimulating biological reactions inside cells. Enzymes are proteins that help the body use food, produce energy, and do work. When a particular enzyme is defective or missing, then the body isn't able to do something that it should do to maintain health. The enzyme involved determines what the body can't do and what the resulting physical features are.

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　　正文： Inborn errors of metabolism affect about 1 in every 5,000 babies born. Some of the more familiar inborn errors of metabolism are cystic fibrosis, hypothyroidism,, phenylketonuria (PKU) and Tay-Sachs disease.

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　　正文： The symptoms of inborn errors of metabolism vary greatly. Each one must be reviewed separately to know what the physical features are. Often, an infant will show signs of failure to thrive by failing to gain weight, not eating well, and generally showing developmental delay. Vomiting and diarrhea are among other symptoms that may signal the healthcare provider to test for an inborn error of metabolism.

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　　What are the symptoms in IMD

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　　正文： The enzyme defects that lead to the inborn errors of metabolism are caused by abnormal genes. In most cases, the abnormal gene is autosomal recessive in character.

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　　正文： 2.1 Phenylketonuria，PKU Phenylketonuria is one of the commonest inherited disorders - occurring in approximately 1 in 10,000 babies born in the U. S. It occurs in babies who inherit two mutant genes for the enzyme phenylalanine hydroxylase (PAH). This enzyme normally breaks down molecules of the amino acid phenylalanine that are in excess of the body's needs for protein synthesis.

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　　正文： Because we inherit two copies of the gene for the enzyme, both must be defective to produce the disease. A laboratory test that measures how quickly an injection of phenylalanine is removed from the blood can distinguish a person who has one PKU gene from a person who has none, but the person with one is perfectly healthy because the unmutated allele produces enough of the enzyme. However, these heterozygous individuals are "carriers" of the disease.

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　　正文： The phenylalanine tolerance test: A short time after administering a measured amount of phenylalanine to the subject, the concentration of phenylalanine in the blood plasma is measured.

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　　正文： The level is usually substantially higher in people who carry one PKU gene (even though they show no signs of disease) than in individuals who are homozygous for the unmutated gene. Both parents must be heterozygous (i.e., must be "carriers" of the trait) to produce a child with PKU. The chance of their doing so is 1 in 4.

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　　正文： Inability to remove excess phenylalanine from the blood during infancy and early childhood produces a variety of problems including mental retardation. Fortunately, a simple test (needing only a drop of blood) done shortly after birth can identify the genetic defect and, with close attention to the amount of phenylalanine in their diet, the children can develop normally.

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　　正文： Genetic screening for "a" (NOTE: not "the" - many different mutations in the PKU gene have been identified) PKU allele.

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　　正文： By treatment, her sister, who suffered from PKU too, got married healthily.

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　　正文： 2.2 albinism Albinism is a defect of melanin production. This defect results in the partial or full absence of pigment from the skin, hair, and eyes.

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　　正文： In Type 1 albinism defects in the metabolism of tyrosine lead to failure in converting this amino acid to melanin. This is due to a genetic defect in tyrosinase -- the enzyme responsible for metabolizing tyrosine.

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　　正文： Type 2 albinism is due to a defect in the "P" gene. Those with this type have slight pigmentation at birth.

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　　正文： In the most severe form of albinism (called oculocutaneous albinism), those affected appear to have hair, skin, and iris color that are white or pink as well as vision defects. This is inherited via an autosomal recessive process.

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　　A patient with oculocutaneous albinism with white eyebrows and lashes.

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　　Left fundus of a patient with albinism. Note the lack of? RPE pigment which allows the choroidal vessels to become clearly visible. The patient also has macula hypoplasia, the temporal arcade of the retinal vessels run almost? horizontally.

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　　正文： 2.3 alkaptonuria Alkaptonuria is a rare inherited disorder of metabolism, characterized by urine?that turns black when exposed to air. Another characteristic is the development of arthritis in adulthood.

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　　正文： Alkaptonuria is an autosomal recessive inherited disorder. In affected individuals, an amino acid known as tyrosine is not properly metabolized, due to a defect in an enzyme called homogentisic acid oxidase.

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　　正文： Because of the defect, homogentisic acid is excreted in the urine and turns a brown color upon exposure to air. This is the result of a dark pigment with an ochre color (earthy red or yellow), which led to the name ochronosis. The bones and cartilage of the body?may be brown-colored.

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　　正文： 2.4 Wilsons disease Wilson's disease is an inherited disorder where there is excessive amounts of copper in the body. This causes a variety of effects, including liver disease and damage to the nervous system.

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　　正文： Wilson's disease is a rare inherited disorder. If both parents carry an abnormal gene for Wilson's disease, there is a 25% chance that each of their children will develop the disorder (i.e., it is an autosomal recessive disease).

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　　正文： Wilson's disease causes the body to absorb and retain excessive amounts of copper. The copper deposits in the liver, brain, kidneys, and the eyes.

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　　正文： Molecular mechanism: ATP7B (wilson copper transporting ATPase)

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　　正文： The deposits of copper cause tissue damage, death of the tissues, and scarring, which causes the affected organs to stop functioning properly. Liver failure and damage to the central nervous system (brain, spinal cord) are the most predominant, and the most dangerous, effects of the disorder. If not caught and treated early, Wilson's disease is fatal.

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　　A patient with Wilson's disease

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　　Kayser-Fleischer rings

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　　正文： Lab findings may include: Serum ceruloplasmin - low (although it is normal in 5% of cases) Serum copper - low in spite of the copper deposits in tissues Urine copper - high CBC - may show hemolytic anemia or decreased white blood cell count Serum uric acid levels - low

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　　正文： The following medications may be used: Zinc acetate (Galzin), which blocks the absorption of copper in the intestinal tract. Trientine (Syprine), which binds or chelates the copper and leads to increased urinary excretion of the metal. Penicillamine (Cuprimine, Depen), which also binds or chelates copper and leads to increased urinary excretion.

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　　正文： 2.5 galactosemia Galactosemia is the inability of the body to use (metabolize) the simple sugar galactose (causing the accumulation of galactose 1-phosphate), which then reaches high levels in the body, causing damage to the liver, central nervous system, and various other body systems.

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　　正文： Galactosemia is an inherited disorder (transmitted as an autosomal recessive trait). It occurs at a rate of approximately 1 out of 60,000 births.

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　　正文： There are 3 forms of the disease: galactose-1 phosphate uridyl transferase deficiency (classic galactosemia, the most common and most severe form), deficiency of galactose kinase, and deficiency of galactose-6-phosphate epimerase.

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　　正文： People with galactosemia are unable to fully break down the simple sugar galactose. Galactose makes up half of lactose, the sugar found in milk. Lactose is called a disaccharide (di meaning 2 and saccharide meaning sugar) because it is made up of two sugars, galactose and glucose, bound together.

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　　正文： If an infant with galactosemia is given milk, derivatives of galactose build up in the infant's system, causing damage to the liver, brain, kidneys, and eyes.

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　　正文： Individuals with galactosemia cannot tolerate any form of milk (human or animal) and must carefully watch intake of other galactose-containing foods. Exposure to milk products may result in liver damage, mental retardation, cataract formation, and kidney failure.

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　　cataract

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　　正文： Treatment??? Once the disease is recognized, treatment consists of strictly avoiding all milk and milk-containing products. The infant can be fed with soy formula, meat-base formula, or Nutramigen (a protein hydrolysate formula), or other lactose-free formula. The condition is lifelong and requires abstinence from milk and milk products for life.

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　　正文： Parents need to take care and educate the child to avoid not only milk and milk products, but also those foods that contain dry milk products. For this reason, it is essential to read product labels and be an informed consumer.

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　　正文： 2.6 G-6-PD deficiency G-6-PD deficiency is a hereditary, sex-linked enzyme defect that results in the breakdown of red blood cells when the person is exposed to the stress of infection or certain drugs.

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　　正文： G-6-PD deficiency is an inheritable, X-linked recessive disorder whose primary effect is the reduction of the enzyme G-6-PD in red blood cells, causing destruction of the cells, called hemolysis. Ultimately, this hemolysis leads to anemia -- either acute hemolytic or a chronic spherocytic type.

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　　正文： Three classes of deficiency are described, corresponding to three types of enzymatic variants. This classification is based on the enzyme residual activity. class 1: very severe deficiency, activity close to 0% class 2: severe deficiency, activity <10% class 3: moderate deficiency, activity between 10 and 60% class 4: variants with normal activity

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　　正文： Drugs that can bring on this reaction include: antimalarial agents sulfonamides (antibiotic) aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) nitrofurantoin quinidine quinine others

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　　正文： 2.8 glycogen storage disease，GSD Glucose is a large energy source for the body. It is stored by the body in the form of glycogen and later released into the body with the help of enzymes.

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　　正文： Glycogen storage disease (GSD) is a group of inherited (born with) disorders where an abnormal amount or type of glycogen settles in the liver and causes failure of the liver's ability to break down glycogen to supply glucose to the rest of the body. This happens when one or more of the many enzymes (proteins produced by the body) needed to convert sugar (glucose) into its storage form (glycogen) are missing.

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　　types of GSD

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　　正文： 2.9 Mucopolysaccharidosis One of a series of inherited metabolic disorders affecting a type of complex carbohydrate called a mucopolysaccharide that is deposited in body tissues because the person lacks the specific enzyme needed to metabolize it.

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　　正文： The deposition of mucopolysaccharide in tissues damages and distorts them, stunts the child's growth and development, limits their joint movement and in some (but not all) types of MPS causes mental retardation.

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　　正文： The condition usually becomes evident in early childhood. That something is wrong may be noticed by parents or doctors. The diagnosis may be suspected by the clinical features. Confirmation of the diagnosis, however, requires biochemical tests of blood, urine, or tissues. Prenatal diagnosis is feasible in all types of MPS.

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　　正文： The classification (as of 2001) is as follows: MPS type I -- Hurler syndrome, Scheie syndrome, and Hurler-Scheie syndrome -- due to varying degrees of deficiency of the enzyme alpha-L-iduronidase MPS type II -- Hunter syndrome -- due to deficiency of the enzyme iduronate sulfatase MPS type IIIA -- Sanfilippo syndrome -- due to deficiency of the enzyme heparan N-sulfatase MPS type IIIB -- Sanfilippo syndrome -- due to deficiency of the enzyme alpha-N-acetylglucosaminidase MPS type IIIC -- Sanfilippo syndrome -- due to deficiency of the enzyme acetyl CoA:alpha-glucosaminide acetyltransferase

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　　正文： MPS type IIID -- Sanfilippo syndrome -- due to deficiency of the enzyme N-acetylglucosamine 6-sulfatase MPS type IVA -- Morquio syndrome -- due to deficiency of the enzyme N-acetylgalactosamine-6-sulfate sulfatase MPS type IVB -- Morquio syndrome -- due to deficiency of the enzyme beta-galactosidase MPS type VI -- Maroteaux-Lamy syndrome -- due to deficiency of the enzyme N-acetylgalactosamine-4-sulfatase MPS type VII -- Sly syndrome -- due to deficiency of the enzyme beta-glucuronidase MPS type VIII -- DiFerrante syndrome -- due to deficiency of the enzyme glucosamine-6-sulfate

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　　正文： All types of MPS are inherited as recessive traits. With one exception, they are autosomal (not sex-linked). Boys and girls alike can have these diseases if they receive two copies of the relevant gene, one from each of their parents. The risk for each subsequent child is 1 in 4.

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　　正文： All types of MPS are lysosomal storage diseases. They involve enzymes found within the cell in lysosomes, miniature structures that are packets of degradative enzymes. In this respect, MPS is like all the other disorders of lysosomal storage such as Gaucher disease, Fabry disease, and Pompe disease.

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　　正文： Symptoms may include: Growth failure Muscle cramps Low blood sugar A greatly enlarged liver A swollen belly

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　　MPS type I

　　MPS type II

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　　正文： 2.10 Lesch-Nyhan syndrome Lesch-Nyhan syndrome is a condition characterized by the overproduction of uric acid, a nitrogen-containing compound found in urine. Problems with the nervous system and behavioral disturbances are characteristic of this disorder.

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　　正文： The overproduction of uric acid can cause gouty arthritis (arthritis caused by uric acid in the joints), as well as kidney and bladder stones. Abnormal involuntary muscle movements such as flexing, jerking, flinging, and flailing are often displayed. Self-injury through biting and head banging is the most common behavioral problem in Lesch-Nyhan patients.

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　　正文： Mutations in the HPRT1 gene cause Lesch-Nyhan syndrome. Mutations in the HPRT1 gene cause a shortage (deficiency) of the enzyme hypoxanthine phosphoribosyltransferase 1. This enzyme is responsible for recycling purines, a type of building material for DNA and its chemical cousin RNA. When this enzyme is lacking, the breakdown of purines results in abnormal levels of uric acid buildup in the body. The mechanism by which high uric acid levels cause neurological and behavioral disturbances is currently not well understood.

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　　正文： This condition is inherited in an X-linked recessive pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome (one of the two sex chromosomes). In males, who have only one X chromosome, one altered copy of the gene is sufficient to cause the condition.

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　　正文： In females, who have two X chromosomes, a mutation must usually be present in both copies of the gene to cause the disorder. Males are affected by X-linked recessive disorders much more frequently than females. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

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　　正文： 2.11 xeroderma pigmentosum Xeroderma pigmentosum (XP) was first described in 1874 by Hebra and Kaposi. In 1882, Kaposi coined the term xeroderma pigmentosum for the condition, referring to its characteristic dry, pigmented skin. XP is a rare disorder transmitted in an autosomal recessive manner. It is characterized by photosensitivity, pigmentary changes, premature skin aging, and malignant tumor development. These manifestations are due to a cellular hypersensitivity to ultraviolet (UV) radiation resulting from a defect in DNA repair.

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