Diseases Flashcards
Nieman-Pick Disease
Types A and B) is an autosomal recessive disease caused by the inability to degrade sphingomyelin. The deficient enzyme is sphingomyelinase–a type of phospholipase C. In the severe infantile form (type A), the liver and spleen are the primary sites of lipid deposits and are, therefore, tremendously enlarged. The lipid consists primarily of the sphingomyelin that cannot be degraded (Figure 17.13). Infants with this disease experience rapid and progressive neurodegeneration as a result of deposition of sphingomyelin in the CNS, and they die in early childhood. A less severe variant (type B) causes little to no damage to neural tissue, but lungs, spleen, liver, and bone marrow are affected, resulting in a chronic form of the disease, with a life expectancy only to early adulthood. Although Niemann-Pick disease occurs in all ethnic groups, both type A and B occur with greater frequency in the Ashkenazi Jewish population than in the general population. In the Ashkenazi Jewish population, the incidence of type A is 1:40,000 live births, and that of type B is 1:80,000. The incidence of Niemann-Pick disease in the general population is less than 1:100,000.
Lactose Intolerance
Greater than 50% of the world’s adults display varying levels of lactose intolerance, a common disaccharide found in dairy products. This is generally an acquired deficiency, since lactase is present in neonates and gradually declines to about 5-10% of the initial level at birth. When there is a lactase deficiency, lactose passes though the small intestine undigested and provides an excellent carbon source for bacteria in the large intestine. Proliferation of bacteria generates hydrogen gas, acetaldehyde, ethanol, formic acid as well as peptide and protein toxins. The resulting symptoms of lactose intolerance include abdominal discomfort, flatulence, diarrhea, headache, light-headedness, nausea and muscle pain.
Diagnosis of lactose intolerance can be made by measurement of hydrogen gas in breath or oral tolerance tests. Treatments include limiting intake of dietary lactose or supplemental provision of lactase in pill form prior to eating.
With the appearance of milk-producing domesticated animals in some regions, selective pressure appears to have increased lactase expression into adulthood in certain populations. Genetic studies indicate that multiple autosomal dominant alleles underlie persistent lactase expression due to an inability to silence lactase gene expression.
Smith-Lemli-Opitz syndrome (SLOS)
a relatively common autosomal recessive disorder of cholesterol biosynthesis, is caused by a partial deficiency in 7-dehydroholesterol-7- reductase, an enzyme involved in converting 7-dehydrocholesterol to cholesterol. SLOS is characterized by multisystem anomalies. The SLOS emphasizes the importance of cholesterol in embryonic development. Cholesterol also plays important roles in the development and the function of the CNS, and in sperm development.
SREBP2
Sterol-dependent regulation of gene expression: Expression of the HMG CoA reductase gene is controlled by a transcription factor (sterol regulatory element-binding protein 2, or SREBP2) that binds to DNA at the sterol regulatory element (SRE) located upstream of the reductase gene. The SREBP2 is initially associated with the ER membrane, but proteolytic cleavage liberates the active form, which travels to the nucleus. When the SREBP2 binds, expression of the reductase gene increases. When cholesterol levels are low, activation of SREBP2 occurs, resulting in increased HMG CoA reductase and other enzymkes in the pathway, and, therefore, more cholesterol synthesis. Conversely, high levels of cholesterol prevent activation of the transcription factor. (
Niemann-Pick C
Niemann-Pick type C (NPC) disease occurs in humans, cats, and in mice. Most patients with NPC have progressive neurological disease; hepatic enlargement and damage is prominent in certain cases. It is a fatal disease; the clinical manifestations occur in children in their late child hood. Development in early childhood seem normal. With time, it becomes apparent that the child is slowly dementing, not able to coordinate movements, falls easily, etc. They eventually have to drop out of school. Almost all of them die in their teens.
Unesterified cholesterol, sphingomyelin, phospholipids, and glycolipids, especially GM2 ganglioside, accumulate within the lysosomes of various organs including liver and spleen.
Tay Sachs
Gangliosides are found in highest concentration in the nervous system, particularly in gray matter, where they constitute 6% of the lipids. Gangliosides are degraded inside lysosomes by the sequential removal of their terminal sugars. Disorders of ganglioside breakdown can have serious clinical consequences. In Tay-Sachs disease, the symptoms are usually evident before an effected infant is a year old. Weakness and retarded psychomotor development are typical early symptoms. The child is demented and blind by age two, and usually dead before age three. Striking pathological changes occur in the nervous system, where neurons become enormously swollen with lipid-filled lysosomes.
The ganglioside content of the brain of an infant with Tay-Sachs disease is greatly elevated. The concentration of ganglioside GM2 is many times higher than normal because its terminal N- acetylgalactosamine residue is removed very slowly or not at all. The missing or deficient enzyme is a specific β-N-acetylhexosaminidase. Tay-Sachs disease is inherited as an autosomal recessive. The carrier rate is 1/30 in Jewish Americans originally from eastern Europe and 1/300 in non-Jewish Americans. Hence, the incidence of the disease is about 100 times higher in Jewish Americans. Tay-Sachs disease can be diagnosed during fetal development. Amniotic fluid is obtained by amniocentesis and assayed for β-N-acetylhexosaminidase activity.
Tangier’s Disease
How does ApoA1 combine with cholesterol and phospholipids at the plasma membranes of various body cells to produce the discoidal nascent HDL? This question stayed unanswered for several decades, but has finally been resolved in recent years by three independent groups of scientists who have been pursuing the molecular basis of a rare genetic disease called the Tangier disease. There are very few of these patients in the world (less than 1000), and most of these patients were immigrants from UK, and live in a remote, relatively primitive area called Tangier Island off shore of Chesapeake Bay. The unique features of TD include large yellow- orange tonsils, neuropathies, splenomegaly, hepatomegaly, ocular abnormalities, hypocholesterolemia, and CVD. Homozygotes have a virtual absence of plasma HDL and apoA- I, low plasma LDL levels (40% normal), and hypertriglyceridemia (>300 mg/dl). They are characterized by an accumulation of cholesteryl esters in reticuloendothelial cells of tissues including tonsils, thymus, lymph node, bone marrow, spleen, liver, gall bladder, and intestinal mucosa. Many patients also have lipid deposits in neuronal Schwann cells, smooth muscle cells, and fibroblasts. Positional cloning experiments and molecular genetic analyses revealed that the TD patients all contain mutations in a novel gene called ABCA1. Defects in ABCA1 cause a severe HDL deficiency.
Choleliathisis
The movement of cholesterol from the liver into the bile must be accompanied by the simultaneous secretion of phospholipid and bile salts. If this dual process is disrupted and more cholesterol enters the bile than can be solubilized by the bile salts and lecithin present, the cholesterol may precipitate and eventually crystallizes in the gallbladder, initiating the occurrence of cholesterol gallstone disease–cholelithiasis (Figure 18.12). This disorder is typically caused by a decrease of bile acids in the bile, which may result from: 1) gross malabsorption of bile acids from the intestine, as seen in patients with severe ileal disease; 2) obstruction of the biliary tract, interrupting the enterohepatic circulation; or 3) severe hepatic dysfunction, leading to decreased synthesis of bile salts, or other abnormalities in bile production. Cholelithiasis also may result from increased biliary cholesterol excretion, as seen with the use of fibrates. [Note: Fibrates, such as gemfibrozil are derivatives of fibric acid, and are used to reduce triacylglycerol levels in blood.]. Surgical removal of the gallbladder is currently the treatment of choice. However, for patients who are unable to undergo surgery, administration of chenodeoxycholic acid to supplement the body’s supply of bile acids results in a gradual (months to years) dissolution of gallstones.
Alkaptonuria
caused by a deficiency in homogentisate oxidase, an enzyme in the pathway for degradation of tyrosine. In this deficiency, homogentisate accumulates and is largely excreted in urine. Homogentisate produces dark pigments upon oxidation, which is apparent in the patient’s urine but is also deposited in joints over time and can lead to severe arthritis. Archibald Garrod (1902) showed that alkaptonuria was transmitted as a single recessive Mendelian trait. His book established the idea of “Inborn Errors of Metabolism” linking a biochemical defects with pathological conditions.
Maple Syrup Urine Disease
is caused by a deficiency in the branched-chain α-keto acid dehydrogenase and leads to an accumulation of leucine, isoleucine, valine as well as their keto-acids. The branched-chain α-keto acid dehydrogenase follows immediately after the aminotransferase reaction in degradation of leucine, isoleucine and valine. This deficiency causes neurological deficits due to a build-up of branched-chain α-keto acids, imparts an odor of maple syrup in patient’s urine and has a high mortality rate. Treatment includes dietary restriction of branched-chain amino acids.
Homocystinuria
the most common cause of homocystinuria is due to a deficiency in the enzyme cystathionine β-synthase, which converts homocysteine to cystathionine. This is in the pathway for catabolism of methionine. Homocystinurias produce osteoporosis, mental retardation and potentially increase risk of cardiovascular disease (this an active area of research). Deficiencies in the vitamin folic acid also produce homocystinuria, more in lecture 34.
PKU
untreated cases of Phenylketonuria, blood levels of Phenylalanine are elevated (20-fold) producing developmental defects, hyperactivity and mental retardation. The relationship between hyperphenylalaninemia and brain dysfunction in PKU is clear although the molecular mechanisms underlying these symptoms remain unknown.
Patients with phenylketonuria also show deficiencies in pigmentation due to defects in formation of the pigment melanin. The hydroxylation of tyrosine by tyrosine hydroxylase is competitively inhibited by the high levels of phenylalanine present in PKU.
PKU is detected by testing for elevated blood levels of phenylalanine in newborns. The therapy for PKU is a low phenylalanine diet (no aspartame) that contains adequate amounts of phenylalanine and tyrosine. Tyrosine is an essential amino acid in PKU.
Metabolic Syndrome
Obesity often is accompanied by a suite of conditions, collectively called “Metabolic Syndrome” or “Syndrome X”. While the root problem is excess caloric in-take, the long- term effects on energy balance cause many problems:
1. Obesity – increase in adipose tissue.
2. Dyslipidemia – increase in circulating FA and VLDL.
3. Hepatic Steatosis – fatty liver (hepatocytes over-loaded with triglyceride).
4. Atherosclerosis.
5. Insulin resistance.
6. Hypertension.
Increased fat seems to be a major factor in Metabolic Syndrome, and leads to insulin resistance via mechanisms described below.
One basic point is that an excess of any fuel source (carbs, protein, fat) will be stored as fat, once glycogen reserves are fully filled.
Orlistat
Also known as Xenical.
Pancreatic lipase inhibitor (covalent “suicide” inhibitor). Triglyceride stays in gut and is excreted in stool.
Can reduce fat absorption by 30%.
Side effects:
1. Mal-absorption of fat-soluble vitamins. Supplementation advised. 1. Loose, oily stools.
Rimonabant
Cannabinoid receptor antagonist. Acts in hypothalamus to suppress orexigenic effect of endogenous cannabinoids (lipid signaling molecules that act in a paracrine fashion). Anorexigenic.
Withdrawn from market in Europe due to psychiatric side effects (depression). Never approved in US.
