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129 Cards in this Set
- Front
- Back
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1. Degradative pathways
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Existing molecule degraded into constitutients to produce substrates for building up new molecules
Errors in these pathways result in accumulation of metabolites that should have been recycled or eliminated Lysosomes degrade many materials: Mucopolysaccharides (glycosaminoglycans) Sphingolipids Glycoproteins and glycolipids |
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2. Lysosomal storage disorders
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Prototypical inborn errors of metabolism
Result from accumulation of substrate due to problems of lysosomal enzyme function. |
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3. Lysosomal disorders
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Most are caused by enzyme deficiencies; some are caused by inability to activate enzyme or transport enzyme to lysosome.
Many of these disorders are found within high prevalence in certain ethnic groups. |
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4. MPS disorders
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Mucopolysaccharidoses reduced abilitiy to degrade one or more GAGs;
GAGs are degradation products of proteoglycans found in the ECM: 1. Heparan sulfate 2. Dermatan sulfate 3. Keratan sulfate 4. Chondroitin sulfate 10 different enzyme deficiencies cause 6 different MPS disorders |
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5. Genetics of MPS disorders
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All are inherited in autosomal recessive fashion except Hunter syndrome; Hunter is an X linked inheritance
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6. Characterization of MPS disorders
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Chronic and progressive multisystem deterioration which causes hearing, vision, joint, and cardiovascular dysfunction.
Hurler, severe Hunter, and San Filippo are also characterized mental retardation. |
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7. Iduronidase deficiency
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Prototypic MPS disorder
Traditionally limited to three groups, Hunter, Hurler-Scheie, and Sheie Hurler and Scheie are mutations in α-1-iduronidase, Hurler is much more severe Hunter is mutation in iduronidate sulfatase |
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8. Symptoms of Hurler-Scheie syndrome
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Course faces
Hepatosplenomegaly Corneal clouding Dysostosis (improper ossification of bone) Mental retardation |
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9. Hunter syndrome
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Course faces
Hepatosplenomegaly Corneal clouding Dysostosis (improper ossification of bone) Mental retardation + Behavioral problems. |
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10. Sphingolipid degradation defects
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Result in gradual accumulation sphingolipids, multi-organ dysfunction
Also lysosomal storage diseases (mucolipidoses) Sphingolipid degradation is deficient |
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11. Gaucher disease
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ß-glucosidase deficiency
Causes accumulation of glucocerebroside 1. Splenomegaly 2. Hepatomegaly 3. Bone marrow infiltration 4. Nervous system involvement in types II and III Type 1 is least severe, type 2 is most severe, type 3 is intermediate |
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12. I-cell Disease
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Phosphotransferase is deficient
Lysosomal enzymes target to lysosomes by having mannose-6-P and lysosomal receptor I-cell Accumulated products appear as inclusions, hence name I-cell for Inclusion Cell 1. Course facial features 2. Skeletal abnormalities 3. Hepatomegaly 4. Corneal opacities 5. Mental retardation 6. Early death No treatment/cure |
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13. Urea cycle disorders
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Primary role of cycle is to prevent accumulatio nof nitrogenous waste.
Deficiencies in the following enzymes: 1. Carbamoyl phosphate synthetase (CPS) 2. Ornithine transcarbamoylase (OTC) 3. Argininosuccinic acid synthetase (ASA) 4. Argininosuccinase (AS) Defects in 4 cause accumulation of urea precursors (ammonium and glutamine) |
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14. Clinical course of urea cycle disorders
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Progressive lethargy and coma
Closely resembling clinical presentation of Reye syndrome Individuals may present in neonatal period or after Wide interfamilial variability and severity |
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15. Arginase deficiency
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Associated w/urea cycle disorders
Progressive spastic quadriplegia and mental retardation |
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16. Genetics of urea cycle disorders
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All are inherited in autosomal recessive pattern
EXCEPT OTC deficiency, which is X linked OTC deficiency is most prevalent of these disorders |
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17. OXPHOS system
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System of catabolism of glucose, ketones, amino acids, and fatty acids for energy
Includes processes such as TCA, or beta oxidation Characterized by the passage of H+ ions thru oxidative phosphorylation |
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18. OXPHOS system continued
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Five multi-protein complexes transfer electrons to molecular oxygen
Genes for proteins primarily coded for by nuclear genes - 13 of them are mitochondrial, the rest are nuclear |
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19. Disorders of OXPHOS
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Inherited in autosomal recessive pattern.
Caused by substitutions, insertions or deletions in the mitochondrial genome and are maternally inherited. |
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20. Glutaric acidemia type 2
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inherited defects in electron transfer protein (ETF) and ETF ubiquinone oxidoreductase
Symptoms: hypotonia, hepatomegaly, hypoketonic or non ketotic hypoglycemia, metabolic acidemia |
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21. Absent oxphos capacity
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End products are pyruvate and lactic acid
Defects in pyruvate metabolism produce lactic acidemia |
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22. Lactic acidemia
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Most common form is deficiency of pyruvate dehydrogenase (PDH)
May be caused by mutations in genes encoded 1 of 5 components of PDH complex E1, E2, E3, X-lipoate or PDH phosphatase. |
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23. Disorders characterized by varying degrees of lactic acidemia
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Developmental delay
Abnormalities of the CNS Suggested that facial features of some children w/these disorders resemble those of Fetal alcohol disorder |
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24. Abnormal cystine transport
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Produces two disorders:
1. Cystinuria 2. Cystinosis Inherited via autosomal recessive pattern |
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25. Cystinuria
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Abnormal cystine transport between cells and extracellular environment
Produces substantial morbidity but early death is uncommon Caused by a defect of dibasic amino acid transport affecting epithelial cells of the GI tract and renal tubules Cystine, lysine, arginine, and ornithine are excreted in urine in quantities higher than normal. |
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26. Complications of cystinuria
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Cystine is very insoluble; leads to renal calculi and kidney stones
Treatment consists of rendering cystine more soluble by administration of pharmacological amts of water, alkalinizing the urine, and chelation |
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27. Genetics of cystinuria
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Type 1 associated w/missence, nonsense and deletion mutations
Type 1: In soluble carrier family 3, member 1 amino acid transporter (SLC3A1) Types 2 and 3 are caused by mutations in SLC7A9 |
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28. Cystinosis
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Caused by diminished ability to transport cystine across the lysosomal membrane.
Causes cystine accumulation in the lysosomes of most tissues Affected individuals are normal at birth but develop electrolyte disturbances, corneal crystals, Ricketts and poor growth by the age of 1 yr |
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29. Treatment of cystinosis
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Dialysis or kidney transplantation is usually necessary in the first decade of life.
Cystine depleting agents i.e. cysteamine, have proved successful in slowing renal deterioration |
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30. Disruption of homeostasis of copper
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Copper is absorbed by eptithelial cells of small intestine via HCTR1 transporter
Some copper is transported to the liver to be incorporate dinto proteins that are distributed to other parts of the body. Excess copper in hepatocytes is normally secreted in the bile and excreted from the body. |
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31. Menke's disease
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Copper transport disorder.
X-linked recessive, characterized by mental retardation, seizures, hypothermia, twisted and hypopigmented hair, loose skin, arterial rupture and early childhood death. Copper can be absorbed by GI epithelium but not exported effectively into the blood stream. Thus, trapped copper is excreted from the body. |
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32. Treatment of Menke's disease
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Restore copper levels in the body to normal by administration thru an alternative route such as subcutaneous injections
Prenatal therapy is being investigated. |
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33. Wilson's disease
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Results from an excess of copper caused by defected excretion of copper into the biliary tract.
Causes progressive liver disease and neurological abnormalities. Patients usually present w/acute or chronic liver disease in childhood If left untreated, liver disease is progressive, resulting in cirrhosis and failure. |
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34. Other symptoms of Wilsons disease
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Dysarthria, diminished coordination
Arthropathy, cardiomyopathy Kidney damage Hypoparathyroidism Kayser-Fleischer ring in the eye |
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35. Biochemical testing for Wilson's disease
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Decreased serum ceruloplasmin
Increased serum non-ceruloplasmin copper Increased urinary copper excretion Increased deposition of copper in liver Most sensitive indicator is reduced incorporation of isotopes of copper into cells cultured in vitro. |
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36. Treatment of Wilson's disease
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Reducing load of accumulated copper via chelation
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37. ATP7A gene
Importance? |
Gene that causes Menke's disease
Encodes adenosine triphosphatase with 6 tandem copies of a heavy metal binding sequence High sequence conservation between human and bacterial binding sequences that indicate ATP7A has had an important role in regulating heavy metal ion transport in other organisms. Usually localized to the golgi network within the cell and then redistributes the plasma membrane to pump copper into the system. |
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38. ATP7B gene
Importance? |
Gene for Wilson's disease
Protein product is highly homologous to ATP7A Expressed predominantly in the liver and kidney Moves between golgi network and either endosomes or cell membrane of hepatocytes Over 200 mutations known Single missense in 40% of Northern European cases |
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39. Acrodermititis enteropathica
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Cuased by a defect in teh absorption of zinc from the intestinal tract
Results in: 1. Growth retardation 2. Diarrhea 3. Dysfunction in immune system 4. Severe dermatitis that affects the skin of the genitals and buttocks, around the mouth and the limbs. Usually presents after children are weaned and can be fatal if not treated w/high doses of supplemental zinc. |
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40. SLC39A4 gene
Importance? |
Mutated in acrodermatitis enteropathica.
Encodes putative zinc transporter protein expressed on the apical membrane of the epithelial cell of the small intestine. |
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41. Hereditary hemochromatosis (HH)
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Excessive iron absorption in intestine
Accumulates in liver, kidney, heart, joints, pancreas Very common in Northern Europeans, 1 in 8 is carrier (Celtic origin?) 1 in 200 to 400 is affected Incomplete penetrance Delayed onset, after 40 in men, 60 in women |
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42. Clinical symptoms and Dx of HH
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1. Fatigue common, varies considerably
2. Joint pain 3. Diminished libido 4. Diabetes 5. Increased skin pigmentation 6. Cardiomyopathy 7. Liver enlargement and cirrhosis Diagnosis – liver biopsy with hemosiderin staining |
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43. Hemochromatosis genetics I
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Found linkage to HLA region
Class I-like gene called HFE Binds transferrin receptor on cell surface Inhibits iron uptake Affects sensor for iron in intestine Affects brush border uptake of iron When defective, no feedback, excess uptake |
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44. Hemochromatosis genetics II
Treatment? |
Common mutation C282Y, cysteine to tyrosine
Cysteine part of disulfide bond at ß-2-microglobulin binding domain Prevalence suggests selective advantage Iron deficiency is common Much less common in heterozygotes Increased uptake could alleviate deficiency Treatment – reduce iron - phlebotomy |
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45. Pharmacogenetics
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Study of genetic modification of variable human responses to pharmacological agents.
Hope is to be able to profile DNA differences among individuals and thereby predict responses to different medicines and personalizing individual healthcare. |
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46. Drug response rates
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Many are between 25 and 75%
Thus, only 1/4 people will benefit from use in some drugs. Approx 1200 drugs approved for use in US 15% are associated with adverse and severe effects |
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47. Challenges of pharmacogenetics
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Selection of targets that might be amenable to manipulation of a drug to treat a symptom or disease that might influence biotransformation of or response to a drug.
Determining relationships of drugs and genotypes is key to proper use |
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48. Pharacogenomics
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Analysis of genome and its products as it results to drug response.
Using genomic technology to design drug treatment regimens and tailor to individuals Need data on genes and variants Need to scan many people for many possible polymorphisms efficiently SNPs – single nucleotide polymorphisms Scattered throughout genome Polymorphic, linkage studies |
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49. UDP-glucose
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Precursor of glycogen and lactose, UDP-glucuronate and glucurinides and the carbohydrate chains of proteoglycans glycoproteins and glycolipids
UDP is a leaving group that provides the energy for the formation of a new bond. |
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50.UDP glucuronate
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formed by NAD dependent dehydrogenase
Present in the diet, can be formed from inositol degradation |
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51. Glucuronate
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increases solubility of bilirubin, drugs, xenobiotics, and other compounds
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52. UDP Glucuronate and charges
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Is a source of negative charges
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53. Formation of glucuronides and glucuronate
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Initiated by glucoronyl transferases located in the endoplasmic reticulum and in the cytoplasm of the liver and kidney
Glycosidic bond formed between anomeric hydroxyl group of glucuronate and the hydroxyl group of a non-polar compound. The negatively charged carboxyl group of glucuronate increases water solubility; it allows otherwise non-polar compounds to be excreted in the urine or bile. |
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54. Formation bilirubin diglucuronide
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Glycosidic is formed between anomeric hydroxyl glucuronate and the carboxylate groups of bilirubin.
Addition of hydrophillic carbohydrate group and the negatively charge carboxyl group of the glucuronate increases the water solubility of the conjugated bilirubin and allows the otherwise insoluble bilirubin to be excreted in the urine or bile. |
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55. UDP Galactose
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Epimer of UDP glucose
Epimerase oxidizes the hydroxyl group to a ketone by transferring e-'s to NAD+, then returns e-'s to other side of the Carbon to reform the alcohol |
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56. Lactose synthesis
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Performed by lactose synthase; enzyme present in lactating mammary gland
Catalyzes the last step of lactose biosynthesis, which is the transfer of galactose from UDP galactose to glucose |
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57. Function of α-lactalbumin
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subunit of lactose synthase, lowers Km of galactose transferase for glucose, thereby increasing the rate of lactose synthesis
In its absence, galactosyltransferase transfers galactosyl subunits to proteins |
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58. Sugar variety for glycoproteins and glycolipids
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Controlled by transferases that produce oligosaccharide and polysaccharide side chains and attach sugar residues to proteins are specific for the sugar moiety and for the donating nucleotide (e.g. UDP, CMP, or GDP).
Variety of relatively specific and different functions |
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59. Glucosamine-6-phosphate
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Amino sugars are derived from this compoudn; an amino group is transferred from the amide of glutamine to fructose-6-phosphate.
N-acetylated by an acetyltranferase. |
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60. N-acetyltransferases
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present in the ER in cytosol, provide another means of chemically modifying sugars, metabolites, drugs, and xenobiotic compounds
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61. Mannose
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Found in the diet in small amounts; is epimer of glucose
Can be interconverted at the level of fructose -6-phosphate to mannose-6-phosphate |
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62. NANA aka N-acetylneuraminic acid
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sialic acid; N-acetylmannosamine is the precursor
negative charge is obtained by the addition of a three carbon carboxyl moiety from phosphoenolpyruvate |
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63. structure of glycoproteins
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short carbohydrate chains covalently linked to either serine, threonine, or asparagine residues in the protein
Oligosaccharide chains are often branched and do not contain repeating disaccharides. |
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64. Function of glycoproteins
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They serve as hormones, antibodies, enzymes, and structural components of the ECM.
Although most are secreted from cells, some are segregated in lysosomes, where they serve as the lysosomal that degrade various types of cellular and extracellular material. Others are produced like secretory proteins, but the hydrophobic regions of the proteins remains attached to the cell membrane, and the carb portion extends into the extracellular space These glycoproteins serve as receptors for compounds i.e. hormones, as transport proteins, cell attached and as cell-cell recognition sites |
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65. Synthesis of glycoproteins
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protein portion is synthesized on the ER; Carb chains are attached in the lumen of the ER and Golgi complex
UDP sugars are precursors for the addition of 4 out of 7 sugars found in glycoproteins |
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66. GDP sugars
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precursors for the addition of mannose and L-fucose and CMP NANA is a precursor for NANA
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67. Dolichol phosphate
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synthesized from isoprene units
involved in transferring branched sugar chains to the amide nitrogen of asparigine residues Sugars are removed and added as the glycoprotein moves from ER through Golgi complex |
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68. Phosphotransferase in I-cell disease
where the fuck is it located? |
Located in the golgi apparatus; recognizes lysosomal proteins because of their 3D structure such that they are tagged for transport to lysosomes by mannose-6-phosphate
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69. Glycolipids
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Derivatives of sphingosine, a lipid.
They include cerebrosides and gangliosides and they contain ceramide, with carb moieties attached to its hydroxymethyl group. Involved in intracellular communication Oligosaccharides of identical composition to that of glycoproteins are associated w/the cell membrane and serve as cell recognition factors. |
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70. Synthesis of cerebrosides
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Synthesized from ceramide and UDP-glucose or UDP-galactose.
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71. Synthesis of gangliosides
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Contain oligosaccharides produced from UDP-sugars and CMP-NANA
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72. Transfer of sphingolipids
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Produced in the golgi complex.
Lipid component buds from the TRANS face of the golgi and the vesicle fuses w/the cell membrane and remains with the cell membrane The carbohydrate component extends into the extracellular space. |
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73. What is the difference in structure between 6-phosphogluconate and glucuronic acid?
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6-phosphogluconate is produced by the first oxidative rxn in the pentose phosphate pathway in which C1 of glucose is oxidized to a carboxylate
In contrast; glucuronic acid is oxidized at C6 to the carboxylate form |
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74. High concentrations of galactose 1-phoshate inhibit phosphoglucomutase, the enzyme that convertes glucose 6-phosphate to glucose 1-phosphate.
How can this inhibition account for the hypoglycemia that accompanies galactose 1-phosphate uridylyltransferanse deficiency? |
The inhibition of phosphoglucomutase by galactose 1-phosphate results in hypoglycemia by interfering w/both the formation of UDP-glucose and the degradation of glycogen back to glucose 6-phosphate
90% of glycogen degradation leads to glucose 1-phosphate, whcih can only be converted to glucose 6-phosphate by phosphoglucomutase. If phosphoglucomutase activity is inhibited, less glucose 6-phosphate production occurs and less glucose is available for export. |
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75. High concentrations of galactose 1-phoshate inhibit phosphoglucomutase
How can this inhibition account for the jaundice that accompanies galactose 1-phosphate uridylyltransferanse deficiency? |
UDP-glucuronate formation is prevented, and it is needed to convert bilirubin to the diglucuronide form for transport into the bile.
Therefore, bilirubin accumulates in the tissues, causing jaundice. |
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76. Can pregnant women that are extremely lactose intolerant breast feed their young?
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Yes, teh injestion of lactose is not required for lactation.
The UDP-lactose in the mammary gland is derived principally from the epimerization of glucose. Breast feeding mothers must then obtain calcium from another source. |
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77. Blood group substance components
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oligosaccharide components of glycolipids and glycoproteins found in most cell membranes
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78. Type A components
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produce an N acetylgalactosamine transferase that attaches N acetylgalactosamine to galactose residue of the H substance
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79. Type B components
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produce galactosyltransferase that links galatose to the galactose residue of the H substance
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80. AB components
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have both alleles and produce both N acetylgalactosamine and galactosyltransferase
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81. Type O components
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Produces defective transferase and therefore do not attach either transferases to the H substance
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82. Biochem of Tay-Sachs
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If one lacks the HexA gene, then only α-chain of hexosaminidase A is lost
If one lacks the HexB gene, then both α- and β-chains are lost. |
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83. Sandhoff activator disease
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Caused by a mutation in the protein that is needed to activate hexoaminidase A activity, so hexoaminidase A activity is minimal.
GM2 initially accumulates in the lysosomes but the mutation has no effect on hexosaminidase B activity. |
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84. What are the four classifications of genetic disorders?
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1. Mendelian
2. Multifactorial 3. Single gene disorders w/non-classic inheritance 4. Chromosomal or cytogenetic disorder |
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85. What are the three categories of mutations?
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1. Genome mutations
-involves loss or gain of whole chromosomes 2. Chromosome mutations -rearrange genetic material giving rise to visible change in chromosome structure 3. Gene mutations -sub microscopic genetic changes which include point mutations, and frameshift mutations |
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86. Point mutations
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Due to single nucleotide substitutions
Includes: 1. Missense 2. Nonsense |
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87. Frameshift mutations
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Due to insertion or deletion of nucleotides.
May have no effect other than adding or removing an amino acid Frameshifts of numbers of nucleotides other than multiples of 3 rapidly lead to defective protein products. |
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88. Missense mutations
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Point mutations in the coding sequences that change the triplet base code and substitute a different amino acid in the final translated product.
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89. Nonsense mutations
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Point mutations in coding sequences that potentially result in the formation of an inappropriate stop codon
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90. Mutations within introns (non-coding regions)
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Point mutations or deletions in enhancer or promoter regions can significantly affect the regulation or level of gene transcription.
Can lead to defective splicing, and a failure to form mature mRNA species. |
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91. Tri-nucleotide repeat mutations
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Leads to 10-200x amplification of three nucleotide sequences
Happens in certain disease states, freq leading to abnormal gene expression. Occurs in diseases such as Huntingtons, and Fragile X syndrome |
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92. Codominance
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Refers to full expression of both alleles of a gene pair in a heterozygote
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93. Genetic heterogeneity
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Production of a given trait by different mutations in multiple loci.
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94. Penetrance
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% of individuals carrying an autosomal dominant gene and expressing the trait
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95. Pleiotropism
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Refers to multiple end effects of a mutant gene
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96. Polymorphism
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Refers to multiple allelic forms of a single gene
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97. Variable expressivity
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Refers to a variable expression of autosomal dominant trait in affected individuals
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98. Three general features of autosomal dominant disorders
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1. Affect structural or regulatory proteins
2. Reduced penetrance and variable expressivity 3. Onset of clinical features may be later than in autosomal recessive disorders |
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99. Dominant negative
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Autosomal dominant allele which can cause severe protein deficiency, such as in osteogenesis imperfecta.
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100. Three general features of autosomal recessive disorders
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1. Age of onset is freq earlier
2. More uniform clinical features 3. In many patients, enzymes are affected rather than structural proteins |
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101. Four consequences of single gene Mendelian disorders
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1. Enzyme defects
2. Defects in receptors and transport systems 3. Alterations in structure, function, or quantity of nonenzyme proteins 4. Genetically determined adverse reactions to drugs. |
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102. Enzyme defects and their consequences
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1. Accumulation of substrate
2. Decreased amt of end product 3. Absence of important regulatory component |
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103. Examples of diseases with defects in receptors and transport systems
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LDL receptors and familial hypercholesterolemia
Chloride in cystic fibrosis |
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104. Disorders associated w/defects in structural proteins
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Marfan syndrome: defect in fibrillin-1 gene
Ehlers-Danlos syndrome: defect in collagen synthesis |
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105. Marfan syndrome symptoms
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Tall stature
Laxity of joint ligaments Spinal deformities Ocular changes (bilateral dislocation of lens AKA ectopia lentis) Retinal detachments Cardiovascular lesions |
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106. Cardiovascular lesions in Marfan syndrome
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1. Mitral valve prolaspe most common although not life threatening; associated w/mitral regurgitation
2. Cystic medial degeneration of aorta; clinically more important and can result in: i. medial dissections ii. aortic rupture Death usually comes from aortic aneurysm |
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107. Ehlers-Danlos syndrome symptoms
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1. Skin is hyperextensible, very fragile and vulnerable to trauma
2. Joints are hypermobile and prone to dislocation 3. Internal complications 4. Rupture of colon and large arteries 5. Ocular fragility with corneal rupture and detachment 6. Diaphragmatic hernias |
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108. Six variants of Ehlers-Danlos syndrome
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1. Classical
2. Hypermobility 3. Kyphoscoliosis^ 4. Arthrochalasia* 5. Vascular 6. Dermatosparaxis*^ *More severe forms of Ehlers-Danlos syndrome ^Autosomal recessive |
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109. Arthrochalasia form of Ehlers-Danlos
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Autosomal dominant
Fundamental defect is in the conversion of Type I procollagen to collagen 1. Severe joint hypermobility 2. Skin changes is mild 3. Scoliosis and bruising. |
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110. Vascular form of Ehlers-Danlos
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Results from abnormalities of type III collagen
Some mutant alleles can behave as dominant negatives. |
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111. Come characteristics of Ehlers-Danlos
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1. Reduced activity of lysyl hydroxylase
2. Abnormalities of Type III collagen 3. Defective conversion of type I procollagen to mature collagen 4. Defective copper metabolism which reduces the activity of enzyme lysyl oxidase which is essential for cross linking of elastin and collagen |
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112. Familial hypercholestolemia
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Results from a mutation in the gene encoding receptor for LDL
LDL is the major transport form of cholesterol in the plasma. |
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113. How does free cholesterol affect processes in the cells
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1. Suppresses cholesterol synthesis inhibiting the rate limiting enzyme hydroxymethylglutaryl CoA reductase
2. Activates enzymes that esterify cholesterol 3. Suppresses LDL receptor synthesis. |
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114. Mutations in familial hypercholesterolemia
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1. Class 1
-Impairs transcription of LDL receptor proteins 2. Class 2 -Prevent transport of newly synthesized LDL receptors from the ER to the golgi complex for export to cell surface 3. Class 3 -Associated w/production of an LDL receptor that has reduced binding capactity 4. Class 4 -Gives rise to proteins that bind LDL but cannot internalize it 5. Class 5 -Results in LDL receptor proteins that bind and internalize LDL but cannot recycle them. |
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115. Clinical features of familial hypercholesterolemia in heterozygotes
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1. Cells possess 50% the normal number of high-affinity LDL receptors (
-Plasma LDL cholesterol is 2-3x higher than normal resulting in impaired clearance and increased synthesis 2. Leads to premature atherosclerosis and accumulation of cholesterol in soft tissues and skin producing xanthomas |
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116. Homozygotes in familial hypercholesterolemia
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Have much greater elevations of plasma LDL cholesterol and are at much greater risk for developing widespread atherosclerosis
Ischemic heart disease often develops before age 20 Xanthomas are also more present in the skin |
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117. Tay-Sachs disease
Clinical features |
Defect in hexosaminidase A
Prevents GM2-ganglioside degradation 1. Motor and mental deterioration commencing about 6 mos of age 2. Blindness 3. Cherry-red spot in the retina 4. Death by age 2 or 3 Dx possible via DNA probe analysis and enzyme assays |
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118. Morphology of Tay-Sachs disease
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1. Ballooning of neurons with cytoplasm of vacuoles staining positive for lipids
2. Whorled configs in the cytoplasmic vacuoles in electron microscopy 3. Progressive destruction of neurons with proliferation of microglia 4. Accumulation of lipids in retinal ganglion cell rendering them pale in color |
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119. Niemann-Pick disease
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Defect in sphingomyelinase
Autosomal recessive Type A is most common variant Hepatocytes and Kupffer cells have a foamy vacuolated appearance owing the deposition of lipids. Electron microscopy in Niemann-Pick disease confirms that the vacuoles are engorged secondary lysosomes that often contain membranous cytoplasmic bodies resembling concentric lamellated myelin figures. Sometimes the lysosomal configurations take the form of parallel palisaded lamellae, creating so called zebra bodies |
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120. Niemann-Pick disease type A
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Most severe infantile form
Diffuse neuronal involvement leading to cell death and shrinkage of the brain Cherry red spots also present Extreme accumulation of lipids and mononuclear phagocytes giving rise to massive splenomegaly and enlargement of liver, lymph nodes, and infiltration of bone marrow. Visceral involvement involving the GI tract and lungs |
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121. Niemann-Pick disease type B
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Patients have organomegaly but generally, no nervous system involvement.
Type B patients usually survive into adulthood. |
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122. Gaucher disease
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Accumulation of gangliocerebroside due to defect in glucocerebrosidase enzyme
Type 1 is non neuronopathic but has thrombocytopenia and pancytopenia Type 2 is the acute neuronopathic form Type 3 is intermediate between types 1 and 2 |
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123. Morphology of Gaucher disease
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Affected cells are distended w/PAS positive material
Has a fibrillary appearance resembling crumpled tissue paper. Gaucher cells also present |
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124. Hepatic form of glycogen storage disorder
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Type I glycogenosis (von Gierke disease)
Results from deficiency of hepatic enzyme glucose-6-phosphatase which is essential for conversion of glucose-6-phosphate to glucose Effects of deficiency are: -Accumulation of glycogen b/c it can't be broken down -Low blood glucose levels |
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125. Myopathic form of glycogen storage disorder
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Results from deficiencies of enzymes that fuel glycolysis in striated muscle
McArdle disease (type V glycogenosis) is caused by lack of muscle phosphorylase Deficiency in this enzyme leads to: 1. Storage of glycogen in the skeletal muscles 2. Muscle weakness 3. Muscle cramps after exercise 4. Absence of exercise induced rise in blood lactate level |
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126. Type 2 glycogenosis (Pompe disease)
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Results from deficiency of the lysosomal enzyme acid maltase (AKA α-glucosidase)
Many organs are involved; storage of glycogen is most prominent in the heart Affected neonates have massive cardiomegaly; death usually results by age 2 |
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127. Neurofibromatosis type 1
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AKA von Recklinghausen disease
Three main features: 1. Multiple neural tumors that involve nerve trunks in skin as well as internal organs 2. Cutaneous pigmentations present in > 90% of patients 3. Cafe au lait spots 4. Lisch nodules (harmartomas) 5. Skeletal lesions (bone cysts, scoliosis, etc...) 6. Increased risk of developing other neoplasms 7. Tendency towards reduced intelligence |
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128. Neurofibromatosis type 2
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Four major characterizations:
1. Bilateral acoustic nerve tumors in all cases 2. Gliomas, particularly ependymomas 3. Cafe au lait spots 4. Absence of Lisch nodules |
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129. NF-1 gene
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Located on chromosome 17 and encodes for neurofibromin, a protein that down regulates the function of the p21 RAS oncoprotein.
It is functionally a tumor suppressing gene. |
