Exam 1 Clinical CorrelationsUTF8

Question 1

Wiskott-Aldrich Syndrome (WAS)

Answer 1

mutated WASP protein controlling actin assembly, skin lesions, immune system defects

Question 2

Hypertrophic Cardiomyopathy

Answer 2

cardiac alpha-actin, problems with contraction and force transmission, leading cause of sudden cardiac death in young adults

Question 3

Amyotrophic Lateral Sclerosis (ALS)

Answer 3

actin protein profilin-1 mutation causes familial form; progressive dysfunction and death of motor neurons; leads to atophy of muscle cells

Extra (I think): also SOD1 mutation affecting fast axonal transport via defect in kinesin but not dynein; 90% sporadic, 10% familial; dying-back neuropathy

Question 4

Alzheimer’s Disease (AD)

Answer 4

microtubule-associated protein Tau involved in trafficking of materials and formation of neurofibrillary tangles, accumulation of IF neurofilaments

Extra: oligomeric amyloid-beta affects kinesin and dynein; modified or unstacked Golgi

Question 5

Frontotemporal Dementia and Parkinsonism (FTDP)

Answer 5

mutation in FTDP-17, presents as a tauopathy in cortical neurons

Question 6

Hereditary Spastic Paraplegia (HSP)

Answer 6

most common is spastin mutation

Extra: presents as dying-back neuropathy in upper motor neurons, can also be heterozygous mutation in neuron-specific kinesin 1A (homozygous is embryonic lethal)

Question 7

Lissencephaly

Answer 7

Most common mutation is Lis1, a dynein-associated protein that anchors dynein to specific locations in cell; defect in neuronal migration, perturbs layering of cortex, which is smooth instead of normal gyri (also mutations in doublecortin and tubulin 1a)

Question 8

Congenital Fibrosis of Extraocular Muscles Type 3 (CFEM3)

Answer 8

beta 3 tubulin mutation affecting motor neurons and causing facial paralysis, also kinesin KIF21A gene

Question 9

Epidermolysis Bullosa Simplex (EBS)

Answer 9

mutation in keratins, presents as blistering disease that differs in location and severity depending on keratin gene affected; can also be plectin if sensory and muscle involved

Question 10

Progeria Syndrome

Answer 10

point mutation in prelamin gene, affects post-translational modification in ER where farnesyl group not removed and becomes progerin accumulation instead of nuclear lamin; presents as premature aging; clinical trial of farnesyltransferase inhibitors

Question 11

Griscelli Syndrome

Answer 11

mutation in myosin V causes delivery of pigments from melanosomes to hair follicle cytoskeleton, presents as silvery sheen in hair, albinism, immunodeficiency; inherited autosomal recessive

Question 12

Usher Syndrome

Answer 12

autosomal recessive, mutation in myosin VII, hearing loss and retinal pigmentosa

Question 13

Snell?s Waltzer Mouse

Answer 13

mutation in myosin VI (myo6), presents as vestibular/balance defects

Question 14

Spinal Muscular Atrophy

Answer 14

mutation in dynein heavy chain

Question 15

Syndromic Male Sterility

Answer 15

mutation in dynein or nexin in cilia, no crosslinking of adjacent doublets in 9+2 microtubule arrangement, ciliary dyskinesia

Question 16

Situs Inversus

Answer 16

mutation in flagellar dynein, causing reversal or random organ locations, ciliary dyskinesia, particularly effecting nodal cilia

Question 17

Charcot-Marie-Tooth Type 2A

Answer 17

mutation in kinesin, presents as peripheral neuropathy

Question 18

Myasthenia Gravis

Answer 18

autoimmune attack on acetylcholine receptor (AChR), reduced number function of NMJs leads to decreased contraction of muscle and later atrophy

Question 19

Cystic Fibrosis

Answer 19

improper folding of CFTCR in ER lumen

Question 20

Role of Integrin in Blood Clot & Cancer

Answer 20

block with RGD tripeptide (Integrillin)

Question 21

HER2+ Breast Cancer

Answer 21

block with Herceptin

Question 22

Cardiac Arrythmia

Answer 22

mutation in ankyrin

Question 23

Proteinuric Kidney Disease

Answer 23

mutation in dynamin involved in pinching off of clathrin-coated pits

Question 24

Irreversible Sickle Cell Disease

Answer 24

mutation in spectrin involved in maintaining shape of RBC

Question 25

Duchenne?s Muscular Dystrophy

Answer 25

mutation in dystrophin; MG53 drug shows promise; protein involved in linking laminin of external lamina to actin; progressive muscular weakness; encoded on X chromosome (almost exclusively seen in males). Over time, atrophied muscle fibers invaded by connective tissue

Question 26

Inherited Deafness

Answer 26

mutation in connexin-26 in gap junctions

Question 27

Cataracts

Answer 27

mutation in connexin-50 in gap junctions

Question 28

Kartagener?s Syndrome

Answer 28

type of primary cilia dyskinesia (PCD) caused by absence of dynein arms in normal 9+2 cilia arrangement

Question 29

Toxic Hepatic Injury

Answer 29

hydropic swelling of hepatocytes leads to enlarged cisternae in ER

Question 30

Chronic Activation of Unfolded Protein Response (UPR)

Answer 30

causes inflammation in obesity, atherosclerosis, diabetes, and cancer

Question 31

I-Cell Disease

Answer 31

lysosomal storage disease, deficiency in phosphotransferase in cis-Golgi; can?t add phosphate to mannose; not recognized by M6-P receptor, no delivery to lysosome, disorder of lysosomal biogenesis, no hydrolases in lysosome; accumulation of GAGs and glycolipids; elevated lysosomal enzymes in serum

Question 32

Clostridium Botulinum

Answer 32

releases toxins that destroy SNARE proteins, affecting exocytosis in neurons and failed contraction in muscle

Question 33

Familial Hypercholesterolemia

Answer 33

mutation in LDL receptor prevents binding of LDL, used in normal individuals to show clathrin-coated endocytosis via ferritin-labeling

Question 34

Tay-Sachs Disease

Answer 34

lysosomal storage disease of sphingolipid degradation, accumulation of GM2 ganglioside via deficiency in hexosaminidase-A

Question 35

Hurler Syndrome

Answer 35

lysosomal storage disorder of GAG degradation, accumulation of dermatan sulfate due to deficiency in alpha-L-iduronidase

Question 36

Gaucher Disease

Answer 36

lysosomal storage disorder of sphingolipid degradation, accumulation of glucosylceramide due to deficiency in beta-glucocerebrosidase (delivery pathway doesn?t involve M6-P but rather TM protein LIMP-2)

Question 37

Multiple Myeloma

Answer 37

treatment with proteasome inhibitor Velcade to allow protein build-up in plasma cells which causes cell death

Question 38

Zellweger?s Syndrome

Answer 38

defect in ability to import proteins into peroxisomes or degradation, build up of LCFA impairs normal function

Question 39

Adrenoleukodystrophy

Answer 39

impaired beta-oxidation results in accumulation of vLCFA in brain and adrenal gland

Question 40

Kearns-Sayre Syndrome

Answer 40

abnormalities or deletions in mtDNA affects eye movement, type of mitochondrial myopathy affecting muscles of eye

Question 41

Mitochondrial disease (mito)

Answer 41

inability to produce enough energy, presents as constant fatigue

Question 42

Pap Smear

Answer 42

female puberty, hormonal changes cause metaplasia in cervix, but also chance for neoplasia (development of cancerous lesions) so check via pap smear

Question 43

Bacterial Induced Food Poisoning

Answer 43

diarrhea and dehydration due to disruption of tight junctions between adjacent intestinal epithelial cells; E.coli attacks ZO proteins (PDZ domains) while Clostridium perfringens attacks claudin, massive fluid loss via paracellular pathway

Question 44

Marfan?s Syndrome

Answer 44

mutation in fibrillin-1 responsible for bundling elastic fibers; long extremities, no pressure on bone due to presence of elastic fibers

Question 45

Ehlers-Danlos Syndrome

Answer 45

mutation in collagen gene, hyperelastic skin, hypermobility in joings, very fragile blood vessels; ?Rubber Man?

Question 46

Scurvy

Answer 46

vitamin C/ascorbic acid deficiency, no hydroxylation of proline and lysine residues in collagen presents as poor wound healing and bone formation

Question 47

Osteopetrosis

Answer 47

disease of malfunctioning osteoclasts, increased bone density but very fragile and break easily; bone formation exceeds resorption

Question 48

Osteoperosis

Answer 48

insufficient bone mineralization often seen in postmenopausal women; bone resorption exceeds formation; associated with decreased estrogen, which normally inhibits osteoclast activity

Question 49

Vitamin D Deficiency

Answer 49

decrease in absorption of calcium by intestines, decreased calcium can cause rickets and osteomalacia

Question 50

Vitamin A

Answer 50

deficiency suppresses endochondral growth of bone while excess leads to fragility and long bone fractures

Question 51

Acromegaly/Gigantism

Answer 51

over-secretion of somatotropin, involved in stimulating cartilage proliferation and bone growth

Question 52

Dwarfism

Answer 52

absence or severe hyposecretion of thyroid hormone during development and infancy leads to failure of bone growth

Question 53

Sickle Cell Anemia

Answer 53

hemoglobin HbS point mutation (glutamic acid … valine) in beta-globin chain gene position 6 chromosome 11; sickled shape cell sticks to walls of blood vessels, especially in smaller capillaries such as those of kidney and brain; heterozygous individual have resistance to malaria, gametocyte of Plasmodium falciparum needs normal Hb inside RBC

Question 54

Thrombocytopenia purpura

Answer 54

red/purple discoloration of skin, associated with reduction in circulating blood platelets

Question 55

Primary metastasis

Answer 55

migration/diapedesis from extravascular marrow across sinusoidal epithelium into the blood in leukemia

Question 56

Rigor Mortis

Answer 56

absence of ATP in muscle cell causes tight binding of myosin-actin (in normal muscle, binding of ATP occurs to induce conformational change and cause uncoupling)

Question 57

Parkinson?s Disease (PD)

Answer 57

loss of dopamine-secreting cells in substantia nigra and basal ganglia of brain responsible for coordination of smooth and focused skeletal muscle activity

Question 58

Multiple Sclerosis (MS)

Answer 58

demyelinating disease; slow, rapid loss of function of oligodendrocytes and myelin, unknown etiology; shadow plaques indicate some level of remyelination; autoimmune targeting of myelin basic protein (MBP), produces plaques

Question 59

Krabbe Disease

Answer 59

autosomal recessive lyososomal storage disease caused by deficiency in lysosomal galactosylceramidase, accumulation of sphingolipids; demyelination, neuronal and muscular atrophy; most cases in infants, Twitcher mouse model

Question 60

Becker Muscular Dystrophy

Answer 60

partial loss of function of dystrophin (as compared to total LOF in Duchenne MD); also X-linked so almost exclusively found in males