Diseases Exam 1

Question 1

Transthyretin amyloidosis

Answer 1

caused by transthyretin misfolding in old age. affects heart, kidneys, and respiratory tract

Question 2

AL amyloidosis

Answer 2

caused by Ig light chain misfolding due to plasma cell dyscrasias (abnormalities). Affects are systemic, sometimes with local foci (excluding brain)

Question 3

AA amyloidosis

Answer 3

caused by serum amyloid A protein overproduction in chronic inflammation, leading to amyloid formation in the spleen and elsewhere

Question 4

Dialysis-associated amyloidosis

Answer 4

caused by hemodialysis (blood cleaning) leading to amyloid formation in the bones and joints. β2- micro globulin is a surface protein involved in immune responses that can detach from cells and deposit in bones and joints, causing arthritis.

Question 5

type 2 diabetes mellitus

Answer 5

one possible cause is oversecretion of islet amyloid protein (secreted with insulin in the vesicles) leading to amyloid accumulation in and around the pancreatic islents

Question 6

Frontotemporal dementia

Answer 6

age related or inherited mutation leading to accumulation of tau protein in the brain. Tau protein stabilizes microtubules in axons and is regulated by phosphorylation and dephosphorylation. Excessive phosphorylation can lead to diseases including Alzheimers and frontotemporal dementia.

Question 7

Parkinson’s disease

Answer 7

α-synuclein- unstably folded membrane protein that can aggregate into granules called Lewy bodies, found in dopaminergic neurons in most patients with Parkinson’s. Increased production of α-synuclein or abnormal α-synuclein protein can lead to early onset Parkinson’s

Question 8

Alzheimer Disease

Answer 8

can be inherited, or related to age or down syndrome. related to β-amyloid precursor protein accumulation causing amyloid plaques. Tau protein stabilizes microtubules in axons and is regulated by phosphorylation and dephosphorylation. Excessive phosphorylation can lead to diseases including Alzheimers and frontotemporal dementia.

Question 9

Prion Diseases

Answer 9

Prion protein is a normal nervous system protein bound to glycosylphosphatidylinositol with a flexible N-terminus that can vary in conformations. It extremely rarely refolds, but can cause normal prion proteins to refold into the abnormal conformation and form aggregates leading to neuron death. The excessive neuron death leads to holes in the brain, which resembles a sponge upon death (hence the term spongiform encephalopathy). This progression describes Creutzfeldt-Jakob disease where someone inherits a mutant prion gene (single AA mutation) or from exposure. There is also a variant form of the disease (vCJD) where it is transmitted from infected cattle, as well as kuru, which is transmitted by cannibalizing an infected individual.

Question 10

Anemia

Answer 10

defined as Hb below the normal range of 12%-17%. This can be due to an impairment in Hb synthesis, a condition called microcytic hypochromic anemia, usually caused by an Fe deficiency. Can also be genetic like in thalassemia where the synthesis of Hb α and β chains is disrupted.

Question 11

Methemoglobinemia

Answer 11

a condition where iron is oxidized from the ferrous to the ferric state, so it cannot transport oxygen. Normally methemoglobin (oxidized Hb) is present at 1% concentration due to the activity of methemoglobin reductase, but a deficiency in this enzyme leads to congenital methemoglobinemia. This condition is treated with methylene blue, a dye that is reduced to leucomethylene blue, which then reduces the ferric iron back to ferrous iron.

Question 12

CO poisoning

Answer 12

• due to 200x affinity for Hb of CO than O2 called competitive antagonism. CO binding also increases O2 affinity of the other subunits, so decreases oxygen delivery. Normal nonsmokers have 2% CO-Hb, but each pack of cigarettes increases this by 2.5%. Hookah smoke is especially high in CO and can cause acute CO poisoning, also seen in car-related suicide attempts. 70% is fatal

Question 13

Niemann-Pick Disease

Answer 13

lipid storage disorder that results from the deficiency of a lysosomal enzyme, acid sphingomyelinase. The original description of NPD referred to what is currently termed NPD type A, which is a fatal disorder of early childhood characterized by failure to thrive, hepatosplenomegaly, and a rapidly progressive neurodegenerative course that leads to death by age 2-3 years.

Question 14

Tay-Sachs

Answer 14

caused by Hexosamindase A deficiency and leads to accumulation of gangliosides in neurons

Question 15

systemic lupus erythematosus (SLE)

Answer 15

the presence of high titer of antibodies to histones is diagnostic for systemic lupus erythematosus (SLE)

Question 16

Rett Syndrome

Answer 16

severe neurological disease in females due to mutation in methyl-cytosine binding protein 2 (MeCP2), which represses transcription when bound to methyl cytosine in DNA. Very rare to be passed on between generations, 99% is due to de novo (spontaneous mutations; increases with advanced PATERNAL age). Begins at 1-2 years of age and leads to loss of motor and cognitive skills, seizures, autism, repetitive movements and death between 12 and 40 years.

Question 17

Huntington’s Disease

Answer 17

Some microsatellite DNA occurs in regulatory sequences. In Huntington’s disease, a 3 NT CAG repeat normally repeated 6-34 times (codes for polyglutamine tract in protein huntingtin) is repeated >36 times, causing protein to form clusters that kill cells in the basal ganglia. The greater the expansion, the easier the onset of disease

Question 18

Leber’s hereditary optic neuropathy (LHON)

Answer 18

mutation in mitochondrial DNA @ bp 11778 that affects complex I of ETC (NADH dehydrogenase) and disables leads to disabilities in areas where aerobic respiration is essential (like optic nerve)

Question 19

Zellweger syndrome

Answer 19

deficiency in any of the 12 PEX genes leading to dysfunctional peroxisomes. Leads to accumulation of VLCFAs and BCFAs in the blood and insufficiency in plasmologen synthesis leading to brain and respiratory problems . Patients can show craniofacial abnormalities (such as a high forehead, hypoplastic supraorbital ridges, epicanthal folds, midface hypoplasia, and a large fontanel), hepatomegaly (enlarged liver), chondrodysplasia punctata (punctate calcification of the cartilage in specific regions of the body), eye abnormalities, and renal cysts. Newborns may present with profound hypotonia (low muscle tone), seizures, apnea, and an inability to eat.

Question 20

beriberi

Answer 20

vitamin B1 deficiency (thiamin)

Question 21

pellagra

Answer 21

vitamin B3 deficiency leading to dermatitis, dementia, and diarrhea

Question 22

Xeroderma pigmentosum (XP)

Answer 22

affected individuals have deficiencies in NER complex; show dry skin (xeroderma) and freckles (pigmentosum) in sun-exposed areas and are extremely sensitive to UV radiation

Question 23

Cockayne syndrome

Answer 23

deficiency in ERCC6 and/or 8 (aka CsB and/or CsA); leads to photosensitivity (not to extent of XP), delayed neurological development, and premature aging.

Question 24

Aneuploidy

Answer 24

abnormal # of chromoromes

Question 25

turners syndrome

Answer 25

(45, XO)

Question 26

Kleinfelder

Answer 26

XXY

Question 27

Philadelphia chromosomes

Answer 27

part of 9 and 22 exchange places and the fusion causes leukemia due to the formation of a constitutively active fusion protein

Question 28

familial hypercholesterolemia

Answer 28

autosomal dominant disease; people who are homozygous can have heart attacks and deaths as early as 30. Most often caused by mutation in LDLR which removed LDL from blood

Question 29

sickle cell disease

Answer 29

Autosomal recessive disease that results in sickle shaped RBCs due to mutation in Hb that causes polymerization

Question 30

X-SCID

Answer 30

X-linked recessive disease. Severe combined immunodeficiency

Question 31

Fragile X-syndrome

Answer 31

• causes intelectual disability; most common mental retardation in males and can cause retardation in females. Symptoms include elongated face, protruding ears, heart problems, skin problems, etc (pleiotropy) inherited in fashion that is very close to X-linked dominant and some females are less affected due to X inactivation
  
  • Caused by trinucleotide repeat expansion (CGG) on. FMR1 gene. Fragile X gene is a subunit of the RNA-induced silencing complex (RISC); disease though to be due to incomplete silencing of specific mRNAs. Normally between 5-40. >200 causes fragile X. In between leads to “premutation” that leads to some manifestation of disease, but not full diagnosis.
  • In women with premutation, gene can expand in gametogenesis. Doesn’t occur in males, can only pass on premutation for reasons unknown
  • Anticipation- tends to happen with trinucleotide repeat disorders. Means that symptoms begin to show at earlier age and severity is greater with each passing generation. e.g. most often in neurological trinucleotide repeat diseases fragile X and Huntington’s disease.

Question 32

ataxia telangiectasia

Answer 32

Deficiency in ATM leads to ataxia telangiectasia (defects in nervous and immune systems and high incidence of cancer)

Question 33

Duchenne muscular dystrophy (DMD)

Answer 33

caused by a mutation in the dystrophin gene, which codes for a protein that is involved in stabilization of the plasma membrane to the cytoskeleton and participates in calcium handling. This gene is the largest human gene known (2.5 million bp long) and has 79 exons. DMD causes wheelchair confinement by age 12 and death by respiratory failure within 10 years of onset. 2/3 of mutations are large deletions; half of which are in frame. When the deletion is out of frame it gives clinical DMD, when it is in frame, it gives a less severe form of the disease (Becker muscular dystrophy- BMD)

Question 34

Retinis pigmentosa

Answer 34

disease due to mutation of rhodopsin which results in night blindness due to apoptosis of photoreceptors due to UPR as a response to the number of misfolded rhodopsin proteins

Question 35

Gaucher’s disease

Answer 35

defficiency in glucocerebrosidase leading to an accumulation of glucocerebroside and increased lysosome size

Question 36

I-cell disease

Answer 36

deficiency in M-6-P tagging of lysosome enzymes, leading to excretion of lysosomal enzymes

Question 37

Cholera

Answer 37

cholera toxin is endocytose into the cell and ADP ribosylates the αs (stimulatory) subunit; inactivates the GTPase activity of the α rendering it permanently active and causing an increase in cAMP. This continuously activates the cystic fibrosis channel (CFTR) causing a big entry of chloride ions and water that follows, causing extreme water loss and dehydration

Question 38

Prader-Wili syndrome

Answer 38

dysfunctional copy of 15q 11-13 received from father; maternal imprinting; father’s copy is the one normally expressed, but if it is mutated, causes hyperphagia, obesity, intellectual disability, hypotonia, and hypogonadism

Question 39

Angleman syndrome

Answer 39

dysfunctional copy of 15q 11-13 received from mother; Paternal imprinting; mother’s copy is the one expressed. Leads to inappropriate laughter (“happy puppet”), seizures, ataxia, and severe intellectual disability

Question 40

Whooping cough

Answer 40

aka pertussis; caused by pertussis toxin. Toxin is endocytosed and ribosylates the αi subunit (inhibitory subunit) resulting in the protein being locked in the GDP bound state, resulting in increased cAMP