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Flashcards in Exam 2 - diseases Deck (90):
1

Lynch;s syndrome

Mutations in MMR assoc w hereditary nonpolyposis colorectal cancer (HNPCC) aka Lynch’s Syndrome

2

Xeroderma pigmentosum

**mutations in NER linked to: (mutations carried in genes)
●Xeroderma pigmentosum-cant fix UV damage, pigment irreg, skin CA

3

Cockayne’s syndrome

**mutations in NER linked to: (mutations carried in genes)
●Cockayne’s syndrome-dwarfism, aging of some tissues, face/limb
abnml

4

Trichothiodystrophy

**mutations in NER linked to: (mutations carried in genes)
Trichothiodystrophy-premature aging of tissues, short stature, brittle
hair, short stature

5

BRCA

BRCA 1/2 involved in homologous recombination error, mutations lead to breast CA

6

Ataxia telangiectasia (AT)

2. Ataxia telangiectasia (AT) – leukemia/lymphoma, gamma ray sensitivity, genome instability – ATM defect

7

ATLD (AT-like disorder)

--hypomorphic mutations in MRE11

8

Werner syndrome

premature aging – accessory 3’ exonuclease and DNA helicase

9

Bloom syndrome

mult ca’s, stunted growth – accessory DNA helicase for replication

10

Fanconi anemia

congenital abnml, leukemia – DNA interstrand cross-link repair, also BRCA2

11

46 BR patient

hypersensitive to DNA-damagin agents – DNA ligase I

12

NBS (Nijmegen breakage syndrome

mutation in NBS1

13

Pellegra

lacks vit B, causes Dementia, Diarrhea, Dermatitis, and Death

14

lactose intolerance

●lactase deficiency  cant break lactose into galactose and glucose
●deficiency can be hereditary, mutation, or acquired
●instead, lactose goes to large intestine where bacteria break it down to reducing sugars, which can be detected in stool/urine!

15

congenital lactic acidosis:

Cant go thru pyr deh step, build up pyruvate and lactate, decreases the pH, decreases NADH production

16

Leu Gerigs or ALS

neuro deg diseases have mutations in superoxide dismutase

17

Glucose 6P dehydrogenase deficiency

impairs ability of RBC to form NADPH, resulting in hemolytic anemia –RBCs not able to make NADPH for detox, thus they lyse and die. This deficiency seen only in RBCs bc RBCs only have this 1 enzyme. Seen in Africans and Mediterranean folks bc it protects against malaria (RBCs die prematurely!), their young RBC’s have active G6PD, activity drops as they age. RBC’s accumulate Heinz bodies = clumps of denatured protein that adhere to p.m. and stain w basic dyes.

18

I Von Gierke

defect in glucose-6Pase [liver and kidney]. Lose glycolysis and gly breakdown. Gly increases. Causes severe hypoglycemia, ketosis, enlarged liver

19

II Pompe disease

defect in lysosomal α1,4 glucosidase [all organs]
Massive increase in glycogen, causes cardioresp. Failure usually resulting in death

20

III Cori disease

defect in amylo-1,6-glucosidase (debranching enzyme) [muscle/liver]
Increased glycogen, short outer branches, similar to type I but less severe

21

IV Andersen disease

defect in Branching enzyme (α1,4 – α1,6) [liver/spleen]
Nml amt glycogen, very long outer branches…liver cirrhosis and then failure

22

V McArdle disease

in phosphorylase [muscle]
Not able to do anaerobic metabolism, inc amt glycogen, not able to do strenuous exercise

23

VI Hers

defect in phosphorylase [liver]
Mild bc you still have gluconeogenesis, increase in glycogen

24

VII

defect in phosphofructokinase [muscle]
Increased glycogen

25

VIII

defect in phosphorylase kinase [liver]
Increased glycogen

26

Essential fructosuria:

defect w fructokinase. Benign, inc fructose in urine

27

Hereditary fructose intolerance

defect w aldolase B. Severe, hypoglycemia, liver/kidney failure. Tx: limit fructose intake

28

Non-classical galactosemia

defect in galactokinase. Accumulated galactose can be shunted to side pathway creating increase in galactitol (causing cataracts).

29

Classical galactosemia-

defect in galactose-1P uridylytransferase, causes accumulation of galactose1P/galactose and appearance of galactose in blood/urine. Severe, failure to thrive, mental retard, cataracts also common.

30

Hunter’s syndrome:

Diseases with mucopolysaccharides (mucopolysaccharadoses or lysosomal storage diseases): unable to break down GAG’s bc they have defect in enzyme w/in lysosomes (where GAGs broken down)
●Hunter’s syndrome: X-linked, physical deform and MR, NO corneal clouding

31

Hurler’s syndrome:

Diseases with mucopolysaccharides (mucopolysaccharadoses or lysosomal storage diseases): unable to break down GAG’s bc they have defect in enzyme w/in lysosomes (where GAGs broken down)
●Hurler’s syndrome: MR, dwarfing, corneal clouding. Deposition in coronary arteryearly death

32

Scheie’s syndrome:

Diseases with mucopolysaccharides (mucopolysaccharadoses or lysosomal storage diseases): unable to break down GAG’s bc they have defect in enzyme w/in lysosomes (where GAGs broken down)
●Scheie’s syndrome: corneal clouding, stiff joints, valve disease, nml intelligence and lifespan

33

Sanfilippo’s syndrome

Diseases with mucopolysaccharides (mucopolysaccharadoses or lysosomal storage diseases): unable to break down GAG’s bc they have defect in enzyme w/in lysosomes (where GAGs broken down)
●Sanfilippo’s syndrome: MR, nervous system disorder, unable to breakdown heparin sulfate

34

Sly’s syndrome:

Diseases with mucopolysaccharides (mucopolysaccharadoses or lysosomal storage diseases): unable to break down GAG’s bc they have defect in enzyme w/in lysosomes (where GAGs broken down)
●Sly’s syndrome: hepatosplenomegaly, physically deformed

35

sulfonamides

blocks synthesis of folic acid, tetrahydrofolate (derivative of folic acid) is required as coenzyme in making purines. Humans cannot make folic acid. Sulfonamide used to inhibit growth of rapidly dividing organisms

36

methotrexate

structural analog to folic acid, interferes w nt synthesis, used as anticancer tx

37

Orotic aciduria

rare genetic defect caused by deficiency of last 2 steps in pathway, results in orotic acid in the urine, diet rich in uridine results in partial improvement

38

gout

decrease intake of foods high in nucleic acids such as organ meats, anchovies, sardines, dried beans).
high levels of uric acid in the blood, needle-shaped crystals of sodium urate deposit in tissues, tx’d w allopurinol which inhibits “Xanthine  uric acid” step, builds precursors hypoxanthine and xanthine which are more soluble. Tx’s: xanthine oxidase inhibitors and allopurinol uloric (febuxostat)

39

Adenine deaminase (ADA) deficiency:

inc dATP thus inhibiting DNA synthesis.

40

SCID (severe combined immunodeficiency)

Lymphocytes have highest ADA activity, thus if you have ADA deficiency, T + B cells cannot replicate. First genetic disease successfully tx’d by gene thearapy

41

Lesch-Nyhan syndrome:

xsome linked recessive disorder from complete deficiency of HPRT, thus cannot salvage hypoxanthine/guanine resulting in inc uric acid. Characterized by self-mutilation, involuntary movements, kidney stones

42

dyskeratosis congenital

mutation in RNA component of telomere, thus defects seen in nearly every organ system of the body that has rapidly dividing cells

43

Zellweger syndrome

Diseases w defect in degradation of fa’s: no functional peroxisomescant degrade fa’s longer than 26. Affects CNS and other organs, usually dies within 1 yr

44

Refsum syndrome

Diseases w defect in degradation of fa’s: defect in degradation of 3-methyl-branched fa’s. Neuro disease w accumulation of phytanic acid. tx: phytanic acid restricted diet- avoid fat from ruminants or high fat fish

45

fatty liver

= increased fa synthesis, stays in the liver. Inc etoh = inc etoh deh which produces NADH, which inhibits isocitrate deh thus kick-starting fa synthesis!

46

Tay-Sachs disease:

-degradation (occurs in lysosome), when sphingolipids accumulate, its called sphingolipidoses, typically affects lysosomes and its tissue in nervous system
Ex: Tay-Sachs disease: missing enzyme to cleave off end sugar, thus ganglioside accumulates
in lysosome, which swell, destroys tissues

47

Gangliosidosis, Sandhoff, Fabry (the only X-linked one!!), Farber, Krabbe, Metachromatic Leukodystrophy, Gaucher
TX: supplement w deficient enzymes, very difficult

Many other diseases that have defect in enzyme to cleave sugar

-degradation (occurs in lysosome), when sphingolipids accumulate, its called sphingolipidoses, typically affects lysosomes and its tissue in nervous system

48

Familial Hypercholesterolemia (FH):

Disorder of high LDL-chol plasma levels, primarily mutations in LDL receptor but also
apoB100, autosomal dominant
Heterozygote: 1/500ppl, chol >300, LDL >220, untreated 85% will have MIs before 60, treat w
statin (blocks synthesis of chol in cell so cell inc receptors to take LDL-chol from blood)
Homozygote: 10-6 ppl, chol 500-1200, MI before 30, treat with LDL apheresis (physical
removal of LDL from blood). They have no receptors at all, HMG-CoA doesn’t respond to
LDL levels outside of cell at all
Possible defects that could cause FH: gene deletion resulting in NO LDL receptors being made, receptors made but not localized properly, receptor has low affinity for apoB100, receptor does not accumulate in pits, receptor wont release LDL in the endosome, receptor gets degraded by lysosome
Another tx method (in addition to statins) is to deplete bile acid, making it so you cant take up chol from diet. (but you need a statin otherwise HMG-CoA will pick up the slack in the cell

49

Steatorrhea

Steatorrhea = stinky floaty stool – due to high fat content in stool. Could be due to:
-decreased bile production, cant solubilize/degrade fat
-decreased pancreatic enzymes, no PTL enzyme
-not able to import into intestinal mucosal cells, would have high levels of MAG

50

Abetalipoproteinamia

Disorders with CM’s
●Abetalipoproteinamia – defect in apo B-100 = deficiency in CMs, VLDL, LDL  no long chain FA absorption, deficiency in fat soluble vits A/D/E/K…GI symptoms and cognitive probs

51

LPL deficiency

Disorders with CM’s
●LPL deficiency – leads to high CM levels, cant break it down. 2 ways of this:
Apo C-II deficiency – necessary on surface of CMs/VLDL required for LPL activation
Low LPL activity – extreme CM/TAG levels..liver and pancreas probs.

52

Hypoketotic hypoglycemia

defect in B-oxidation
Cant use fa for energy. Symptoms=muscle weakness, sleepiness, mood changes. Tx= dietary modification, freq intake every 2-6hrs of low fat high carb food

53

Cystinuria

defective lys/arg/cys-cys/ornathine transporter. Think “COAL”!! Cystine builds
and forms k stones, aa of the transporter excreted in urine, tx: drink water solubilize cys!

54

Hartnup Disease

Hartnup Disease (neutral amino aciduria): defect in neutral aa transport, aa’s excreted – esp
Trp. Symptoms= pellagra rash, HA, psych. Tx: high protein, nicotinamide supplements (form
of niacin/vit B3 – precursor to trp), trp supplements

55

-Deficiencies in urea cycle:
●General facts and tx

●General facts:
Symptoms: lethargy, vomiting, poor muscle tone, sz, coma, death
Incidence: 1/25000-30000
Findings: hyperammonemia, dec BUN (blood urea N), elevated glutamine and aa’s

GENERAL TX’S:
1) Reduce N intake (low protein diet, but still w enough essential aa’s and calories)
2) Increase alternative N excretion (supplement w benzoate or phenylacetate- both take up NH4 in their degradation and are easily degraded)
3) Stimulate residual urea cycle activity (supplement w arginine, stimulates urea cycle)

56

Hyperammonemia:

PROXIMAL ENZYME DEFICIENCES: (more severe)
●Hyperammonemia: could be from NAGS enzyme deficiency (makes N-acetyl glutamate), or from CPS I deficiency. Autosomal recessive

57

OTC deficiency

PROXIMAL ENZYME DEFICIENCES: (more severe)
●OTC deficiency: most common, X-linked, inc uracil/orotic acid in blood in urine (bc inc CP leaks into cytosol where CPSII converts it to orotic acid-think pyrmidine degradation!)

58

Citrullinemia

DISTAL ENZYME DEFICIENCES: (less severe, buildups can be excreted)
●Citrullinemia – arg synth deficiency

59

Argininosuccinic acidura (ASA)

DISTAL ENZYME DEFICIENCES: (less severe, buildups can be excreted)
●Argininosuccinic acidura (ASA) – arg lysase deficiency

60

Arginemia

DISTAL ENZYME DEFICIENCES: (less severe, buildups can be excreted)
●Arginemia- arginase deficiency, rare

61

Nonketotic hyperglycemia, also glycine encephalopathy

defect in glycine cleavage process, inc levels of gly in blood, severe mental
retardation/sz’s/death

62

Maple Syrup Urine Disease

Defect in branched-chain α-keto acid deh. Urine has odor of maple syrup. Mental/physical retardation, abnml muscle tone, ketosis, coma, short lifespan. 1/200,000. Tx: decrease intake branched aa’s, supplement w thiamine

63

PKU (phenylketonuria)–

-Classical PKU is defect in phenylalanine hydroxylase
-Non-classical PKU is defect in BH4 cofactor synthesis (dihydropteride reductase)
BH4 is cofactor needed for PheTyr conversion, made in body, NOT a vitamin, also req’d
for catecholamine and serotonin synthesis. Dec Phe diet wont help non-classical PKU, but
supplementing w BH4, 5-hydroxytryptophan, dopa will help
-Phenylalanine and phenylketones accumulate
-common inborn error of aa metabolism, 1/10000-15000 newborns, ~1.5% population
-untreated phenotype= MR, sz, trmor, hyperactive, failure to walk/talk, hypopigment, restrict
diet of Phe to control symptoms
-neonatal disease= no phenotype, huge risk of MR, irreversible damage to myelination, Phe-
free formula
-irreversible risk much decreased at 5 yrs. Still can lose 10-20 IQ pts, still get acute toxic
behavioral changes, lifelong restriction of dietary Phe
-“heal-stick” done on newborns before releasing from hospital (detects elev Phe in blood)
-maternal PKU – mothers high blood phe has teratogenic effect on nml fetus, fetus inc risk for
MR, microcephaly, cardiac defects, growth retardation, low birth weight. Mother needs to be
on phe restricted diet prior to conception

64

Tyrosinemia I

defect in tyrosine aminotransferase

65

Alcaptonuria

defect in homogentisate oxidase, homogentisate accumulates in urine causing it
to turn black, rare and relatively benign, at later ages homogentisate deposits cause arthritis

66

Tyrosinemia II

enzyme at end of ring oxidation/cleavage

67

Albinism

defect in tyrosinase (rate limiting step of melanin production) leading to deficient
melatonin production

68

Homocystinuria:

-Most common= defect in transsulfuration pathway (either cystathione synthase deficiency or reduced affinity for cofactor B6)
-Or it can be defect in remethylation pathway (methionine synthase deficiency)
-accumulates homocysteine or dimer form and met in blood/urine
-neurotube defect, MR, vascular disorders, heart defect, lens probs, osteoporosis
-Tx: restrict met intake, supplement w vits B6, B12, folate
-appearance: long limbs similar to Marfan’s syndrome

69

Cystinuria:

disease w defective aa transport in intestine:

defective lys/arg/cys-cys/ornathine transporter. Think “COAL”!! Cystine builds
and forms k stones, aa of the transporter excreted in urine, tx: drink water solubilize cys!

70

Hartnup disease

disease w defective aa transport in intestine:

Hartnup Disease (neutral amino aciduria): defect in neutral aa transport, aa’s excreted – esp
Trp. Symptoms= pellagra rash, HA, psych. Tx: high protein, nicotinamide supplements (form
of niacin/vit B3 – precursor to trp), trp supplements

71

ALT and AST

1) transamination: “ping pong” mechanism, transfers amino (NH4) group from aa to glutamate, aa becomes keto acid. catalyzed by aminotransferase/transaminase, requires cofactor pyridoxal phosphate (PLP, derivative of vit B6). **reversible!
**aminotransferase levels in blood (shld be intercellular enzymes!) can indicate liver/muscle damage. ALT (alanine amino transferase) and AST (aspartate aminotransferase)
**use transamination to treat hyperammonemia- replace aa with keto acids, aminotransferases can convert back to aa’s w/o inc nitrogen levels

72

Hyperammonemia

-Deficiencies in urea cycle: PROXIMAL ENZYME DEFICIENCES: (more severe)

●Hyperammonemia: could be from NAGS enzyme deficiency (makes N-acetyl glutamate), or from CPS I deficiency. Autosomal recessive

73

OTC deficiency:

-Deficiencies in urea cycle: PROXIMAL ENZYME DEFICIENCES: (more severe)

●OTC deficiency: most common, X-linked, inc uracil/orotic acid in blood in urine (bc inc CP leaks into cytosol where CPSII converts it to orotic acid-think pyrmidine degradation!)

74

Citrullinemia

-Deficiencies in urea cycle: DISTAL ENZYME DEFICIENCES:

●Citrullinemia – arg synth deficiency

75

Argininosuccinic acidura (ASA)

-Deficiencies in urea cycle: DISTAL ENZYME DEFICIENCES:

●Argininosuccinic acidura (ASA) – arg lysase deficiency

76

Arginemia

-Deficiencies in urea cycle: DISTAL ENZYME DEFICIENCES:

●Arginemia- arginase deficiency, rare

77

Nonketotic hyperglycemia, also glycine encephalopathy

-defect in glycine cleavage process, inc levels of gly in blood, severe mental
retardation/sz’s/death

78

Maple Syrup Urine Disease

Maple Syrup Urine Disease=Defect in branched-chain α-keto acid deh. Urine has odor of maple syrup. Mental/physical retardation, abnml muscle tone, ketosis, coma, short lifespan. 1/200,000. Tx: decrease intake branched aa’s, supplement w thiamine
Research shows some autistic children have defects in a α-keto acid deh

79

PKU (phenylketonuria)–

-Classical PKU is defect in phenylalanine hydroxylase
-Non-classical PKU is defect in BH4 cofactor synthesis (dihydropteride reductase)
BH4 is cofactor needed for PheTyr conversion, made in body, NOT a vitamin, also req’d
for catecholamine and serotonin synthesis. Dec Phe diet wont help non-classical PKU, but
supplementing w BH4, 5-hydroxytryptophan, dopa will help
-Phenylalanine and phenylketones accumulate
-common inborn error of aa metabolism, 1/10000-15000 newborns, ~1.5% population
-untreated phenotype= MR, sz, trmor, hyperactive, failure to walk/talk, hypopigment, restrict
diet of Phe to control symptoms
-neonatal disease= no phenotype, huge risk of MR, irreversible damage to myelination, Phe-
free formula
-irreversible risk much decreased at 5 yrs. Still can lose 10-20 IQ pts, still get acute toxic
behavioral changes, lifelong restriction of dietary Phe
-“heal-stick” done on newborns before releasing from hospital (detects elev Phe in blood)
-maternal PKU – mothers high blood phe has teratogenic effect on nml fetus, fetus inc risk for
MR, microcephaly, cardiac defects, growth retardation, low birth weight. Mother needs to be
on phe restricted diet prior to conception

80

Tyrosinemia I

Tyrosinemia I – defect in tyrosine aminotransferase

81

Alcaptonuria

defect in homogentisate oxidase, homogentisate accumulates in urine causing it
to turn black, rare and relatively benign, at later ages homogentisate deposits cause arthritis

82

Tyrosinemia II

Tyrosinemia II – enzyme at end of ring oxidation/cleavage

83

Albinism

Albinism – defect in tyrosinase (rate limiting step of melanin production) leading to deficient
melatonin production

84

Homocystinuria:

Homocystinuria:
-four forms:
1. cystathione synthase deficiency or reduced affinity for cofactor B6
2. decreased affinity of cystathione synthase for pyridoxal phosphate (related to B6??)
3. homocysteine methyltransferase/met synthase deficiency
4. deficiency in met THF reductase (preps THF for remethylation pathway)
-accumulates homocysteine or dimer form and met in blood/urine
-neurotube defect, MR, vascular disorders, heart defect, lens probs, osteoporosis
-Tx: restrict met intake, supplement w vits B6, B12, folate
-appearance: long limbs similar to Marfan’s syndrome

85

MMA

Breakdown of Propionyl-CoAsuccinyl-CoA:
-requires biotin and B12
-Met/Val/Ile/Thr all precursors to propionyl-CoA
-defect in last step converting methylmalonyl-CoA---methylmalonyl-CoA mutase-->succinyl-CoA, called MMA (methylmalonic acidemia). Methylmalonic acid accumulates in blood/urine, can interfere w malonyl-CoA of fa synthesis, 1/48000 newborns, tx: semisynthetic diet low in met/val/ile/thr. Give B12

86

Folic acid deficiency

●Folic acid deficiency: caused by dec intake, impaired absorption, impaired/inhibited metabolism (methotrexate!), increased demand (pregnant). Dx w measure of folic acid or FIGlu test. Symtoms: irritable, anemia, forgetful

Folic acid needed for: 1) purine/pyr synthesis (affects short lived cells, thus anemia!)
2) homocysmet conversion (remethylation. “hyperhomocystenemia”)
3) glycine cleavage
4) aa metabolism

87

Vit B12 deficiency

●Vit B12 deficiency
-animal-derived foods
-stored in liver for yrs, generally deficiency is rare
-impaired absorption more common prob
-IF (intrinsic factor) made by stomach parietal cells which helps transport/absorb B12 in intestine
-structure: cobalt in center with 6 surrounding coordination centers
-B12 needed for:
1) methylmalonyl CoAsuccCoA (MMA!!)
2) homocysmet (hyperhomocysteinemia. Step that regenerates free THF)
-pernicious anemia: deficiency in IF, leads to impaired absorption of B12, causes hematopoietic defects (megaloblastic anemia) and neuro defects. Tx with B12 and folate (relieves anemia but not neuro probs bc those (2 listed above) need direct B12)

88

Jaundice:

yellow pigmentation of skin/eyes due to bilirubin deposition. This can be from inc bili production or from dec bili excretion…
1. Excess hemolysis (liver can’t keep up!) = “hemolytic or prehepatic jaundice”
2. Liver damage = “hepatocellular or intrahepatic jaundice”
3. Bile duct obstruction(decreased bili secretion) = “obstructive or posthepatic jaundice”
-Neonatal jaundice – inc levels unconjugated bili in newborns due to low bili glucuronyltransferase (liver not fully dev yet!), severe jaundice will require tx w fluorescent light

89

AIP

Neuropsychiatric: accumulates ALA and PBG, causes neuropsych probs. Due to defects early in pathway: ALA deh and PBG deaminase
-AIP (acute intermittent porphyria): def in PBG deaminase, PBG/ALA accumulate- both are neurotoxic. Causes “attacks” of neuropathy/anxiety/paranoia/AP, precipitated by infections/drugs/fasting/stress/acidosis/hormone changes. Most common of the acute porphyrias. TX: avoid/tx the precipitators, high carb diet to prevent acidosis (precipitator), IV heme injection)

90

PCT

Cutaneous: accumulates porphyrinogens in skin/tissues, spont oxidize to porphyrins, causes photosensitivity (porphyrins produced free radicals when exposed to light). Die to defects last in pathway: uroporphyrinogen synthetase, uroporphyrinogen decarboxylase, ferrochetalase
PCT (porphyria cutaneous tarda): defect in uroporphyrinogen decarb. Most common porphyria. Uroporphyrinogen III accumulates in skin, oxidizes and causes photosensitivity. TX: avoid sunlight, avoid RF’s like ETOH, use chloroquine to complex w porphyrin and inc excretion, ingest beta-carotene (free radical scavenger)