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Flashcards in Genetics, Biochem Deck (138)
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1

Turner's syndrome

Missing X (XO phenotype)
--> lose ovarian follicles after birth "streak ovaries"
--> increased LH, FSH

Symptoms:
- Short, shield chest, webbed neck
- Lymphedema: cystic hygroma (posterior triangle of neck) at birth--> lymph outflow problems
- CV malformations= coarctation of aorta, bicuspid aortic valve, aortic dissection
- Horseshoe kidney
- Dysgerminoma

* most common cause of primary amenorrhea

2

Leukocyte adhesion syndrome

Genetic CD18 deficiency--> no integrin formation--> leukocytes can't migrate from vasculature

Symptoms:
- No pus formation
- Late separation of umbilicus
- Poor wound healing

Labs:
- Neutrophilia

3

MPO deficiency

Can't produce H2O2

Neutrophils turn blue on nitro blue tetrazolium test

Normal NADPH activity: close to normal/normal immune system function

4

Chronic granulomatous disease

No NADPH oxidase
- No respiratory burst in neutrophils

Symptoms:
- Susceptible to catalase-positive infections (can break down H2O2 produced by MPO)= S. aureus, E. coli, aspergillus

Labs:
- Neutrophils don't turn blue on nitro blue tetrazolium test
- Abnormal dihyrorhodamine (DHR) flow cytometry test)

5

Late complement component deficiency

Increased risk of Neisseria infection

6

Carbamoyl phosphate

1. de Novo pyramidine synthesis
2. Urea cycle
- Ornithine transcarbamoylase deficiency (OTC)--> accumulation of carbamoyl phosphate--> orotic acid

7

Hydroxyurea

Inhibits ribonucleotide reductase
- UDP can't be converted to dUDP (CTP buildup)

8

6-mercaptopurine (6-MP)

Blocks PRPP amidotransferase--> blocks de novo purine synthesis
- Azathioprine--> 6-MP
- de novo purine synthesis requires Glycine, Aspartate, Glutamine (GAG) and THF (tetrahydrofolate)
- PRPP amidotransferase also inhibited by AMP, GMP, IMP, allopurinol

9

5-fluorouracil (5-FU)

Inhibits thymidylate synthase
--> can't produce dTMP

"F U thymidylate synthase"

10

Methotrexate (MTX)

Inhibits dihydrofolate reductase
---> can't produce dTMP

Supplement with Folinic acid (Leucovorin) to reverse methotrexate toxicity

11

Trimethoprim (TMP)

Inhibits BACTERIAL dihydrofolate reductase
--> can't produce dTMP

12

Orotic aciduria

UMP synthase defect (autosomal recessive)
- Can't convert orotic acid to UMP

Symptoms:
- Orotic acid in urine (NO hyperammonemia)
- Megaloblastic anemia (can't help with B12 or folic acid)
- Failure to thrive

Tx:
- Oral uridine monophosphate administration

13

OTC deficiency

Ornithine transcarbamoylase deficiency (OTC)--> accumulation of carbamoyl phosphate--> orotic acid

Symptoms:
- Orotic acid in urine
- Megaloblastic anemia (can't help with B12 or folic acid)
- Failure to thrive
- Hyperammonemia

14

Adenosine deaminase deficiency

--> buildup of excess ATP, dATP--> feedback inhibition of ribonucleotide reductase--> inhibition of DNA synthesis
--> decreased lymphocyte count (high turnover cells)--> SCID

Autosomal recessive

15

Lesch-Nyhan syndrome

Absence of HGPRT
- Normally converts hypoxanthine to IMP, guanine to GMP

--> excess uric acid, de novo purine synthesis

X-linked recessive
- Retardation, self-mutilation, aggression, hyperuricemia, gout, choreoathetosis

16

Missense mutation

Changed amino acid
- Conservative change: new amino acid is similar in chemical structure/function

17

Nonsense mutation

Early STOP codon (Stop the nonsense!)

18

Frameshift mutation

Changed from multiples of 3--> all nucleotides downstream misread
--> truncated, non-functional protein

19

Xeroderma pigmentosum

Nucleotide excision repair defect
- Can't repair thimine (pyramidine) dimers formed due to UV exposure (bulky adducts)

20

HNPCC

Hereditary nonpolyposis colorectal cancer
- Mutation in mismatch repair (unable to repair mismatched Watson-Crick nucleotides)

21

Ataxia telangiectasia

Mutation in nonhomologous end joining (bring together 2 ends of broken dsDNA)

22

Start codon

AUG
- Eukaryotes= methionine (may be removed before translation completed)
- Prokaryotes= formylmethionine

23

Stop codons

UGA (U Go Away)
UAA (U Are Away)
UAG (U Are Gone)

** Does not code for Amino Acid--> stop codon causes Releasing Factor (RF) to bind to ribosome

24

Amatoxins

Mushroom poison
Inhibits RNA polymerase II= halts mRNA synthesis--> cell death
- Found in Amanita phalloides= "death cap mushrooms)
- Severe hepatotoxicity if ingested

25

RNA polymerases

Eukaryotes:
- RNA Pol I= rRNA
- RNA pol II= mRNA (opens DNA at promoter site)
- RNA pol III= tRNA
** No proofreading function

Prokaryotes:
- RNA polymerase= multisubunit complex (all 3 RNA types)

26

snRNPs

Splice pre-mRNA
- Make lariat that is spliced out (intron), 2 exons joined

** Lupus= antibodies to spliceosomal snRNPs

27

I-cell disease

Inclusion cell disease
- Failure to add mannose-6-phosphate to lysosome proteins (needed to traffic protein from golgi to lysosome)
- Lysosome enzymes secreted outside cell instead of to lysosome

Symptoms:
- Coarse facial features
- Clouded corneas
- Restricted joint movement
- High plasma levels of lysosomal enzymes
- Fatal in childhood

28

Chediak-Higashi syndrome

Mutation in lysosomal trafficking regulator gene (LYST)
- Need LYST for microtubular sorting of endosomal proteins--> late multivesicular endosomes

Symptoms:
- Pyogenic infections (defective destruction of bacteria)
- Partial albinism (can't transport melanin)
- Peripheral neuropathy (can't transport proteins)

29

Kartagener's syndrome

Dynein (retrograde + --> - microtubule movement) arm defect in cilia

Symptoms:
- Male infertility (immotile sperm)
- decreased female fertility
- Bronchiectasis
- Recurrent sinusitis
** Associated with situs inversus (reversed organs)

30

Osteogenesis imperfecta

Type I collagen defect
- Type I collagen= Bone, skin, tendon, dentin, fascia, cornea, wound repair

Pathogenesis:
- Normal: Glycosylation of pro-alpha-chain hydroxylysine residues, formation of procollagen (H- and S-S bonds)--> triple helix
- OI= problem with formation of triple helix in Endoplasmic reticulum

Autosomal dominant (incomplete penetrance)

Symptoms:
- Multiple fractures with minimal trauma
- Blue sclerae (translucent connective tissue over choroidal vins)
- Hearing loss (abnL middle ear bones)
- Dental issues (lack of dentin= type I collagen)

31

Ehlers Danlos

Type III collagen defect
- Type III collagen= reticulin (skin, blood vessels, uterus, fetal tissue, granulation tissue)

- Normal: Covalent lysine-hydroxylysine cross linkage (by Cu+2- containing lysyl oxidase)--> collagen fibrils
- Ehlers Danlos= unable to cross link (reinforce tropocollagen triple helix molecules in ECM)
** Lysyl oxidase requires copper, can be inhibited by sweet pea ingestion

Symptoms:
- Hyperextensible skin
- Tendency to bleed (vessel wall defects)
- Hypermobile joints
- Can be associated with joint dislocation, berry aneurysms, organ rupture
- Mitral valve prolapse

32

Alport syndrome

Type IV collagen defect
- type IV collagen= basement membrane, basal lamina of kidneys, ears, eyes

X-linked recessive (boys)

Symptoms:
- Progressive nephritis
- Deafness
- Ocular disturbances

33

Scurvy

Vit C (ascorbic acid) deficiency:
- Hydroxylation of proline and lysine residues on Collagen (in rough ER) requires ascorbic acid
- Vit C deficiency--> defective collagen

Features:
- Malnourished
- Gingival bleeding
- Petechiae
- Ecchymoses
- Perifollicular hemorrhage
- Poor wound healing

34

Southern blot

DNA: electrophoresis
- Filtered on paper
- Radiolabeled DNA probe anneals to complementary strand

35

Northern blot

RNA: electrophoresis
- Filtered on paper
- Radiolabeled RNA probe anneals to complementary strand
- Useful for studying mRNA

36

Western blot

Protein: electrophoresis
- Labeled antibody binds protein

37

Southwestern blot

DNA-binding proteins (transcription factors)
- ID using labeled oligonucleotide probes

38

ELISA

Enzyme-linked immunoabsorbent assay
- Indirect= looking for antibodies in patient's blood (ex: anti-HIV) by adding antigens
- Direct= looking for the antigen in patient's blood (ex: HIV particles) by adding antibodies

39

RNA interference

dsRNA complementary to mRNA sequence of interest added to human cells (transfection)
--> dsRNA separates, binds and promotes degradation of target mRNA--> knock down gene expression

40

Variable expressivity

Phenotype varies among individuals with same genotype (ex: NF-1)

* Heteroplasmy= presence of normal and mutated mtDNA--> variable expression of mitochondrial inherited disease (ex: Ragged red fiber)

41

Pleiotropy

One gene--> multiple phenotypic effects

Ex: PKU--> unrelated symptoms (hair/skin changes, mental retardation)

42

Imprinting

Gene expression depends on whether gene came from paternal or maternal origin

Ex: 15q partial deletion
- Praeder-Willi= paternal not expressed; maternal 15q partial deletion
- Angelman= maternal not expressed

43

Dominant negative mutation

Heterozygote produces nonfunctional altered protein--> prevents normal protein function

44

Linkage disequilibrium

alleles at 2 linked loci occur together more often than expected by chance
** measure in population, not family

45

Achondroplasia

AD
Cell-signaling defect of FGF receptor 3
--> dwarfism with normal trunk
- Advanced paternal age

46

Autosomal dominant polycystic kidney disease

- 85% of cases show mutation in PKD 1 gene on chromosome 16 (40s-50s, worse outcome)
» Protein = polycystin-1
– 15% of cases show mutation in PKD 2 gene on chromosome 4 (70s-80s, better prognosis)
» Protein = polycystin-2 – Both proteins reside in tubular cell cilia
» Defects affect calcium signaling
» Mutations result in abnormal renal tubular growth

** associated with polycystic liver disease, berry aneurysms, mitral valve prolapse

47

Familial adenomatous polyposis

AD
Mutations on chrom 5 (APC gene)
- Colon covered in polyps after puberty; colon must be ressected to prevent progression to cancer

48

Familial hypercholesterolemia (hyperlipidemia type IIA)

AD
Defective/absent LDL receptor--> elevated LDL, cholesterol
- Heterozygote: cholesterol= 300
- Homozygote: cholesterol= 700

Severe atherosclerosis, tendon xanthomas
Corneal arcus
MI before age 20

49

Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu)

AD
Disorder of blood vessels
Telangiectasias, AVM

50

Hereditary spherocytosis

AD
Spectrin or ankyrin defect--> spheroid erythrocytes
- Increased MCHC
- Splenectomy= curative

51

Huntington's disease

AD
CAG trinucleotide repeat on Chrom 4
- Decreased GABA, Ach in brain

52

Multiple endocrine neoplasias (MEN)

AD
MEN1= pituitary, pancreatic, parathyroid tumor (3 Ps, diamond)

MEN2A= Parathyroid, medullary thyroid, pheochromocytoma (2 Ps, square)
- Defect in ret gene (tyrosine kinase)

MEN2B= Medullary thyroid, pheochromocytoma, oral mucosal neuroma (1 P, triangle)
- Defect in ret gene (tyrosine kinase)

53

Neurofibromatosis Type 1 (von Recklinghausen's)

AD
Long arm of chrom 17
- Cafe au lait, neural tumors, Lisch nodules, optic pathway gliomas

54

Neurofibromatosis Type 2

AD
NF gene on chrom 22
- Bilateral acoustic Schwanomas, juvenile cataracts

55

Tuberous sclerosis

AD
TSC1, TSC2

Facial lesions: hypopigmented "ash leaf spots"
Coritcal, retinal hamartomas
Seizures, mental retardation
Renal cysts, angiomyolipomas
Cardiac rhabdomyomas
Increased astrocytomas

56

von Hippel-Lindau

AD
Deletion of VHL tumor suppressor gene on Chrom 3p--> continuous HIF expression

- Hemangioblastomas of retina, cerebellum, medulla
- Liver cysts
- Multiple bilateral renal cell carcinomas

57

Cystic fibrosis

Autosomal recessive: CFTR gene on Chrom 7 (CFTR channel= ATP-binding cassette transmembrane protein)

Causes:
1. Deletion of Phe 508--> abnL protein folding--> Cl- channel never reaches cell surface
2. Premature termination of CFTR protein (Ashkenazi Jews)
3. Defective ATP binding of transmembrane protein
4. Impaired Cl- conduction (milder disease)
5. Fewer active CFTR genes

Features:
- Thick mucus plugs (decreased Na, Cl secretions in lungs)
- Pulmonary infections
- Pancreatic insufficiency
- Meconium ileus in newborns
- Bilateral absence of vas deferens
- Fat soluble vitamin deficiencies (A, D, E, K)

Diagnosis:
- Increased concentration of Cl- ions in sweat test

Treatment:
- N-acetylcysteine: loosens mucus by cleaving disulfide bonds within glycoproteins

58

Fragile X syndrome

X-linked defect: methylation and expression of FMR1 gene (CGG trinucleotide repeat)
- 2nd most common cause of mental retardation after Down's
- eXtra large testes, jaw, ears

59

Trinucleotide repeat disorders

Fragile X: CGG
Friedreich's ataxia: GAA
Huntingtons: CAG
Myotonic dystrophy: CTG

60

Down syndrome

Trisomy 21
- 95% due to meiotic nondisjunction of homologous chrom (advanced maternal age)
- 4% due to Roberstonian translocation
- 1% mosaics with no maternal assn

Path features:
- Duodenal atresia, ASD, VSD, AV septal defect, early-onset Alzheimer's

Screening: maternal quad screen:
- Decreased alpha-fetoprotein, estriol
- Increased beta-hCG, inhibin A
Ultrasound: increased nuchal translucency in first trimester (fluid in neck)

61

Edward's syndrome

Trisomy 18
- Mental retardation
- rocker-bottom feet
- small gaw (micrognathia)
- low set Ears
- clenched hands
- congenital heart disease
- Death after 1 year

Maternal quad scereen:
- Decreased alpha-fetoprotein
- decreased beta-hCG
- decreased estriol
- normal inhibin A

62

Patau's syndrome

Trisomy 13
- Mental retardation
- rocker-bottom feet
- Mircophthamia, microcephaly
- Cleft liP/Palate
- holoProsencephaly
- Polydactyly
- congenital heart disease
- Death after 1 year

Cause:
- Nondisjunction in maternal meiosis I

Pregnancy screen:
- decreased free beta-hCG
- decreased PAPP-A
- Increased nuchal translucency

63

Cri du chat

Microdeletion of short arm chrom 5p

Microcephaly, mental retardation
- High pitched mewing
- Epicanthal folds
- VSD

64

Williams syndrome

Microdeletion of long arm of Chrom 7 (including elastin gene)

Findings:
- Elfin facies
- intellectual disability, good verbal skills
- Hypercalcemia (increased sensitivity to Vit D)
- Friendliness
- CV problems

65

22q11 deletion syndrome

Aberrant development of 3rd and 4th pharyngeal pouches
"CATCH-22"
- Cleft palate
- Abnormal facies
- Thymic aplasia--> T-cell deficiency
- Cardiac defects: truncus arteriosus, tetralogy of Fallot
- Hypocalcemia (parathyroid aplasia)

DiGeorge: Thymic, PTH, cardiac
Velocardiofacial: palate, facial, cardiac

66

Fat soluble vitamins

Vitamin A (retinol)
Vitamin D (chole/ergocalciferol)
Vitamin E
Vitamin K

- Overdose possible, accumulates in fat
- Malabsorption (cystic fibrosis, sprue, gastric bypass)--> deficiency

67

Water soluble vitamins

All the Bs + vitamin C
- All wash out easily except B12 (cobalamin) and B9 (folate)--> store in liver

Deficiency: dermatitis, glossitis, diarrhea

68

Vitamin A (retinol)

Function:
- Antioxidant
- Visual pigments (retinal)
- Differentiation of epithelial cells--> pancreatic, mucus-secreting cells
- Prevents squamous metaplasia
- Treat measles, AML (M3)
- Found in leafy vegetables, liver

Deficiency:
- Night blindness
- Dry skin

Excess:
- Arthralgias, fatique, H/A, skin changes, sore throat, alopecia
- Cerebral edema, papilledema (blurred vision)
- Teratogenic (cleft palate, cardiac anomalies- pregnancy monitoring in isotretinoin tx)

69

Vitamin B1 (thiamine)

Function:
Thiamine pyrophospate, cofactor for **ATP synthesis**:
- Alpha-ketoglutarate dehydrogenase (TCA)
- Transketolase (Pentose-phosphate pathway); see decreased RBC transkelotase activity early in deficiency
- Pyruvate dehydrogenase (glycolysis to TCA)
+ Branched-chain amino acid dehydrogenase

Deficiency:
- Impaired glucose breakdown--> ATP depletion (worsened by glucose infusion; aerobic tissues- heart and brain- affected 1st)
--> Wernicke-Korsakoff (medial dorsal nucleus of thalamus, mamillary body damage)
--> Dry beriberi (polyneuritis, symmetrical m. wasting)
--> Wet beriberi (dilated cardiomyopathy, edema)

70

Vitamin B2 (riboflavin)

Function:
- Cofactor in oxidation, reduction (FADH2, FMN)

Deficiency:
- Cheliosis (inflammation of lips, scaling, fissures at corner of mouth)
- Corneal vascularization

71

Vitamin B3 (niacin)

Function:
- Constituent of NAD+, NADP+ (redox reactions)
- Derived from tryptophan
- Need B6 to synthesize B3

Deficiency:
- Glossitis
- Pellagra (Hartnup disease--> decreased tryptophan OR malignant carcinoid syndrome--> inceased tryptophan metabolism). Pellagra= diarrhea, dementia, dermatitis
- INH (decreased B6)

Excess:
- Facial flushing (treatment of hyperlipidemia= suppress FFA release from tissue--> decreased VLDL synthesis, more LDL conversion); pre-treat with aspirin

72

Vitamin B5 (pantothenate)

Function:
- Component of CoA (cofactor for acyl transfer) and fatty acid synthase

Deficiency:
- Dermatitis
- Enteritis
- Alopecia
- Adrenal insufficiency
- Dysesthesias, GI distress

73

Vitamin B6 (pyridoxine)

Function:
1. Converted to pyridoxal phosphate
- cofactor in transamination--> ALT, AST
- Decarboxylation reactions
- Glycogen phosphorylase
2. Synthesis of cystathionine, heme, niacin, histamine, neurotransmitters (5-HT, epi, NE, GABA)

Deficiency: (INH, oral contraceptives can cause deficiency)
- Convulsions
- Hyperirritability
- Peripheral neuropathy
- Sideroblastic anemia (first step in heme synthesis; impaired hemoglobin synthesis--> iron excess)
- Increased endogenous oxaloacetate production (increased calcium oxalate stones); therefore, supplement patient with calcium oxalate stones with B6

** increases metabolism of Levodopa (de-carboxylation)

74

Vitamin B7 (biotin)

Function:
- Cofactor for **carboxylation** enzymes:
1. Pyruvate carboxylase (pyruvate--> oxaloacetate)
- replenish TCA cycle or used in gluconeogenesis
2. Acetyl-CoA carboxylase (acetyl coA--> malonyl coA)
3. Propionyl-CoA Carboxylase (propionyl CoA--> methylmalonyl coA)

Deficiency:
- Caused by antibiotics or excessive raw egg ingestion
- Dermatitis, alopecia, enteritis

75

Vitamin B9 (Folic acid)

Function
- tetrahydrofolate= coenzyme for 1-carbon transfer/methylation (pyramidine salvage, methionine synthesis)
- Synthesis of nitrogenous bases in DNA, RNA
- Found in foliage, stored in liver

Deficiency:
- Marocytic, megaloblastic anemia
- Homocysteine elevations (without Methylmalonyl coA elevation)
- NO neurologic symptoms
- Seen in alcoholism, pregnancy
- Caused by phenytoin, sulfonamides, MTX

76

Vitamin B12 (cobalamin)

Function:
- cofactor for homocysteine methyltransferase (methylcobalamin)
- cofactor for methylmalonyl-coA mutase
- Animal products, stored in liver

Deficiency:
- Macrocytic, megaloblastic anemia
- Hypersegmented PMNs
- Neurologic symptoms due to abnL myelin: paresthesias, subacute combined degeneration--> prolonged irreversible damage
** due to malabsorption:
- lack IF (pernicious anemia (attack parietal cells), gastric bypass)
- absence of terminal ileum (Crohn's)

** Use Schilling test to detect etiology of deficiency:
1. radio-labeled B12 + IM injection
- Radio urine= B12 deficiency in diet
2. radio-labeled B12 + IF
- Absorption--> urinary excretion
- No radio detected in urine= absorption problem due to: pancreatic insufficiency (give pancreatic enzymes), intestinal bacterial overgrowth (give antibiotics), ileal disease

77

S-adenosyl-methionine (SAM)

ATP+methionine--> SAM
- Transfers methyl units
- Dependent on B12 and B9 for regeneration
- Required for conversion of NE to epi

78

Vitamin C (Ascorbic acid)

Function:
- Antioxidant
- Facilitates iron absorption: keeps iron in Fe+2 state
- Hydroxylation of proline, lysine residues in collagen synthesis
- Dopamine beta-hydroxylase: DA--> NE

Deficiency:
- Scurvy
- Weakened immune response

Excess:
- N/V/D
- Fatigue, sleep problems
- Iron toxicity in transfusion pts, hemochromatosis (keeps iron in reduced Fe2+ state)

79

Vitamin D

D2= ergo (plants)
D3= cholecalciferol (milk, skin-produced)

25-OH D3= storage form
1,25-(OH)2 D3= calcitriol, active form (converted by kidneys)

Function:
- Increased intestinal absorption of calcium, phosphate
- Increased bone mineralization

Deficiency:
- Rickets (children), osteomalacia (adults
- Hypocalcemic tetany

Excess:
- Hypercalcemia, hypercalciuria
- Loss of appetite, stupor
** seen in Sarcoidosis: epithelioid macrophages activate vitamin D via increased 1-alpha-hydroxylase expression)

**Type 1 rickets= 1alpha-hydroxylase deficiency
Type 2 rickets= no Vit D receptors

80

Vitamin E

Function:
- Antioxidant (protects erythrocytes and membranes from free radical damage)

Deficiency:
- Increased erythrocyte fragility
- Muscle weakness, posterior column and spinocerebellar tract demyelination (like Friederich's Ataxia

Excess:
- Warfarin + Vit E--> massive increase in INR

81

Vitamin K

Function:
- gamma carboxylation of glutamic acid on Factors II, VII, IX, X, proteins C and S--> blood clotting
** Synthesized by intestinal flora

Deficiency:
- Neonatal hemorrhage (increased PT, aPTT, normal bleeding time)
- Seen in babies, prolonged broad-spectrum antibiotic use (both deficient in intestinal flora)
** Warfarin= Vit K antagonist (blocks epoxide reductase which converts K2 (inactive) to K1)

82

Zinc

Function;
- Zinc fingers (transcription factor)
- 100s of enzymes

Deficiency:
- Delayed wound healing
- hypogonadism
- decreased adult hair
- Dysgeusia (taste weird), anosmia
- May predispose to alcoholic cirrhosis

83

Ethanol hypoglycemia

Alcohol dehydrogenase:
Ethanol + NAD+ --> acetaldehyde+ NADH + H+
- Thus increased ethanol--> increased NADH/NAD+ ratio

NADH > NAD+: need to create NAD+:
1. Pyruvate converted to lactate
2. Oxaloacetate converted to malate
* Both--> inhibited gluconeogenesis, stimulate FA synthesis--> hypoglycemia, fatty liver
* Overproduction of lactate--> acidosis
* Oxaloacetate depletion--> shut down TCA--> ketosis
* Malate excess--> increased NADPH--> FA synthesis

84

Lipoic acid

Cofactor for:
1. Pyruvate dehydrogenase complex
- Deficiency: backup of substrate--> lactic acidosis
- Cause: mutation in x-linked gene for E1-alpha subunit of PDH complex
- Findings: Neurologic defects, in infancy
- Treatment: ketogenic diet (high fat, Lysine and Leucine= ketogenic amino acids)

2. Alpha ketoglutarate DH

3. Branched-chain ketoacid DH
- Deficiency--> Maple syrup urine disease

** Arsenic inhibits Lipoic acid--> vomiting, rice water stool, garlic breath

85

Glucose transport pumps

GLUT-1= insulin independent
- RBCs, Brain
- Low Km (enters steadily)

GLUT-2= bidirectional
- Beta-islet cells
- Liver, kidney, small intestine (insulin-independent uptake)
- High Km (proportional to blood [glucose]

GLUT-4= muscle, adipocyte
- Insulin-dependent pump

86

Pyruvate Kinase deficiency

RBC maintains structure via:
- Glycolysis--> ATP to pump out waste products
- PPP (HMP shunt)--> NADH to reduce methemoglobin

Symptoms:
1. Hemolytic anemia (#2 cause worldwide)
- Can't maintain pumps in membrane without ATP generated by PK
2. Increased 2,3-BPG--> backup in glycolysis pathway
- Changes O2 affinity--> decreased affinity (shift O2 curve to right)--> increased exercise tolerance
- 2,3-BPG kicks O2 off hemoglobin by binding beta heme groups (may have increased exercise tolerance)
3. No Heinz bodies (vs G6PD deficiency)

87

PFK-2

Phosphofructokinase-2= enzyme in LIVER
- Activated by insulin after HIGH carb meal
- Produces Fructose 2,6-BP--> reactivates PFK-1 (turned off by excess ATP)
- Overrides inhibition of PFK-1--> glyolysis continues--> pyruvate--> FA synthesis

88

Tender loving care for Nancy

Enzymes requiring:
- Thiamine
- Lipoic Acid
- Co-A
- FAD (riboflavin= B2)
- NAD (niacin= B3)

1. Alpha ketoglutarate dehydrogenase
2. Pyruvate dehydrogenase
3. Branched-chain ketoacid DH

89

Electron transport inhibitors

Rotenone: Block complex I
Cyanide, CO: block complex IV
Antimycin A: block complex III

- Inhibit electron transport
- Cause decrease proton gradient--> block ATP synthesis

90

ATP synthase inhibitors

Oligomycin
Block complex V= mitochondrial ATPsynthase
- increased proton gradient--> no ATP produced as electron transport stops

91

Uncoupling agents

2,4-DNP, aspirin (fever after aspirin overdose), thermogenin in brown fat (babies)
- Increases mitochondrial membrane permeability--> decreased proton gradient--> increased O2 consumption
- **electron transport continues--> HEAT

92

Gluconeogenesis

Liver (kidney, intestinal epithelium)

Irreversible:
1. Pyruvate carboxylase (mitochondria)
2. PEP carboxylase (cytosol)
3. Fructose-1,6-BPase (cytosol)
4. Glucose-6-phosphatase (ER)
* deficient in vonGierke's

* Odd-chain FA--> propionyl coA--> TCA
- Even chain--> acetyl CoA (no glucose)

93

HMP shunt= pentose phosphate pathway

Source of NADPH (not ATP)- needed for reduction (glutathione in RBCs)
Ribose for nucleotide synthesis, Glycolytic intermediates

Sites:
- RBCs
- Lactating mammary glands
- Liver
- Adrenal cortex (FA or steroid synthesis)

** Requires thiamine

94

Glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency)

HMP pathway produces inadequate levels of NADPH
- NADPH needed to detoxify free radicals, peroxides

Decreased NADPH--> symptoms:
- RBC--> hemolytic anemia (poor defense against oxidizing agents= fava beans, sulfonamides, primaquine, anti-TB drugs)
- Infection--> hemolysis due to inflammatory response (RBCs can't deal with free radicals generated

X-linked recessive
- Most common human enzyme deficiency (more prevalent in blacks, Mediterranean) d/t increased malaria resistance

Histo:
- Heinz bodies= oxidized hemoglobin precipitate
- Bite cells= splenic macrophages phagocytose Heinz bodies from RBCs

95

Essential fructosuria

Defect in Frutctokinase
- Autosomal recessive

Benign, asymptomatic
- See fructose in blood, urine

96

Fructose intolerance

Defect in Aldolase B
- Fructose-1-phosphate accumulation--> decrease in available phosphate--> inhibit glycogenolysis, gluconeogenesis

Symptoms: presents as baby eats food (not breastmilk)
- Hypoglycemia
- Jaundice, cirrhosis
- Vomiting

Treatment:
- Decrease fructose and sucrose (fructose + glucose) intake

** Phosphofructokinase= rate-limiting step of glycolysis for fructose metabolism. Aldolase B bypasses PFK (thus consumption of fructose activates aldolase B)

97

Galactokinase deficiency

Hereditary deficiency of galactokinase
- Galacticol accumulates with galactose consumption

Autosomal recessive
- Milder condition (vs galactosemia)

Symptoms: presents at birth (breastmilk)
- Galactose in blood, urine
- Infantile cataracts (fail to track objects/social smile as infant)

98

Classic Galactosemia

Absence of Galactose-1-phosphatase uridyltransferase
- Accumulation of galactitol

Autosomal recessive

Symptoms: prevents at birth (breastmilk)
- Failure to thrive
- Jaundice, heptomegaly
- Infantile cataracts
- mental retardation
- More serious defects= phosphate depletion

Tx:
- No galactose or lactose (galactose + glucose) in diet

"Fructose is to Aldoase B as Galactose is to Uridyl Transferase= FAB GUT"

99

Sorbitol

Aldose reductase converts trapped tissue glucose into sorbitol
- Sorbitol dehydrogenase then converts sorbitol to fructose
- Tissues with insufficient sorbitol dehydrogenase (Schwann cells, retina, kidneys)--> excess sorbitol--> osmotic damage

Diabetes= excess glucose--> sorbitol accumulation
- cataracts, retinopathy, peripheral neuropathy (eyes, nerves don't have as much sorbitol dehyrogenase)

100

Ornithine Transcarbamoylase deficiency (OTC deficiency)

Urea cycle enzyme:
- Excess NH4+--> deplete alpha-ketoglutarate
- Inhibit TCA cycle

X-linked recessive (baby boys)

Body can't eliminate ammonia:
- Excess carbamoyl phosphate--> orotic acid--> orotic aciduria, decreased BUN, hyperammonemia

Treatment:
- Limit protein in diet
- Benzoate, phenylbutyrate--> bind aa
- Lactulose to acidify GI tract, trap NH4+--> excretion

Ammonia intoxication (due to liver disease or urea cycle enzyme deficiencies):
- Tremor (asterixis)
- Slurring speech, Somnolence
- Vomiting
- Cerebral edema, blurred vision

101

Phenylketonuria

Causes:
- Decreased phenylalanine hydroxylase
- Decreased tetrhydrobiopterin cofactor (malignant phenylketonuria= rare)--> decreased serotonin, DA, NE, epi (tyrosine and tryptophan require BH4 to be converted to neurotransmitters)

- Increased phenylalanine--> excess phenylketones (phenylacetate, phenyllacetate, phenylpyruvate) in urine
- Tyrosine NOT synthesized: becomes essential aa

Autosomal recessive
- Screened 2-3 days after birth (normal to miss enzyme at birth as mother supplied it)

Symptoms:
- Mental, growth retardation
- Seizures
- Fair skin, eczema
- Hypopigmentation of skin, eyes, basal ganglia
- Mousy body odor

Treatment:
- NO phenylalanine in diet (aspartame)
- Increase tyrosine ingestion

**Maternal PKU= lacking proper diet during pregnancy
- Infant: microcephaly, mental retardation, growth retardation, congenital heart defects

102

Alkaptonuria

Deficiency of homogentisic acid oxidase
- Can't degrade Tyrosine--> fumarate
- Excess tyrosine--> converted to melanin

Autosomal recessive, benign

Symptoms:
- Dark connective tissue, brown sclera/ears (ochronosis), urine blackens on air exposure
- Debilitating arthralgias (homogentisic acid toxic to cartilage)

103

Albinism

Deficiency of:
- Tyrosinase (can't synthesize melanin from tyrosine): autosomal recessive
- Tyrosine transporters (decreased tyrosine--> decreased melanin

* can be due to lack of migration of neural crest cells (piebaldism, Waardenburg syndrome)
* variable inheritance: locus heterogeneity (vs ocular albinism= x-linked recessive

Lack of melanin--> increased risk of skin cancer

Piebaldism= partial albinism
Waardenburg syndrome --> mongolian spots (blue-gray) due to partial migration toward skin surface

104

Homocysteinuria

3 forms (all AR):
1. Cystathionine synthase deficiency (can't degrade methionine)
- Tx: decrease Met, increase Cys, B12, B9 in diet **Cysteine becomes essential aa

2. Decreased affinitiy of cystathionine synthase for pyridoxal phosphate
- tx: increased B6 in diet (pyridoxal phosphate)

3. Homocysteine methyltransferase (needs B12) deficiency

Symptoms:
- Increased homocysteine in urine
- Mental retardation
- Osteoporosis, tall stature, kyphosis
- Lens subluxation (down and in)
- Atherosclerosis, AV emboli--> stroke, MI
- thin hair, fair skin

Labs:
- Increased serum homocysteine, methionine
- Homocysteine in urine

105

Cystinuria

AR defect in PCT transporter for cystine, ornithine, lysine, arginine
--> cystine precipitation (hexagonal crystals)--> renal staghorn calculi

Tx: hydration, urinary alkalinization

106

Maple syrup urine disease

Autosomal recessive
Deceased alpha-ketoacid dehydrogenase
- Blocked degradation of branched amino acids (Ile, Leu, Val)
- Increased ketoacids in blood (Leu)

Symptoms:
- CNS defects, mental retardation, death

"I Love Vermont Maple syrup from branched maple trees"

107

Hartnup disease

Autosomal recessive
- Defective neutral aa transporter on renal, intestinal epithelial cells
- Tryptophan excretion in urine, decreased intestinal absorption

Pellagra:
- tryptophan synthesizes Niacin (B3)--> deficiency--> diarrhea, dementia, dermatitis

Tx: Niacin supplementation

108

Von Gierke's disease

Type I glycogen storage disease
- Glucose-6-phosphatase deficiency (can't remove phosphate from glucose to excrete from cell)

Autosomal recessive

Symptoms:
- Severe fasting hypoglycemia
- Increased NORMAL glycogen in liver
- Increased blood lactate
- Hepatomegaly
- Hyperuricemia, hyperlipidemia

Glycogen storage diseases: Very Poor Carb Metabolism (VPCM)

109

Pompe's disease

Type II glycogen storage disease
- Lysosomal alpha-1,4-glucosidase deficiency (can't degrade glycogen within lysosomes)

Autosomal recessive

Symptoms:
- Cardiomegaly (Pompe's trashes the Pump)
- Systemic findings leading to early death
- Normal glycogen type, levels
- NO hypoglycemia

Glycogen storage diseases: Very Poor Carb Metabolism (VPCM)

110

Cori's disease

Type III glycogen storage disease
- Debranching enzyme deficiency (alpha-1,6-glycosidase)= can't debranch limit dextrans (have 4 or less glucose on 1,6 branch point)

Autosomal recessive

Symptoms:
- Milder form of VonGierke's: fasting hypoglycemia, hyperuricemia, hyperlipidemia, hepatomegaly
- NORMAL blood lactate levels
- Normal gluconeogenesis (vs Type I)

Glycogen storage diseases: Very Poor Carb Metabolism (VPCM)

111

McArdle's disease

Type IV glycogen storage disease
- Skeletal muscle glycogen phosphorylase deficiency (can't break down branched glycogen (not limit dextrans))

Autosomal recessvie

Symptoms:
- Increased glycogen in muscle
- Painful muscle cramps, myoglobinuria with strenuous exercise (can't get energy)

Glycogen storage diseases: Very Poor Carb Metabolism (VPCM)

112

Fabry's disease

X-linked recessive
Deficiency of alpha-galactosidase A
- Accumulation of ceramide trihexoside

Symptoms:
- Peripheral neuropathy
- Angiokeratomas (papules between umbilicus and knees)
- CV/renal disease

113

Gaucher's disease

Autosomal recessive (Ashkenazi Jews)
Deficiency of glucocerebrosidase
- Accumulation of glucocerebroside

Symptoms:
- Hepatomegaly
- Aseptic necrosis of femur
- Bone crises
- Gaucher's cells (Macrophages deformed)

114

Niemann-Pick disease

Autosomal recessive (Ashkenazi Jews)
Deficiency of Sphingomyelinase
- Accumulation of sphingomyelin

Symptoms:
- Neurodegeneration
- Hepatosplenomegaly
- Cherry-red spot on macula
- Foam cells

"No man picks (Niemann-Pick) his nose with hisphinger (sphingomyelinase)"

115

Tay-Sachs disease

Autosomal recessive (Ashkenazi Jews)
Hexosaminidase A deficiency
- Accumulation of GM2 ganglioside

Symptoms:
- Neurodegeneration
- Cherry-red spot on macula
- Lysosomes with onion skin
- Abnormal startle reflex with acoustic stimuli

"Tay-SaX lacks heXosaminidase"

116

Krabbe's disease

Autosomal recessive
Galactocerebrosidase deficiency
- Accumulation of galactocerebrosidase, galactosyl-sphingosine

Symptoms:
- Peripheral neuropathy
- Developmental delay
- Optic atrophy
- Globoid cells

117

Metachromatic leukodystrophy

Autosomal recessive
Arylsulfatase A deficiency
- Cerebroside sulfate accumulation

Symptoms:
- Central and peripheral demyelination--> ataxia, dementia

118

Hurler's syndrome

AR
alpha-L-iduronidase deficiency
- Heparan sulfate, dermatan sulfate accumulation

Symptoms:
- Developmental delay,
- gargoylism,
- airway obstruction,
- corneal clouding,
- hepatosplenomegaly

119

Hunter's syndrome

X-linked recessive
Iduronate sulfatase deficiency
- Heparan sulfate, dermatan sulfate accumulation

Symptoms:
- Mild Hurler's (- corneal clouding)
- Aggressive behavior

"Hunters see clearly and aim for the X"

120

Hyperchylomicronemia (familial dyslipidemia Type I)

AR
- LPL deficiency OR altered Apo C-II

Symptoms:
- Pancreatitis
- Hepatosplenomegaly
- Xanthomas
- NO increased risk of atherosclerosis (vs familial type IIa)

Labs:
- Elevated chylomicrons, TG, cholesterol

121

Hypertriglyceridemia (familial dyslipidemia type IV)

AD
- Hepatic overproduction of VLDL

Symptoms:
- Pancreatitis (exceed albumin binding capacity--> binds to acinar cells and pancreatic capillaries

Labs:
- VLDL, TG elevated

122

Abetalipoproteinemia

AR
- Mutation in microsomal triglyceride transfer protein (MTP) gene
- Decreased B-48, B-100--> decreased chylomicron, VLDL synthesis/secretion

Symptoms:
- Neonate with failure to thrive, steatorrhea,
- Acanthocytosis
- Ataxia
- Night blindness

Labs:
- Intestinal biopsy with lipid accumulation in enterocytes

123

Dihydropterin Reductase deficiency

Unable to convert BH2---> BH4 (after oxidized by phenylalanine hydroxylase, tyrosine hydroxylase, tryptophan hydroxylase)

- BH4 deficiency--> decreased production of DA, NE, Epi, Serotonin
- Increased blood Phe, Tyr (after Phenylketonuria suspected, patient supplemented with Tyrosine, which likewise builds up in blood)

124

Rb protein

located on Chrom 13 (RB1)
- Loss of heterogeneity in patients with one defective Rb--> early manifestations of cancer
- Retinoblastomas, osteosarcomas

125

Locus heterogeneity

Mutations at different loci can produce same phenotype
Ex: Marfanoid habitus seen in Marfan syndrome, MEN2B, homocystinuria
- Albinism

vs: Allelic heterogeneity= different mutations at same locus--> similar phenotypes (DMD vs Becker's muscular dystrophy)

126

Acyl-CoA dehydrogenase deficiency

Inability to synthsize ketone bodies from acetyl Co-A--> acyl coA
- Presents in first few years of life with any period of starvation (once glycogen stores are depleted)
- Results in increase in dicarboxylic acids, decreased glucose and ketones in blood
- Symptoms= N, V, hypoglycemia

127

Neonatal adrenoleukodystrophy

Defect in VLCFA metabolism
- Peroxisome defect

Gradual decline in function after normal development in early childhood

128

Bloom syndrome

Defect in DNA helicase gene (RecQL3) or base excision repair
- Photosensitivity, erythema, telangiectasia
- Short stature
- Lymphoproliferative and GI malignancies

129

Dopamine hydroxylase deficiency

Converts DA to epi, NE
- Deficiency: hypotension, ptosis, nasal congestion, ejaculation problems

130

Pyruvate dehydrogenase deficiency

X-linked E1-alpha gene defect in PDH (normally activated in exercise--> TCA cycle)
- Presentation: lactic acidosis, hypotonia

Treatment: increased ketogenic nutrients (high fat, high lysine, leucine intake)

**PDH cofactors: Thiamine (B1), Lipoic acid, CoA (B5), Flavin (B2), Niacin (B3)

131

Friederich's ataxia

Autosomal recessive trinucleotide repeat disorder (GAA on Chromosome 9)
--> mitochondrial function impaired

1. Cerebellar dysfunction--> ataxia
- staggering gait, frequent falling, nystagmus, dysarthria
2. Degeneration of dorsal columns--> loss of position, vibration sensation
- pes cavus, hammer toes
- May see DM in 10%

Presents in childhood with kyphoscoliosis

Death due to hypertrophic cardiomyopathy:
- Arrhthmias
- CHF
- Bulbar dysfunction (can't protect airway)

132

Fomepizole

Inhibits alcohol dehydrogenase
- Antidote for methanol, ethylene glycol poisoning

133

Fanconi Anemia

AR disease
Defect in base excision repair enzymes
- Hypersensitivity to cross-linking agents
- Excrete proline, hydroxyproline, arginine in urine

Develop cancers: AML (t(15;17), auer rods)

134

Essential Amino acids

Glucogenic= Met, Val, His
Glucogenic/ketogenic= Ile, Phe, Thr, Trp
Ketogenic= Leu, Lys

135

Acidic amino acids

Asp, Glu (negative charge at body pH)

136

Basic amino acids

Arg, Lys, His
most basic= Arg
His= no charge at body pH

** both Arg, His increased in histones, required in periods of growth

137

Energy in 1 g carb, protein, fat

Protein/Carb= 4 kcal
Fat= 9 kcal

138

Familial Dysbetalipoproteinemia

Deficiency in ApoE
- Liver can't remove remnants

Increased LDL, cholesterol, TG (decreased HDL)

Symptoms:
- Xanthomas
- Pancreatitis
- Premature CAD, PVD