Genetics, Biochem Flashcards

1
Q

Turner’s syndrome

A

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
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2
Q

Leukocyte adhesion syndrome

A

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

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3
Q

MPO deficiency

A

Can’t produce H2O2

Neutrophils turn blue on nitro blue tetrazolium test

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

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4
Q

Chronic granulomatous disease

A

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)
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5
Q

Late complement component deficiency

A

Increased risk of Neisseria infection

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6
Q

Carbamoyl phosphate

A
  1. de Novo pyramidine synthesis
  2. Urea cycle
    - Ornithine transcarbamoylase deficiency (OTC)–> accumulation of carbamoyl phosphate–> orotic acid
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7
Q

Hydroxyurea

A

Inhibits ribonucleotide reductase

- UDP can’t be converted to dUDP (CTP buildup)

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8
Q

6-mercaptopurine (6-MP)

A

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
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9
Q

5-fluorouracil (5-FU)

A

Inhibits thymidylate synthase
–> can’t produce dTMP

“F U thymidylate synthase”

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10
Q

Methotrexate (MTX)

A

Inhibits dihydrofolate reductase
—> can’t produce dTMP

Supplement with Folinic acid (Leucovorin) to reverse methotrexate toxicity

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11
Q

Trimethoprim (TMP)

A

Inhibits BACTERIAL dihydrofolate reductase

–> can’t produce dTMP

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12
Q

Orotic aciduria

A

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

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13
Q

OTC deficiency

A

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
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14
Q

Adenosine deaminase deficiency

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

Autosomal recessive

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15
Q

Lesch-Nyhan syndrome

A

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

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16
Q

Missense mutation

A

Changed amino acid

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

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17
Q

Nonsense mutation

A

Early STOP codon (Stop the nonsense!)

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18
Q

Frameshift mutation

A

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

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19
Q

Xeroderma pigmentosum

A

Nucleotide excision repair defect

- Can’t repair thimine (pyramidine) dimers formed due to UV exposure (bulky adducts)

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20
Q

HNPCC

A

Hereditary nonpolyposis colorectal cancer

- Mutation in mismatch repair (unable to repair mismatched Watson-Crick nucleotides)

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21
Q

Ataxia telangiectasia

A

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

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22
Q

Start codon

A

AUG

  • Eukaryotes= methionine (may be removed before translation completed)
  • Prokaryotes= formylmethionine
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23
Q

Stop codons

A

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

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24
Q

Amatoxins

A

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

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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
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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)
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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)
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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"
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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)
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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
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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
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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)
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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
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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
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Cystinuria
AR defect in PCT transporter for cystine, ornithine, lysine, arginine --> cystine precipitation (hexagonal crystals)--> renal staghorn calculi Tx: hydration, urinary alkalinization
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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"
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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
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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)
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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)
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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)
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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)
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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
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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)
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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)"
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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"
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Krabbe's disease
Autosomal recessive Galactocerebrosidase deficiency - Accumulation of galactocerebrosidase, galactosyl-sphingosine Symptoms: - Peripheral neuropathy - Developmental delay - Optic atrophy - Globoid cells
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Metachromatic leukodystrophy
Autosomal recessive Arylsulfatase A deficiency - Cerebroside sulfate accumulation Symptoms: - Central and peripheral demyelination--> ataxia, dementia
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Hurler's syndrome
AR alpha-L-iduronidase deficiency - Heparan sulfate, dermatan sulfate accumulation Symptoms: - Developmental delay, - gargoylism, - airway obstruction, - corneal clouding, - hepatosplenomegaly
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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"
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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
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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
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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
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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)
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Rb protein
located on Chrom 13 (RB1) - Loss of heterogeneity in patients with one defective Rb--> early manifestations of cancer - Retinoblastomas, osteosarcomas
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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)
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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
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Neonatal adrenoleukodystrophy
Defect in VLCFA metabolism - Peroxisome defect Gradual decline in function after normal development in early childhood
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Bloom syndrome
Defect in DNA helicase gene (RecQL3) or base excision repair - Photosensitivity, erythema, telangiectasia - Short stature - Lymphoproliferative and GI malignancies
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Dopamine hydroxylase deficiency
Converts DA to epi, NE | - Deficiency: hypotension, ptosis, nasal congestion, ejaculation problems
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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)
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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)
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Fomepizole
Inhibits alcohol dehydrogenase | - Antidote for methanol, ethylene glycol poisoning
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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)
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Essential Amino acids
``` Glucogenic= Met, Val, His Glucogenic/ketogenic= Ile, Phe, Thr, Trp Ketogenic= Leu, Lys ```
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Acidic amino acids
Asp, Glu (negative charge at body pH)
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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
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Energy in 1 g carb, protein, fat
``` Protein/Carb= 4 kcal Fat= 9 kcal ```
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Familial Dysbetalipoproteinemia
Deficiency in ApoE - Liver can't remove remnants Increased LDL, cholesterol, TG (decreased HDL) Symptoms: - Xanthomas - Pancreatitis - Premature CAD, PVD