Genetics, Biochem Flashcards
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
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
MPO deficiency
Can’t produce H2O2
Neutrophils turn blue on nitro blue tetrazolium test
Normal NADPH activity: close to normal/normal immune system function
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)
Late complement component deficiency
Increased risk of Neisseria infection
Carbamoyl phosphate
- de Novo pyramidine synthesis
- Urea cycle
- Ornithine transcarbamoylase deficiency (OTC)–> accumulation of carbamoyl phosphate–> orotic acid
Hydroxyurea
Inhibits ribonucleotide reductase
- UDP can’t be converted to dUDP (CTP buildup)
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
5-fluorouracil (5-FU)
Inhibits thymidylate synthase
–> can’t produce dTMP
“F U thymidylate synthase”
Methotrexate (MTX)
Inhibits dihydrofolate reductase
—> can’t produce dTMP
Supplement with Folinic acid (Leucovorin) to reverse methotrexate toxicity
Trimethoprim (TMP)
Inhibits BACTERIAL dihydrofolate reductase
–> can’t produce dTMP
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
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
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
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
Missense mutation
Changed amino acid
- Conservative change: new amino acid is similar in chemical structure/function
Nonsense mutation
Early STOP codon (Stop the nonsense!)
Frameshift mutation
Changed from multiples of 3–> all nucleotides downstream misread
–> truncated, non-functional protein
Xeroderma pigmentosum
Nucleotide excision repair defect
- Can’t repair thimine (pyramidine) dimers formed due to UV exposure (bulky adducts)
HNPCC
Hereditary nonpolyposis colorectal cancer
- Mutation in mismatch repair (unable to repair mismatched Watson-Crick nucleotides)
Ataxia telangiectasia
Mutation in nonhomologous end joining (bring together 2 ends of broken dsDNA)
Start codon
AUG
- Eukaryotes= methionine (may be removed before translation completed)
- Prokaryotes= formylmethionine
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
Amatoxins
Mushroom poison
Inhibits RNA polymerase II= halts mRNA synthesis–> cell death
- Found in Amanita phalloides= “death cap mushrooms)
- Severe hepatotoxicity if ingested
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)
snRNPs
Splice pre-mRNA
- Make lariat that is spliced out (intron), 2 exons joined
** Lupus= antibodies to spliceosomal snRNPs
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
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)
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)
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)
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
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
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
Southern blot
DNA: electrophoresis
- Filtered on paper
- Radiolabeled DNA probe anneals to complementary strand
Northern blot
RNA: electrophoresis
- Filtered on paper
- Radiolabeled RNA probe anneals to complementary strand
- Useful for studying mRNA
Western blot
Protein: electrophoresis
- Labeled antibody binds protein
Southwestern blot
DNA-binding proteins (transcription factors)
- ID using labeled oligonucleotide probes
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
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
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)
Pleiotropy
One gene–> multiple phenotypic effects
Ex: PKU–> unrelated symptoms (hair/skin changes, mental retardation)
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
Dominant negative mutation
Heterozygote produces nonfunctional altered protein–> prevents normal protein function
Linkage disequilibrium
alleles at 2 linked loci occur together more often than expected by chance
** measure in population, not family
Achondroplasia
AD
Cell-signaling defect of FGF receptor 3
–> dwarfism with normal trunk
- Advanced paternal age
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
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
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
Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu)
AD
Disorder of blood vessels
Telangiectasias, AVM
Hereditary spherocytosis
AD
Spectrin or ankyrin defect–> spheroid erythrocytes
- Increased MCHC
- Splenectomy= curative
Huntington’s disease
AD
CAG trinucleotide repeat on Chrom 4
- Decreased GABA, Ach in brain
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)
Neurofibromatosis Type 1 (von Recklinghausen’s)
AD
Long arm of chrom 17
- Cafe au lait, neural tumors, Lisch nodules, optic pathway gliomas
Neurofibromatosis Type 2
AD
NF gene on chrom 22
- Bilateral acoustic Schwanomas, juvenile cataracts
Tuberous sclerosis
AD
TSC1, TSC2
Facial lesions: hypopigmented "ash leaf spots" Coritcal, retinal hamartomas Seizures, mental retardation Renal cysts, angiomyolipomas Cardiac rhabdomyomas Increased astrocytomas
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
Cystic fibrosis
Autosomal recessive: CFTR gene on Chrom 7 (CFTR channel= ATP-binding cassette transmembrane protein)
Causes:
- Deletion of Phe 508–> abnL protein folding–> Cl- channel never reaches cell surface
- Premature termination of CFTR protein (Ashkenazi Jews)
- Defective ATP binding of transmembrane protein
- Impaired Cl- conduction (milder disease)
- 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
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
Trinucleotide repeat disorders
Fragile X: CGG
Friedreich’s ataxia: GAA
Huntingtons: CAG
Myotonic dystrophy: CTG
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)
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
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
Cri du chat
Microdeletion of short arm chrom 5p
Microcephaly, mental retardation
- High pitched mewing
- Epicanthal folds
- VSD
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
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
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
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
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)
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)
Vitamin B2 (riboflavin)
Function:
- Cofactor in oxidation, reduction (FADH2, FMN)
Deficiency:
- Cheliosis (inflammation of lips, scaling, fissures at corner of mouth)
- Corneal vascularization
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
Vitamin B5 (pantothenate)
Function:
- Component of CoA (cofactor for acyl transfer) and fatty acid synthase
Deficiency:
- Dermatitis
- Enteritis
- Alopecia
- Adrenal insufficiency
- Dysesthesias, GI distress
Vitamin B6 (pyridoxine)
Function:
- Converted to pyridoxal phosphate
- cofactor in transamination–> ALT, AST
- Decarboxylation reactions
- Glycogen phosphorylase - 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)
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
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
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
- Use Schilling test to detect etiology of deficiency:
- 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
S-adenosyl-methionine (SAM)
ATP+methionine–> SAM
- Transfers methyl units
- Dependent on B12 and B9 for regeneration
- Required for conversion of NE to epi
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)
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
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
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)
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
Ethanol hypoglycemia
Alcohol dehydrogenase:
Ethanol + NAD+ –> acetaldehyde+ NADH + H+
- Thus increased ethanol–> increased NADH/NAD+ ratio
NADH > NAD+: need to create NAD+:
- Pyruvate converted to lactate
- 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
Lipoic acid
Cofactor for:
- 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) - Alpha ketoglutarate DH
- Branched-chain ketoacid DH
- Deficiency–> Maple syrup urine disease
** Arsenic inhibits Lipoic acid–> vomiting, rice water stool, garlic breath
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
Pyruvate Kinase deficiency
RBC maintains structure via:
- Glycolysis–> ATP to pump out waste products
- PPP (HMP shunt)–> NADH to reduce methemoglobin
Symptoms:
- Hemolytic anemia (#2 cause worldwide)
- Can’t maintain pumps in membrane without ATP generated by PK - 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) - No Heinz bodies (vs G6PD deficiency)
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
Tender loving care for Nancy
Enzymes requiring:
- Thiamine
- Lipoic Acid
- Co-A
- FAD (riboflavin= B2)
- NAD (niacin= B3)
- Alpha ketoglutarate dehydrogenase
- Pyruvate dehydrogenase
- Branched-chain ketoacid DH
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
ATP synthase inhibitors
Oligomycin
Block complex V= mitochondrial ATPsynthase
- increased proton gradient–> no ATP produced as electron transport stops
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
Gluconeogenesis
Liver (kidney, intestinal epithelium)
Irreversible:
- Pyruvate carboxylase (mitochondria)
- PEP carboxylase (cytosol)
- Fructose-1,6-BPase (cytosol)
- Glucose-6-phosphatase (ER)
* deficient in vonGierke’s
- Odd-chain FA–> propionyl coA–> TCA
- Even chain–> acetyl CoA (no glucose)
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
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
Essential fructosuria
Defect in Frutctokinase
- Autosomal recessive
Benign, asymptomatic
- See fructose in blood, urine
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)
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)
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”
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)
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
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
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)
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
Homocysteinuria
3 forms (all AR):
- Cystathionine synthase deficiency (can’t degrade methionine)
- Tx: decrease Met, increase Cys, B12, B9 in diet **Cysteine becomes essential aa - Decreased affinitiy of cystathionine synthase for pyridoxal phosphate
- tx: increased B6 in diet (pyridoxal phosphate) - 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
Cystinuria
AR defect in PCT transporter for cystine, ornithine, lysine, arginine
–> cystine precipitation (hexagonal crystals)–> renal staghorn calculi
Tx: hydration, urinary alkalinization
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”
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
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)
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)
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)
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)
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
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)
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)”
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”
Krabbe’s disease
Autosomal recessive
Galactocerebrosidase deficiency
- Accumulation of galactocerebrosidase, galactosyl-sphingosine
Symptoms:
- Peripheral neuropathy
- Developmental delay
- Optic atrophy
- Globoid cells
Metachromatic leukodystrophy
Autosomal recessive
Arylsulfatase A deficiency
- Cerebroside sulfate accumulation
Symptoms:
- Central and peripheral demyelination–> ataxia, dementia
Hurler’s syndrome
AR
alpha-L-iduronidase deficiency
- Heparan sulfate, dermatan sulfate accumulation
Symptoms:
- Developmental delay,
- gargoylism,
- airway obstruction,
- corneal clouding,
- hepatosplenomegaly
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”
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
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
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
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)
Rb protein
located on Chrom 13 (RB1)
- Loss of heterogeneity in patients with one defective Rb–> early manifestations of cancer
- Retinoblastomas, osteosarcomas
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)
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
Neonatal adrenoleukodystrophy
Defect in VLCFA metabolism
- Peroxisome defect
Gradual decline in function after normal development in early childhood
Bloom syndrome
Defect in DNA helicase gene (RecQL3) or base excision repair
- Photosensitivity, erythema, telangiectasia
- Short stature
- Lymphoproliferative and GI malignancies
Dopamine hydroxylase deficiency
Converts DA to epi, NE
- Deficiency: hypotension, ptosis, nasal congestion, ejaculation problems
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)
Friederich’s ataxia
Autosomal recessive trinucleotide repeat disorder (GAA on Chromosome 9)
–> mitochondrial function impaired
- Cerebellar dysfunction–> ataxia
- staggering gait, frequent falling, nystagmus, dysarthria - 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)
Fomepizole
Inhibits alcohol dehydrogenase
- Antidote for methanol, ethylene glycol poisoning
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)
Essential Amino acids
Glucogenic= Met, Val, His Glucogenic/ketogenic= Ile, Phe, Thr, Trp Ketogenic= Leu, Lys
Acidic amino acids
Asp, Glu (negative charge at body pH)
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
Energy in 1 g carb, protein, fat
Protein/Carb= 4 kcal Fat= 9 kcal
Familial Dysbetalipoproteinemia
Deficiency in ApoE
- Liver can’t remove remnants
Increased LDL, cholesterol, TG (decreased HDL)
Symptoms:
- Xanthomas
- Pancreatitis
- Premature CAD, PVD
