Diseases Flashcards
Familial Hypercholesterolemia
High levels of LDL (transports cholesterol)
Mutations in LDL receptor result in:
- Inability to bind LDL
- Poor ability to bind LDL
- Failure of LDL receptor to associate w/ coated pits
Neiman-Pick Disease
Defect in sphingomyelinase
Causes sphingolipid accumulation
CNS defects, death <18 mos
Tay Sachs Disease
Defect in hexosaminidase A (breaks down phospholipids (GM2-ganglioside))
Causes accumulation in brain
Mental retardation, death <4 yrs
Hurler’s Syndrome
Defect in alpha-L iduronidase (breaks down mucopolysaccharides)
Mental retardation, death <10 yrs
Inclusion Cell Disease
Almost all hydrolases missing from lysosome, but found in blood
Lysosomes don’t function
Buildup of material (inclusions)
Death <7 yrs
Cystic Fibrosis (CAUSE)
CTFR gene defect (autosomal recessive) –> reduced quantity/function of CFTR protein –> defective ion transport (Cl- and bicarb) –> airway surface liquid depletion –> defective mucociliary clearance –> mucus obstruction, infection, inflammation –> scarring –> end stage lung disease
Cystic Fibrosis (SYMPTOMS/DIAGNOSIS)
salty sweat mucus obstruction in lungs, pancreas, vas deferens bacterial infections airway dilation diabetes chronic pancreatitis meconium ileus (in neonate) rectal prolapse NBS: immunoreactive trypsinogen, mutation analysis, sweat chloride testing hypochloremia hyponatremia hypoproteinemia vitamen E and K and zinc deficiency
Cystic Fibrosis (TREATMENT)
Gene therapy to replace defective CFTR protein
Pharmacotherapy to rescue CFTR function
Oral pancreatic enzyme supplements
Kalydeco for G551D mutations (unlocks chloride function)
Early treatment to avoid infection
Chest therapy
CFTR gene
Chromosome 7
CFTR protein (structure, function)
- Structure: 2 sets of 6 transmembrane domains, 2 ATP-binding cassettes, regulatory domain in middle, regulated by cAMP (PKA phosphorylation of R), gated by ATP
- Function: conducts Cl- across plasma membrane, regulates activity of some Na+ channels
CFTR mutations
Class I: stop codons introduced, splicing defects, CFTR not synthesized due to transcriptional errors (5-10%)
Class II: protein synthesized as immature form, degraded by ubiquitin-proteasomal pathway and never reaches cell surface, deltaF508 in NBD1 (>85%)
Class III: CFTR synthesized and transported to cell surface, but not functional (2-3%)
Class IV: CFTR protein is expressed at cell surface, but level of chloride conduction is reduced ( reduced amount expressed at cell surface (<1%)
CF and sweat ducts
Normal: good reabsorption, Cl- is taken back to blood circulation, Na+ is also reabsorbed to balance the charge, but there’s more Na+ coming into blood than Cl-, so the ductal lumen of sweat gland has negative charge, forms NaCl in lumen
CF: Cl- is not reabsorbed, less Na+ reabsorbed to try to balance more negative charge in lumen, produces lots more NaCl in sweat
CF and airway epithelium
Normal: Cl- and Na+ both reabsorbed at mucosal surface, some NaCl formed in airway lumen
High-salt model: Cl- isn’t reabsorbed, Na+ reabsorption is reduced, more NaCl is formed in lumen, water should follow NaCl into airway lumen (like sweat gland)
Low-volume model: Cl- isn’t reabsorbed, but Na+ is reabsorbed much more (for some reason), other Cl- reabsorption pathways work harder, more NaCl forms in blood, water follows NaCl to blood
Cholera
Cause: bacteria that produces toxin that crosses intestinal epithelium (A1 subunit gets into cytoplasm, activates adenylate cyclase all the time –> cAMP –> activates all ion transport systems –> causes electrolyte imbalance –> water follows ions
Signs/symptoms: diarrhea
Treatment: CF reduces water loss
Arsenic Poisoning (arsenate)
Symptoms: headaches, confusion, diarrhea, drowsiness, lactic acidosis eventually leading to convulsions, hair loss, blood in urine, cramping muscles
Cause: Arsenate (structural analog of phosphate) binds glyceraldehyde-3-phos, prevents formation of 1,3-bisphosphate by glyceraldehyde-3-phosphate dehydrogenase, forms 3-phosphoglycerate by hydrolysis w/o producing ATP; occurs in glycolysis; occurs in tissues that rely on glycolysis (RBCs, brain)
Treatment: chelation to remove As, K+ supplement to decrease risk of heart problems
Pyruvate Kinase Deficiency
Symptoms: Chronic anemia (b/c of affected RBCs), splenic hemolysis (lack of ATP causes cellular swelling)
Cause: Mutations in enzyme lead to loss of activity, expression, or stability of pyruvate kinase, which prevents formation of pyruvate from phosphoenol-pyruvate; occurs in last step of glycolysis; occurs in RBCs (explode)
Treatment: splenectomy, blood transfusions, iron chelation, gene therapy
Lactic acidosis
Symptoms: nausea, vomiting, hyperventilation, abdominal pain, lethargy, anxiety, anemia, hypotension, tachycardia
Cause: Under anaerobic conditions pyruvate accumulates, cant enter TCA cycle –> forms excess lactate –> acidosis; occurs in glycolysis; occurs in tissues
Arsenic poisoning (arsenite)
Symptoms: Headaches, confusion, diarrhea, drowsiness, lactic acidosis eventually leading to convulsions, hair loss, blood in urine, cramping muscles
Cause: Arsenite binds to lipoate cofactor and inhibits pyruvate dehydrogenase –> prevents conversion of pyruvate to acetyl CoA before TCA cycle; occurs in glycolysis; occurs in tissues that rely on glycolysis (brain, RBCs)
Treatment: chelation to remove As, K+ supplement to decrease risk of heart problems
Pyruvate Dehydrogenase deficiency
Symptoms: lactic acidosis at birth (neonatal death with metabolic form, psychomotor retardation with chronic neurological form)
Cause: X-linked, mutations in PDH limits conversion of pyruvate to acetyl CoA, accumulation of lactate, reduction of ATP, neuro symptoms b/c brain depends on glucose ox; occurs entering TCA cycle; occurs in tissues
Treatment: high fat/low carb diet (ketogenic), thiamin supplement
Pyruvate Carboxylase Deficiency
Symptoms: buildup of pyruvate, lactic acidosis, hypoglycemia (lack of gluconeogenesis b/c of less oxaloacetate), neurological dysfunction (affects myelin sheath and NTs), developmental delay (different types w/ different severities)
Causes: mutations in enzyme lead to loss of activity, expression, or stability of PC. which prevents formation of oxaloacetate from pyruvate and acetyl CoA for gluconeogenesis; occurs exiting TCA cycle; occurs in tissues
Treatment: none, avoid fasting, implement high carb/high protein diet (prevent activation of gluconeogenesis), add biotin cofactor to increase enzyme activity, hydration, citrate
Cyanide poisoning
Symptoms: hyperventilation from massive lactic acidosis
Causes: CN blocks ETC by binding Fe3+ in cytochrome oxidase (transporter) –> backs up e- flow and reduces ATP production
Treatment: nitrite oxidizes Hb to met-Hb (w/ Fe3+), which binds CN and removes it from cytochrome oxidase, rhodonase (liver) detoxifies CN from dietary sources or medicine
MELAS (mitochondrial encephalopathy)
Symptoms: progressive neurodegeneration
Causes: mutation in tRNA leucine; occurs in OxPhos (mitochondria)
Kearns-Sayre Syndrome
Symptoms: Late-onset ptosis (droopiness of body part), opthalmoplegia (weakness/paralysis of extraoccular muscles)
Causes: deletions of tRNA and OxPhos genes; occurs in OxPhos (mitochondria)
NARP (neurogenic weakness ataxia w/ retinitis pigmentosa)
Symptoms: sensory neuropathy, ataxia, blindness, dementia
Causes: mutated ATP6; occurs in OxPhos (mitochondria)
Pearson Syndrome
Symptoms: sideroblastic anemia (RBCs), pancreas dysfunction
Causes: deletions of tRNA and OxPhos genes; occurs in OxPhos (mitochondria)
MERRF (myoclonic epilepsy and ragged red fibers)
Symptoms: progressive myoclonic epilepsy, clumps of diseased mitochondria stain red
Causes: point mutation in mtDNA gene MT-TK that encodes tRNA lysine; occurs in OxPhos; manifests in muscle
Treatment: none, coenzyme Q-10 and L-carnitine (for fatty acid oxidation)
Leber’s hereditary optic neuropathy
Symptoms: Sudden onset of blindness caused by degeneration of optic nerve
Causes: Mutation in NADH-Q reductase (complex I) or other mutations that impair resp chain (ex. NADH-Q reductase, QH-2 cytochrome c reductase, cytochrome oxidase); occurs in OxPhos; affects optic nerve (relies on OxPhos)
Treatment:
Leigh Disease (subacute necrotizing encephalopathy)
Symptoms: Progressive neurodegeneration (death within 2 years), movement disorders, dystonia, breathing abnormalities, mental retardation
Causes: mutations in complex I or IV, X-linked form causes mutations in pyruvate dehydrogenase; occurs in OxPhos
Treatment:
Propionyl CoA Carboxylase Defect
*** Propionyl CoA is a product of odd chain FA breakdown, converted to succinyl CoA
Symptoms: Priopionic acidemia (an organic acidemia), frequent vomiting, protein intolerance, metabolic acidosis, ketoacidosis, lethargy, developmental delay, mental retardation, hypoglycemia, hypotonia, hyperammonemia
Causes: Defect in enzyme that converts propionyl-CoA to methylmalonyl-CoA; occurs in B-ox of FA
Treatment: bicarb to correct acidosis, diet low in valine, methionine, isoleucine, threonine (minimizes propiogenic substances)– i.e. low protein/high carb diet, biotin cofactor
Methylmalonyl-CoA mutase defect
Symptoms: metabolic acidosis, failure to thrive, hypoglycemia, hypotonia, hyperammonemia, neurological symptoms, coma, seizure, mental retardation
Causes: Defects in MCM enzyme that converts methylmalonyl-CoA to succinyl-CoA leads to buildup of methylmalonic acid (excreted in urine), ALSO defects in B12 synthetic enzymes; occurs in B-ox of FA
Treatment: Diet low in branched AAs and odd chain FA, vitamin B12 supplement, carnitine supplement
Jamaican vomiting sickness
Symptoms: severe hypoglycemia (b/c more glucose must be oxidized as fuel)
Causes: Ingestion of hypoglycin inhibits short and med chain acyl CoA dehydrogenases, blocks entry of FA into mitochondria; occurs in B-ox of FA
Treatment:
CPT II deficiency
*** Carnitine transports FA into mitochondrial matrix
Symptoms: Recurrent episodes of acute myoglobinuria (myoglobin overflow in muscles) triggered by exercise or fasting
Causes: Transporter CPT II, different types; occurs in B-ox of FA
Treatment: avoid fasting and exercise, high carb/low fat diet, med chain FA triheptanoin (tri-C7), less LCFA and more SCFA in diet, carnitine supplement
MCAD (med chain acyl-CoA dehydrogenase) deficiency
Symptoms: intermittent hypoketotic hypoglycemia triggered by prolonged fasting, exercise, illness; sometimes SIDS
Causes: mutation in MCAD (A985G) impairs ability to break down MCFA (first step in B-ox spiral- cleaving 2Cs off end of FAs), clinical heterogeneity; occurs in B-ox of FA
Treatment: high carb/low fat diet, avoid fasting
Zellweger syndrome
Symptoms: Hypotonia, facial dysmorphia, seizures, liver dysfunction; in less severe forms, progressive loss of hearing, vision, smell, motor function
Causes: mutations in PEX (peroxin) family genes –> defect in peroxisome biogenesis –> accumulation of VLCFA (C26:0, C26:1) and branched FA (phytanic acid) in blood, resulting in disruption of myelin sheath –> neurological damage and progression to vegetative state; occurs in B-ox of FA
Treatment:
Refsum disease
Symptoms: late-onset, retinitis pigmentosa, blindness, anosmia (inability to perceive odor), deafness, sensory neuropathy, cerebral ataxia
Causes: defect in alpha-oxidation enzymes phytanoyl-CoA 2 hydroxylase (PAHX, type 1) or peroxin 7 (type 2) –> accumulation of branched FA (phytanic acid) in blood; occurs in B-ox of FA
Treatment: dietary restrictions, avoid sources of phytanic acid (milk and meat from ruminants)
Adrenoleukodystrophy
Symptoms: progressive motor dysfunction, neurological damage and progression to vegetative state (2 phenotypes)
Causes: X-linked defect in ABCD1 gene (encodes peroxisomal VLCFA transporter ALDP) –> accumulation of VLCFA (C26:0, C24:0) in blood; occurs in B-ox of FA
Kwashiorkor
Symptoms: fatigue, lethargy, edema, distended abdomen, skin pigmentation changes, coma (rapid progression, high mortality)
Diagnosis: enlarged liver
Cause: diet lacking in protein
Treatment: providing enough calories (carbs first, THEN protein)
Hartnup Disease
Symptoms: dermatitis, diarrhea, dementia
Cause: bacteria in GI tract convert unabsorbed AAs to indoles, kynurenine, and serotonine– absrbed and appear in urine, can’t synthesize nicotinamide (vitamin, cofactor) from tryptophan
Diagnosis: tryptophan degradation products in urine
Treatment: niacin supplement
Cystinuria
Symptoms: cystine stones, infections
Causes: defect in absorption of Arg, Lys, cystine, and ornithine from gut and renal tubules
Treatment: fluids, penicillamine
Glutathionuria
Symptoms: hemolytica anemia, mental retardation, peripheral neuropathy, ataxia
Cause: GGT deficiency
Diagnosis: excess glutathione in urine and blood
Treatment: none, avoid hemolytic crisis
Oxoprolinuria
Symptoms: acidosis, hemolytic anemia, electrolyte imbalance, jaundice, CNS symptoms
Cause: defect in glutathione synthetase, glutamyl cysteine synthetase, or 5-oxoprolinase
Diagnosis: mass spec analysis of 5-oxoproline
Treatment: Na-bicarb to blood
*** Complete GSH deficiency is LETHAL
Hyperammonemia
Symptoms: tremor, slurring of speech, blurred vision, somnolence, vomiting, cerebral edema, coma, death
Causes: defect in liver function- fails to detoxify ammonium (viral hepatitis, ischemia, hepatotoxins, cirrhosis, mutations in enzymes in urea cycle)
Diagnosis: elevated ammonia in blood (normal = 12-48 uM, abnormal > 1mmol)
Treatment: restrictive protein diet
Prader-Willi Syndrome
Symptoms: morbid obesity, overeating, obsession w/ food, death before 30
Cause: genetic mutation in chromosome 15 that causes overproduction of ghrelin
Pheochromocytoma
Endocrine tumor of adrenal medulla secreting excessive amounts of epinephrine and norepinephrine, UCP-1 gene is activated
Lipoma
Common benign tumor of adipose tissue
Cause: chromosomal aberration (chromosome 12)
Classified by morphology:
- Conventional lipoma: mature white adiposcytes
- Fibrolipoma: adipocytes surrounded by fibrous tissue
- Angiolipoma: adipocytes separated by unusually high number of vascular channels
Liposarcoma
Malignant tumor in deep adipose tissue
Rare
Hiberoma
Tumor of brown adipose tissue
Rare
Benign
Slow-growing
Marasmus
Symptoms: growth retardation, wasting away of fat and muscle tissues, but mental alertness and appetite present (slow progression and low mortality)
Cause: protein calorie malnutrition
Obesity
Excessive accumulation of adipose tissue, often set at a body weight 20% + above reference standard for height of individual
Keshan disease
Selenium deficiency
Endemic cardiomyopathy
Kashin-Beck disease
Selenium deficiency
Endemic deforming arthritis
Myxodematous cretinism
Selenium deficiency
Mental retardation
Xeropthalmia
Symptoms: blindness, keratinization of cornea
Cause: deficiency of vitamin A
Polar Bear Syndrome
Symptoms: rash, hair loss, hemorrhage, birth defect, fracture, liver failure, death
Cause: vitamin A toxicity
Ricketts
Symptoms: bowed legs, poor calcification of bones
Cause: vitamin D deficiency in children
Osteomalacia
Symptoms: demineralization of skeleton
Cause: vitamin D deficiency in adults
Scurvy
Symptoms: swollen legs, loose teeth, bleeding gums, poor wound healing
Cause: vitamin C deficiency
Beri beri
Symptoms: mental confusion, anorexia, muscle weakness, peripheral paralysis, edema, muscle wasting, tachycardia, enlarged heart
Cause: thiamin deficiency
Pellagra
Symptoms: dermatitis, dementia, diarrhea (3Ds)
Cause: niacin deficiency
Anorexia Nervosa
Weight loss or improper growth
Maintenance of body weight <85% of expected
Extreme fear or weight-gain
Irrational perception of figure/weight status
Amenorrhea
Often accompanied by depression, OCD, anxiety
Can be restricting or binging-purging type
Bulimia Nervosa
Repeated binge eating followed by inappropriate compensatory behavior (eg. vomiting, fasting, laxative use, excessive exercise)
Over 3 mo period at least 2x/wk
Irrational perception of figure/weight status
Often accompanied by depression
Can be purging or non-purging type
Big-orexia
Muscle dysmorphia
Repeated obsession w/ appearance/muscle size
Inappropriate compensatory behavior (eg. viewing in mirror, excessive exercise and dieting in controlled mannter)
Irrational perception of figure/weight status
Accompanied by use of drugs (steroids), inability to maintain job, family, relationships
Zollinger-Ellison syndrome
Excessive acid secretion due to certain pancreatic islet cell tumors that secrete large amounts of gastrin (indicating there may possibly be G cells in islets)
Diabetes Mellitus Type 1
Body doesn’t produce insulin at all b/c immune system mistakenly destroys B-cells in pancreas
- Young
- Sudden onset
- Severe symptoms
- Recent weight loss
- Autoimmune
- Usually thin
- Insulin is only treatment that works
Diabetes Mellitus Type 2
Insulin resistance and decreased insulin production
- Older
- Gradual onset
- May have no symptoms
- Often no weight loss
- Accelerated gastric emptying
- Impaired incretin effect
- Usually obese
- Pills/insulin or non-insulin therapies for treatment
Gestational diabetes
Insulin resistance caused by pregnancy
Increased risk for T2DM
Clinical manifestation of diabetes (numbers)
Fasting BG
- Normal: 125 mg/dL
2hr OGTT
- Normal: 200 mg/dL
HbA1c
- Normal: 6.5%
Goals for patients w/ diabetes
A1c < 7% BP < 130/90 Fasting BG: 90-130 mg/dL Postmeal BG: 100 WC <35in (females)
Clinical manifestation of diabetes (signs/symptoms)
Hyperglycemia Polydipsia Polyuria Blurry vision Weight loss Fatigue Hunger Emergency (dizziness, syncope, confusion, vomiting, abdominal pain)
Long-term consequences of uncontrolled diabetes
Macrovascular
- Heart: MI, heart failure
- Brain: stroke, cognitive impairment
- Extremities: ulcers, amputations, aneurysms
Microvascular
- Eye: retinopathy, cataract, glaucoma –> blindness
- Kidney: nephropathy (microalbuminuria, gross albuminuria) –> kidney failure
- Nerves: neuropathy (peripheral, autonomic) –> amputation
Diabetic Ketoacidosis (DKA)
d
Metabolic Syndrome
d
Genetic risk factors for diabetes (associated w/ disease)
CF Hemochromatosis- iron overload Pheochromocytoma- tumor of adrenal medulla --> lots of norepinephrine Chronic pancreatitis Insulin receptor defects Proinsulin cleavage enzyme defect MELAS- mtDNA mutation MNGIE- mtDNA mutation Kearns-Sayre Myotonic dystrophy- muscle wasting MODY HLA status
MODY
Mature onset diabetes of the young Presents like a combo of T1 and T2 Hypoinsulinism Gradual onset Loss/dysfunction of B-cells of pancreas Treated w/ sulfonylurea
Turner Syndrome
45X aneuploidy
Survivors are infertile
Trisomy 21
47XX + 21
Downs syndrome
Osteogenesis Imperfecta
Autosomal dominant
LOF
Brittle bones
- Type 1: fractures heal normally (half amount of normal collagen)
- Type 2: fractures heal w/ mutated collagen
Achondroplasia
Autosomal dominant GOF Dwarfism Mutation in Fibroblast Growth Factor- causes ligand-independent stabilization of protein, so it ALWAYS shuts off long bone growth Homozygous is lethal
Huntington’s
Autosomal dominant
Anticipation- occurrence of genetic disease increasing in severity or earlier onset in successive generations
Polyglutamine tract repeats (CAG)
100% penetrance by age 80
Fragile X Syndrome
LOF
triplet repeat expansion in 5’-UTR
Myotonic Dystrophy
Triplet repeat expansion in 3’-UTR
Friedrich’s ataxia
LOF
Triplet repeat expansion in intron
Spinal Muscular Atrophy
Autosomal recessive
LOF
Mutation in SMN1 genes that prevents incorporation of exon 7 for normal protein function
“Floppy Baby Syndrome”
Duchenne Muscular Dystrophy
X-linked recessive
Mutation in dystrophin protein that acts as force transducer between muscle fibers and ECM
Gaucher Disease
Deficiency: Glucocerebrosidase
Accumulates: Glucosylceramide
Tay Sachs Disease
Deficiency: B-hexosaminidase (a subunit)
Accumulates: GM2 ganglioside
Sandhoff Disease
Deficiency: B-hexosaminidase (B subunit)
Accumulates: GM2 ganglioside, oligosaccharides
Krabbe Disease
Deficiency: Galactosylceramidase
Accumulates: Gal-ceramide, gal-sphingosine
Neimann Pick Disease
Deficiency: Sphingomyelinase
Accumulates: Sphingomyelin
Aspartylglycosaminuria
Deficiency: Aspartylglycosaminidase
Accumulates: N-linked oligosaccharides
a-Mannosidosis
Deficiency: a-Mannosidase
Accumulates: a-Mannosides
Hurler Syndrome
Deficiency: a-L-iduronidase
Acumulates: Dermatan sulfate, heparan sulfate
Hunter Syndrome
Deficiency: L-iduronate-sulfatase
Accumulates: Dermatan sulfate, heparan sulfate
Maroteaux-Lamy Syndrome
Deficiency: GalNAc 4-sulfatase/arylsulfatase B
Accumulates: Dermatan sulfate
Pompe Disease
Deficiency: a-1,4-glucosidase
Accumulates: glycogen
Wolman Disease
Deficiency: acid lipase
Accumulates: cholesterol esters, triglycerides
Canavan Disease
Deficiency: Aspartoacylase
Accumulates: N-acetylaspartic acid
Inclusion cell disease
Deficiency: GlcNAc-1-phosphotransferase
Accumulates: lysosomal hydrolases not present in lysosomes
Danon Disease
Deficiency: Lamp2
Accumulates: presence of autophagic vacuoles
Cystinosis
Deficiency: Cystinosin
Accumulates: Cystine
Parkinson Disease
Decreased Ubiquitin-Proteasome Activity
Lewy bodies
Alzheimers Disease
Decreased ubiquitin-proteasome activity
Amyloid plaques
Amyotrophic lateral sclerosis
Decreased ubiquitin-proteasome activity
Superoxide dismutase aggregates in motor neurons
Sjogren Syndrome
Decreased ubiquitin-proteasome activity
Chronic inflammation
Cataract formation
Decreased ubiquitin-proteasome activity
Aggregated oxidized proteins
Systemic lupus erythrematosus
affects SNPs that regulate splicing/removing introns
Testicular feminization
Androgen receptor (TRANSCRIPTION FACTOR) Cells don't respond to testosterone b/c they don't have the right androgen receptor
Chronic Myelogenous Leukemia
DNA rearrangement (translocation) between 9 and 22
Methotrexate resistance
Gene amplification, competitive inhibition between methotrexate and enzyme DHFR
(When DHFR is inhibited, cells don’t produce enough thymine for DNA synthesis, so they amplify DHFR gene and become resistant to methotrexate)
Iron deficient anemia
Take more iron
Sickle Cell
Single AA substitution on chromosome 11, leads to mutation in B-globin (2 genes)
S = Glu6Val
E = Glu26Lys (less severe)
C = Glu6Lys (usually milder)
D = several variants (usually milder)
Molecule becomes hydrophobic instead of hydrophilic
Protective against malaria
alpha-Thalassemia
Missing/ineffective alpha chains on chromosome 16 (4 genes)
- Constant spring mutation (Hbcs)- missense mutation leads to elongation of protein chain and instability of protein molecule
- “Silent” carrier- 1 missing/dysfunctional gene, asymptompatic, but can be detected through genetic testing
- “Trait”/”minor”- 2 gene deletion (trans or cis- SE Asian)), microcytic anemia (resembles iron deficient anemia)
- “major”: Hb H disease, 3 gene deletion, all Bs come together and aren’t functional, transfusion dependent
- Hb H + constant spring- 2 gene deletion from 1 parent + constant spring mutation from other parent, transfusion-dependent
- Hb Barts- no functional alpha genes, y tetramers form
Beta-Thalassemia
Missing/ineffective B chains on chromosome 11 (2 genes)
- “Trait”: 1 gene deletion, reduced Hb A, increased Hb A2, Hb F may be present –> microcytic anemia
- “Homozoygous B+”- mutations in both genes, elevated Hb A2, Hb F, maybe Hb A
- :Homozygous B0”- deletion of both genes, no normal Hb A, a subunits bond w/ d or y to make some Hb A2 or Hb F, transfusion dependent
Hereditary spherocytosis
Abnormality in ankyrin, band 3, spectrin genes = no central pallor; small dense cells (spherocytes); reticulocytes and erythropoietin b/c trying to keep up w/ destruction by spherocytes
Hereditary elliptocytosis/ovalocytosis
Abnormality in spectrin and ankyrin 4.2 genes causes spectrin dimer-dimer interaction
Hereditary pyropoikilocytosis
Abnormalities in spectrin and ankyrin 4.1 genes causes spectrin dimer-dimer interaction
Hereditary stomatocytosis
Abnormality in band 3 gene resulting in increased intracellular Na+, retains water, loses biconcave shape
Glucose-6-phosphate dehydrogenase deficiency
X-linked recessive
With no G6PD, no NADPH is produced, so it can’t supply reduced glutathione, which can’t mop up ROS
Oxidative damage –> hemoglobin denaturation on surface of RBCs –> “bite” cells
Lissencephaly
Tubulin assembly inside neuron doesn’t work because a missense mutation (Arg to Thr) affects chaperone-mediated folding
Smooth brain
Prion disease
Misfolded protein can be infectious
Normal protein doesn’t form misfolded protein, but if you seed it with misfolded protein, it acts as a template and forms an amyloid aggregation –> infectious and can be taken up in environment
Myasthenia Gravis
Body makes antibody against ACh receptors, can’t bind ACh
Treatment: Acetylcholinesterase inhibitors
