BLOCK 1 DISEASES

Amyloid Disease

DISEASE CATEGORY: PROTEIN MISFOLDING

accumulation of insoluble aggregating proteins

Alzheimer's Disease (AD)

DISEASE CATEGORY: PROTEIN MISFOLDING, MULTIFACTORIAL

accumulation of amyloid B (AB) and accumulatio of neurofibrillary tangles

AB is a neurotoxic when aggregated - causes cognitive impairment

Abnormal tau form creates neurofibrillary tangles

mutations in APP Gene on chromsome 21, can also occurs with those who have trisomy 21 (Down Syndrome)

Prion Disease

DISEASE CATEGORY: PROTEIN MISFOLDING

prion protein (PrP) becomes an infectious agent, which is an altered version of the protein

alpha-helices are replaced with beta-sheets - resistance to proteolytic degradation

causative agent of transmissible spongiform encephalopathies (TSEs) which are fatal and have no current treatments

Crentzfelat-Jakob Disease (CJD) - dementia due to changes in secondary and tertiary structure

Sickle Cell Disease

DISEASE CATEGORY: AUTOSOMAL RECESSIVE

point mutation in HbA - charged glutamate is replaced by nonpolar valine (HbA into HbS)

sickle/cresent shape red blood cells

mutation blocks the flow of blood in narrow capillaries, resulting in O2 interruption = localized anoxia = eventual ischemic death of cells

Increase sickling = decrease PO2, increase pCO2, decrease pH, and increase in 2,3-BPG

Hemoglobin C Disease

DISEASE CATEGORY: AUTOSOMAL RECESSIVE

mutation of beta genes = glu (-) replaced with lys (+)

leads to hemolytic anemia (RBCs destroyed faster than made)

Hemoglobin SC disease

DISEASE CATEGORY: AUTOSOMAL RECESSIVE

some beta chains have sickle cell mutation (HbS), others have HbC

leads to higher hemoglobin levels than HbS alone = less severe anemia

Methemoglobinemia

DISEASE CATEGORY: AUTOSOMAL RECESSIVE

oxidation of heme ferrous iron (Fe2+) to ferric iron (Fe3+) which forms methemoglobin

cannot bind to oxygen

symptoms: chocolate cyanosis (brownish blue coloration of the skin and mucous membranes and brown-colored blood)

treatment: methylene blue (reducing agent) = allow oxidation of iron

alpha-Thalassemias

DISEASE CATEGORY: AUTOSOMAL RECESSIVE

synthesis of alpha-globin chain decreased or absent due to deletions of nucleotides (involves four alpha-globin genes)

1 of 4 defective = silent carrier with no physical manifestations

2 of 4 = has alpha-thalassemia

3 of 4 = Hb H disease = severe hemolytic disease

4 of 4 = Hb Bart syndrome = hydrops fetalis (fetal death due to excess fluid build up before birth)

beta-Thalassemias

DISEASE CATEGORY: AUTOSOMAL RECESSIVE

synthesis of beta-globin chain decreases or absent while alpha-globin chains are involved (involves two-beta globin genes)

1 of 2 defective = minor thalassemia (mild anemia)

2 of 2 = major thalassemia (severe anemia that requries regular transfusions)

treatment: hematopoietic stem cell transplanation

Scurvy

DISEASE CATEGORY: MALNUTRITION

Caused by vitamin C defiency, which is also a cofactor required for hydroxylation

decreased hydroxylation = vitamin c deficiency

bleeding gums and loose teeth - correlated to collagen (type I)

Osteogenesis Imperfecta (OI)

DISEASE CATEGORY: AUTOSOMAL DOMINANT

caused by abnormal collagen (type I), leads to fragile bones and retarded wound healing

Ehlers-Danlos Syndrome

DISEASE CATEGORY: AUTOSOMAL DOMINANT

results from defect in cross-linking of triple helix, making it not mature

not matured triple helix = lax skin

defiencies are common due to mutations in type III

result from collagen processing enzymes (lysyl hydroxylase or procollagen peptidase)

Marfan's Syndrome

DISEASE CATEGORY: AUTOSOMAL DOMINANT

results from a defect in fibrillin glycoprotein

defect in fibrillin = elastic fibers are affected = connective tissue is abnormal

characteristic symptoms: tall and lanky statuer, long arms and fingers, eye problems (lens subluxation), heart problems (i.e. aortic aneurysm)

Emphysema

DISEASE CATEGORY: AUTOSOMAL DOMINANT

results in defiency in alpha-1-antitripsin

defiency = increase elastase = increase elastin breakdown = destroys structure of lungs

Tropical Sprue

DISEASE CATEGORY: MALABSORPTION

small intestines' ability to absorb nutrients is impaired

marked by abnormal flattening of villi and inflammation of lining of small intestine

affects small intestine, leads to defiency in folic acid

chronic diarrheal disease

Whipple's Disease

DISEASE CATEGORY: MALABSORPTION

infection of small intestine lining by bacteria T. Whipplei

interferes with normal digestion by impairing breakdown of foods - cannot absorb nutrients (fats and carbs)

affects joints and digestive system

infection can spread to heart, lung, brain, joints and eyes

Celiac Sprue

DISEASE CATEGORY: MALABSORPTION, AKA Nontropical Sprue

gluten-sensitive enteropathy

autoimmune disorder

Disaccharidase Defiency

DISEASE CATEGORY: MALABSORPTION

causes malabsorption of carbohydrates

unabsorbed sugars cause osmotic load in small intestine - draws fluid into lumen = intestinal distension and rapid propulsion into colon

Abetalipoproteinemia

DISEASE CATEGORY: MALABSORPTION

apoB defiency - defect in chylomicron synthesis

affects fat absorption by intestine and mobilization to liver

rare inherited disorder

Pancreatic Insuffiency

DISEASE CATEGORY: MALABSORPTION

pancreas does not make enough of a specific enzyme required to digest fats in small intestine

malabsorption of fat soluble vitamins (A, D, E, K)

can be caused by cystic fibrosis (thickened secretions make it harder for enzymes to reach intestine)

Pellagra

DISEASE CATEGORY: MALNUTRITION

results from niacin (and/or tryptophan) defiency

3 D's: dermatitis in sun exposed skin, diarrhea, dementia

Kwashiorkor

DISEASE CATEGORY: MALNUTRITION

caused by protein deprivation or malabsorption (caloric intake is adequate)

main symptoms: edema (swollen belly), non pigmented hair, skin lesion

marked by muscle atrophy with normal or increased body fat

reduced regeneration of intestinal epithelial cells = poor malabsoprtion

MEAL: malnutrition, edema, anemia, liver

Marasmus

DISEASE CATEGORY: MALNUTRITION

caused by overall malnutrition (protein and calorie)

affects skeletal muscle (wasting), and body fat stores (depletion)

affects liver (protein storage)

symptoms: loose skin, tissue and muscle wasting

Anorexia nervosa

DISEASE CATEGORY: MALNUTRITION

caused by self-induced starvation

clinical symptoms similar to Kwashiorkor and marasmus

amenorrhea is common

Bulimia

DISEASE CATEGORY: MALNUTRITION

binge-eating followed by self-induced vomitting

more common than anorexia nervosa

amenorrhea is less comon

Cachexia

DISEASE CATEGORY: MALNUTRITION

secondary protein-energy malnutrition caused by illness (i.e. cancer, sepsis, uncontrolled diabetes, hiv, burns)

marked by tissue and muscle wasting

Huntington's Disease

DISEASE CATEGORY: AUTOSOMAL DOMINANT, TRIPLE REPEAT MUTATIONS

affects the coding region of the HTT gene, causing tandem CAG triplet repeats (polyglutamine disorder)

symptoms: chorea, dystonia, incoordination, cognitive decline, behavior difficulties

Fragile X Syndrome

DISEASE CATEGORY: X-LINKED RECESSIVE (OR DOMINANT), TRIPLE REPEAT MUTATIONS

affects noncoding region of FMR1 and FMR2 genes, causing tandem CGG triplet repeats

symptoms: long face with large ears, large jaw, bilateral enlargement of testes

Friedreich Ataxia

DISEASE CATEGORY: AUTOSOMAL RECESSIVE, TRIPLE REPEAT MUTATIONS

characterized by GAA triplet repeats

Myotonic Dystrophy

DISEASE CATEGORY: AUTOSOMAL DOMINANT, TRIPLE REPEAT MUTATIONS

characterized by CTG triplet repeats

Prader-Willi Syndrome

DISEASE CATEGORY: DELETIONS, GENETIC IMPRINTING

caused by either the microdeletion of paternal 15q12 or maternal uniparternal disomy (2 maternal chromosomes)

imprinted maternal 15q12 gene

symptoms: intellectual disability, short stature, hypotonia, obesity, hypogonadism

Angelman Syndrome

DISEASE CATEGORY: DELETIONS, GENETIC IMPRINTING

caused by microdeletion of maternal 15q12 or paternal uniparental disomy (2 paternal chromosomes)

imprinted paternal 15q12 gene

symptoms: mental retardation, intellectual disability, ataxia, seizures, happy puppet syndrome (inappropriate laughter)

Mucopolysaccharidoses (MPS1)

DISEASE CATEGORY: AUTOSOMAL RECESSIVE, LYSOSOMAL STORAGE DISEASE

enzyme deficiency of alpha-L-iduronidase (GAG degrading enzyme)

causes accumulation of dermatan sulfate and heparan sulfate = increased GAGs in urine

symptoms: large head (macrocephalus, build up of fluid in brain (hydrocephalus), coarse face

Niemann-Pick Disease A & B

DISEASE CATEGORY: AUTOSOMAL RECESSIVE, LYSOSOMAL STORAGE DISEASE

enzyme deficiency in sphingomyelinase

causes accumulation of sphingomyelin in neurons and phagocytes, affecting the liver, spleen, bone marrow, and lymph

symptoms (BOTH): swelling in abdomen (hepatosplenomegaly), early childhood death

TYPE A: neural damage

TYPE B: no neural damage

Niemann-Pick Disease C

DISEASE CATEGORY: AUTOSOMAL RECESSIVE, LYSOSOMAL STORAGE DISEASE

enzyme defiency affecting cholesterol transport

accumulation of cholesterol and gangliosides in neurons

symptoms: severe liver disease, breathing difficulties, developmental delay, seizures, poor muscle tone (dystonia), lack of coordination, problems with feeding, inability to move eyes vertically

Tay-Sachs Disease

DISEASE CATEGORY: AUTOSOMAL RECESSIVE, LYSOSOMAL STORAGE DISEASE

enzyme deficiency in hexoaminidase A

accumulation of GM2 gangliosides in the CNS

symptoms: intellectual disability, blindness (cherry spot), motor weakness, death

Gaucher Disease

DISEASE CATEGORY: AUTOSOMAL RECESSIVE, LYSOSOMAL STORAGE DISEASE

enzyme deficiency in beta-glucosylceramidase

accumulation of glucosylceramide in mononuclear phagocytic cells

symptoms (I): enlarged phagocytes in liver, spleen and bone marrow

symptoms (II and III): affects neurons

GM1 Gangliosides

DISEASE CATEGORY: LYSOSOMAL STORAGE DISEASE

enzyme deficiency in beta-galactosidase

accumulation of GM1 gangliosides

Von Gierke Disease

DISEASE CATEGORY: AUTOSOMAL RECESSIVE, GLYCOGEN STORAGE DISEASE (GSD Type Ia)

enzyme deficiency in glucose-6-phosphatase, from the mutations in G5PC

predominantly affects the liver = pleiotropic glucogenesis problems

symptoms: hypoglycemia, accumulation of GNS components, overwhelming TCA cycle and lipid biosynthesis (fatty liver and hyperlipidemia)

GSD Type Ib

DISEASE CATEGORY: GLYCOGEN STORAGE DISEASE

enzyme deficiency of glucose-6-phosphate translocase, from mutations in SLC37A4

predominantly affects the liver = impaired gluconeogenesis

symptoms: hypoglycemia, excess pyruvate leading to lactic acidosis, hyperalaninemia, hyperlipidemia, gout

Pompe Disease

DISEASE CATEGORY: AUTOSOMAL RECESSIVE, GLYCOGEN STORAGE DISEASE (GSD Type II)

enzyme deficiency of lysosomal acid maltase, from mutations in GAA causing glycogen buildup in the lysosome

affects all organs, the heart predominantly

infantile-onset symptoms: myopathy, hypotonia, enlarged liver (heptamegaly), heart defects

Cori Disease

DISEASE CATEGORY: AUTOSOMAL RECESSIVE, GLYCOGEN STORAGE DISEASE (GSD Type III)

enzyme deficiency in 1,6-alpha-glucosidase, leading to accumulation of shorter than normal branching of glycogen

symptoms: (infancy) hypoglycemia, hyperlipidemia, and elevated blood levels of liver enzymes

(childhood) hepatomegaly

McArdle Syndrome

DISEASE CATEGORY: AUTOSOMAL RECESSIVE, GLYCOGEN STORAGE DISEASE (GSD Type V)

enzyme deficiency in myophosphorylase (glycogen phosphorylase), mutations in PYGM

cannot break down muscle glycagon for energy

symptoms: fatigue, muscle cramps within first few minnutes of exercise, myoglobinuria

DiGeorge Syndrome

DISEASE CATEGORY: (MICRO)DELETIONS

22q11.2 microdeletion

symptoms: spasms, thymic hypoplasia with diminished T-cell immunity (frequent infections) and parathyroid hypoplasia with hypocalcemia (low calcium levels)

Velocardiofacial Syndrome (VCFS)

DISEASE CATEGORY: (MICRO)DELETIONS

22q11.2 microdeletion

symptoms: congenital heart disease (CHD) affecting outflow tracts, facial dysmorphism, developmental delay

Williams Syndrome

DISEASE CATEGORY: (MICRO)DELETIONS

ch 7 microdeletion

elevated calcium levels

symptoms: puffiness around eyes, short nose with broad nasal tip, wide mouth, full cheeks, full lips, small chin, long neck, sloping shoulders, short stature, limited mobility in joints and curvature of spine

Cri-du-chat syndrome

DISEASE CATEGORY: (MICRO)DELETIONS

5p deletion on chromsome 5

symptom: "cry of the cat" - unqiue high-pitched cry of infant due to abnormal larynx development

Philadelphia (ph) chromosome

DISEASE CATEGORY: TRANSLOCATIONS, AUTOSOME DISEASES

reciprocal and balanced translocation

cytogenetic nomenclature: t(9,22)(q34,q11)

- causes CML (chronic myleogenous leukemia)

Down Syndrome

DISEASE CATEGORY: AUTOSOME DISEASES, AUTOSOMAL TRISOMY

three types

MAJOR: trisomy 21 (47,XX,+21)

MINOR: robertsonian (46,XX,rob(14,21)(q10;q10)+2)

RARE: mosaic (46XX/47,XX,+21)

symptoms: large tongue, flat face, slanted eyes, thick neck skin, single crease across palms, intellectual disability (for some)

Edwards Syndrome

DISEASE CATEGORY: AUTOSOME DISEASES, AUTOSOMAL TRISOMY

two types

trisomy 18 (47, XX,+18)

mosaic (46,XX, 47,XX,+18)

symptoms: mental retardation, short neck, overlapping fingers, congenital heart defects, renal deformations, rocker-bottom feet

Patau Syndrome

DISEASE CATEGORY: AUTOSOME DISEASES, AUTOSOMAL TRISOMY

three types

trisomy 13 (47,XX,+13)

translocation (46,XX,+13,der(13,14)(q10;10)

mosaic (46,XX/47,XX,+13)

symptoms: microcephaly, mental retardation, polydactyly (< 5 fingers), renal defects, cardiac defects, cleft lip and palette

Klinefelter Syndrome

DISEASE CATEGORY: SEX CHROMOSOME ANEUPLOIDY

two types:

main: 47,XXY or 48,XXXY (at least two X and one or more Y)

mosaic due to x-inactivation, creating Barr Bodies in males: 46,XY/47,XXY

Barr Bodies: 1

symptoms: male hypogonadism - physical and cognitive development, testosterone shortage, breast development, small testes, delayed or incomplete puberty, reduced facial/body hair, infertility

Turner Syndrome

DISEASE CATEGORY: SEX CHROMOSOME ANEUPLOIDY

three types:

main: 45,X

isochromosome: 46,Xi(Xq)

deletion in arms: 46,XXq- or 46,XXp-

No Barr Bodies

affects females - primary hypogonadism

symptoms: short stature, ovarian function loss (i.e. sterile or no estrogen), extra skin on neck, absence of menstrual period

XYY Syndrome

DISEASE CATEGORY: SEX CHROMOSOME ANEUPLOIDY

karyotype: 47,XYY

Trisomy X

DISEASE CATEGORY: SEX CHROMOSOME ANEUPLOIDY

karyotype: 47,XXX

Familial hypercholesterolemia

Autosomal Dominant

Phenylketonuria (PKU)

Autosomal Recessive

Galactosemia

Autosomal Recessive

Cystic Fibrosis

Autosomal Recessive

- CTFR gene impaired, CFTR = Cl- transport channel

symptoms: thickened mucosal secretions, saltier sweat

implicated in: pancreatic insufficiency

Neurofibromatosis

Autosomal Dominant

Hemochromatosis

Autosomal Recessive

Achlorhydria

DISEASE CATEGORY: MALABSORPTION

HCl deficiency causes decreased protein digestion and absorption

Steatorrhea

DISEASE CATEGORY: MALABSORPTION

Lipid malabsorption - excess lipid in feces

May result from pancreatic insuffiency

Peptic Ulcer

DISEASE CATEGORY: MALABSORPTION

Bicarbonate deficiency - acid from stomach is not neutralized = mucosal erosions

Lesch-Nyhan Syndrome

DISEASE CATEGORY: X-LINKED RECESSIVE, METABOLIC DISORDER

enzyme deficiency of the HPRT (hypoxanthine phosphorybosyl transferase) enzyme

causes uric acid overproduction

symptoms: neurological and behavioral problems (involuntary uncoordinated movements, uncontrollable self-injury [i.e. lip biting until injury]), orange crystals in diapers

Maple Syrup Urine Disease (MSUD)

DISEASE CATEGORY: AUTOSOMAL RECESSIVE, METABOLIC DISORDER

caused by mutations in the BCKDHA, BCKDHB, and DBT genes - normal functionality allows to break down leucine, isoleucine, and valine

mutations causes enzyme deficiency of branched-chain alpha-keto acid dehydrogenase

symptoms: sweet-smelling urine, feeding difficulties, lethargy, seizures, vomitting, coma

McCune-Albright Syndrome

Mosacism