Biochem 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 = scurvy

• 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 (Nontropical Sprue)

DISEASE CATEGORY: MALABSORPTION

• 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 I-III

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 (GSD Type Ia)

DISEASE CATEGORY: AUTOSOMAL RECESSIVE, GLYCOGEN STORAGE DISEASE

• 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 (GSD Type II)

DISEASE CATEGORY: AUTOSOMAL RECESSIVE, GLYCOGEN STORAGE DISEASE

• 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 (GSD Type III)

DISEASE CATEGORY: AUTOSOMAL RECESSIVE, GLYCOGEN STORAGE DISEASE

• 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 (GSD Type V)

DISEASE CATEGORY: AUTOSOMAL RECESSIVE, GLYCOGEN STORAGE DISEASE

• 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 causes CML (chronic myleogenous leukemia)

DISEASE CATEGORY: TRANSLOCATIONS, AUTOSOME DISEASES

• reciprocal and balanced translocation

• cytogenetic nomenclature: t(9;22)(q34;q11)

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 (46,XX/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,XXY

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

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