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BiochemistryDiseases Exam 1
PROTEIN STRUCTURE
TSE- Transmissib le Spongi form
Prion Disease
Creutzfe ldt- Jacob Disease
Bovine Spongi form Encephalopathy
Kuru
Fatal fami l ia l insomnia
Spongiform changes in the brainDegeneration of neurons astrocytesResistant to proteases
Cyst inur ia Inher i ted autosomal recessive
Mutat ions is SLC3A1 and SLC7A9
Incomplete reabsorption of cysteine during filtration in thekidney results in high cysteine in urineExcess cystine forms stones
Amyloid D isease
Alzheimers
!-amylo id structural defect
Protein oligomers from the plaque normally associatedwith this disease!-amyloid (transmembrane protein) is a peptide of 39-43
amino acids, main constituents of amyloid plaques in thebrain of Alzheimers patients
!-amyloid is formed by proteolysis of APP
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Taupathies Tau aggregates and tangles
Tau is a protein only present in neurons that stabilizes themicrotubules.Hyperphosphorylation results in aggregation
Associated with Alzheimers and Parkinsons
HEMOGLOBINOP THIES
Sickle Cel l Anemia S ingle-nucleot ide polymorphism (A-T)
!-globin gene
Glutamic acid subst i tuted by Val ine in posi t ion
6
Red blood cells that assume abnormal, rigid, sickle shape.(20 day lifespan)Vaso-occlusive crisisSpleen damageRenal problems
PriapismTreatment Hydroxyurea which stimulates production offetal hemoglobin; Bone marrow transplant
Hemogobin C Subst i tu ion of G lutamic acid residue wi th a
Lysine residue at the 6
th
posi t ion of the
!-
globin
Forms Hb crystals and causes hemolytic anemia
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! thalassemias Autosomal recessive HBA1 and HBA2
Decreased alpha-globin production- One allele missing: silent carriers- Two affected: mild symptoms sometimes
confused with iron deficiency
-
3 Affected: Hemoglobin H Disease HbH whereBeta tetramers present very high affinity to O2
- 4 Affected: Hydrops fetalis. Dominance ofHbBarts so no O2 delivery
Iron overload, cardiovascular illness, bone deformetiesMild to severe anemia
Beta - Thalassemias Mutat ions in the HBB gene on chromosome 11
-
Minor:1 copy missing, mostly undetected.Presence of HA2 (2alpha + 2delta)
- Major: alfa tetramers precipitate
Bone deformities, Slenomegaly, Mycrocytic anemia,Reticuocytes and nucleated RBC appearsID by elevated levels of Hb2ATreatment: Transfusions, Iron Chelation
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PROTEIN N LYSIS
Alpha 1-ant i trypsin def ic iency Missense mutat ion (single base pair
subst i tut ion)
Causes emphysema and various liver diseasesIsoelectric focusing (IEF) 4.5-5.5
Link to enzymes: alpha 1-antitrypsin is a proteaseinhibitor which regulates the elasticity in lung tissue
COLL GEN
Osteogenesis Imperfecta (OI) COL1A1 and COL1A2
-Type1: (mild)| premature stop codon decreases stability
of pro alfa1 mRNA. Collagen is made but amountdiminished-Type2,3,4: mutation of pro alfa 1 or 2. Most common isGly substitution. Lethal in carboxyl terminal of triple helix
Non traumatic fractures, dentinogenesis imperfecta,hearing loss, skeletal deformities, short stature, skinbruising, arterial dilation and valve prolapseTreatment: Biphosphonates (prevent osteoclast oneresorption)
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Ehler-Danlos Syndrome (EDS) Nonsense mutat ion COL5A1 and COL5A2
Vascular type COL3A1
Heterogenous
Diminished amounts of normal collagen VMutation prevents proper chain associations
Skin hyperextensibility, abnormal wound healing, jointsdislocate easily, fragile blood vessels
Alport Syndrome X- l inked
Mutat ions in col lagen type IV COL4A5
Characterized by glomerulonephritis (hematuria,
proteinuria), endstage kidney disease, and hearing loss
Atopic Dermat i t is Mul t i factor ia l Col lagen 29
Chronic skin inflammation disorderMajor allergic disease
Scurvy
Dietary Vitamin C Deficiency which is needed for thehydroxylation of Proline to Hydroxyproline
Weak collagen: too few H bondsSkin, bone and teeth malformations and weaknessWeakened blood vessels - bleeding
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EL STIN
Wi l l iams Syndrome Gene delet ion of the Wi l l iams-Beuren
syndrome cr i t ica l region that encompasses
elast in ELN gene at 7q11.23
Cardiovascular disease (SVAS supravalvular aorticstenosis), distinctive faces, connective tissueabnormalities, mental retardation, growth abnormalities,endocrine abnormalities, unique personality (happy)
Marfan Syndrome Mutat ions in f ibr i l l in 1 (FBN1)| gene
Autosomal Dominant Inher i tance
Ectopia lentis, Disproportional bone growth, Scoliosis,Valve prolapse, Risk of aneurysms due to dilation of aorta
MARFAN DIFFERENTIALMASS Phenotype Fibr i l l in-1
Mitral valve prolapse, aortic enlargement, skin/skeletaldeformities
Mitra l va lve prolapse syndrome Fibr i l l in-1
Mitral valve prolapse, skeletal deformities, no aorticenlargement
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Congeni ta l -contractural
arachchnodactyly (CCA)
Fibr i l l in-2 Heterozygous mutat ion
Long slender fingers and toesMuscular hypoplasiaCamptodactyly
Homocyst inur ia Autosomal recessive
Cystat ione-beta-synthasase def ic iency
Variable intellectual disabilityMarfan similar cardiovascular problems
Str ick ler Syndrome COL3 genes
Ocular findings, hearing loss, cleft palate
L MININ
Junct ional Epydermolysis Bul losa Laminin 5 or 6
Cohesion of dermis and epidermisBlistering of the skin and mucous membrances
Congeni ta l Muscular Dystrophy Lack of Laminin 2 tr iggers apoptosis
Muscle dystrophyWobbly babyMotor delay
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PROTEOGLYC NS
Mucopol isacchar idoses Hunter
Syndrome
X- l inked recessive IDS gene
Deficiencies in lysosomal glycosidases causesaccumulation of carbohydrates in lysosomes
Abnormal hernias and distinct facial features and mentalretardationImpairment of liver and spleen function (among others)
INTEGRINS
Leukocyte Adhesion Def ic iency LAD Mutat ions in beta- integr ins
Autosomal recessive
Unable to activate integrins to localize WBC to sites ofinfectionDelayed Umbilical chord separation, gingivitis
IMMUNODEFICIENCIES
THI Transient Hypogammaglobul imia
Extension of Normal Nadir of IgG at 3-4 months of ageHypogammaglobulenimia beyond 6 monthsSpontaneous Recovery of IgG Synthesis between 18-36monthsMay need antibiotics
IgA Def ic iency
Diagnosed at 4+IgA is decreased. Recurrent sinopulmonary infections
mostly asymptomatic.Patients with severe infections likely have IgG Sub Classdeficiency
B-cell
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X-Linked Agammaglobul imia (XLA) Loss of Tyrosine K inase gene (BTK)
Most severe B cell disorderRecurrent sinopulmonary infections in first year of life;absent lymphoid tissue
No IgG in serumVery low peripheral B cells
Monthly IVIG
Common Var iable Immunodef ic iency
(CVID)
Mult ip le B cel l defects, most ly occur at stage
pr ior to p lasma cel ls or memory cel ls
No memory B cells, secondary response is lost, therefore
no vaccination effects are observedImmunoglobin replacements needed
Di Georges Syndrome Microdelet ion of Chromosome 22
(spontaneous mutat ion)
Triad thymic aplasia, cardiac defects andhypoparathyroidismLearning disabilitiesDistinctive face (ear position, cleft lip, fallen eyelids)
T-cell
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Severe Combined Immunodef ic iency
(SCID)
Commonly X- l inked; 16 Adenosine
Deaminase def ic iency
Absent lymph nodes and tonsilsSmall ThymusSepsis, pneumonia, skin infections (first months)
Chronic Granulomatous Disease (CGD) X- l inked (70 ) Autosomal Recessive (22 )
Results from mutations of NADPH Oxidase Gene
ENZYMES
Fructosur ia
Transferase (fructose fructose 1-phosphate)In liverFruktokinase deficiency, rare but benign inheriteddisorderDiagnosed though detection of abnormal excretion offructose in urine
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C NCER
Oncogenes
D1 (cycl in D) B-cell lymphoma, bladder, breast, liver, lung and esophageal cancer
erb-B2/her-2/neu Breast and ovarian cancerras Thyroid, colon, lung, pancreatic, and acute myeloid and lymphocytic
leukemia
src colon and breast carcinomas
abl Chronic myeloid leukemia, acutelymphocytic leukemia
CML clonal hematopoetic stem celldisorder due to chromosomaltranslocation. Philadelphiachromosome is a shortenedchromosome 22 from a reciprocaltranslocation between 9 and 22.Forms bcr-abl fusion protein
raf Melanoma, colon carcinoma
c-myc Burkitts lymphoma c-myc is translocated fromchromosome 8 to a locationcloser to the enhancers of theantibody heavy chain genes onchromosome 14
bcl-2 Follicular B-cell lymphoma
akt Breast, ovarian and pancreatic carnimas
Tumor Suppressors
Rb Retinoblastoma; sarcomas, bladder, breast and lung cancer
P53 Li-Fraumeni syndrome: brain tumors, breast, colon/rectum, esophageal,liver, and lung carcinomas, sarcomas, leukemias and lymphomas
Smads Colon/rectum and pancreatic carcinoma
APC Colon/rectum carcinoma
BRCA 1,2 Breast and ovarian cancer
PTEN Brain tumors, melanoma, prostate, endometrial, kidney and lung cancer
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DNA Alterations
Xenoderma pigmentosum Any of the Nucleot ide Excis ion Repain
mutat ion
Patients cannot protect themselves against thyminedimers therefore continuous cancer develops on skinMust be in darkChildren of the Night
NON-MENDELIAN TRAITS
Neurofr ibromatosis Type 1 NF1 gene AAutosomal Dominant with complete penetrance andvariable expressivity
Caf-au-lait spots, neurofibromas, freckling in axillary oringuinal regions
Myotonic Dystrophy DMPK gene trinucleotide repeat of CTG (anticipation)
Wasting of muscles (flobby baby)
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Hunt ingtons D isease Hungtinton gene 4p16, CAG (codes for glutamine)trinucleotide repeat
Polyglutamine disorderProgressive neurodegenerative disorder, which affectsmuscle coordination and leads to cognitive decline and
dementia
Fragi le X Syndrome Trinucleotide repeat expansion (CGG) on the XChromosome (Xq27)
Results in a failure to express the protein coded FMR1gene (DNA Methylation which causes silencing thatsrequired for normal neural development)Most common form of inherited mental retardationPectus excavatum, hypotonia, mitral valve prolapse
Achodroplasia G380R missense mutation (de-novo)
Spontaneous G to A or C change in FGFR3 geneDisorder of bone growth that causes most types ofdwarfism
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Thanatophor ic Dysplasia FGFR3 gene mutation
Severe skeletal disorder characterized by adisproportionally small rib cage, extremely short limbsand folds of extra skin on the arms and legs
Beckwi th-Wiedemann Syndrome UPD of 11p15, maternal copy of this region is replacedwith an extra paternal copyIGF2 expression
Overgrowth disorder present at birth characterized by
and increased risk of childhood cancers
Angelman Syndrome Deletion or inactivation/imprinting of genes on thematernally inherited 15q11 (UBE3A) UPD
Neuregenetic disorder with developmental delay, sleepdisturbance, jerky movements, frequent laughter andhappy demeanor
Congeni ta l adrenal hyperplasia Autosomal recessive with variable gene expression
Excessive or deficient production of testosteroneAmbiguous genitalia
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Incont inent ia p igment i ( IP) X-linked dominant (male lethality)
Skin lesionsSwirling macular hyperpigmentation, linearhypopigmentation
Myopathy-encephalopathy- lact ic-
acidosis (MELAS)
Mitochondrial
Muscle weakness, headaches, seizures
Id iopathic Chronic Pancreat i t is CFTR geneSPINK geneModifier genes
Leading cause of non-alcoholic pancreatitis
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Melanoma (skin cancer) CDKN2A (cyclin dependent kinase inhibitor 2A) inducescell cycle arrest in G1MC1R (Melanocortin-1 receptor gene) melanine binds toreceptor and increases eumelanin synthesis to protectfrom UV radiaton
Changes in lumps, moles, lesions
Ret in i t is p igmentosa Peripherin, Rom1
Unlinked genes encoding photoreceptor proteins
COMPLEX DISORDERS
Hirschsprung Disease (HSCR) Multiple genes RET
Congenital intestinal aganglionosis
Defect of the neural crest migration to he intestinal tractInability to defecate causes abdominal distention
Neural tube defects (NTD) NTHFR gene association
Abnormal or incomplete closure of the neural tube atweeks 3-4 of gestation
Homocysteine metabolism/genes in the motherFolic acidSpina bifida
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Clef t L ip & C lef t Palate TBX1 and FGFR1 gene association
Problems breathing and swallowing, range of severity,chances increase with smoking during pregnancy
Cardiovascular D isease Multiple genes (MTHFR, LDL receptor)
Leading cause of death in USCompromises coronary artery disease, cardiomyopathy,hypertension, stroke, aneurysm
Environmental: diet, smoking, exercise
Hypercoagulabi l i ty D isorders Factor V Leiden clotting factor missense mutationProthrombin clotting factor: 3 UTR variantTetrahydrofolate reductase
Idiopathic cerebral vein thrombosis, placentary arterythrombosis, deep venous thrombosis
Environment: oral contraceptives, surgery, immobility,malignancy
Diabetes Mel l i tus: Type 1 MHC major histocompatibility complex gene
Autoimmune destruction of pancreatitic islet B-cellsleading to the lack of insulin productionEnteroviruses
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Diabetes Mel l i tus: Type 2 Glucokinase (GCK), HNF4
Insulin resistance at the target cellsWeight loss by 5-7% reduces risk by 60-70%