Biochemistry Diseases 1

7/23/2019 Biochemistry Diseases 1

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Carla Tamayo Cintrn MS1

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%

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Biochemistry Diseases 1

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