Final Review Sheet

From Iusmgenetics

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Contents

Molecular and Biochemical Genetics

Disease Profiles

Disease Clinical Presentation Mode of Inheritance Relevant Gene / Defect Pathogenesis Treatment
Achondroplasia Short limbs, frontal bossing, midface hypoplasia, normal intelligence, normal fertility, delayed motor dev, hydrocephalus AD, Incomplete Dominance, advanced paternal age, 80% de novo FGFR3 Constitutive activation decreases bone dev (stat / mapk, SOC) Screen for hydroceph (shunt), spinal stenosis (fuse), kyphosis (fuse), bowed legs (osteotomy), ear infections (rx). Increase height by GH or sx.
Thanatophoric dysplasia Perinatal death, severe bone deformation, excess skin folds. (Similar to homozygous achondroplasia.) ? FGFR3 Excess production of FGFR3. Did not address
Osteogenesis imperfecta Types 1-4; Severity: 2 > 3 = 1 < 4; Type 2: perinatal death, dark sclerae; Type 1: brittle bones, tendency for fractures, fractures heal without deformity, deafness, blue sclerae; Type 4: tendency for fractures, normal sclerae. Autosomal dominant Pro-alpha1, Pro-alpha2 Normal collagen has 2 alpha1 and 1 alpha 2 chains and trimmed terminals. OI demonstrates dominant negative effect and haploinsufficiency when alpha1 or alpha2 make bad product or no product, respectively. Did not address
Ehlers Danlos Syndrome Hyper extensibility, increased skin fragility / thinness, joint laxity, fragility of major arteries, type 4: arteries and colon especially affected AD, AR, XR; dominant negative col5a (Type 1), col3a1 (Type 4), plod (Type 6), mnk (Type 9) type 1 & 4: dominant negative to abnormal collagen (glycine mutations); type 6 & 9: decreased cross-linking (lysyl hydroxylase deficiency, copper binding / lysyl oxidase deficiency) Did not address
Marfan Syndrome AD; dominant negative effect; 75/25% inherited / de novo Pleotropic (ocular, cardiovascular, skeletal): lens subluxation, myopia, detachment, catracts; mitral valve prolapse, aortic dilation; dolichostenomelia, pectus / spinal curvature deformations, narrow palate, joint laxity, arachnodactyly, Walker-Murdoch wrists, Steinberg thumbs fbn1 (fibrillin-1); EGF-like molecule Ca++ binding fails in EGF-like domain mutations; TGF-beta binding protein mutations fail to sequester TGF-beta; Up-regulation of TGF-beta causes malformed matrix. Multidisciplinary management; Ocular: lens correction, screening, sc (cataracts, ectopic lens); CV: echochardiography to monitor valves / aorta, beta-blockers; Counseling: isometric exercise, impact sports, pregnancy.
Familial Hypercholesterolemia Early-onset atherosclerosis, elevated serum cholesterol, elevated LDL, Xanthomas (tendons, skin, eyelids), childhood MIs in homozygotes AD, AR; semi-dominant LDL receptor (binds APOB100 on LDL for metabolism), APOB100 (surrounds LDL, binds receptor), ARH adapter protein (binds LDL receptos with APOB100 / LDL into clathrin pits), PCSK9 protease (degrades LDL receptor); locus heterogeneity; LDLR mutations are classified I-V from failure to synthesize to failure to remove from surface Loss of function: LDL receptor, APOB100, ARH adapter protein; Gain of function: PCSK9 protease. Deplete bile: bile acid binding resins allow bile (with cholesterol in it) to be passed; Inhibit HMG-CoA reductase: statins inhibit HMG-CoA reductase so it doesn't make cholesterol out of acetyl CoA (hepatocytes).
Homocysteinuria Pleiomorphic (skeletal, ocular, vascular; like Marfan): long / thing bones, lens dislocation (downward), thromboembolism AR Cystathionine beta synthase (CBS), with much locus heterogeneity Homocysteine is the toxic substance that causes disease; homocysteine may impair disulfide bridges in FBN1 and thus cause Marfan like S&S. B6 (pyridoxine) supplemenatation (a cofactor for CBS); low methionine diet (meth is the aa most often converted to homocysteine); betaine / folate / b12 supplements to augment the homocysteine -> methionine converstion (to reduce homocysteine levels)
Cystic Fibrosis Pleiomorphic: respiratory (cough, infection, bronchiectasis), pancreas (deficient enzyme secretion, fibrosis), endocrine (diabetes mellitus), GI (meconium ileum, failure to thrive, jaundice, cirrhosis, steatorrhea), reproductive (males lack vas deferens (congenital bilateral absence of vas deferens), females can be infertile, too), etc (clubbing, sweat chloride elevated) AR CFTR, deltaF508; also ORCC and ENaC; genotype strongly predicts pancreatic phenotype but poorly predicts pulmonary phenotype (and all other phenotypes); loss of exon 9 occurs when only 5 thiamines are found in intron 8; R117H is a mild form Mutants fail to move chloride and thus to move water; mutants are classified 1-4 based on type of CFTR failure (synthesis, processing, regulation, function) Aminoglycosides (inhibit p. aeruginosa, allow read through; gentamicin, ataluren, ptc124); antimicrobials; anti-inflammatory tx; mechanical clearing of airway; CFTR modulators: chaperones / correctors / PBA to increase CFTR fxn
Hemochromatosis Vague vignette: lethargy, abd pain, hepatosplenomegaly, bronzing, diabetes, hypogonadism, loss of libido, amenorrhea, loss of body hair Obfuscated: AR?, variable expressivity, incomplete penetrance; yet even homozygotes may have no phenotype HFE, C282Y (especially common in caucasians, founder effect?); also TFR2, HAMP, and HJV HFE mutants inhibit hepcidin which is supposed to inhibit Fe release from enterocytes; hence excessive absorption of Fe Phlebotomy
Alpha-1-anti-trypsin Deficiency ZZ: full disease state (early emphysema, pulmonary fibrosis, liver cirrhosis); MM, MS, and SS: no disease AR AAT; M: wild-type, S:50-60% activity, Z:10-15% activity; Null: 0% activity Defective AAT (a serine protease inhibitor) doesn't inhibit elastase (from neutrophils); chronic destruction of ECM in lungs and liver Enzyme inhibitor injections (like AAT); liver transplant (ZZ / nulls)
Phenylketonuria (PKU) Pleomorphic: Neuro (dev delay, microcephaly, "severe" mental retardation, seizures, autistic-like behavior), Integumentary (pale skin, eczema, mousy odor (phenylacetate), maternity issues (mid-facial hypoplasia, growth deficiency, heart defects; affects the fetus regardless of its genotype) AR, allelic heterogeneity (pts usually compound heterozygotes) pah (phenylalanine hydroxylase, converts phenylalanine to tyrosine); dihydropteridine Phe not converted to Tyr (<5% activity), toxicity of Phe; malignant PKU results from deficiency of biopterin recycling (mutant dihydropteridine) Low Phe diet (250-500 mg); malignant PKU will still develop neuro issues (because biopterine / BH4 is cofactor for making dopamine / cats / serotonini); Sapropterine (kuvan) as BH4 supplementation
Tay-Sachs Disease Ocular (cherry red macula), Neuro (hyperacusis, lose CNS function after 18 months, spaciticy, swallowing, seizures, hypotonia, demntia, paraylsis, vegetative and dead by age 5) AR, allelic heterogeneity, homozygotes don't live to reproduction hexa / hexb (hexB = Sandhoff disease), hexosaminidase A / B degrades GM2 sphingolipid in neurons GM2 gangliosides (cell signaling glycosphingolipids) not broken down in lysosome, GM2 accumulation -> Neuron Cell body distension -> Neuronal cell death -> Eventual brain atrophy Anti-seizure drugs, gene therapy?, stem cell transplant?, enzyme replacement therapy doesn't work b/c of BBB; test high school Ashkenazis for carrier status; screen in vitro embryos
Galactosemia GALT deficiency (vomiting, f2t, liver disease--hepatomegally / jaundice, cataracts, edema, sepsis, encephalopathy, seizures, brain damage), Epimerase deficiency (similar to GALT deficiency), Galactokinase deficiency (cataracts, no liver / neuro involvement); IQ decreases with age; female gonadal dysfunction AR, locus heterogeneity (GALT, GALK, GALE) GALT (galactose 1-p uridyltransferase), galactokinase, epimerase; each required for galactose metabolism to glucose (UDP-glucose) Accumulation of Gal-1-P and Galactitol and depletion of UDP lead to liver toxicity and cataracts, respectively. Galactose-free diet (very challenging)
Maple Syrup Urine Disease Classic (lethargy, weight loss, encephalopathy, acidosis, hyper-ammoniemia, sweet smelling urine; <2% BCKD activity), Intermediate (similar to classic; 2-30% BCKD activity), Intermittent (symptoms only upon comorbidity) AR BCKD (branched chain ketoacid dehydrogenase) Branched chain amino acids and alpha keto acids accumulate leading to neurologic disorders and development disruption. Low-leucine diet (isoleucine and valine, too; requires special medical food and measured amounts of natrual foods), liver transplant, thiamine (in E2 protein mutation pts)
Biotinidase Deficiency Pleiomorphic: Derm (alopecia, perioral rash, conjuctivitis), Neuro (psychomotor retardation, ataxia, seizures, deafness, blindness), Metabolic (hypoglycemia, hyperammonemia, acidosis) AR Biotin (a cofactor, not a gene Inability to release biotin for recycling Biotin supplementation (cannot reverse hearing loss, visual abnormalities, dev delay)
Rett Syndrome Progressive disease with 4 stages; disability in mobility, speech, repetitive movements, breathing difficulties, "severe" cognitive impairment; first signs (6-18 months): head growth deceleration, loss of words / hand skills XD; sex dependent phenotype (affects mainly girls: some in utero lethality in males, fathers more likely to pass mutant); heterogenity and variable expressivity MeCP2 (methyl CpG binding protein 2), binds / methylates dinucleotides, recruits factors, prevents HDAC, prevents transcription MeCP2 fails to bind / inhibit gene expression, allows dedifferentiation, dysregulates brain dev Symptomatic only; naticonvulsants, occupational therapy, hydrotherapy (scoliosis), IGF-1
Lesch-Nyhan Syndrome Irritable, poor head support, impaired motor dev (spacticity, dystonia, hypotonia), uric acid overproduction (gout, gritty / orange urine, soft tissue sweeling in the olecranon bursa), self-mutilation XR HPRT (hypoxanthine-guanine phophoribosyltransferase) salvages purines (from hypoxanthine / guanine) HPRT defect results in uric acid overproduction and in striatum deficiency (60-80% loss of dopamine) Decrease uric acid (hydration; allopurinol inhibits xanthine oxidase from converting hypoxanthine and guanine to uric acid), motor impairment (assistive devices, benzodiazepines, baclofen), behavior modifying drugs
Duchenne Muscular Dystrophy Gower sign, muscle wasting, hypertrophic gastrocs, walks on toes, inability to run, progressive muscle weakness, elevated serum creatine kinase (can ID female carriers), early death (14-20 yo) via respiratory failure / cardiomyopathy XR Dystrophin, binds actin to the sarcolemma membrane Deletion (usually) of dystrophin means sarco-cytoskeleton is not connected to the membrane; contraction is futile Did not address
Becker Muscular Dystrophy Less severe than DMD, later onset (16yo); carriers may have skeletal / cardiac abnormalities XR Dystrophin, connects sarco-cytoskeleton to sarcolemma Frameshifts or small deletions result in "reduced function" Did not address
X-linked Dilated Cardiomyopathy No dystrophin expression in cardiac muscle XR Dystrophin, ... 5' promotor mutations
Congenital Muscular Dystrophy CNS involvement AR Merosin / Laminin, parts of the complex that connects the sarcolemma to ECM Did not address Did not address
Oculopharyngeal Muscular Dystrophy Ptosis, Dysphagia, onset over 50 AD or AR Polyadenylation binding protein 2 Did not address Did not address

Objectives

  • Important terms:
    • "Incomplete" dominance or "semi-dominant": homozygous individuals have a worse manifestation than heterozygous individuals (achondroplasia).
    • "Distinct disorder": consistent clinical and radiological findings.


  • For individual diseases, know: clinical features, mode of inheritance, genes involved / gene defect, pathogenesis, treatment (sometimes)

Dominant Diseases

  • Dominant disease are defined as those manifested when only one allele is mutated.
    • Recall that some diseases can be both dominant and negative because of allelic heterogeneity and locus heterogeneity.

Recessive Diseases

  • Requires two mutant alleles to show the phenotype or disease state.


Newborn Screening

  • The following criteria for newborn screening assure that our screening has analytic validity, clinical validity, and clinical utility:
    • The disorder must be well defined.
    • The disorder must be fairly high in population frequency (to justify the cost of newborn screening by the cost saved in care for the true-positives).
    • The disorder must be poorly clinically detected early in life (assymptomatic) (otherwise it is more cost effective to let physicians identify the disease at newborn checkups).
    • The disorder must be significant in morbidity / mortality if left untreated (otherwise we might start treating things that have little consequence).
    • The disorder must be treatable such that there is an improved condition (lest we start adding anxiety to insult).
    • The test must be rapid, inexpensive, specific AND sensitive over an entire population.
    • The test must be acceptable and cost-effective.
    • The test must be appropriately administered.


General Molecular / Biochemical Pathogenesis Principles

  • Dominant diseases usually result from:
    • Gain of abnormal function
    • Haploinsufficiency
    • Dominant-negative effects (think multi-subunit proteins)
  • Recall that dominant disease can be "incomplete" and thus have more severe phenotypes when presented as homozygous conditions.
  • Recessive diseases usually result from:
    • Loss of normal function
  • Heterozygotes of recessive diseases (carriers) usually have enough wild-type gene product to function properly.
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