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89 Cards in this Set
- Front
- Back
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marfan syndrome inheritance?
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AD
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marfan syndrome genetic characteristics common to AD inheritance?
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pleiotropy
genetic heterogeneity variable expressivity incomplete penetrance |
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whats the gene defect in Marfan's?
what does this cause? |
mutation in fibrillin 1 gene on chromosome 15
loss of fibrillin and CT instability |
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what does fibrillin do?
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codes for a protein that stabilizes elastin filaments in CT
defective in Marfan's |
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Who gets Marfan's syndrome?
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1/5000 (M=F, all ethnicities)
75% have FH; 25% new mutations |
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what are the systemic effects of marfan's?
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since the syndrome is pleiotropic, it affects many systems:
skeleton--long teeth--maxillary overjet eyes--cataract/glaucoma CV--aortic dissection *but variable expressivity and incomplete penetrance |
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what are the skeletal effects of marfan's?
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1. arachnodactyly (spider fingers)
2. long head 3. risk of scoliosis 4. long arms/ft 5. flat feet 6. joint instability 7. hollow/ "pigeon" chest |
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what are the teeth defects of marfan's?
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1.high, narrow palatal vault
2. maxillary and mandibular retrognathy (receding jaw) 3. crowded teeth 4.extreme maxillary overjet |
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dislocation of the lens, cataracts, glaucoma
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eye defects seen in Marfan's syndrome
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what are the cardiovascular effects of marfan's?
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1. aortic dissection resulting in sudden cardiac death
2. dilation of the aortic root 3.mitral valve prolapse |
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what's the differential diagnosis for Marfan's?
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congenital contractural arachnodactyly
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what's congenital contractural arachnodactyly
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DDX for Marfan's:
mut in fibrillin 2 (FBN2) gene not fully pleiotropic: skel, dental changes similar to marfans hip contractures bigger problem no cardiac problems |
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are pts w/ congenital contractural arachnodactyly at risk for aortic aneurysm?
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NO, they have skeletal, dental problems but no CV problems
they have more problems w/ hip contractures |
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where are the fibrillin genes located?
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FBN1: chrom 15
FBN2: chrom 5 |
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what's the inheritance pattern of sickle cell?
who gets it most commonly? |
AR
african ameriacans=1:500 |
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Sickle cell anemia
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AR globin protein disorder
common in Af Am (1:500) causes chronic hemolytic anemia and occlusion of small bld vsl w/ subsequent ischemic tissue damage |
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cause of Sickle cell?
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single pt mut in beta globin gene (chrom 11)
(glu-->val) |
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what does sickle cell disease cause (homozygotes)?
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red cell lysis, anemia
blockage of small vessels and sequelae severe infections |
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what are some common results of blocking small vessels in sickle cell?
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splenic fibrosis
organ infarcts (pain in sleen/lungs) bone changes: painful swelling of hands/ft |
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α- and β-Thalessemias
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Autosomal recessive globin protein disorders
common in parts of Africa, SE Asia, Mediterranean countries Different genotypes reflect dif muts common to particular regions Type of defect and/or gene dosage defines phenotype severity |
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what defines the severity of thalassemia phenotype?
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type of defect and/or gene dosage
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what are some blood findings in thalassemia pts?
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mutant globin genes mean decreased synth of α or β chain of HbA (α2β2)
hypochromia (due to low intracell Hb) microcytic RBCs w/ subnl O2 carrying capacity insoluble inclusions (aggregates of xs nl globin) causes RBC membrane damage |
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what happens to the nl chains synthesized along with the defective chains of thalassemia?
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they aggregate and form insoluble inclusions
cause destruction of maturing RBCs (membrane damage) |
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β-Thalessemia: caused by deficient synthesis of the β chain of HbA (α2 β2∗)
general features of beta? |
1. >100 dif causative mutations (mostly pt)
2. βο-Thal: no β-globin produced by homozygous 3. β+-Thal: reduced (but detectable) synth of β-globin in homozygous 3. 3 clinical categories based on severity of anemia: due to defect (βο or β+) and gene dosage (homo or heterozyg) |
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3 clinical categories of β-Thalessemia based on defect (βο or β+) and gene dosage (homozygous or heterozygous)?
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1. β-Thal major (βο/βο or β+/β+ homoz): severe transfusion-dependent anemia
2. β-Thal minor: (βο/β or β+/β heterozyg): mild microcytic anemia; asymptomatic 3. β-Thal intermedia: intermediate in severity (no regular transfusions) and genetically heterogeneous (e.g. milder β+/β+ or β+/βο homozygous variants or unusually severe heterozygous variants of β-Thalessemia) |
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α-Thalessemia
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1. deficient synth of α chain
2. usually caused by 1-4 deletions of nl α-globin genes 3. 4 clinical cats due to severity of anemia |
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how many clinical categories of Beta thal?
alphs thal? |
3
4 |
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what determines the severity of anemia in alpha thalassemia?
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due to # of deleted α−globin genes (i.e. gene dosage for 4 alleles at 2 loci)
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what are the 4 clinical cats of α-Thalessemia?
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1. Silent carrier ( -/α, α/α): asymptomatic
2. α−Thal trait: asymptomatic, like β-Thal minor 3. HbH disease: (-/α, -/-) intermediate severity; similar to β-Thal intermedia 4. Hydrops fetalis: (-/-, -/-): lethal in utero |
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hemophilia A
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X linked recessive
inability to form clots most common hered dz w/ serious bleeding mut in Factor VIIIc gene (on chrom Xq28) |
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where's the defect in hemophilia A?
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Factor VIIIc mutation (chrom Xq28)
causes 85% hemophilia |
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who gets hemophilia A?
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30% pts w/o FH
1:10,000 males (hemizygous) 1:100,000 fem (homo) *hetero fem may have xs bleed due to unfav. lyonization |
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which tissues are affected by xs bleeding in hemophilia A?
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joints, muscles, mucous membranes, peripheral nerves, etc
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what effect does hemophilia A bleeding into joints have?
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arthropathy (chronic joint pain)
swelling limited motion |
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what effect does hemophilia A bleeding have on muscle?
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pain and atrophy
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what effect does hemophilia A bleeding into mucous membranes have?
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damage, mouth, teeth, epistaxis
GIT |
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what effect does hemophilia A have on periph nerves?
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hemorrhage causes nerve lesions especially in legs/arms
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what are some other sites of damage due to bleeding in hemophilia A?
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brain-intracranial hemorrhage
intraspinal, retropharyngeal, retroperitoneal |
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what do serum studies show in hemophilia A dx?
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prolonged PPT (clot w/ kaolin, cephalin, and Ca+2)
decreased Factor VIIIc normal PT (clot w/ thromboplastin and Ca+2), bleeding time, thrombin time, platelets, factor VIIIvW |
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what factors are added to measure PTT?
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kaolin, cephalin and calcium
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what factors are added to measure PT?
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thromboplastin and Calcium
(2 letters in "PT"--2 additives) |
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what are some normal findings of serum studies in pts w/ hemophilia A?
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nl PT
bleeding time, thrombin time, platelet count, Factor VIIIvW |
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what are 3 categories of hemophilia A severity?
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1. severe: (<1% nl VIIIc levels)
2. moderate: (2-5% nl levels) 3. mild: (>6% nl Factor VIIIc |
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clinical characteristics of severe hemophilia A?
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<1% nl Factor VIIIc:
onset of bleeding in newborn (90% by age 1) spontaneous bleeding |
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clinical Sx of moderate hemophilia A?
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2-5% nl VIIIc levels:
onset in infancy xs bruising w/ ambulation some arthrosis sometimes spontaneous (usually after mild/mod trauma) |
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clinical Sx of mild hemophilia A?
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>6-50% nl Factor VIIIc levels:
onset during childhood bleeding NOT spontaneous--follows mod/sever trauma (dental work/surgery) |
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What's christmas disease?
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hemophilia B
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what's the deal w/hemophilia B?
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X linked Recessive
indistinguishable from Hem A causes 15% cases mutation in Factor IX gene (assay levels) |
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what's the differential ddx for hemophilias?
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genetic bleeding disorders that are NOT X linked:
Von Willebrand Dz |
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what's the defect in von willebrand dz?
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mutation in vWF gene
alters both platelet function and coagulation pathway |
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what does a defect in vWF gene affect?
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alters both platelet function and coagulation pathway
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who gets von willebrand dz?
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very common=1% of population!
20 genetic variants: mostly AD, some AR M=F |
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what's the effect of nl vWF on Factor VIII?
what happens w/ von willebrand dz to Factor VIII? |
normally binds and stabilizes Factor VIII
causes decreased Factor VIII too |
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clinical findings in Von Willebrand dz?
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spontaneous bleeding from mucous membranes
x.s. bleeding from wounds menorrhagia prolonged bleeding time w/ nl platelet count |
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how is von willebrand dz dx?
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no single test due to variability of cause:
immunologic tests ristocetin aggregation test |
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what's the ristocetin aggregation test?
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decreased aggregation of platelets in the presence of Antibiotic ristocetin
due to decreased vWF protein levels or abnl vWF |
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what are ways that diseases are inherited in a non-mendelian fashion?
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other single gene defects (triplet repeats, imprinting, mito mutation)
can be complex/multifactorial |
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what are some single gene defects that are inherited in a non-mendelian manner?
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(a) changes in the number of triplet repeats in a gene
(b) loss or gain of a gene region that is “imprinted” (genomic imprinting disorders) (c) mutation in a mitochondrial gene |
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what are toxic "gain of function" mutation mechanisms in triplet repeat disorders?
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triplet repeat in gene coding region
often CAG/ polyglutamine expansion abnl protein interferes w/ nl abnl protein can aggregate in nucleus neurodegeneration progressive w/ age |
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what's a "dominant negative effect"
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abnl protein interferes w/ the normal protein as in a triplet repeat expansion
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What are "loss of function" mutation mechanisms that can be pathogenic in triplet repeat disorders?
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triplet repeats in non-coding regions
protein synth is suppressed many body systems affected |
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how does hungtington's appear?
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usually in adulthood
first as loss of motor control: stagger, grimace then progressive dementia |
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what causes huntington's dz?
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expansion of CAG triplet repeats in coding region of huntintin gene
nl (unaffected)=11-34 copies HD=35 to >100 copies incomplete penetrance=35-38 copies |
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on what chromosome is the huntingtin gene found?
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4p
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mutation rate of Huntington's?
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almost none (one of the lowest mutation rates of human dz)
1/million/generation |
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how is huntington's dz inherited?
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AD BUT...
increasing risk w/ expansion of 3x repeat in successive generations (aka "Sherman's paradox", "anticipation") |
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what's the age of onset for Huntingtons?
what does it depend on? |
avg age 30-50 yo
larger repeats=earlier onset (even at 2 yo) 80% juvenile onset before age 20=paternally transmitted w/ lg repeats |
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what's different about the inheritance of juvenile onset Huntington's dz?
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Paternally transmitted w/ lg repeats
80% juvenile cases w/ onset before 20 yo |
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what do CAG repeat expansions in the Huntingtin protein (Htt) cause?
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the lengthened protein causes buildup of toxic protein aggregates w/in and near neuronal nuclei
causes neuronal inclusions to form leading to neuronal death |
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what is the actual function of Huntingtin?
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unclear:
may reg BDNF levels and CREB-binding protein (reg cell survival) |
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what are the major features of Huntington's disease?
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loss of motor control (stagger, tremor, sluggish, rigid)
dementia, affective disorder loss striatal neurons: dysreg basal ganglia 15 yrs dx to death |
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what does loss of striatal neurons in huntington's cause?
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dysregulation of the basal ganglia
(brain size can decrease 25%) |
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common causes of death in Huntington's dz?
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aspiration pneumonia
cardioresp failure subdural hematoma suicide (higher than nl pop) |
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treatments for Huntington's?
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benzos for choreic mvmts
antipsychotics and tricyclics (affective disorders) |
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what are the features of loss of motor control seen in Huntington's?
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staggering walk (looks drunk)
facial grimace later-tremor, decreased mobility, sluggish, rigidity |
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how are mitochondrial myopathies transmitted?
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mother to all kids
via mutant mtDNA in cytoplasm of her eggs rare trans from father's sperm |
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which organs are affected most by mitochondrial myopathies and encephalopathies?
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those most dependent on oxidative phos:
CNS, skeletal muscle, liver, kidneys |
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how are mitochondrial disorders expressed?
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extremely variable in various body tissues (random dispersion of mutant mito to daughter cells)
extremely variable in different offspring of same mom (due to random distribution in eggs) |
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what are 3 pathological features of mito myopathies?
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1. aggregates of abnl mito in sk musc fibers (blotchy red on Gomori trichome stain)
2. ragged red fibers (abnl aggregates of mito distort myofibril arrangement) 3. parking lot inclusion (paracrystalline structures=abnl mito cristae) |
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What does MERRF stand for?
what's an "RRF"? |
myoclonic epilepsy and ragged red fibers
abnl aggregates of mito distort myofibrils which look irregular in x section |
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what is the defect in MERRF?
what are the results? |
tRNA mutation disorder causes abnl mitochondria
myopathy, epilepsy, deafness, dementia |
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what characterizes the myopathy due to MERRF?
how would you stain for it? |
musc weakness in yg adulthood
blotchy red abnl mito which distort myofibrils muscle has ragged red look stain w/ modified Gomori trichrome |
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What kind of disorder is Leber's hereditary optic neuropathy?
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mito disorder causing optic nerve degeneration
Leber's "Electrocutes Optic Mitochondria" (Electric=cardiac conduction Optic=opt nerve degen, Mito=minor neuro) |
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what are the Sx of Leber's hereditary optic neuropathy (LHON)?
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1. optic nerve degen--progress to bilateral loss of vision
2. cardiac conduction defects 3. minor neuro manifestations Leber's "Electrocutes Optic Mitochondria" (Electric=cardiac conduction Optic=opt nerve degen, Mito=minor neuro) |
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what's the threshold model of multifactorial disease?
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bell shaped curve indicate distribution of phenotype for given trait
threshold line drawn--pt at which dz manifests (e.g. bld glucose level in DM) |
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what are the characteristics of multifactorial inheritance?
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1. familial w/o distinctive pattern
2. risk related to # mut genes inherited 3. risk to 1st deg relative>than to 2nd degree> general population 4. recurrence risk>> w/ >1 family member affected or severe manifestation |
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what's the inheritance pattern for diabetes mellitus?
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multifactorial
affects 3% of the world not a single dz--more a group of metabolic disorders sharing common feature of hyperglycemia |
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what are the features of DM inheritance that make it a classic multifactorial dz?
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increased incidence among 1st deg relatives
usually not simple inher pattern environmental factors critical besides genetics (diet, iron, viral infections-type I) |
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type 1 DM
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10% of cases
"juvenile onset" usually <20 but up to 40 yo autoimmune susceptibility locus on chrom 6 (HLA locus) linkage w/ insulin gene allele possible viral infection, vaccine induced |
