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Path 5 Genetics

LECOM Path Ch 5 Genetic Disorders

AD man marries normal woman, chance of their child having the AD disease 50%
Inherit an AD gene but are phenotypically normal due to incomplete penetrance
In genetic diseases, those that have delayed onset are usually inherited how? AD
If a disease is caused by LOF of an enzyme protein, would you expect it to be AD? No, you can lose 50% of enzyme and compensate
2 major catagories of affected proteins in AD disorders regulators of metabolic pathways i.e. LDH receptors; and Key structural proteins i.e. spectrin and collagen
GOF mutations are almost always inherited as AD
AD, AR, or X-Linked Recessive?: Huntington disease AD
AD, AR, or X-Linked Recessive?: NF AD
AD, AR, or X-Linked Recessive?: Myotonic Dystrophy AD
AD, AR, or X-Linked Recessive?: Tuberous Sclerosis AD
AD, AR, or X-Linked Recessive?: PCKD AD
AD, AR, or X-Linked Recessive?: Familial Polyposis Coli AD
AD, AR, or X-Linked Recessive?: Hereditary spherocytosis AD
AD, AR, or X-Linked Recessive?: von Willebrand disease AD
AD, AR, or X-Linked Recessive?: Marfan syndrome AD
AD, AR, or X-Linked Recessive?: Ehler-Danlos both, gotcha bitch
AD, AR, or X-Linked Recessive?: Osteogenesis Imperfecta AD
AD, AR, or X-Linked Recessive?: Achondroplasia AD
AD, AR, or X-Linked Recessive?:Familial Hypercholesterolemia AD
AD, AR, or X-Linked Recessive?: Acute intermittent porphyria AD
A child is born with AR disease, parents have normal phenotype, what is the chance a new sibling will have the disease 25%
A mutation causing an AR disease is very rare in a population. Child is born with the AR disease. What is inferred about the parents? Consanguineous
A more uniform expression of defects tends to be seen in which disorders AR
Complete penetrance is more common in AR or AD? AR
AR disorders usually present when? early in life
Enzyme mutations are more common in AD or AR? AR
Inborn errors of metabolism are all inherited how? AR
AD, AR, or X-Linked Recessive?: CF AR
AD, AR, or X-Linked Recessive?: PKU AR
AD, AR, or X-Linked Recessive?: Galactosemia AR
AD, AR, or X-Linked Recessive?: Homocytinuria AR
AD, AR, or X-Linked Recessive?: Lysosomal storage diseases AR
AD, AR, or X-Linked Recessive?: alpha 1- antitrypsin deficiency AR
AD, AR, or X-Linked Recessive?: Wilson disease AR
AD, AR, or X-Linked Recessive?: Hemochromatosis AR
AD, AR, or X-Linked Recessive?: Glycogen storage diseases AR
AD, AR, or X-Linked Recessive?: Sickle Cell anemia AR
AD, AR, or X-Linked Recessive?: Thalassemias AR
AD, AR, or X-Linked Recessive?: CAH AR
AD, AR, or X-Linked Recessive?: Alkaptonuria AR
AD, AR, or X-Linked Recessive?: neurogenic Muscular Dystrophy AR
AD, AR, or X-Linked Recessive?: Friedreich ataxia AR
AD, AR, or X-Linked Recessive?: Spinal Muscular Dystrophy AR
Vitamin-D resistant Rickets is inherited X-liinked dominant
AD, AR, or X-Linked Recessive?: Duchenne Muscular dystrophy X-Linked Recessive
AD, AR, or X-Linked Recessive?: Hemophilia A and B X-Linked Recessive
AD, AR, or X-Linked Recessive?: Chronic Granulomatous Disease X-Linked Recessive
AD, AR, or X-Linked Recessive?: G6PD Deficiency X-Linked Recessive
AD, AR, or X-Linked Recessive?: Agammaglobulinemia X-Linked Recessive
AD, AR, or X-Linked Recessive?: Wiskott-Aldrich syndrome X-Linked Recessive
AD, AR, or X-Linked Recessive?: Diabetes Insipidus X-Linked Recessive
AD, AR, or X-Linked Recessive?: Lesch-Nyhan sydrom X-Linked Recessive
AD, AR, or X-Linked Recessive?: Fragile-X syndrome X-Linked Recessive
Protein involved: Phenylalanine hydroxylase PKU
Protein involved: Hexosaminidase Tay-Sachs
Protein involved: Adenosine deaminase SCID
Protein involved: α1-antitrypsin (2) emphysema and liver damage
Protein involved: LDL receptor Familial hypercholesterolemia
Protein involved: Vitamin D receptor Vitamin D resistant rickets
Protein involved: Hemoglobin(3) α and β- thalassemia and Sickle cell
Protein involved: Collagen (2) Osteogenesis imperfecta and Ehlers-Danlos
Protein involved: Fibrillin Marfan Syndrome
Protein involved: dystrophin (2) Duchenne/Becker muscular dystrophy
Protein involved: Spectrin, ankyrin, or protein 4.1 Hereditary Spherocytosis
Protein involved: Factor VIII Hemophilia A
Protein involved: Rb protein hereditary Retinoblastoma
Protein involved: Neurofibromin NF type 1
Marfan syndrome: Gene mutated, loci, and inheritance? FBN1, 15q21.1, AD
Marfan Diagnosis criteria Major involvement of 2: cardiovascular, ocular, skeletal, skin, minor in 1other organ.
MCC of death in Marfans ruptured aortic dissection
Vascular layer affected in Marfans, media
Marfan’s dialation of aorta by what type cystic medionecrosis
Pt presents with bilateral ocular lens displacement. Susspect what? Marfans
Thin skin, small joint hyperflexibility, arterial or uterine rupture Dx? Vascular type EDS
Congenital scoliosis, joint laxity, corneal rupture Dx? kyphoscoliosis type EDS
Skin and joint hypermobility, atrophic scars, diaphragmatic hernia Dx? Classic type EDS
MC AR form of EDS kyphoscoliosis type
Kyphoscoliosis type EDS: inheritance, Gene mutation and typical finding? AR, lysl hydroxylase deficiency, ocular fragility
Vascular type EDS: inheritance, Gene mutation, classic finding? AD, COL3A1, spontaneous vessel rupture
3 types of defects in Vascular type EDS rate of synthesis, and secretion of pro α1(III), abnormal Type III collagen
Arthrochalasia type EDS: inheritance, Gene mutation, characteristic finding AD, COL1A1 or COL1A2, severe joint hypermobility
Dermatosparaxis type EDS: inheritance, Gene mutation, characteristic finding AR, Procollagen N-peptidase, Severe skin fragility
Classical type EDS: inheritance, Gene, characteristic finding AD, COL5A1 or COL5A 2, skin and joint hypermobility
Hypermobility type EDs: inheritance, Gene, characteristic findings AD, unknown, joint only, pain, dislocation
What is the failure in Class I LDL-R mutation? failed synthesis
What is the failure in Class II LDL-R mutation? failed transport from ER to Golgi because of folding defect; fairly common
What is the failure in Class III LDL-R mutation? failure of binding, binding domain mutation
What is the failure in Class IV LDL-R mutation? failure to localize to the coated pit
What is the failure in Class V LDL-R mutation? failure of recycling, can’t disassociate LDL at pH and is degraded
This is attached to lysosomal enzymes in the Golgi Complex terminal mannose-6-phosphate groups
Tay-Sachs disease: Deficient enzyme and what accumulates hexoaminidase α subunit; GM2 ganglioside
Balooned neurons, Fat stains, whorled configurations in lysosome with onion skin membranes Tay-Sachs, hexoaminidase α
Niemann-Pick A vs B? B lives to adulthood with no nervous system involvement
Niemann-Pick A and B: enzyme deficient and metabolite accumulating? Sphingomyelinase; sphigomyelin
Niemann-Pick Type A outcome death by age 3
Ballooned neurons, Fat stain +, lipid laiden phagocytic foam cells, zebra bodies on EM Niemann-Pick Type A
Gross Brain appearance w/ Niemann-Pick Type A shrunken gyri, widen sulci
Niemann-Pick Type C; Genes affected NPC1 95% and NPC2
What is wrong moleculary with NPC? defective lipid transport from lysosome to cytoplasm.
What accumulates in NPC? cholesterol and gangliosides
MC presentation of NPC childhood, ataxia, vertical supernucular gaze palsy, psychomotor regression
Gaucher disease: enzyme deficient and what accumulates glucocerebrosidase ; glucocerebroside
MC lysosomal storage disorder Gaucher Disease
MC type of Gaucher disease and fiindings Type I, non-neuropathic, splenic and skeletal involvement, accumulate in mononuclear phagocytes
Type I vs Type II Gaucher disease: enzyme activity? Type I has reduced activity; Type II has none
Distented phagocytic cells in spleen, liver, bone marrow. Crumpled tissue paper cytoplasm Gaucher disease
Large >100um cell w/ 1 or more eccentric nuclei, PAS+, fibrillary cytoplasm Gaucher Cell
Huge spleen, moderate total body LA, bone marrow accumulation of large PAS+ cells with areas of bone erosion Gaucher type I
Pancytopenia, thrombocytopenia, huge spleen, pathologic Fx. Dx? Gauchers
4 GAGs that accumulate in MPSs dermatan, heparan, keratin, and chondroitin sulfate
Non-AR MPSs Hunters, X-linked recessive
Characteristics of MPSs coarse facial features, clouded cornea, joint stiffness, mental retardation[ Important causes of death in MPSs
Hurler Syndrome: Enzyme deficient α-L-iduronidase
Hurler syndrome outcome hepatosplenomegaly by 2, death by 10 from CV complications
Hunter Syndrome; inheritance, enzyme, and difference from Hurler X-linked recessive, L-iduronosulfate sulfatase; no corneal clouding and milder
van Gierke disease: form, enzyme deficient hepatorenal form; Glucose-6-phosphatase
McArdle syndrome: form, enzyme deficient Myopathic form, muscle phosphorylase
Pompe Disease: form, enzyme deficient Generalized; lysosomal glucosidase (acid maltase)
Clinical findings in von Gierke disease glycogen accumulation, hepatomegaly, renomegaly, stunted growth, bleeding, hyperlipidemia
Clinical findings in McArdle syndrome glycogen accumulation in skeletal muscle only, painful cramps with exercise, creatine kinase always elevated, myoglobinuria
Clinical findings in Pompe disease mild hepatomegaly, cardiomegaly, skeletal muscle glycogen accumulation, cardiorespiratory failure in 2 years
Alkaptonuria: enzyme deficiency, accumulant? homogentistic oxidase; homogentistic acid
Clinical finding in Alkaptonuria urine turns black when let stand, degenerative arthropathy starts at 30, blue/black nose/ears/cheeks
Joints most involved in Alkaptonuria vertebral disks, knees, shoulders hips.
Karyotype of normal male and female somatic cells 46 XY ; 46XX
Cells arrested in what phase for karyotyping metaphase
Most common stain in karyotyping Giemsa Stain G banding
Resolution of G banding increased in what phase prophase
An exact multiple of 23 is termed euploidy
Non-multiple of 23 aneuploidy
Nondisjunction in gametogenesis will give either one extra or one less chromosome
Anaphase lag will produce one normal cell and one monosomy
Monosomy in an autosome will usually cause what to happen to a fetus loss of too much genetic info and death
Most common isochrome in live births i(X)(q10); monosomy of the short arm and trisomy of the long arm
MC chromosomal disorder down syndrome[ MCC of Downs
40% of Down syndrome Pt’s have congenital heart disease usually of endocardial cushion origin
Majority of early deaths in Down syndrome Pt’s is frome cardiac problems
Other common congenital malformations in Down’s Pt’s esophageal and small bowel atresia
Down’s Pts have 10-20x likelihood of developing ALL or AML
Downs Pt older than 40 will develop Alzheimers
Name of Trisomy 18 Edwards syndrome
Name of trisomy 13 Patau Syndrome
Cleft lip and palate, microcephaly, polydactyl, renal defects. Trisomy? Trisomy 13, Patau[ Prominent occiput, micrognathia, low ears, short neck, overlapping fingers, limited hip abduction Trisomy?
25% of adults with this syndrome develop schizophrenia 22q11.2 deletion syndrome
Inactivated X chromosomes cause these Barr bodies
Gene responsible for X inactivation XIST
Gene that dictates testicular involvement SRY
MC karyotype in Klinefelter 47 XXY
Klinefelter Pt’s have increased incidence of (6) Type 2 DM, autoimmune disease, metabolic syndrome, breast CA, nontesticular germ cell tumors, mitral valve prolapse
IQ in Klinefelters slightly lower
Hypogonadism in Klinefelters results from nonrandom X inactivation based on shortest CAG repeat in androgen receptor gene
3 common karyotypic abnormalities in Turner syndrome X monosomy, mosaicism, partial deletions
Common defective chromosome karyotypes in Turners 46, X,[ iX(Xq), del(Xq), del(Xp), r(X) ]
Common mosaic karyotypes of Turners 45, X/ 46 XX, 45X/46XY, 45X/47XXX, 45X/46X, i(X)(q10)
Common fetal finding in severe Turners Pt’s lymphedema of the hand and feet, “webbed” neck from cystic hygroma
Causes of increased mortality in children w. Turners L sided congenital heart defects, preductal coarctation of the aorta, bicuspid aortic valve
Autoantibody produced in Turners Pt’s auto-thyroid Ab
Turners pt also show intolerance to what? insulin, glucose, leading to obesity
Most repeats usually have what 2 nucleotides C and G
3 diseases from expansion in non-coding regions Fragile X, Friedreich Ataxia, Myotonic Dystrophy
Repeat usually found in those affecting coding regions CAG
Typical coding region expansion disease Huntington disease
Fragile-X syndrome repeat, what locus CGG; Xq27.3
How many repeats in Fragile X to become “full” >230
2nd MCC of genetic mental retardation Fragile-X syndrome
Gene name affected in Fragile X Familial Mental Retardation gene 1 FMR-1
In fragile X syndrome transmission through male or female causes muutiplication of repeats female ie oogenesis
Common features in Fragile X men long face, large mandible, large everted ears, huge testicles
mtDNA comes from your mother
mtDNA is mostly responsible for what type of proteins enzymes used in oxidative phosphorylation
mtDNA mutations affect which tissues preferentially CNS, skeletal muscle, cardiac muscle, liver and kidneys
Prototypic mtDNA disease Leber Hereditary Optic Neuropathy
Leber hereditary optic neuropathy presents as progressive bilateral loss of central vision by 15-35yo and progresses to blindness
Maternal Imprinting causes silencing of maternal allele
Paternal Imprinting causes silencing of paternal allele
Angelman Syndrome results from deletion of the 15q12 region on the maternal allele
Prader-Willi Syndrome results from deletion of the 15q12 region on the paternal allele
Mental retardation, short stature, hypotonia, profound hyperphagia, obesity, small hands and feet, and hypogonadism Dx? Prader-Willi Syndrome
Mental retardation, ataxic gait, seizures, inappropriate laughter. Dx? Angelman Syndrome
Gene linked with Angelman Syndrome UBE3A, imprinted on paternal allele
6 reasons to do prenatal cytogenic testing maternal age >35, parent with chromosomal structural abnormality, previous child w. chromosomal abnormality, carrier of x-linked disease, abnormal AFP, BHCG, or estriol levels, ultrasound abnormalities
6 reasons for postnatal peripheral lymphocyte testing multiple congenital abnormalities, unexplained MR, Suspected chromosomal abnormality, Suspected fragile X, infertility, recurrent abortions(both parents)
4 indirect DNA detection methods restriction enzymes, PCR with immunofleurescent nucleotides, real time PCR with oligonucleotide probes, mutations of length can be seen with PCR/restrictive fragment digestion
2 cases where Southern Blotting is still useful large repeats (fragile X) and clonal immunoglobulin gene rearrangements (lymphoma)
2 phases chromosomes are stopped in for FISH metaphase spread, interphase nuclei
Created by: csheck