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Path 5 Genetics
LECOM Path Ch 5 Genetic Disorders
| Question | Answer |
|---|---|
| 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
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