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Genetic Disorders

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thabiso's version from 2016-12-11 17:56

Connective Tissue Disorders

SyndromeInheritance and DefectFeatures
Marfan's SyndromeFibrillin, AD, (CHR15)Tall stature, arachnodactyly, pectus escavatum, lens subluxation, aortic root dilatation and dissecting aortic aneurysms, mitral valve prolapse
Ehlers-Danlos SyndromeCollagen, (Type III most common)Hypermobile joints, easy bruising, hyperextensible skin, berry aneurysms, joint dislocation, organ rupture
Osteogenesis imperfectaType 1 collagen, ADBrittle bones and multiple fractures, Blue sclerae, hearing loss, dental imperfections, can be confused with child abuse, (type II fatal in utero/neonatal period)
Alport's SyndromeType IV collagen, X-recessiveHereditary nephritis and deafness, possible ocular disturbances
Emphysema (hereditary)alpha-1-antitrypsinexcess elastase activity
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Autosomal Dominant Diseases

SyndromeInheritance and DefectFeatures
AchondroplasiaFGFR3Dwarfism (short limbs, normal head and trunk size), associated with advanced paternal age
Autosomal dominant polycystic kidney disorder (ADPKD)APKD1, AD, CHR16Bilateral enlargement of kidneys with multiple cysts, presents with flank pain, hematuria, hypertension, progression renal failure. Associated with berry aneurysms, polycystic liver disease, mitral valve prolapse
Familial adematous polyposisAPC, CHR5Colon becomes covered with adematous polyps after puberty. Progression to colon cancer unless colon is resected.
Familial hypercholesterolemia (Hyperlipidemia Type IIA)Defective/absent LDL receptorElevated LDL (300 mg/ml), severe atherosclerotic disease early in life, Achilles tendon xanthomas
Hereditary hemorrhagic gelaniectasia (Osler-Weber-Rendu syndrome)Blood vessel disorderTelangiectasia, recurrent epistaxis, skin discolorations, AVMs
Hereditary spherocytosisspectrin or ankyrinSpheroid erythrocytes, hemolytic anemia, increased MCHC. Increased osmotic fragility. Cure with splenectomy.
Huntington's diseaseHuntingin, CHR4, CAG trinucleotide repeatdepression, progressive dementia, choreiform movements, caudate atrophy, decreased GABA and ACh. Ages 20-50.
Marfan's SyndromeFibrillin, AD, (CHR15)Tall stature, arachnodactyly, pectus escavatum, lens subluxation, aortic root dilatation and dissecting aortic aneurysms, mitral valve prolapse
Multiple endocrine neoplasias (MEN)MEN 2A and B -- Ret oncogeneTumors of endocrine glanes (pancreas, parathyroid, pituitary, thyroid, adrenal medulla)
Neurofibromatosis Type I (von Recklinghausen's disease)Long arm of CHR17Cafe-au-lait spots, neural tumors, Lisch nodules (pigmented iris hamartomas), skeletal disorders, optic pathway gliomas, pheochromocytomas, increased tumor susceptibility
Neurofibromatosis Type IINF2 gene, Chromosome 22Bilateral acoustic neuromas, juvenile cataracts
Tuberous sclerosisFacial lesions (adenoma sebaceum), hypopigmented ash leaf spots, cortical and retinal hamartomas, seizures, mental retardation, renal cysts, renal angiomyolipomas, cardiac rhabomyomas, increased incidence of astrocytomas
von Hippel-Lindau diseaseDeletion of VHL gene, CHR 3p, constitutive expression of HIFHemangioblastomas of retina/cerebellum/medulla, multiple bilateral renal cell carcinomas
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Autosomal Recessive Diseases

SyndromeInheritance and DefectFeatures
AlbinismAbsent tyrosinase (AR), defective tyrosine transporters, or lack of migration of neural crest cells. Ocular albinism is XRLack of melanin, increased risk of skin cancer. Inheritance actually variable b/c of locus heterogeneity.
ARPKDNo one specific gene. Sorry.Bilateral cystic disease with enlarged kidneys at birth. Cysts in liver --> congenital hepatic fibrosis --> portal HTN. Maternal oligohydramnios, Potter's facies, low-set ears, parrot beak nose, and lung hypoplasia.
Cystic fibrosisCTFR, CHR7, (Deletion of Phe 508 causes abnormal protein folding and degradation of channel)Infertility in males (bilateral absence of vas deferens), failure to thrive in infancy, pancreatic insufficiency amd fat-soluble vitamin deficiency, recurrent pulmonary infections with Pseudomonas and S. aureus, chronic bronchitis, bronchiectasis
Orotic AciduriaDefect in orotic acid phosphoribosyltransferase or orotidine 5'-phosphate decarboxylaseInability to convert orotic acid to UMP (de novo pyrimidine synthesis pathway). Increased orotic acid in urine, megaloblastic anemia that doesn't improve with administration of B12 or folate, failure to thrive. No hyperammonemia. Rx: Uridine administration
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X-linked recessive disorders

Be Wise, Fool's GOLD Heeds Silly Hope
SyndromeInheritance and DefectFeatures
Bruton's agammaglobinemiaDefect in tyrosine kinase gene blocks B-cell differentiationRecurrent bacterial infections after 6 months due to opsonization defect. Increased in boys, Labs: normal pro-B, decreased maturation, decreased number of B cells, decreased immunoglobulins of all classes.
Wiskott-Aldrich syndromeProgressive deletion of B and T cellsThrombocytopenic purpura, infections, ezcema (TIE triad). Labs: increased IgE, IgA, decreased IgM
Fabry's diseaseDeficiency of alpha-galactosidase A, accumulation of ceramide trihexosidePeripheral neuropathy of hands/feet, angiokeratomas, cardiovascular/renal disease
G6PD defieicncyG6PDDecreased glutathione --> increased RBC susceptibility to oxidant stress. Hemolytic anemia triggered by oxidant stress (sulfa drugs, infections, fava beans)
Lesch-Nyhan syndromeAbsence of HGPRT :: Defective purine salvage, excess uric acid production. Mental retardation, self-mutilation, aggression, hyperuricemia and gout, choreoathetosis
Duchenne's Muscular DystrophyDMD, frame-shift mutationWeakness in pelvic girdle muscles (use of Gower's maneuver) progressing superiorly, Pseudohypertrophy of calf muscles, fibrofatty replacement of calve muscles, cardiac myopathy, onset before age 5. Diagnose with CPK and muscle biopsy. Dystrophin anchors muscle fibers.
Becker's Muscular DystrophyDMDWeakness in pelvic girdle muscles (use of Gower's maneuver) progressing superiorly, Pseudohypertrophy of calf muscles, fibrofatty replacement of calve muscles, cardiac myopathy, onset in adolescence or early adulthood. Diagnose with CPK and muscle biopsy. Dystrophin anchors muscle fibers.
Hunter's syndromeDeficiency of Iduronate sulfatase, accumulation of heparan sulfate, dermatan sulfateMild developmental delay, gargoylism, airway obstruction, hepatosplenomegaly. Aggressive behavior. NO corneal clouding
Hemophilia A and BA -- deficiency in factor VIII; B -- deficiency in factor IXIncreased PTT. Macrohemorrhage (hemarthroses, easy bruising)
Fragile X syndromeFMR1, CGG trinucleotide repeat2nd most common cause of mental retardation, macroorchidism, long face with large jaw, large everted ears, autism, mitral valve prolapse
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Trinucleotide Repeat Expansion Diseases

Try (trinucleotide) hunting for my fried eggs (X)
SyndromeInheritance and DefectFeatures
Huntington's disease (AD)Huntingin, CHR4, CAGdepression, progressive dementia, choreiform movements, caudate atrophy, decreased GABA and ACh. Ages 20-50.
Fragile X syndrome (XR)FMR1, CGG2nd most common cause of mental retardation, macroorchidism, long face with large jaw, large everted ears, autism, mitral valve prolapse
Myotonic Dystrophy (AD)CTGMyotonia (inability to relax muscles; sustained grip), frontal balding, cataracts, testicular atrophy, cardiac involvement, facial weakness. Increased serum CK from wasting of type 1 fibers.
Friedrich's Ataxia (AR)Frataxin, GAAImpaired mitrochondrial functioning. Staggering gait, frequent falling, nystagmus, dysarthria, pes cavus, hammertoes. Cause of death is hypertrophic cardiomyopathy. Presents in childhood with kyphoscoliosis.
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Autosomal trisomies

SyndromeInheritance and DefectFeatures
Down SyndromeTrisomy 21Flat facies, prominent epicanthal folds, simian crease, gap b/w 1st and 2nd toes, duodenal atresia, congenital heart disease, increased risk of ALL and Alzheimer's. 95% due to nondisjunction, 4% due to Robertsonian translocation.
Edward's SyndromeTrisomy 18Severe mental retardation, rocker-bottom feet, micrognathia (small jaw), clenched hands, low-set ears, prominent occiput, congenital heart disease. Death occurs within 1 year. Most common trisomy resulting in live birth after Down Syndrome.
Patau's SyndromeTrisomy 13Severe mental retardation, rocker-bottom feet, micropthalmia, microencephaly, cleft lip/palate, holoprosencephaly, polydactyly, congenital heart disease. Death within 1 year.
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Chromosomal Deletion Syndromes

SyndromeInheritance and DefectFeatures
Cri-du-chat SyndromeMicrodeletion of short arm of Chr5 (5p-)microcephaly, moderate to severe mental retardation, high-pitched crying/mewing, epicanthal folds, cardiac abnormalities
Williams SyndromeMicrodeletion of long arm of Chr7 (includes elastin gene)"Elfin" facies, mental retardation, hypercalcemia (due to increased sensitivity to vitamin D), well-developed verbal skills, extreme friendliness with strangers, cardiovascular problems
DiGeorge Syndrome22p11 deletionThymic, parathyroid, and cardiac defects. Aberrant development of 3rd and 4th branchial pouches. Variable presentation (cleft palate, abnormal facies, thymic aplasia, cardiac defects, hypocalcemia)
Velocardiofacial Syndrome22p11 deletionPalate, facial, and cardiac defects. Aberrant development of 3rd and 4th branchial pouches. Variable presentation (cleft palate, abnormal facies, thymic aplasia, cardiac defects, hypocalcemia)
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Imprinting Disorders

Active allele is deleted, leading to disease.
SyndromeDefect (parent)Features
Prader-Willi SyndromeDefect of Paternal allele (Chromosome 15)Mental retardation, hyperphagia, obesity, hypogonadism, hypotonia
Angelman's SyndromeDefect of Maternal allele (Chromosome 15)Mental retardation, seizures, ataxia, inappropriate laughter (happy puppet)
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Familial Dyslipidemias

SyndromeIncreasedElevated Blood LevelsPathophysiology
Type I (hyperchylomicronemia)ChylomicronsTG, CholesterolLipoprotein lipase deficiency or altered apolipoprotein C-11. Causes pancreatitis, hepatosplenomegaly, and eruptive/pruritic xanthomas. NO increased risk for atherosclerosis
Type IIa (familial hypercholesterolemia)LDLCholesterolAD, absent or decreased LDL receptors , causes accelerated atherosclerosis, tendon (Achilles) xanthomas, corneal arcus
Type IV (hypertriglyceridemia)VLDLTGHepatic overproduction of VLDL, causes pancreatitis.
AbetalipoproteinemiaN/AN/AAR, Inability to synthesize lipoproteins due to defects in apoB-100 and apoB-48. Lipid accumulation within enterocytes on intestinal biopsy. Failure to thrive, steatorrhea, acanthocytosis, ataxia, night-blindness.
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