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DISEASE Sickle Cell Disease (SCD) GENETICS Autosomal recessive: missense mutation (GAG → GTG) of βglobin in E6V DEFICIENCY EPIDEMIOLOGY 1/200 to 1/650 in African American births E6V hemoglobin S (HbS) possess a highly ordered and rigid β-globin, distorting the shape of the RBCs Exception: compound heterozygote inheritance High carrier rate: Africa (8%), Mediterranean, Middle East, India, Caribbean SYMPTOMS TREATMENT Infants appear healthy until HbF levels decrease and HbS levels increase: delayed growth, hemolysis with chronic anemia, intermittent vascular occlusion, autoinfarction of the spleen, chronic organ dysfunction Reduced α-globin synthesis, affecting HbF (α2γ2) and HbA1/HbA2 (α2β2) by causing a chain imbalance and subsequent O2-carrying deficiency Autosomal recessive: deletion in HbA1 and/or HbA2 gene α-Thalassemia Carrier states: α0-Thalassemia (dysfunction of 2 αglobin genes) and α+-Thalassemia (dysfunction of 1 αglobin gene, resulting in a silent carrier state) Most common: mutation in the STOP codon of HbA2, extending Hb Bart (Hydrops Fetalis Syndrome): loss of all 4 α31 amino acids more than globin alleles, causing an off-balance of γ-globin with a normal high affinity for O2 which cannot be released to the fetal tissues HbH: loss of 3 α-globin alleles, causing an off-balance of β-globin that precipitate in RBCs High rate in Africa, Mediterranean, Arabic, India, and southeast Asia Hb Bart: 1/200 in India HbH: 1/50 in India α+-Thalassemia: 1/6 in Sardinia β0-Thalassemia Major: microcytic hypochromic hemolytic anemia, nucleated RBCs, growth delays, hepatosplenomegaly (requiring blood transfusions) β+-Thalassemia Intermedia: mild hemolytic anemia with a risk of iron overload Thalassemia Minor: asymptomatic with possible very mild anemia (yet visible RBC abnormality) Reduced β-globin synthesis, affecting HbA (α2β2) by causing a chain imbalance and subsequent O2-carrying deficiency β-Thalassemia Autosomal recessive: 200+ possible missense or frameshift mutation in HbH gene X-linked recessive: F8 gene mutation by gene inversion of intron 22-A (45%) Hemophilia A Exceptions: missense or frameshift mutations, complete or partial deletion, RNA splicing, insertions, duplications β0-Thalassemia Major: loss of β-globin, causing an excess of α-globin that precipitates in RBC precursors β+-Thalassemia Intermedia: reduced synthesis of βglobin Thalassemia Minor: heterozygous carriers Reduction in coagulation Factor VIII of the intrinsic hemostasis pathway for blood clotting (with normal von Willebrand Factor), leading to poor blood clotting 1/10,000 in U.S. Severe Form: <1% active Factor VIII Moderately Severe Form: 1-5% active Factor VIII Mild Form: 6-35% active Factor VIII α0/α+-Thalassemia: normal to moderate symptoms Hb Bart: fetal onset of generalized edma, ascites, pleural and pericardial effusions, severe hyperchromic anemia → neonatal death HbH: mild microcytic hypochromic hemo lytic anemia, hepatosplenomegaly Severe Form: By age 1—prolonged and renewed (abnormal) bleeding after injuries , large goosebumps with head injuries, 2-5 episodes of spontaneous joint bleeding (without treatment) Moderately Severe Form: By age 6— prolonged and renewed (abnormal) bleeding after injuries Mild Form: Later in life—prolonged and renewed (abnormal) bleeding after injury, minimal bleeding episodes Infusion of gene corrected bone marrow to reach threshold protein levels DISEASE Hemophilia B GENETICS X-linked recessive: F9 gene mutation by missense, nonsense, frameshift, complete or partial deletion, RNA splicing DEFICIENCY Reduction in coagulation Factor IX of the intrinsic hemostasis pathway for blood clotting (with normal von Willebrand Factor), leading to poor blood clotting Severe Form: <1% active Factor IX Moderately Severe Form: 1-5% active Factor IX Mild Form: 6-35% active Factor IX Reduced von Willebrand Factor (vWF) synthesis or functionality, leading to poor platelet aggregation Autosomal disorder: missense von Willibrand Disease (VWD) mutation (Cys → Arg) in C386R (VWF gene) Autosomal dominant (with anticipation): >40 CAG repeats (poly Q expansion) in the 5’ region of IT15 gene for huntingtin Huntington’s Disease Premutation: 27-35 CAG repeats, acting as a reservoir for new mutations due to instability (higher risk in males) Autosomal dominant (with anticipation): >50 CTG repeats (poly L expansion) in the 3’ UTR of DMPK gene Myotonic Dystrophy (MD) Severe form: >2000 CTG repeats for more severe form) Type 2: 3q1 CCTG repeats in intron 1 of ZNF9 Type 1—autosomal dominant: reduced synthesis of vWF (75%) Type 2—autosomal dominant/recessive: reduced functionality of vWF (2A/2B, 2M, 2N) (10-15%) Type 3—autosomal recessive: reduced synthesis of vWF and Factor VIII EPIDEMIOLOGY 1/25,000 males in U.S. Associated with the European and Russian royal families Expanded mRNA accumulates in the cell nucleus, binding to CUG-BP (a CUG RNA-binding protein) Mother: transmits early onset form Father: transmits juvenile onset form TREATMENT Severe Form: By age 1—prolonged and renewed (abnormal) bleeding after injuries , large goosebumps with head injuries, 2-5 episodes of spontaneous joint bleeding (without treatment) Moderately Severe Form: By age 6— prolonged and renewed (abnormal) bleeding after injuries Mild Form: Later in life—prolonged and renewed (abnormal) bleeding after injury, minimal bleeding episodes Infusion of gene corrected bone marrow to reach threshold protein levels Type 1: Any age—lifelong ease of bruising, heavy menstrual bleeding (but may be asymptomatic) Type 2: Any age—lifelong ease of bruising, 1/10,000 worldwide nose bleeds, heavy menstrual bleeding 1/200 in Venetian region Type 3: Rare—nose bleeds, severe skin bleeding, muscle hematomas, severe joint of Italy bleeding Most common bleeding disorder 1/10,000 worldwide Shows anticipation, making it more severe in succeeding generations SYMPTOMS Onset @ 30-50 years of age 1/8,000 worldwide Higher risk in German descendants Adult: chorea (subtle involuntary muscle movement), dementia, anxiety, mood changes and associated depression, alcohol abuse Juvenile (5%): rigidity of muscles and associated clumsiness, dementia Adult: progressive weakness in the neuromuscular tissues, myotonia (tonic muscle spasms with prolonged relaxation), cataracts, cardiac conduction defects, disturbed GI peristalsis Earlier onset: more severe symptoms Genetic counseling and prenatal diagnosis Caspase inhibitors Stem cell transfer in affected brain regions Genetic counseling and prenatal diagnosis DISEASE GENETICS DEFICIENCY EPIDEMIOLOGY Autosomal dominant/recessive or X-linked Hereditary Sensory and Motor Neuropathy (HMSN) (or Carcot-Marie-Tooth Disease/ Peritoneal Muscle Atrophy) Neurofibromatosis (or Recklinghausen Syndrome) Duchenne Muscular Dystrophy (DMD) (and Becker Muscular Dystrophy (BMD)) Cystic Fibrosis (CF) HMSN-Ia: autosomal dominant point muta- tion in PMP-22 or duplication of 17p (containing PMP-22) during spermatogenesis HMSN-Ib: myelin protein zero (MPZ) muta- ti X-linked dominant HMSN: GJB1 connexin 32 mutation in males HMSN-II: possible mitofusion (MFN2), neu- rofilament protein, and light peptide (NEFL) mutation NF1: autosomal dominant HMSN-I—nerve biopsy: seg- mental demyelination → “onion” bulb formation HMSN-II—nerve biopsy: axon- al degredation 17q11.2 for neu- rofibromin (tumor suppressor) mutation (shows homology with GTPaseactivating protein that down regulates RAS) NF2: 22q for scwannomin (a membrane cytoskeletal scaffold tumor suppressor) MDM—X-linked recessive: deletion (66%) of dystrophin gene during maternal unequal crossMales rarely reproduce due to incredibly low over at “hot spot” exons 1-20 and genetic fitness 45-53 Exceptions: nonsense, frameshift, splicing, and promoter mutations BMD: point mutations during paternal meiosis, translating full dystophin gene Autosomal recessive: deletion of 508F (Phe508del) in CFTR gene (70%) Exceptions: G551D mutation (3%) in North Americans and G542X mutation (12%) in Ashkenazi Jews Mutation rate: 1/10,000 gam- etes 1/2,500 worldwide NF1: 1/3,000 world- wide NF2: 1/35,000 world- wide DMD: 1/3,500 males BMD: 1/20,000 1/2,000 to 1/3,000 worldwide Reduced or loss of Cl– chan- nel function, increasing NaCl concentration which, in turn, inhibits defensin activity (due to thickened mucus) → chron- ic bacterial lung infections 1/15,000 in AfricanAmericans 1/31,000 in AsianAmericans Higher risk in western European descendants SYMPTOMS TREATMENT HMSN-I: slowly progressive distal muscle weakness and wasting followed by the upper limb involvement, ataxia, and tremors (generating “inverted champagne bottle” low- er limbs) X-linked dominant HMSN: typical HMSN symptoms (but milder in females) HMSN-II: Later onset—milder distal muscle weakness and wasting (but possibly asymptomatic) NF1: By age 5 (100%)—Café au lait HMSN-III: Rare early onset— spots delay in reaching ( minimum of 6 >5motor mm pigmented milestones lesions with truncal freckling), neurofibromas (soft and fleshy benign tumors that increase in preva- lence with age) NF2: early development of vestibular “schwannomas” (acoustic neuromal tumors), café au lait spots, neurofibromas DMD: By age 3-5—slowly Segmental NF: manifests in 1 area progressive of the body muscle weakness, awkward gait development which prevents running, Gower’s sign (inability to get up from the floor without climbing the legs and thighs), pseudohypertrophy (replacement of muscle fibers by fat and connective tissue) → cardiorespiratory failure and death by age 18 BMD: By age 11—milder Chronic lung disease from symptomology (possibly recurrent infections produces asymptomatic) fibrotic changes → secondary cardiac failure (cor pulmonale) Others: impaired pancreatic function (85%), leading to malabsorption; rectal prolapse; nasal polyps; cirrhosis; diabetes mellitus type 2 Sterility in males due to congenital absence of vas Carrier detection for serum Creatine Kinase (higher in DMD patients) Physical therapy to maintain muscle Gene therapy: myoblast implants from stem cells, intramuscular injection of dystrophin, or geneswitching to utrophin Symptom specific: heartlung transplant, pancreatic enzyme supplements Gene therapy: adenoviral or liposome delivery systems Genetic counseling and prenatal diagnosis Disease Genetics 47xy + 21, Trisomy 21 Downs syndrome Deficiency Can be due to translocation or nondisjunction, mosaicism accounts for 1-2% Familial downs syndrome is due to Roberstonian translocation where a piece of 21 get on 14 or 13 and it appears to be a trisomy. Female with this translocation have a 10% risk of producing Down’s offspring Epidemiology Symptoms Increased prevalence as Intellectual and developmental disabilities, flattened nose and mom increases in age face, upward slanting eyes, single palmer crease, short 5th finger that curves inward, wide spaced toes, increased skin creases Trisomy 13, Mom is responsible Can be partial or entire chromosome 85% of the time. Characterized by small head, absent eyebrows, cleft palate, malformed ears, clenched hands Trisomy 18, Mom is responsible can be partial or entire chromosome 90% of the time. Characterized by large occiput, malformed ears, small jaw, small mouth, upturned nose, flexed big toe, prominent heels, shield chest, prominent sternum and wides set nipples Inversion/Duplication - 22q11 coloboma of the iris, anal atresia with fistula, frequent occurrence of heart and renal malformations, normal or near normal mental development Patau Syndrome Edward's Syndrome Cat Eye Syndrome (Schmid-Fraccaro Syndrome) Partial chromosome increase or deletion Treatment Disease Genetics Deficiency Deletion - 4p- Deletion of short 85-90% of cases occur as the result of a de arm (p) of chromosome 4 novo deletion, meaning the parents did not have this. In the remaining cases one of the parents carries a balanced translocation Epidemiology Symptoms Developmental delays, characteristic facial appearance, variety of birth defects Wolf-Hirschhorn Syndrome Deletion of 5p or 5p monosomy 90% of cases de novo, the rest are due to a parental with an unequal crossing over of a balanced translocation Newborns have a cat-like cry, underdeveloped larynx, difficulty swallowing and sucking, poor growth, behavioral problems Deletion of 22q11.2 Palatal defects, heart defects (Tetrology of Fallot), hearing loss, abnormal ears exams, malformed kidney, hypocalcemia, small head, mental retardation, severe T cell defects Cri Du Chat DeGeorges critical region includes 30 genes. DiGeorge Syndrome Female monosomy (45, x) due to non-disjunction, father 80% Loss of X chromosome in females responsible Turner Syndrome Treatment Disease Genetics Deficiency Epidemiology Symptoms 47, XXY or 48, XXXY, father responsible 100% Klinefelter Syndrome 47, xxx- mom 95% responsible Triple X These are both due to uniparental disomy The presence of two homologus chromosomes inherited from 1 parent Angelman’s syndrome A-syndrome 2 copies of 15/DAD PW-syndrome 2 copies of And 15/Mom Prader Willi syndrome Autosomal Ressesive Tay-Sachs Disease GM2-gangliosidosis the Ashkenazic Jews (northern European descent vs Sephardic Jews-Mediterranean descent) the carrier frequency is 1/30 (10x higher than a control population of the non Ashkenazic Neurological degenerative disorder resulting in death by 6 months. Treatment Disease Retinitis pigmentosa Genetics Epidemiology Locus Heterogenicity Genes where mutations involving RP have been found: Rhodopsin (RHO:20-30%); U4/U6 small nuclear riboprotein (PRPF31:5-10%); peripherin-2 (PRPH2: 5-10%) Allelic Heterogenicity Cystic Fibrosis Sex influenced missense mutation Cys282Tyr Hemochromatosis X-Linked Rett Syndrome Deficiency Mutation in MECP2- a DNA binding protein- usually spontaneous mutation. Males that are 47,xxy or 46 (der x) can survive Symptoms Common cause of visual impairment caused by photoreceptor degeneration with autosomal dominant, autosomal recessive and Xlinked forms Caucasian population 1/2000 children has the disease (virtually nonexistent in Asian population and rare in African Americans) frequency of carriers: 1/29 A mutation in the HFE gene (missense Occurs in approx.0.5% of Cys282Tyr) that is homozygous Cys282Tyr European ancestry HFE mutation permits enhanced absorption of iron classic cystic fibrosis: severe progressive lung disease, pancreatic insufficiency and congenital absence of the male vas deferens Provides advantage to females that may have higher iron requirements due to menstruation and dietary habits Normal prenatal and neonatal growth; rapid onset of neurological symptoms Loss of milestones between 6-18 months Children become spastic , some autistic, purposeless flapping or arms and legs, 50% cases see seizures (after a couple years deterioration stops and child lives with severe disabilities) Treatment Disease Genetics Deficiency Loss of function mutation in RET gene (receptor tyrosine kinase) Failure to develop colonic ganglia-defect in colon motility and severe constipation (dominant) Fragile site marker at Xq.27.1 Fragile site marker at Xq.27.1 chromatin does not condense properly mitosis-CCG repeat located in 5’ untranslated region of gene FMR1-normal repeat =60 > 1000 repeats seen in patients (excessive methylation interferes with chromatin condensation or DNA replication or bothtriplet repeats of 60-200 premutation – unstable in mother child transmission. Shows anticipation Epidemiology Symptoms Severe constipation Hirschsprung Disease Fragil X Syndrome Autosomal dominant CTG triplet repeat Myotonic Dystrophy (DM): Autosomal recessive Triplet repeat: AAG (poly Lysine) located in intron of frataxin Friedreich Ataxia (FRDA) Largest kindred of HD patients –Lake Maracaibo Venezuela-shows founder effect-descendants of a single individual with either mutation or permutation. Adults with premuation— onset of fragile X associated tremor/ataxia syndrome 25% Females with premutation premature ovarian failure by age 40 Congenital form: severe-child offspring of an affected female who may only be mildly affected Repeat unit: CTG triplet located in 3’ untranslated region of protein kinase DMPK normal repeat range=5-30 premutation range=38-54 ) asymptomatic severely affected >2000 repeats almost always transmitted by affected mother. Shows anticipation Myopathy, cataracts , hypogonadism, diabetes and frontal balding. Triplet repeat: AAG (poly Lysine) located in intron of frataxin (encodes mitochondrial protein)-normal repeat: 7-34 copies repeat expansions: 100-1200 copies. Expansion in the intron interferes with normal expression. 1-2% of FRDA patients are compound heterozygotes one allele is expansion allele one is a nucleotide change in FRDA Manifests before adolescence, incoordination of limb movements, cardiomyopathy, scoliosis, speech difficulty, diminished tendon reflexes, foot deformities. Lack of penetrance, pleiotropy and variable expression of clinical severity and age of onset Treatment Disease Marfan Syndrome Burkitt’s Lymphoma Genetics Epidemiology T(8;14). C-myc is on 8q24 and it Reciprocal translocation puts the IGH is moved to 14q24 where the Ig promoter driving c-myc expression in an heavy chain enhancer is found. uncontrolled fasion- uncontrolled cell proliferation and tumor formation. A rarer translocation position cmyc to be driven by the lg light chain enhancer on 22 and 2 1 translocation (Ph ) t(9;22) proto-oncogene ABL (tyrosine kinase) is moved from normal position on chromosome 9 to the “break point cluster region” (BCR) –unknown function---at chromosome 22q. Result: a chimeric fusion protein larger than normal Abl protein with enhanced kinase activity ABL BCR-ABL 210 , BCR-ABL Seen in children in equatorial Africa, Treatment B cell derived tumor of the jaw Cancer 190 , BCR- 185 Chromosome translocation BCL2 (mitochondrial inner membrane protein linked to apoptosis regulation) is seen in B cell lymphoma translocated from 18 to IgH enhancer t(14;18) Follicular B Cell Lymphoma Symptoms Autosomal dominant- defect in Autosomal dominant disease effects the the fibrillin 1 gene. eye, the skeleton and the cardiovascular system Fibrillin 1 gene encodes a component of connective tissue that is expressed in the tissues affected by Marfan’s where unusually strechable tissue is found. Philadelphia chromosome Chronic Myelogenous Leukemia Deficiency region on 14 (another fusion protein with dysregulated expression. Drives up expansion of B cells because normal apoptosis is inhibited Cancer Potential “drug target” for therapy is the associated kinase activity imatinib has been developed to inhibit this kinase activity shown to be effective in treating CML Disease Genetics Germline mutation TP53 gene Deficiency Epidemeology P53 mutation causes multiple types of cancer, heritable Symptoms Cancer Li-Fraumeni Genes involved in nucelotide excision repair (XPC, ERCC2, POHL) XPC Xerodoma Pigmentosa Franconi’s anemia Potentially 15 genes autosomal seen in Ashkenazi Jews recessive and X-linked (FRACB) and Afrikaners of S. complex of proteins that deal with DNA Africa incidence repair—defective complex 1/350,000 PLOG (DNA polymerase Mitochondiral Depletion Syndrome gamma), A467T mutation - loss of fidelity in mitoDNA replication Alpers Syndrome (4A) and MNGIE (4B) Predominately mutated Sensitivity to UV light in US patients increased incidence of skin cancer by age 10 in some patients neurological issues too. acute myelogenous leukemia and bone marrow failure, other congenital abnormalities (short stature) Mitochondrial DNA depletion and loss of mitochondrial function Treatment Disease Lynch Syndrome Genetics Deficiency Lynch syndrome in MSH2 and MLH1 defects may account Lebanese family MSH2 mutation (DNA repair) for up to 60% of cases also endometrial involvement in women Hereditary Nonpolyposis Colorectal cancer type 1 Kearns-Sayre Syndrome (KSS) Symptoms early onset (25-40 yrs) colorectal cancer; at least two relatives with it estimated to account for 46% of early onset HNPCC BLM is defective gene (recQ helicase) check integrity of DNA and DNA stability short stature and sun sensitive skin can develop any cancer type but earlier than general population Mitochondrial Disease mtDNA mutation Complex I: NADH dehydrogenase, mtDNA tRNA (MT-TL1) affects the nervous system and muscles, muscle weakness, headaches, seizures, lactic acidosis Mitochondrial tRNA gene MTTL1 Mitochondrial Disease mitochondrial deletions opthalmoplegia, pigment denegeration, cardiomyopathy, facial weakness, deafness, small stature Bloom’s Syndrome Mitochondrial myopathy, encephalmyopathy, lactic acidosis and stroke (MELAS) Epidemiology Treatment Disease Leber's Hereditary Optic Neuropathy (LHON) Genetics Deficiency Mitochondrial Develops young adult with painless, Most LHON patients (90%) have bilateral subacute visual failure males one of 3 identified point 5X more likely than females to be mutations in the mtDNA affected m. 3460G>A, m. 11778G>A or females with the disease may go on to m.14484T>C mutations affect develop an MS-like illness. different respiratory chain complex I subunit genes ATP6 - ATP synthase Mitochondrial disease Mitochondrial Disease - mutation, can't make ATP Epidemiology Symptoms Legally blind Nervous system: sensory neuropathy, muscle weakness, ataxia, vision loss Neuropathy, ataxia, retinitis pigmentosa (NARP) TYMP (thymidine phosphorylase) Mitochondrial Disease Mitochondrial Neurogastrointestinal autosomal recessive 2nd to 5th decade of life, multisystem disorder, GI tract - poor mobility, pseudo-obstruction with peristalsis, malabsorption, weight loss; neurological neuropathy and myopathy Encephalopathy Syndrome (MNGIE) multiple mtDNA mutations Myoclonic epilepsy with ragged red fibers (MERRF) Mitochondrial Disease - consistent with heteroplasmy, deficiencies in Complex I and IV Elevated serum levels of pyruvate and/or lactate, deficiencies in enzyme complexes of respiratory chain Treatment Largely supportive, provision of visual aids, occupational therapy Families with known risk: members should be encouraged to avoid alcohol and smoking or other environmental exposures that might exacerbate disease Leigh Syndrome (LSP) Mutations have also been Mitochondrial respiratory complex noted in mitochondria tRNA defects mutations have been noted in proteins (MTTV, MTTK, both mtDNA and nuclear encoded MTTW, MTTL1) genes functioning in the mitochondria respiratory chain. X-linked recessive and autosomal recessive modes of inheritance (involvement of nuclear genes)