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Genetic Disorders

Disease
Hemoglobinopathies
Microcytic Hypochromic Anemia

Gene/ Chromosome
Uneven production of & chains

Product/Lab/Dx
Fe deficiency Lead poisoning

Presentation
Thalassemias Excess chains precipitate leading to RBC hemolysis

Rx

Clinical Correlation
-Thalassemias exemplify reduced gene dosage. -Thalassemias exemplify reduced functional product. Sickle cell HbS chain sub Glu6Val Homozyg = disease Heterozyg = trait (normal clinically except in crises) -African Americans 1 in 600 have disease, 8% carriers HbC chain Glu6Lys Thrombosis, PE, retinal abnormalities

Normocytic Normochromic Anemia (Sickle cell novel property mutation)

Hemorrhage Bone marrow failure Dx with electrophoresis of Hb Mst II RFLP normally creates 2 small fragments. HbS mutation destroys one of the Mst sites, which then creates one large fragment. Point mutation Small deletion b/c of slipped mispairing Asp99Asn Asn102Thr chain Insertion 2bp, changes reading frame = deletes stop codon, Glu26Lys structurally abnormal fusion globin-like Both fusion and globin 4 Unstable globin Phe42Ser (F42S) Heme falls out Unstable tetramer hemolysis ( chain) locks Hb into R state alters interface btwn 1 & 2 subunits Locks Hb into T state Also in the interface Extends chain

Hb Hammersmith (drops the hammer) Hb Gun Hill Hb Kempsey (keepsy) (gain of fxn enhanced fxn) Hb Kansas (kick out O2) Hb Tak (takes O2)

Sickle cell disease forms fibers in RBC -Hemolytic anemia -crises caused by infection, dehydration, deoxygenation -HbC disease forms crystals in RBC -mild anemia, hemolysis RBCs look like targets (codocytes) Cyanosis (low O2 affinity) hemolysis

High O2 affinity polycythemia Low O2 affinity cyanosis High O2 affinity polycythemia

Will also see hemolysis

Hb E (variant Hb) Lepore Hb (variant Hb) Anti-Lepore (variant Hb) Hb Barts (-Thalassemia)

synthesis is reduced b/c of impaired RNA splicing Due to uneven crossing over as in Lepore Deletion of all 4 genes = no HbF and no HbA

Thalassemia phenotype Symptomatic No phenotypic expression Unable to release O2 Massive fluid accumulation

Homozygotes are asymptomatic, but mildly anemic Have neither nor genes Hb Miyada Hydrops fetalis lethal

Genetic Disorders
Disease Hb H (-Thalassemia) Hb Constant Springs (-Thalassemia) Gene/ Chromosome 4 Substitution in stop codon Add 31 aa to chain (- -/cs) 2 alleles affected Non-deletion type single base pair substitution See more 22 (HbA2) & 22 (HbF) -splice site mutation Single thalassemia allele See more 22 (HbA2) -intron or exon mutation -capping and tailing of RNA mutations posttranscriptional Large deletions brings enhancers closer to genes OR Substitutions alter affinity of regulatory proteins reqd for postnatal repression gene Product/Lab/Dx Deletion of 2 genes Globin is unstable Reduced synthesis Extended polypeptide tail Heinz body due to precipitated chains. No Hb A production= null Thalassemia If some HbA is detectable = + Thalassemia Electrophoresis can Dx HbF and HbA2 Hypochromic, microcytic severe anemia Transfusio n Control Fe accumulat ion Bone marrow transplant Hypochromic, microcytic RBC Slight anemia Presentation Rx Clinical Correlation Most severe form in SE Asia -null (- /) Non Deletional Thalassemia Most pts are genetic compounds not true homozygotes. NOT seen in utero. Splice Jxn mutations most common cause: -cryptic (no globin produced if 0) -intron mutations (+ conditions, HbA low) -exon mutations (cryptic donor used 40% of time nonfxnal , + condition, low HbA) -defects in capping & tailing mRNAs -deletions in LCR

Thalassemia Major (-null-Thalassemia)

Thalassemia Minor (-Thalassemia Trait)

HPFH Hereditary Persistence of Fetal Hb (heterochronic gene expression)

Fetal Hb left on

Genetic Disorders

Dx of HbS and HbC with electrophoresis

Dx Thalassemias with electrophoresis

Disease Multifactorial Diseases Retinitis Pigmentosum Hypercoagulability

Gene/ Chromosome digenic -peripherin locus

Product/Lab/Dx

Presentation

Rx

Clinical Correlation

Increased levels of Factor V, X, and prothrombin 9 partially independent genes esp. HSCR 1 (RET, chrom 10q), HSCR 6 (chrom 3p)& HSCR 7 (NNX3, chrom 19q) Intestinal aganglionosis lack intrinsic ganglion cells in myenteric & submucosal complexes.Dx within 24hr of delivery. Loss of peristalsis, S/S of bowel obstr. & massive dilatation of colon proximal to aganlionic segment

Hirschsprung Disease (HSCR)

Oral contraceptives in these susceptible pts increase risk of DVT and CVT 30150 fold. 1 in 5000 newborns.

Genetic Disorders
Disease Diabetes Mellitus Type 1 Gene/ Chromosome 20 genes implicated. Largest contributor fr genes of MHC (6p) Product/Lab/Dx Autoimmune destruction of pancreatic cells Presentation Rx

Diabetes Mellitus Type 2

Heterogeneous disorder (multiple diseases) Primarily environmental influences.

Insulin production or insulin resistance

Weight loss of 5-7% inciden ce of DM by 70%

Clinical Correlation Most common chronic disease in peds, 2/1000. Undefined relationship with Coxsackie Virus. Most common form of DM

Alzheimer Disease (AD)

Alzheimer Disease (continued)

Early onset: 3 genes amyloid precursor protein (APP on 21q), presenilin 1 (PSEN1, 14q), presenilin 2 (PSEN2). Postmitotic dinucleotide deletions of microsatellite rgns for APP. Late onset: 100s of genes focus on 4 allele (19q) for ApoE 7-10% monogenic highly penetrant form AD Mutations in genes encoding -amyloid precursor protein, presenilin 1 & 2, ApoE gene mutations lead to slight increase in nonfamilial AD MTHFR gene ala22val (as in neural tube defects). Major environmental influences. >80 possible genes focus on MTHFR gene (ala677val). Folic acid (vit B9) deficiency.

Postmortem demonstration of amyloid deposits, neurofibrillary tangles and neuronal plaques.

Most common neurodegenerative disease. 3/1000 in US. Chance of remaining unaffected by AD by 80 y/o for 4/4 homozygote is <10%. For 2/3 heterozygote is >80%. Progressive deterioration of memory & high cognitive fxn (due to the neurofibrillary tangles) 1-4% of people in developed countries. 4 allele of ApoE gene risk factor for AD

Degeneration of neurons due to deposits of amyloid peptide and tau protein. A peptide (from APP protein) found in amyloid/senile plaques in extracell space of brain.

Cardiovascular Disease

Incl: CAD (>50%), cardiomyopathies, conduction abnormalities, HTN, stroke, aneurism, PVD Abnormal closure of neural tube in wk 3-4 of gestation. Folic acid deficiency in mother she develops hyperhomocysteinemia as a result of mutated MTHFR gene (which converts homocysteine to methionine.)

Neural Tube Defects (NTD)

Genetic Disorders
Autism (part of Autism Spectrum Disorder) 7q speech/language 15q maternally inherited duplications (Angelman) 3/1000.Onset <3y/o, 3:1 preponderance for males. Heritability about 2-8% (population 0.2% risk). Immunizations risk? Clinical Correlation -Homogentisic acid is an intermediate in the formation of Phe and Tyrosine -Garrod (1908) -Mass newbor n screeni ng -Early Rx with dietary modific ations to avoid Phe accumu lation -BH4 defect Rx with lg doses of BH4 orally & admin 5HT, Epi, NE prn For all lysoso mal storage disease s: based on ability to In USA, 1 in 50 has PKU allele Incidence is 1 in 15,000 but in Turkey is 1 in 2600 Epitome of inborn errors -Normal plasma [Phe] <0,4mM

Disease Enzymopathies Alkaptonuria

Gene/ Chromosome

Product/Lab/Dx Homogentisic acid oxidase deficiency

Presentation -Black urine -Deposition of homogentisic acid and substrates of the enzyme = ochronosis -Osteoarthritis -Plasma [Phe] >1mM -Impaired brain fxn -Increased pheylpyruvic acid thru alternate paths -Seizure, albinism, musty odour to sweat and urine -Non PKU plasma [Phe] <1mM -Variant PKU in between the two

Rx

Phenylketonuria, PKU

Classic PKU, Variant PKU and nonPKU HyperPHEemia = 12q Impaired BH4 recycling: PCD=10q;DHPR=4p Impaired BH4 synth: GTP-CH=14q; 6PTS=11q -most PKUs are compound heterozygotes

Phe Hydroxylase deficiency OR deficiency in synthesis or recycling of BH4

Tay Sachs (lysosomal storage disease)

Chromosome 15 Hexosamidase A Deficiency (product of 3 gene system)

Inability to degrade GM2 ganglioside (sphingolipid) which accumulates in brain.

Infants normal until 3-6 months, progressive neuro degeneration. Cherry red Macula Adult HEXA alleles with residual activity, later onset neuro

1 in 27 Ashkenazi Jews are carriers, most commonly caused by 4bp insertion TATC (premature STOP)

Genetic Disorders
uptake enzyme from extrace llular fluid. Transpl ant normal cells. Bone marro w transpl ant. Enzym e replace ment therapy (ERT) e.g. Alduraz yme for -Liduroni dase

Hurler (lysosomal storage disease: mucopolysaccharidoses) MSPI (type I)

AR

-L-Iduronidase deficiency

Dx early: Corneal Clouding, skeletal changes, hepatosplenomegaly, coarse facies

Death <10y/o Due to alleles that impair enzymatic activity.

Scheie (lysosomal storage disease: mucopolysaccharidoses)

AR

-L-Iduronidase deficiency

Onset after 5y/o, normal intelligence & life span, Corneal Clouding, valvular heart disease

Due to alleles that confer residual activity.

Hunter (lysosomal storage disease: mucopolysaccharidoses)

XR -see genetic complementation

Iduronate Sulfatase deficiency

Similar to Hurler with slower progression

Milder phenotype, variable CNS involvement.

I-Cell Disease (lysosomal storage disease: loss of glycosylation post translational modification) Mendelian Susceptibility to Mycobacterial Disease (MSMD) (lysosomal storage disease: gain of glycosylation post translational modification) Homocystinuria

AR -defect in UDP-Nacetylglucosamine:Nacetylglucosaminyl-1phosphotransferase GNTPA gene chr 4 AR Missense mutation in interferon--receptor 2 (IFNGR2).

AR Deficiency of cystathionine synthase

Loss of glycosylation Abnormal lysosomes or inclusions throughout cytoplasm Novel Nglycosylation sites in mutant IFNGR2 protein. Overly glycosylated receptor fails to respond to interferon-. Accumulation of hymocysteine.

Acid hydrolases in excess in body fluids. Cellular levels diminished. Facial & skeletal changes, growth & mental retardation. Susceptibility to infection with moderately virulent mycobacterial sp.

Enzyme transfers phosphate to mannose residues. Death by 7 y/o.

Dislocation of lens Mental retardation Osteoporosis Long bones Thrombosis of veins & arteries Megaloblastic anemia Failure to thrive

Admin lg amts of pyridox ine (vitami n precurs or of the cofacto r)

First genetic disease responsive to vit therapy.

Genetic Disorders
1-Antitrypsin Deficiency (1AT) (along with HbS example of conformational mutations) AR Z allele - 1AT gene (SERPINA1) Chr 14 Inhibited elastase release from neutrophils in lower resp tract. Aggregation of mutant protein in RER of hepatocytes. Risk of emphysema & liver cirrhosis Infuse 1AT which then inhibit elastas e in lungs Caucasian high frequency of Z allele. Environmental variable = cigarettes. Survival after age 60 is ~60% in nonsmokers and 10% in smokers. [heme] reducers incl drugs, steroids, reducing diets, illness, surgery.

Acute Intermittent Porphyria Lebers Hereditary Optic Neuropathy (LHON) Kearns-Sayre Syndrome

AD Deficiency of porphobilinogen deaminase ND4 gene on mitochondria NADH dehydrogenase complex Mitochondrial disease (deletions in mtDNA) Mitochondrial disease Trisomy 21 (47,+21) or translocation

Intermittent neuro dysfxn. Manifests in response to precipitating factors that decrease [heme] in liver. Eyes & red ragged fibers Accumulation of mtDNA in substantia nigra Ophthalmoplegia Complete Heart block short stature Cerbellar ataxia Skeletal muscle with irregular shape and blotchy red appearance Hypotonia, failure to suckle, Epicanthal folds, small ear with over-folded helix, Single flexion crease in hand, clinodacytyly of 5th digit, Delayed dental eruption, congenital heart disease, mental retardation, premature AD Infants have large malformed & low set ears, microcephaly, mental retardation, micrognathia, glenched fists with digital overlap, rocker bottom feet and hands with syndactyly. prominent occiput Hypertonia Sever CNS malformations: arhinencephaly, failure of frontal lobe to separate, mendtal deficiency, polydactyly, syndactyly, rocker bottom feet, cleft lip, microcephaly, cardian & renal defects. Enhanced Tumors (on face)

Myoclonic epilepsy with Red Ragged Fibers Syndrome Downs Syndrome

Overexpression of DSCR1 and DYRK1A on chr 21. DSCR encodes inhibitor of calcineurin (CN) & inhibits VEGF inhibiting bld vessel formation during N brain and heart formation

1/800 Recurrence risk about 1% (+mothers age risk)

Edward Syndrome

Trisomy 18 (47,+18)

1/8000 live birth Recurrence risk about 1% High incidence of congenital heart & kidney defects. 50% die in first week, 90% die within first year. 1/19,000 Recurrence risk about 2%

Patau Syndrome

Trisomy 13 (47,+13)

Trisomy 8 Burkitts Lymphoma

Trisomy 8 Translocation btwn chr

1/25000 1/50000

Genetic Disorders
8 and 14 Gene/ Chromosome X CGG repeat expansion in 5UTR of FMR1 gene (>200 copies) expression of c-myc Product/Lab/Dx FMRP (RNA binding protein) is silenced due to gene methylation.

Disease Fragile X Syndrome (& Fragile X Tremor/Ataxia Syndrome forms intranuclear neuronal inclusions from FMR1 [mRNA] increase) Xeroderma Pigmentosum

Presentation Prominent ears, lg jaw & testes (JET), mental retardation.

Rx

Clinical Correlation 2nd largest cause of moderate mental retardation in males 1/4000 live births

AR - Defects in nucleotide-excision repair XPAC protein of excision repair system Defects in nucleotideexcision repair Defects in nucleotideexcision repair

Individuals unable to reverse T-T dimerization

Freckle like spots on skin, sensitivity to sun, predisposition to skin Ca & ocular neoplasms Dawrfism, sensitive to sun, premature aging, deafness, mental retardation Brittle hair, skin abnormalitites, short stature, immature sexual development, characteristic facies Predisposition to colon cancer

30% of pts have neuro manifestations such as microcephaly, cognitive losses

Cockayne Syndrome

Trichothiodystrophy

Hereditary nonpolyposis colon cancer Fanconi Anermia

Defects in mismatch repair in MutS and MutL AD AR - Defects in repair of interstrand cross links Mutation in one of 12 genes FANC A-N AR - Defects in DNA damage detection and response b/c of mutation to ATM gene AD, Defects in DNA damage response AR- ReQ Helicase Repair issue (unwinds DNA for replication, transcription, repair) Mutation of BLM gene whose product is helicase Chr 5p deletion

2-10% of all colon Ca Marro w transplant Bone marrow failure w/ failure of hematopoiesis Telangiectasis red spider veins

Increased chrom breaks

Ataxia Telangiectasia

Truncated or exon skipping mutation.

Li-Fraumeni Syndrome Bloom Syndrome

p53 mutation Prone to chromosome & gene mutations leading to premature aging & increased Ca. Increasing size of deletion translates into increased mental retardation.

Cri-du-Chat Syndrome

Wolf-Hirschhorn

4p deletion

Increased skin pigmentation, abnormalities of skeleton, heart and kidneys, predisposition to leukemia Defective ms coordination, dilation of bld vessels in skin and eyes, immune deficiencies, sensitivity to ionizing radiation, predisposition to Ca Predisposition to Ca in many different tissues Small body size, sun sensitivity, immunodeficiency, male infertility, hypo/hyperpigmented skin, predisposition to malignant tumors. High-pitched, cat-like cry. Microcephaly, epicanthal folds, low set ears and micrognathia, congential heart disease, mental retardation Prominent forehead and

Prone to Ca, DM, chronic lung disease. Common among Ashkenazi Jewish pop where 1/100 is carrier 1/20,000 to 1/50,000 live births More common in females (3:1). Pts are fertile and can reproduce.

Genetic Disorders
Syndrome broad nasal root (Greek Warrior Helmet), downturned mouth, congenital heart defects, growth retardation & sever mental retardation. Presentation Elfin-like facial features, heart and blood vessel stenosis in 70%, dental & kidney abnormalities, musculoskeletal problems, Hyperacusis with remarkable musical and verbal abilities. Cocktail Party syndrome Hypoplasia or aplasia of thymus & parathyroids, truncal cardiovascular malformations & abnormal facies. Primary hypoparathyroidism manifests as hypocalcemic tetany. Fish mouth, cleft palate, elfin ears. Lissencephaly (smooth brain), microcephaly, high & furrowing forehead, multiple organ anomalies. Obesity, excessive & unusual eating habits, macrophasia, mental retardation. Severe menatal retardation, spacticity, seizures & unusual facial features, laughing, stance & gait. Obesity, short stature, subcutaneous calcifications Brachydactyly Pseudohypoparathyroidism PHP1a has signs of AHO

Disease Williams Syndrome

Gene/ Chromosome 7q deletion where ELN and LIMK1 genes are located

Product/Lab/Dx Deletion of elastin leads to vascular disease. LIM Kinase strongly expressed in brain & is involved in the regulation of the actin cytoskeleton. Abnormal migration of 3rd & 4th pharyngeal pouches

Rx

Clinical Correlation

DiGeorge/Velocardiofacial Syndrome

22q deletion AD but 95% are de novo. TBX1 & CRKL genes may be involved. TBX1 (T box) play roles in formation of normal large arteries.

1/2000 to 1/4000 live births

Miller-Dieker Syndrome

Prader-Willi Syndrome

17p deletion 80% de novo, 20% unbalanced translocations Haploinsufficiency of gene LIS1 15q deletion

Lack of paternally imprinted copy Lack of maternally imprinted copy

1/10,000 to 20,000

Angelman Syndrome

15q deletion

1/15,000

Albright Hereditary Osteodystrophy (AHO)

Defect in GNAS gene

Pseudohypoparathyroidism (PHP)

PHP type 1a = PHP+AHO Pseudophseuodhypopar athyroidism (PPHP) is AHO without renal tubule dysfxn

Abnormality in Ca2+ metabolism. Deficient in parathyroid hormone.

Genetic Disorders

Sex Chromosome 46,XX males

46,XY females Klinefelter Syndrome

47,XYY Syndrome

Diseases Translocation of Y sequences on short arm of X SRY gene translocated onto X SRY gene deleted/mutated from Y 47,XXY Errors in paternal meiosis I Errors in maternal meiosis I or II, or postzygotic mitotic error Mosaic karyotype 46,XY/47,XXY most common Paternal nondisjunction at Meiosis II (YY sperm)

Phenotypic males

1/20000

Phenotypic females Androgen deficiency Increased FSH & LH Barr body present Low semen count Low serum testosterone High serum estradiol Normal testosterone levels Phenotypic male Tall, thin, small testes Gynecomastia Pear body shape Infertile male (3%) Lowered IQ Poor social adjustment Phenotypic males Increased childhood growth, acne, normal sexual development & fertility, IQ 10-15 points below sibs, attention deficits Phenotypic female Above avg height, normal sexual development, normal fertility, IQ 10-15 pts below sibs At birth: edema of dorsum of foot, neck webbing, hypoplastic left-sided heart or coarctation of aorta. At puberty: short stature, 1 or 2 amenorrhea, unusual facies, webbed neck, low posterior hair line, broad chest, widely spaced nipples, renal & cardiovascular abnormalities. Normal IQ Ambiguous external genitalia Frasier=complete gonadal dysgenesis X linked mental retardation. Undescended testes, mircropenis. Variants of XY sex reversal Testost erone Rx 1/1000 Most common sex chromosome disorder

1/1000

47,XXX Syndrome

Maternal nondisjunction at meiosis I

1/1000

Turner Syndrome

45,X (50% of pts) Paternal chromosomal error. Single X is maternal in origin

Barr body absent

1/4000

Sexual Development Denys-Drash and Frasier Syndromes X-linked ATRX gene

Disorders WT1 gene on 11p mutations disrupt teste development

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Genetic Disorders
45,X Cytogenic aberrations on Xq Mutations on FOXL2 gene Germ cell loss, oocyte degeneration, ovarian dysgenesis Male and female reproductive organs. Ambiguous genitalia Gonadal tissue of only one sex. Female hermaphroditism ovarian tissue with ambiguous or male external genitalia due to congenital adrenal hyperplasia (CAH). Male pseudoH testes present with incompletely developed genital ducts, external genitalia Most commonly deficiency in 21hydroxylase. 5-reductase= feminization of external genitalia. Screen to detect enzyme defect. Hormo nal replace ment. Surgery Apparently normal female, blind vagina. Testes present (no uterus, no uterine tubes) Axillary & pubic hair almost absent. Sterile. Branchial cleft, defects of inner or middle ear, renal abnormalities Neurofibromas in skin Caf-au-lait spots Neurofibrosarcomas, brain tumours Short-limbed dwarfism with large head & low nasal bridge Atheromas Xanthomas Arcus cornea 1/12500

Hermaphroditism Pseudohermaphroditism 46,XX = female pseudohermaphroditism 46,XY = male pseudohermaphroditism

Congenital Adrenal Hyperplasia (CAH)

Androgen Insensitivity Syndrome

46,XY

Deletion/Point mutation of receptor gene or androgen binding domain or DNAbinding domain of androgen receptor protein.

1/20000

Single Gene BOR Syndrome (Branchio-oto-renal) Von Recklinghausen Neurofibromatosis (NF1) Achondroplasia Familial Hypercholesterolemia

Autosomal Disorders AD mutation in EYA1 gene (encodes protein phosphatase) AD, 17q de novo mutation of NF1 gene, negative regulator of RAS oncogene AD, mutation of FGFR3 gene on chromosome 4 80% de novo LDL receptor mutation on 19p (most common) -clear gene dosage effect -also see mutations in ApoB100, Autosomal Recessive

Tumors of nerve sheaths

1/3000 100% penetrant by age 5 Complete penetrance Cholest erol reducin g meds Dietary restrict Hetero & homozygotes develop early CHD

-6 different classes of LDL receptor mutations -PCSK9 protease mutations lead to GAIN of Fxn

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Genetic Disorders
Hypercholesterolemia & PCSK9 protease ions & lifestyle change s Impairs Cl- channel, which decreases amt of Cl- leaving cell and thus H2O will not leave cell -Pulmonary disease: thick secretions, increased infections, COPD, death by 33. -Pancreatic disease: maldigestive syndrome due to deficient secretion of pancreatic enzymes. -Nonclassical has CF-like pulmonary infections, less severe GI disease, increased sweating of Cl-ms weakness by 3, wheelchair by 12 -respiratory/cardiac failure -death by 20 -moderate decrease in IQ -increased creatine kinase Milder phenotype compared to DMD Early Dx Newbo rn screeni ng Couples screeni ng Prenata l Dx 1012wks chorion ic villus 1/2500 caucasian CFTR genotype = good predictor of pancreatic fxn but poor predictor of pulmonary disease 1/50 caucasians have F508

Cystic Fibrosis

AR - CF Transmembrane Regulator protein gene mutation CFTR gene on 7q Most common mutation is F508 partially fxnal CFTR=Arg11His. Non-classical mutation on SCNN1 gene. Modifier gene TGF1 has 2 variants assoc with more severe lung disease X linked Recessive Mutations in dystrophin gene

Duchenne Muscular Dystrophy

Becker Muscular Dystrophy

Osteogenesis Imperfecta 4 types

X linked Recessive Mutations in dystrophin gene -60% of males have gene deletion at either 5 or central rgn AD: Type I procollagen formed from 2 pro1 chains encoded by COL1A1 and COL1A2. -Type I: Normal collagen, decreased quantity -Type II-IV: Abnormal collagen due to Gly sub

Mutations in carboxyl end of collagen structure prevents subunits assoc (triple helical collagen Gly-X-Y)

-brittle bones, skeletal deformities depending on locus and allelic heterogeneity -Type I, II have dark sclerae

Screeni ng only avail for families with Hx Detect with ultraso und, analysi s of collage n from chorini c villus, and family Hx Braces

1/3300 male births 2/3 of pts have carrier mom Fitness 70% 80% of males have no family Hx 1/15000

Parkinson Disease Friedreich Ataxia

Somatic mtDNA deletions AR expansion of GAA repeat in FRDA gene

Loss of fxn of frataxin = increased mt Fe, impaired heme synthesis, reduced activity of Fe-S proteins (e.g.

Cardiomyopathy, Type 2 DM.

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Genetic Disorders
complexes I and II of ETC) CUG rpts bind to RNA binding protein which alters splicing Mutant Huntingtin protein has NOVEL property. Insoluble aggregates of the mutant protein and other polypeptides in nuclear inclusions. Soluble nonaggregated form of mutant huntingtin also pathogenic. Deficiency in factor VIII Vit D resistance

Myotonic Dystrophy 1 (DM1) DM2 Huntington Disease (HD)

AD expansion of CTG rpt in 3UTR end of DMPK gene AD expansion of CCTG repeat AD expansion of >40rpts of codon CAG in HD gene. Mutant protein has abherrant polyglutamine residues which have interactions with transcription factors which impairs transcription of many proteins. X-linked recessive X-linked Dominant Defect in gene for endopeptidases X-linked Dominant Mutation in MECP2

Ms weakness, wasting, cardiac conduction, testicular atrophy, insulin resistance, cataract Similar to DM1 Neurodegeneration, athetosis, loss of cognition

Hemophilia A X-linked Hypophosphatemic Rickets Rett Syndrome

Bleeding, hematomas and hemarthroses. Less severe in females Rapid onset of neuro S/S at 6-18months Autis features Wringing hands, flapping arms Microcephaly develops Seizures 50% Mental deterioration can stop Retinoblastoma, small lung carcinomas, breast Ca -sporadic form 70% of cases: unilateral, presents later in childhood (2430months) -familial form (AD) bilateral, early infancy, high risk of other primary tumors Clear cell renal carcinoma

Retinoblastoma

Mutation in RB1 gene (gatekeeper)

Mutation in p110 cell cycle regulation altered

Tumor suppressor gene mutation

von Hippel-Lindau Syndrome Familial Breast & Ovarian Ca

Mutation in VHL gene (gatekeeper) Mutation in BRCA-1 (27q) & BRCA-2 (13q) genes (caretaker)

mutation in VHL normally part of complex to inhibit angiogenesis BRCA are responsible for chromosome repair (double stranded breaks)

Tumor suppressor gene mutation Tumor suppressor gene mutation. Mutation in BRCA2 can lead to Fanconis Anemia

Breast & Ovarian Ca

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Genetic Disorders
Rubenstein-Taybi Syndrome Stickler Syndrome Loss-of-Fxn in a transcriptional coactivator Robin Sequence Unknown cause Abnormalities in transcription Mutations in gene encoding for type II collagen Mental retardation, broad thumbs and large toes, distinctive facial features, congenital heart defects Restriction of mandibular growth before 9th week gestation, cleft palate, small mandible, defects in stature, joints

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