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Pathobiology: Genetic Diseases (Poulik) GENERAL PRINCIPLES OF GENETIC DISEASES AND SINGLE GENE DISORDERS: Genetic Mutations: Definition: stable, heritable alteration in DNA Different Types of Mutations: o Chromosomal Level: result in cytogenic or karyotypic abnromalities Genome mutation: loss or gain of a whole chromosome (ie. trisomy) Chromosome mutation: structural changes in chromosome that gives rise to visible structure changes in the chromosome (ie. translocations, deletions) Trinucleotide repeats: although gene mutations, may be visible by karyotype when cells cultured in different media (ie. Fragile X syndrome visible in foalte deficient media) o Gene Level: most are NOT visible by karyotype (some trinucleotide repeats are the exception) and therefore require molecular genetics techniques to define mutation (ie. DNA sequencing) Point Mutations: single base substitution In exon: protein coding sequence of enzyme, structural or regulatory protein In intron: in non-protein coding sequences (promoter, enhancer etc.) o May lead to reduction or loss of transcription Frameshift Mutations: caused by deletions or insertions in coding sequence and alterations in reading frame of DNA Trinucleotide Repeats Pathological Significance of Genetic Alterations: may do a number of things o Directly cause disease (ie. Tay Sachs) o Predispose to disease (ie. X-linked agammaglobulinemia) o Alter response to another disease (sickle cell anemia protection against malaria) Manifestations of Genetic Disease: o Abnormal metabolism or physiology o Abnormal development that may result in major or minor malformations o Spontaneous abortion or stillbirth (with or without malformations) o Asymptomatic or subclinical (ie. female carrier of X-linked trait) Single Gene Disorders with Mendelian Inheritance: Definition: diseases resulting from a mutation in a single gene of large effect, inherited according to Mendelian patterns Inheritance Patterns: most are recessive* o Autosomal Dominant: clinical phenotyp occurs with single copy of mutant allele Usually non-enzymatic proteins 1 parent affected (if not affected, de novo mutation) Both males and females affected 1 in 2 chance of transmitting disorder Clinical features modified by reduced penetrance and expressivity o Autosomal Recessive: clinical phenotype occurs only when both alleles are defective (although defect in both alleles does not have to be the same) Usually enzymatic proteins Trait usually does not affect parents Both males and females affected 1 in 4 chance of transmitting disorder More uniform expression of defect than AD disorders (complete penentrance common) Onset usually early in life o X-linked: more common in males (only 1 X cs) Mechanisms of Pathogenesis of Single Gene Disorders: o Mutations: Enzymes or enzyme inhibitors Receptors Transport or structural proteins o Enzyme Defects: result in reduce or absent enzyme leading to specific block in metabolism (usually of a catabolic pathway) leading to Abnormal accumulation of metabolites (substrates) Decreased amount of end product that is necessary for normal function Failure to inactivate a tissue damaging substance ENZYME DEFECTS- LYSOSOMAL STORAGE DISEASES: Lysosomal Storage Diseases- General: Lysosomes: “intracellular digestive tract” involved in turnover of macromolecules within the cell o Contain degradative enzymes called hydrolases o Function in acid environment of the lysosome o Made in the ER, sent to the Golgi, undergoes post-translational modification to target it to lysosomes Lysosomal Storage Diseases: due to lack of any protein essential for normal function of lysosomes o Distribution of non-degraded material (ie. organ affected) due to an LSD is determined by: Tissue where most of the degraded material is found Location where most of the degradation usually occurs o Rare (1/8000 births) o Most are autosomal recessive Exceptions: both are X-linked recessive Fabry Disease Hunter Syndrome o Grouped based on type of macromolecule undergoing degradation: Mucopolysaccharides Sphingolipids Sulfatidoses Cerebrosides Mucopolysaccharidoses (MPS): General: o Mucopolysaccharides: group of macromolecules composed of glycosaminoglycans (GAGS), which are long chain carbohydrates with disaccharide repeating units GAG Examples: Dermatan sulfate (heart, blood vessels, skin) Heparan sulfate (lung, arteries, skin) Keratan sulfate (cartilage, cornea, intervertebral discs) Chondroitin sulfate Hyaluronic acid Proteoglycans: GAG + protein (secreted by GAG synthesizing cells) Function: involved in structural integrity of the ECM GAG Synthesizing Cells: fibroblasts, endothelial cells, leukocytes Secrete proteoglycans GAGs that are not secreted are degraded by lysosomal hydrolases (enzyme deficiency results in accumulation in lysosomes and free GAGs in urine) o Mucopolysaccharidoses (MPS): Usually progressive disorders Classified numerically from MPSI-MPSIV Share similar clinical features: Multi-system involvement Organomegaly Abnormal facies Joint stiffness and deformity Mental retardation Diagnosis: Presence of GAGS: o Urinary: age-dependent (present in normal infants up to a year old) Look for larger than normal amounts of heparan and dermatan sulfate (normal urine contains mostly chondroitin sulfate) o Amniotic fluid Enzyme Assays: o Prenatal: Cultured cells from amniotic fluid Chorionic villus biopsy less suitable (have low enzyme activity) o Postnatal: measure enzyme activity in plasma, leukocytes or skin fibroblasts - - Hurler Syndrome (MPS I): o Inheritance Pattern: autosomal recessive o Deficiency: α-L-idurondase enzyme activity o Onset: 6-8 months o Common Features: severe mental and motor regression with death usually before 10 years of age Respiratory disease Storage in airway epithelium and bone Small ribcage (oar-shaped ribs) and stiff joints Decreased expansion due to hepatomegaly Upper airway obstruction due to storage in tongue, lymphoid tissue, airway epithelium, pharyngeal soft tissue Coarse facial features Ophthalmic disease with early corneal clouding (retinal disease, glaucoma) CV disease (valve disease, CAD, congestive heart failure) Accumulation of GAGs in histiocytes, mycocardial cells, heart valves, coronary arteries and aorta Dwarfing Accumulates in bone (growth plates) and prevents linear growth Stiff joints Hepatosplenomegaly Storage in hepatocytes and Kupffer cells of lvier Storage in histiocytes in the spleen CNS disease (mental retardation, hydrocephalus, spinal cord compression) Storage in neurons, macrophages and meninges Deafness Alder-Reilly anomaly (accumulation of MPS in PMNs- granular appearance) o Diagnosis: urinary excretion of dermatan and heparan sulfate Hunter Syndome (MPS II): o Inheritance Pattern: X-linked recessive o Deficiency: iduronate sulfatase o Onset: in early infancy or childhood o Common Features: similar clinical features to Hurler, but LESS severe (mental deterioration with varying degrees of neurological involvement) Coarse facial features Dwarfing Stiff joints Progressive deafness NO corneal clouding* o Diagnosis: urinary excretion of dermatan and heparan sulfate Sphingolipidoses: General: o Cause: defect in metabolism of sphingolipids o Sphingolipids: long-chain amino alcohols (sphingosine) attached to a fatty acid to produce a complex lipid (ceremide) Membrane Lipids: Sphingomyelin Glycosphingolipids: o Cerebrosides (add sugar to ceremide) o Sulfatides o Globosides o Gangliosides (add polysaccharide + N-acetylnueramic acid to ceramide) Niemann-Pick Disease: o General: Type I (A and B): Cause: deficiency of sphingomyelinase enzyme, leading to progressive accumulation of sphingomyelin (ubiquitous component of cellular organellar membranes) o Type I: o - Type II (C and D): Cause: defect in cholesol esterification causing lysosomal accumulation of unesterified cholesterol Type A (Severe Infantile): Most common of type I: 70-80% of all cases (often in Eastern European Jews) Presentation: within the first weeks of life (death occurs by age 3 or 4) o Severe neurologic impairment (hypotonia, progressive psychomotor retardation) o Failure to thrive o Hepatosplenomegaly (marked) o Macular cherry red spot (50% of patients) o Accumulation of foamy lipid macrophages in many tissues (liver, lung, spleen, LNs, kidneys, bone marrow, peripheral and central neurons) o Atrophy of the brain Type B (Chronic Visceral): Less common than Type A: also often seen in Eastern European Jews Presentation: infancy or childhood (typically survive into adulthood) o Organomegaly (often present with splenomegaly and then develop generalized visceral involvement) o Generally NO CNS involvement Type II: Type C: Most common: more common than A and B combined Cause: defect in NPC-1 (95%) or NPC-2 gene that encodes for a protein involved in cellular trafficking of exogenous cholesterol (normally brings free cholesterol from the lysosome to the cytoplasm) Clinical Features: variable o Classic Phenotype (Neurovisceral): presents in childhood (2-4 years) with death typically occurring between 5-15 years of age Variable hepatosplenomegaly Vertical supranuclear opthamoplegia (supranuclear palsy) Progressive ataxia Seizures Psychomotor regression (accumulation of cholesterol in neurons is lethal to those cells) Bone marrow contains Niemann-pick cells (foamy) and sea blue histiocytes o May present at birth with hydrops fetalis and still birth o Fatal neonatal liver disease (giant cell hepatitis) o If live into adulthood, may present with dementia and psychosis Type D: Rare variant of type C: found in Nova Scotia (less severely affected) Gangliosidoses: o GM1 Gangliosidoses: Deficiency: deficiency in β-galactosidase enzyme that results in accumulation of ganglioside in neurons (clinical variability depends on amount of residual enzyme activity) Β-Galactosidase Enzyme: 3 isoenzymes (A,B,C) o Transcription of this enzyme requires an activator that may cause similar features if deficient Type I (Generalized/Infantile): Deficiency: virtual absence of all 3 isoenzymes of B-galactosidase Onset: birth to 6 months (death often before age 2) Clinical Features: o Progressive neurologic deterioration (seizures) o Coarse facial features o Hepatosplenomegaly (accumulation of gangliosides in liver, spleen, renal tubular epithelium) o o o - Macular cherry red spots (50% of patients) Skeletal deformities (dystosis multiplex) Has features of both neurolipidoses and MPS, leading to a “pseudoHurler phenotype” Type II (Juvenille): Deficiency: absence of A and B isoenzymes only Onset: juvenile (1-2 years old) with death occurring by age 3-10 Clinical Features: o Slower psychomotor retardation o Less visceromegaly o Milder skeletal disease Diagnosis: Measurement of B-galactosidase activity in peripheral blood leukocytes: o Type I: virtually no activity o Type II: 5-10% activity Peripheral Blood Smear: vacuolization of lymphocytes (crude method due to the fact that many LSDs have this feature) o GM2 Gangliosidoses: Cause: inability to catabolize GM2 ganglioside (required 3 polypeptides encoded by 3 separate loci) Tay Sachs Disease: defect in α subunit of Heaminidase A Sandhoff’s Disease: defect in β subunit of Hexaminidase A GM2 Activator Deficiency Gangliosidosis: defect in GM2 activator Clinical Features: similar because they all result in GM accumulation GM2 accumulates in many tissues, but CNS and retina are the dominant features of the disease o Neurons are swollen and contain cytoplasmic vacuoles o Lysosomes contain whorled material by EM o Brain first enlarges, and then becomes atrophic Infants appear normal at birth, followed by rapidly progressive neurodegenerative disease with seizures, dementia and blindness o Loss of motor skills at 3-6 months o Death by 2-4 years of age Macular cherry red spot Ethnic Risk: 1/30 carrier rate in the Askenazi Jewish population Sulfatidoses: o Metachromatic Leukodystrophy: Cause: deficiency of arylsulfatase A enzyme, leading to the accumulation of non-degradeable galactocerebroside sulfate in the white matter of the brain, peripheral nerves, liver and kidney Results in breakdown of myelin sheath (demyelination and gliosis) As a result, predominantly a neurodegenerative disorder Arylsulfatase A also requires presence of saposin B (solubilizes hydrophobic lipid to allow it to be accessible to the enzyme) and therefore, absence of SAP will cause similar disease 3 Forms: Late Infantile: most common (diagnosed by age 2; death before age 5) o Regression of motor skills (hypotonia, muscle weakness) o Mental deterioration (loss of milestones) o Rigidity and convulsions o Unusual loss of white matter on CNS imaging Juvenile: diagnosed between 3-16 years of age; death 6-8 years after diagnosis o Changes in gait and cognitive skills o Progressive regression of all skills Adult Onset: diagnosed after 16 years of age o Psychiatric or cognitive symptoms occur first o Motor symptoms (neurologic) appear later - Diagnosis: Urine: spot screening test (shows metachromasia due to presence of sulfatide) Imaging: usual loss of white matter due to demyelination Biopsy: usually of a sural nerve (demyelination, metachromatic granules and unusual cytoplasmic inclusions) o Stains: PAS +, Alcian blue, acidified Cresyl violet Arylsulfatase A activity levels Genetic testing: gene located on long arm of cs 22 o Multiple Sulfatase Deficiency: Cause: reduction in activities of several sulfatidases (arylsulfatidase A,B,C) resulting in the accumulation of sulfatides, sulfated GAGs, sphingolipids and steroid sulfates Clinical Presentation: combines clinical features of metachromatic leukodystrophy and MPS Cerebrosidoses: o Gaucher Disease: most common lysosomal storage disease* Defect: glucocerebrosidase enzyme (results in accumulation of glucocerebrosides and other glycolipids) Glucocerebrosides: derived from breakdown of the membranes of senescent leukocytes and RBCs Accumulation: incompletely metabolized substrate stored in monocytes and macrophages (stains positively with PAS) o Gaucher Cell: crumpled paper appearance to cytoplasm with eccentrically displaced nucleus Type 1 (Chronic Non-Neuronopathic Form): Cause: reduced levels of glucocerebrosidase Most common type: 99% of cases Population affected: children and adults (common in Ashkenazi Jews) Clinical features: accumulation of glucocerebrosidase limited to mononuclear phagocytes throughout the body, WITHOUT brain involvement o Hepatosplenomegaly o Cytopenias secondary to (hypersplenism and bone involvement) o Bone involvement: Avascular necrosis (esp. of the hip) Osteopenia with fractures (radioluscent bones due to replacement by Gaucher cells) Lytic lesion Bone crises (collections of Gaucher cells interfere with vascularization, causing SEVERE pain) Erlenmeyer flask deformity (abnormality in new bone formation resulting in flattened ends of femurs) Type 2 (Acute Neuronopathic Form): Cause: absent glucocerebrosidase Population affected: infants, with death usually by age 2; no predilection for Ashkenazi Jews (panethnic) Clinical features: o Progressive CNS involvement o Hepatosplenomegaly o Cytopenias (secondary to hypersplenia) o NO bone involvement Type 3 (Sub-Acute, Intermediate Form): Cause: reduced glucosidase activity Population affected: rare, juvenile form Clinical features: o Progressive CNS involvement (begins in teens and twenties) o Hepatosplenomegaly o Cytopenias (secondary to hypersplenism and bone involvement) o Bone involvement Diagnosis: measurement of glucocerbrocidase activity (peripheral blood leukocytes or fibroblast culture) - Treatment: Replacement therapy with recombinant enzymes Bone marrow transplantation Future gene therapy Other Sphingolipidoses: o Fabry Disease o Krabbe Disease ENZYME DEFECTS- DISORDERS OF CARBOHYDRATE METABOLISM: Galactosemia: Cause: deficiency of galatose-1-phosphate uridyltransferase enzyme Inheritance: autosomal recessive Clinical Features: o Symptoms: appear a few days after milk ingestion Vomiting Failure to thrive Diarrhea Liver dysfunction o Accumulation of galactose-1-phosphate: causes damage to liver, CNS, and other body systems (eyes, liver and brain most affected) Renal failure Hepatomegaly and cirrhosis Cataracts Brain damage Increased frequency of E.coli septicemia o Pathologic Findings: Marked steatosis of hepatocytes (eventually leading to cirrhosis) Brain shows edema, gliosis and neuronal necrosis Lab Diagnosis: o Galactosuria (clintest will be positive) o Generalized aminoaciduria, proteinuria and hyperchloremic acidosis common Newborn Screening: will likely never see a case because of this Other causes of elevated levels of galactose: o Galactokinase deficiency o UDP-galactose-4-epimerase deficiency Glycogen Storage Diseases: General: o Cause: defects in enzymes involved in degrading and in synthesizing glycogen Note: glycogen also degraded by lysosomes by acid maltase; deficiency in this enzyme will result in lysosomal accumulation of glycogen o Glycogen: Liver: maintains normal blood glucose during fasting Defects: storage of glycogen in the liver leading to reduced blood glucose Muscle: provides substrates for generation of ATP through glycolysis for muscle contraction Defects: storage of glycogen in the muscle leading to muscle weakness o Presentation: with either liver or muscle involvement, or a more generalized picture Hepatic Forms: o General: cause hepatomegaly and hypoglycemia o Von Gierke Disease (Type I): Defect: glucose-6-phosphatase enzyme Clinical Presentation: Hepatomegaly (leading to adenomas and eventually carcinomas) Renomegaly Short stature Excessive fat in the face and buttocks (doll-like appearance) Marked lipidemia (causing eruptive xanthomas) Severe fasting hypoglycemia - - Pathologic Findings: Liver: uniform distribution of glycogen within hepatocytes (distended) Renal tubular cells: accumulation of glycogen Muscle: normal Myopathic Forms: o General: causes glycogen storage in muscles o McArdle Disease (Type V): Defect: deficiency in muscle phosphorylase enzyme (required to convert glycogen to G1P) Clinical Presentation: Muscle weakness and painful cramps after exercise WITHOUT increased lactate Prolonged exercise can result in muscle fiber necrosis (rhabdomyolysis), myoglobinuria and acute renal failure Marked decline in muscle function and wasting of individual muscle groups with age (typically presents in 2nd/3rd decade of life) Pathologic Findings: Skeletal Muscle: o Subsarcolemmal accumulation of glycogen (forms vacuoles and blebs seen by LM) o Can also stain for muscle phosphorylase enzyme Systemic Forms: o General: do not fit in hepatic or myopathic categories o Pompe Disease/Generalized Glycogenosis (Type II): Defect: lysosomal enzyme acid maltase (alpha-1-4 glucosidase) Clinical Features: Presentation: infantile (death by 1-2 years of age) Symptoms: o Muscle weakness (hypotonia and wasting) o Heart involvement (cardiomegaly leading to progressive heart failure)* o Hepatomegaly o Enlarged tongue Pathologic Findings: Glycogen deposits in lysosomes: in myocardium, skeletal muscle, liver, smooth muscle of vessels, neurons of CNS o PAS: glycogen o PAS diastase: shows empty space where glycogen was digested o EM: glycogen in packets within lysosomes o Anderson’s Disease/Brancher Glycogenosis (Type IV): Defect: amylo-1,4-to 1,6-transglucosidase (brancher enzyme) Clinical Features: Presentation: more generalized disease presenting in infancy with death within 2 years due to cirrhosis Symptoms: o Hepatomegaly and failure to thrive in the first year of life o Progresses to portal fibrosis, cirrhosis and death o Cardiomyopathy o Muscle atrophy Pathologic Findings: Liver: diffuse fibrosis and remaining hepatocytes contain cytoplasmic accumulations of chunky, hyaline or vacuolated material o Abnormal deposits are PAS+ but diastase resistant ENZYME DEFECTS- DISORDERS OF AMINO ACID METABOLISM: Phenylketonuria (PKU): Cause: o Classic: deficiency of phenyalanine hydroxylase (PAH; 98% of cases) Cannot convert Phe Tyr o Other: in these cases, the patients are also unable to metabolize tyrosine and tryptophan, and dietary restriction will not prevent neurologic impairment - - - - Abnormalities in BH4 (cofactor for PAH) Abnormalities in dihydropteridine reductase (DHPR) enzyme that recycles BH4 Clinical Features: o Mental retardation o Fair hair and blue eyes o Musty body odor o Eczema Laboratory Screening: o Newborn screening o Urinary excretion of minor pathways of phenylalanine metabolism Phenylpyruvic acid, phenyllactic acid, phenylacetic acid o Serum phenyalanine levels Management: o Infant strict dietary restriction (to prevent mental retardation) o Children over 10 may be able to tolerate normal diet (more common thinking is diet for life) o Pregnancy requires dietary restriction Pathologic Findings: o Gray and white matter changes Demyelination and gliosis in white matter DEFECTS IN MEMBRANE PROTEINS: Familial Hypercholesterolemia: Defect: in LDL receptor that transports cholesterol, leading to hypercholesterolemia Pathologic Consequences: o Accelerated atherosclerosis o Skin xanthomas (focal accumulations of cholesterol in macrophages) DEFECTS IN TRANSPORT PROTENS: Cystic Fibrosis: Inheritance: autosomal recessive Cause: mutation in CFTR gene (can be severe or mild) that codes for a transporter necessary for chloride transport o Location: lungs, intestines, pancreas, sweat glands, reproductive tract o Result: defective transport results in defective passage of chloride and water, resulting in production of thick secretions o Most common genotype: F508 (70% of all cases) mutation that results in loss of aa at 508 position Result: little or no functional CFTR Clinical Features: due to F508 mutation (most severe) o Lungs: thick bronchial secretions, leading to obstruction and infections o Pancreas: thick secretions block ducts, leading to backup of enzymes and autodigestion of pancreas Results in fibrosis and loss of pancreatic parenchyma o Intestines: thick secretions lead to blockage and in utero atresia o Vas deferens: thick secretions lead to blockage and resultant sterility DEFECTS IN STRUCTURAL PROTEINS: Marfan Syndrome: Cause: defect in FBN1 gene coding for fibrillin-1 (located on cs 15q21) o Fibrillin-1: major component of microfibrils in the ECM (abundant in aorta, ligaments and ciliary zonules supporting lens) Mutant fibrillin-1 disrupts the assembly of normal microfibrils Inheritance: autosomal dominant (7-85% of cases) Clinical Features: o CV: Dilated ascending aorta, aneurysms, dissection due to cystic medionecrosis Mitral valve prolapse o Skeletal abnormalities: Tall stature Abnormal joint mobility o Scoliosis and pectus excavatum Arachnodactyly (abnormally long fingers) Ocular Abnormalities: Ectopia lentis Myopia DEFECTS IN PROTEINS REGULATING CELL GROWTH: Neurofibromatosis Type 1 (NF-1): General: o Inheritance: autosomal dominant o Frequency: 1/3000 o Penetrance: 100% o Expressivity: variable Cause: defect in NF-1 gene located at cs 17q11.2, which codes for neurofibromin protein (normally down regulates p21 and ras NIH Diagnostic Criteria: must have 2 or more of the following o 6 or more pigmented skin lesions (café au lait spots; found in over 90% of patients) o Freckling in the axillary or inguinal regions o Pigmented iris hamartomas (Lisch nodules; found in over 94% of patients) o 2 or more neurofibromas of any type OR 1 plexiform neurofibroma Neurofibromas: benign tumors involving peripheral nerves (but are at increased risk for developing malignant transformation to malignant peripheral nerve sheath tumors/MPNST) Plexiform neurofibromas: less common but can cause disfigurement and loss of function o Optic glioma Tumor that can lead to blindness o 1st degree relative with NF1 Other Manifestations: o Skeletal abnormalities (scoliosis) o 2-4x increased risk of developing other tumors Neurofibromatosis Type 2 (NF-2): General: o Inheritance: autosomal dominant o Penetrance: 100% by age 60 o Less common than NF1: 1/40,000 Cause: defect in NF-2 gene located on cs 22, which codes for the protein merlin o Merlin: may function to mediate communication between extracellular milieu and cytoskeleton Clinical Features: o Presents in 2nd and 3rd decades (with 100 % penetrance by age 60) o Bilateral acoustic schwannomas o Multiple menangiomas (can be deadly) o Ependymomas of the spinal cord MULTI-FACTORIAL AND CHROMOSOMAL DISORDERS: Multifactorial Conditions: result from the interaction of 2 or more mutant genes and environmental influences General Characteristics: o Increased occurrence in families o Aggregation shown to be genetic rather than environmental o Familial pattern does not fit Mendelian patterns More Specific Characteristics of Multifactorial Disorders: o Risk of expressing a disorder is related to the number of deleterious genes inherited o Environmental risk factors modify the risk of expressing the disease o Rate of recurrence is the same for all first degree relatives (2-7%) o Risk of recurrence depends on the outcome in previous pregnancies One child affected, 7% chance Two children affected, 9% chance Examples of Multifactorial Conditions: o Coronary Heart Disease, HTN, Type I Diabetes Mellitus, Colorectal cancer, Cleft lip/palate Chromosomal/Cytogenic Disorders: Cause: abnormal number of cs or a structural abnormality of a cs (sex chromosomes or autosomes) o Constitutional/Congenital: involving all cells in the body o Acquired post-natally: involving a limited cell population KARYOTYPIC DISORDERS- NUMERIC DISORDERS: Trisomy 21 (Down’s Syndrome): Incidence: 1/700 o Affected by maternal age: <20: 1/1500 >45: 1/25 Cause: o 47 XX, +21: most common (95%); due to MEIOTIC non-disjunction o Translocation: 4% o Mosaicism- 46 XX/47XX +21: 1%; due to MITOTIC non-disjunction Clinical Features: o Intrauterine growth retardation (reduced growth rate and stature) o Neurologic findings Mental retardation Hypotonia at birth Alzheimer’s Disease o Minor dysmorphisms: Characteristic facial features (epicanthic folds, flat facial profile, low set ears) Hand anomalies (Simian crease) Hyperextensibility of the joints o GI abnormalities Duodenal atresias (double bubble sign) Hirschsprung Disease o Congenital heart defects o Predisposition to leukemia o Immunologic defects leading to infections (leading cause of death) Detection: karyotype, FISH Trisomy 18 (Edward’s Syndrome): Incidence: 1/8000 Genotype: most are 47XX, +18 (95%); mosaicism also possible Outcome: only 5-10% live beyond first year of life Clinical Features: o Craniofacial dysmorphisms Prominent occiput Microcephaly Micrognathia Low set ears (flat pinna with pointed upper portions) Clenched fists with overlapping fingers o Neurologic abnormalities: Mental retardation Feeding difficulties and apnea o Malformations: Congenital heart defects Renal malformations (horseshoe kidneys) Rocker bottom feet o Visceral abnormalities: Tracheoesophageal fistula Esophageal atresia Trisomy 13 (Patau’s Syndrome): Incidence: 1/15000 Cause: most result from non-dysjunction - Clinical Features: o Dysmorphisms: Microcephaly Microopthalmia Midline facial defects (bilateral cleft lip, proboscis- nose defect) Umbilical hernia o Neurologic abnormalities: Mental retardation o Malformations: Polydactyly Aplasia cutis congenital (hole in the scalp) Congenital heart defects Renal malformations Rocker bottom feet Klinefelter Syndrome (47XXY): General: one of the most common causes of hypogonadism in men Incidence: 1/500 live male births Karyotypes: XXY most common o Others: XY/XXY and XXY/XXXY mosaics, XXYY (rare, severe phenotype) Clinical Features: o Elongated body (increased length between sole and pubic bone) o Small atrophic testes and small penis o Lack of secondary male characteristics o Gynecomastia o Renal and ureteral abnormalities Renal cysts Hydronephrosis Hyroureter Ureterocele Turner Syndrome (45 X): Incidence: 1/2500 Fetal Mortality: very high (99% of conceptuses spontaneously aborted) Karyotypes: o Monosomy (45 X): 57% o Mosaics: 29% o Structural abnormalities of X cs: 14% Clinical Features: o Short stature o Webbed neck o Broad chest with wide spaced nipples o Ovarian dysgenesis (streak gonads) o Many pigmented nevi (birthmarks) o Cardiac defects (coarctation of the aorta) o Congenital lympedema (with residual puffiness in hands/feet) KARYOTYPIC DISORDERS- STRUCTURAL ABNORMALITIES: Deletion 22q11 Syndrome (DiGeorge and Velocardial Facial Syndromes): Cause: deletion of band 11 on long arm of cs 22 (at least 30 genes in this segment, and therefore, patients have significant clinical heterogeneity) Clinical Features: o Congenital heart defects o Cleft palate (NOT cleft LIP) o Facial dysmorphism Prominent nose with hypoplastic nares Upslanted palpebral fishers Small mouth with everted lip Small abnormal ears Developmental delay (with possible psychotic illness) Variable degrees of T cell immunodeficiency Thymic hypoplasia or dysgenesis o Hypocalcemia (if PT glands absent) Diagnosis: o FISH o Prenatal testing available for fetuses with congenital heart defects or cleft palate detected by ultrasound o o - Fragile X Disease: General: common genetic cause of mental retardation Incidence: 1/1500 for males; 1/8000 for females FMR 1 Gene: located on X cs (q27.3) o Encodes FXMR protein found in the cytoplasm of many cells (esp. abundant in neurons and gonads) Cause: CGG repeats in the FMR1 gene o Normal: 10-55 repeats o Premutation: 55-200 repeats (transmitting males, carrier females) At risk for developing the following issues: Mild cognitive/behavioral deficits Premature ovarian failure o Occurs in FEMALES with premutation (~20%) o Menopause before age 40 Fragile X associated tremor/ataxia syndrome (neurodegenerative disorder) o Occurs in MALES with premutation o Late onset cerebellar ataxia and intention tremor o White matter lesions in the middle cerebellar peduncles and/or brain stem (on MRI) Transmitting males: transmit repeats with small changes in repeat numbers (no amplification during spermatogenesis) Carrier females: high probability of significant amplification of these repeats (during oogenesis) and thus transmission of disease causing full mutation o Full mutation: >200 repeats Abnormal DNA methylation also present with full mutation Results in transcriptional suppression of the gene Clinical Features of Full Mutation: o Mental impairment (learning disabilities progressing to mental retardation) o Abnormal facies Elongated face Prominent forehead and jaw Large protruding ears o Other abnormalities: Hyperextensible joints Mitral valve prolapse o Macro-orchidism GENOMIC IMPRINTING: General: Functional differences between paternal and maternal genes result from selective inactivation of either the maternal or paternal allele by nucleotide specific methylation or inactivation by another method o Non-expressed allele is termed IMPRINTED Maternal imprinting: inactivation of maternal allele Paternal imprinting: inactivation of paternal allele o Imprinting occurs in the ovum or sperm, and is transmitted to all somatic cells Prader Will Syndrome: Normal: maternal imprinting (genes on 15q11-13 on maternal cs imprinted/silenced, and functional allele provided by the paternal cs) PW Syndrome: develops when you lose the paternal cs, and all that is left is silenced maternal cs o Paternal allele deleted (only silenced maternal allele remains) o Uniparental disomy, resulting in both copies of alleles from the mother (both silenced/imprinted) Clinical Features: o Poor muscle tone at birth o Mental retardation o Short stature, with small hands and feet o Hypogonadism o Obesity (progresses with age) o Face with narrow bifrontal diameter, almond eyes, and full cheeks Angelman Syndrome: Normal: paternal imprinting (set of genes on 15q of paternal cs imprinted/silenced, and functional allele provided by the maternal cs) Angelman Syndrome: develops when you lose the maternal cs, and all that is left is silenced paternal cs o Deletion of maternal allele (only silenced paternal allele remains) o Uniparental disomy, resulting in both copies of alleles from the father (both silenced/imprinted) Clinical Features: o Mental retardation o Large mouth and prominent chin o Ataxic gait o Seizures o Inappropriate laughter (happy puppets) GONADAL MOSAICISM: Cause: mutation that occurs postzygotically during early embryonic development Only affects cells destined for gonads Gametes carry the mutation; somatic cells are normal Significance: explains how 2 “normal” parents will have 2 or more children with an autosomal dominant defect SINGLE GENE DISORDERS WITH NONCLASSIC INHERITANCE (MITOCHONDRIAL GENE MUTATIONS): General: Mitochondrial Diseases: can be caused by one of 2 issues o Defects in mtDNA: maternally inherited (passes on to ALL children); FOCUS ON THESE* o Defects in nuclear genes: that encode proteins that function in the mitochondria Inheritance: most are autosomal recessive Two Groups: Abnormalities with altered number and structure of mitochondria Secondary degenerative and destructive changes due to impaired function of mitochondria Mitochondria DNA: mitochondria contain their own DNA o Inheritance: inherited MATERNALLY (inherit mtDNA to all children, male and female) o Heteroplasmy: coexistence of normal mtDNA and abnormal mtDNA in the same cell Proportion of each is variable in daughter cells (due to mitotic segregation) o Threshold: different cell types have different minimal oxidative requirements (ie. higher energy requiring organs will have greater defects) Mutations in Mitochondrial DNA: o Encode for enzymes involved in production of ATP through oxidative phosphorylation o Mutations lead to: Abnormal function of cells (ATP not made efficiently) Accumulation of free radicals and excess metabolites (ie. lactate) that are harmful o Defects most noticeable in organs with high energy requirements: Eyes Skeletal and cardiac muscle Liver Kidneys MERRF (Myoclonal Epilepsy and Ragged Red Fiber Disease): Myoclonus, ataxia, lactic acidosis, weakness, seizures, progressive dementia, hearing loss MELAS (Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke-Like Episodes)