Download Pathology Ch5 pp137-167 Genetic Disorders

Pathology Ch5 pp137-167
Genetic Disorders
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Genes and Human Diseases
o Mutations = permanent change in DNA(@ germ cells > transmitted to progeny)
 Point mutations within coding sequences
 Single base substituted with another base > lead to different AA coded
 Missense mutations = alter meaning of sequence of encoded protein
o Conservative = similar AA, little/no protein function change
o Nonconservative = ex. sickle cell, hemoglobin fxn altered
 Nonsense mutation = change codon to stop codon
 Mutations within noncoding sequences
 Introns may signal for upregulation/downregulation or splicing
 May affect mRNA processing
 Ex. Thalassemias
 Deletions and insertions
 If insertion/deletion is 3 or multiple of 3 > produce normal amounts of abnormal protein
 Not 3 or multiple of 3 > frameshift mutation, many errors
 Trinucleotide-repeat mutations
 Amplification of sequence of 3 nucleotides
 Sequence differs between disorders, but all share C & G
 Ex. Fragile X - CGG repears @ FMR1
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Mendelian Disorders
o Transmission Patterns of Single-Gene Disorders
 Autosomal Dominant Disorders
 Some proportion of patients do not have affected parents (new mutations)
 Clinical features can be modified by variations in penetrance and expressivity
o ex. 50% Penetrance = 1/2 of people who carry gene express the trait
o Variable expressivity = trait in all individuals w/ gene, but expressed differently
 Age of onset is delayed in many conditions (ex. Huntington disease)
 Biochemical mechanism of disorders depend on mutation and type of protein affected
o Dominant vs recessive depends on normal gene being able to compensate
 Types of deleterious mutations
o Regulation of complex metabolic pathways subject to feedback inhibition
o Key structural proteins
 Gain-of-function mutations: Increase proteins normal function or new function added
 Common Examples
o Nervous: Huntington, neurofibromatosis, myotonic dystrophy, tuberous
sclerosis
o Urinary: polycystic kidney disease
o Gastrointestinal: familial polyposis coli
o Hematopoietic: hereditary spherocytosis, von Willebrand disease
o Skeletal: Marfan, Ehlers-Danlos, osteogenesis imperfecta, achondroplasia
o Metabolic: familial hypercholesterolemia, acute intermittent porphyria
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Autosomal Recessive Disorders
 Trait does not usually affect the parents
 Siblings have 1/4 chance of having trait
 If rare gene, chances are because of consanguineous marriage
 Expression tends to be more uniform
 Complete penetrance is common
 Onset frequently early in life
 Many go undiagnosed since heterozygotes do not manifest symptoms
 Almost all inborn errors of metabolism are autosomal recessive
 Common Examples
o Metabolic: cystic fibrosis, phenylketonuria, galactosemia, homocystinuria,
lysosomal storage disease, antitrypsin deficiency, wilson disease,
hemochromatosis, glycogen storage diseases
o Hematopoietic: sickle cell anemia, thalassemias
o Endocrine: congenital adrenal hyperplasia
o Skeletal: Ehlers-Danlos syndrome
o Nervous: neurogenic muscle atrophies, Friedreich ataxia, spine muscle atrophy
X-Linked Disorders
 All sex-linked disorders are X-linked
o Males are hemizygous for X-linked, no homolog to compensate on Y
 Most mutations affecting Y-linked genes result in infertile males > not passed on
 Male does NOT pass it only sons, but all daughters are carriers
 Sons of carrier women have 1/2 chance of receiving mutant gene
 CAN be expressed to varying degrees in females, depending on proportion of cells using
mutated or normal gene
o Ex. glucose-6-phosphate dehydrogenase deficiency
o Always more severe in males
 Common Examples
o Musculoskeletal: Duchenne muscular dystrophy
o Blood: hemophilia, chronic granulomatous disease, G6PD deficiency
o Immune: agammaglobulinemia, wiskott-aldrich syndrome
o Metabolic: diabetes insipidus, lesch-nyhan syndrome
o Nervous: fragile X syndrome
Biochemical and Molecular Basis of Single-Gene (Mendelian) Disorders
 Table of Mendelian Disorders
 Enzyme: phenylketonuria, tay-sachs disease, severe combined immunodeficiency
 Enzyme inhibitor: emphysema, liver disease
 Receptor: familial hypercholesterolemia, vitamin D-resistant rickets
 Transport:
o Oxygen: thalassemia, sickle cell anemia
o Ion channels: cystic fibrosis
 Structural:
o Extracellular: osteogenesis imperfecta, ehlers-danlos syndrome
o Cell membrane: marfan syndrome, duchenne/becker muscular dystrophy
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 Hemostasis: hemophilia A
 Growth regulation: hereditary retinoblastoma, neurofibromatosis
Enzyme Defects and Their Consequences
 Result in enzyme w/ reduced activity or reduced amount of normal enzyme
 Accumulation of substrate
o Tissue injury may result if accumulations are toxic in high concentrations
o Ex. galactosemia > excess galactose accumulation > tissue damage
o Accumulation of substrates within lysosomes > lysosomal storage diseases
 Metabolic block and decreased end product
o Ex. melanin deficiency from lack of tyrosinase > albinism
o If end product is feedback inhibitor en enzymes, the deficiency may permit
overproduction of intermediates (ex. Lesch-Nyhan syndrome)
 Failure to inactivate a tissue-damaging substrate
o Ex. alpha-antitrypsin deficiency > unable to inactivate neutrophil elastase in lung
Defects in Receptors and Transport Systems
 Transport via receptor-mediated endocytosis mutation > familial hypercholesterolemia
o Reduced LCL receptors > defective LDL transport
 Chloride ion transport system mutation > cystic fibrosis
Alterations in Structure, Function, or Quantity of Nonenzyme Proteins
 Ex. sickle cell disease = structure of globin molecule
 Ex. thalassemias = globin gene mutation > dec amount of globin chains synthesized
 Ex. collagen, spectrin, dystrophin > osteogenesis imperfecta, muscular dystrophy
Genetically Determined Adverse Reactions to Drugs
 Ex. G6PD deficiency + antimalarial drug > hemolytic anemia
Disorders Associated with Defects in Structural Proteins
 Marfan Syndrome
 1/5000, mostly autosomal dominant inheritance, some new mutations
 Pathogenesis: defect in fibrillin-1 protein
o Loss of structural support in microfibril rich CT
o Excessive TGP-beta activation
 Morphology:
o Skeletal abnormalities: tall, long extremities, lax joint ligaments, deformed chest
o Ocular changes: bilateral subluxation or dislocation of the lens
o Cardiovascular lesions: mitral valve prolapse, ascending aorta dilation/dissection
 Clinical Features:
o Majority of death from aortic dissection, followed by cardiac failure (mitral)
o Major involvement of 2/4 organ systems and minor involvement of another
organ is required for diagnosis
o Rx: beta blockers to reduce heart stress
 Ehler-Danlos Syndrome (EDS)
 Defect in collagen synthesis or assembly > joint hypermobile, skin hyperextensible, poor
wound healing, ruptures involving colon, cornea, or large arteries
 All 3 modes of Mendelian inheritance
 6 types:
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Classic (I/II) - skin/joint hypermobility, atrophic scars, easy bruising - auto
dominant - COL5A1, COL5A2
Hypermobility (III) - joint hypermobility, pain, dislocation - auto dominant
Vascular (IV) - thin skin, arterial/uterine rupture, bruising, small joint
hyperextensibility - auto dominant - COL3A1
Kyphoscoliosis (VI) - hypotonia, joint laxity, congenital scoliosis, ocular fragility auto recessive - lysyl hydroxylase
Arthrochalasia (VIIa,b) - severe joint hypermobility, skin changes, scoliosis,
bruising - auto dominant - COL1A1, COL1A2
Dermatosparaxis (VIIc) - severe skin fragility, cutis laxa, bruising - auto recessive
- procollagen N-peptidase
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Disorders Associated with Defects in Receptor Proteins
 Familial Hypercholesterolemia
 Mutation in LDL receptor gene > transport and metabolism of cholesterol
 Loss of feedback control > elevated levels of cholesterol > premature atherosclerosis
 1/500 are heterozygotes for mutation (2-3x cholesterol elevation)
 Homozygotes (5-6x cholesterol elevation): myocardial infarction can occur <20 yo
 Xanthomas: cholesterol deposited along tendon sheaths
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Disorders Associated with Defects in Enzymes
 Lysosomal Storage Diseases
 Accumulation of metabolite within lysosomes (primary accumulation) > lysosomes grow
larger enough to interfere with other cellular functions
 Autophagy diminished (secondary accumulation) > accumulation of dysfunctional
mitochondria
 Rx: enzyme replacement therapy, exogenous competitive inhibitors that can bind
enzyme and act as folding template (molecular chaperone therapy)
 Table of Diseases:
o Glycogenosis: glycogen accumulation
o Sphingolipidoses: Tay-Sachs, ganglioside accumulation
o Sulfatidoses: Gaucher, Niemann-Pick, sulfatide/glucocerebroside, sphingomyelin
o Mucopolysaccharidoses (MPSs): Hurler, Hunter, dermatan + heparan sulfate
o Mucolipidoses (MLs): pseudo-Hurler, mucopolysaccharide, glycolipid
 Tay-Sachs Disease (Gm2 gangliosidosis: hexosaminidase alpha deficiency)
o Gm2 gangliosidoses = 3 lysosomal storage diseases
 Inability to catabolise Gm2 gangliosides
 Accumulation of Gm2 gangliosides in CNS > retardation, blindness,
motor weakness, early death (2-3yo)
 Different enzyme defect for each
o Morphology:
 Gm2 ganglioside accumulates in heart, liver, spleen, nervous system
 Neurons in CNS and ANS and retina dominate clinical
 Neurons are balooned w/ cytoplasmic vacuoles
 Cytoplasmic inclusions: whorled configurations within lysosomes
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Progressive destruction of neurons, proliferation of microglia,
accumulation of complex lipids in phagocytes within brain
 Similar process on cerebellum, basal ganglia, brain stem, spinal cord,
dorsal root ganglia, and ANS
 Ganglion cells in retina > cherry-red spot in macula
 Affected infants are normal at birth > manifest signs at 6 mo
 Relentless motor/mental deterioration
 Vegetative state reached within 1 or 2 years, death by 2 or 3 years
Niemann-Pick Disease Type A and B
o Deficiency in sphingomyelinase > lysosomal accumulation of sphingomyelin
o Type A: severe infantile form, evident by 6 mo. death by year 1 or 2.
o Type B: organomegaly, but no CNS involvement. reach adulthood.
o Morphology:
 Affected cells become enlarged, due to distention w/ sphingomyelin +
cholesterol
 Vacuoles stain for fat
 Involvement of spleen produces massive enlargement
 Vacuolation and ballooning of neurons in brain
 Retinal cherry-red spot in 1/3 to 1/2
Niemann-Pick Disease Type C
o Distinct from A and B biochemically and genetically
o More common than type A and B combined
o NPC1 and NPC2 mutations > problem with cholesterol transport
o Cholesterol and gangliosides accumulate in nervous sytem
o Presents are hydrops fetalis and stillbirth, neonatal hepatitis, or progressive
neurologic damage (ataxia, vertical supranuclear gaze palsy, dystonia,
dysarthria, psychomotor regression)
Gaucher Disease (MOST COMMON LYSOSOMAL STORAGE DISORDER)
o Cluster of autosomal recessive disorders
o Mutation in gene encoding glucocerebrosidase > glucocerebroside accumulates
in phagocytes and in CNS
o Type I: 99%, chronic nonneuronopathic form, storage only in phagocytes. Shows
up in adult life, related to splenomegaly or bone. Bone pain if enough expansion
of marrow.
o Type II: acute neuronopathic, infantile, early death
o Type III: intermediate between I and II, progressive CNS disease, later onset
o Morphology:
 Distended phagocytic cells (Gaucher cells) found in spleen, liver, bone
marrow, lymph nodes, tonsils, thymus, and Peyer patches
 Cells rarely vacuolated, instead look like crumpled paper cytoplasm
 Fibrillary cytoplasm can be resolved as elongated, distended lysosomes
under electron microscope
 Type I: spleen is enlarged, up to 10kg + Gaucher cells accumulate in
bone marrow > bone erosion
 Lymphadenopathy is mild to moderate
o Rx: enzyme replacement therapy ($$$$)
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Mucopolysaccharidoses (MPS)
o Mutation in enzymes involved in degradation of mucopolysaccharides
(glycosaminoglycans)
o Accumulation of dermatan sulfate, heparan sulfate, keratan sulfate, chondroitin
sulfate
o Different enzymes mutated > MPS I to MPS VII
 All autosomal recessive, except Hunter syndrome (x-linked)
o Progressive disorders
o Coarse facial features, clouding of cornea, joint stiffness, mental retardation
o Morphology:
 Mucopolysaccharides found in mononuclear phagocytic cells,
endothelial cells, intimal smooth muscle cells, and fibroblasts
 Common at spleen, liver, bone marrow, lymph nodes, vessels, heart
 Cells are distended and have clearing of cytoplasm > baloon cells
 Hepatosplenomegaly, skeletal deformities, valvular lesions,
subendothelial arterial deposits, lesions in the brain
 Myocardial infarction common cause of eath
o Hurler syndrome: MPS I-H, deficiency of alpha-1-iduronidase (most severe)
 Hepatosplenomegaly by 6-24 mo, growth retarded, skeletal deformities
 Death by 6-10 years due to cardiovascular complications
o Hunter syndrome: MPS II - x-linked
 NO corneal clouding, milder clinical course
Glycogen Storage Diseases (Glycogenoses)
 Mutation in enzymes for synthesis or degradation of glycogen
 Storage of normal or abnormal glycogen in liver or muscles
 Hepatic forms (von Gierke disease)
o Liver cells store glycogen b/c lack of hepatic G6P
o Hepatomegaly + Renomegaly
o Failure to thrive, stunted growth, hypoglycemia, hyperlipidemia, hyperuricemia,
bleeding
o With treatment, most survive and develop later complications
 Myopathic forms (McArdle disease)
o Muscle phosphorylase lacking > storage in skeletal muscle
o Painful cramps associated w/ exercise
o Onset in adulthood, normal longevity
 Glycogen storage diseases associated with deficiency of glucosidase (acid maltase) and
lack of branching enzyme (Pompe disease)
o All organs affected, but heart predominant
o Mild hepatomegaly, cardiomegaly, skeletal muscle
o Massive cardiomegaly, muscle hypotonia, cardiorespiratory failure by 2 yo
Disorders Associated with Defects in Proteins That Regular Cell Growth
 Proto-oncogenes or tumor suppressor genes mutated
 Most cancer mutations NOT in germ line, 5% are and can be inherited
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Complex Multigenic Disorders
o Interactions between variant forms of genes and environmental factors
o Gene w/ 2 alleles = polymorphic
 Each variant allele = polymorphism
o Common disease/common variant hypothesis: complex genetic disorders when many may
polymorphisms (modest effect, low penetrance) are inherited together
o Individual genes mutations contribute varying severity to the disorders
o Some polymorphism are common to multiple diseases, while others are disease specific
o Environmental influences significantly modify phenotypic expression
o Requirements: familial clustering + exclusion of Mendelian/chromosomal modes of transmission
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Chromosomal Disorders
o Normal Karyotype
 Somatic cells: 46 chromosomess (22 autosomal pairs, 1 sex pair)
 Karyotyping: size from largest to smallest, followed by sex chromosomes
o Structural Abnormalities of Chromosomes
 Euploid = multiple of haploid (23)
 Aneuploid = NOT multiple of 23 (result from nondisjunction or anaphase lag)
 Mosaicism = mitotic errors in early development give rise to 2+ populations of cells with
different chromosomal complement
 Most often sex chromosome, as autosomal mosaicism usually nonviable
 Deletions = chromosomal breakage and fragment loss
 Ring chromosome = break at both ends + fusion of both ends
 Inversion = rearrangement of fragment
 Isochromosome = one arm of a chromosome is lost, remaining arm is duplicated
 Translocation = segment transferred from anther chromosome (balanced/unbalanced)
 Robertsonian translocation (centric fusion) = between 2 acrocentric chromosomes
o Cytogenetic Disorders Involving Autosomes
 Trisomy 21 (Down Syndrome)
 Most common chromosomal disorders, major cause of mental retardation
 Meiotic nondisjunction, maternal origin
 Maternal age has strong influence
 4% of cases, extra chromosomal material from robertsonian translocation
 1% are mosaics, mixture of 46 and 47 chromosome cells
 Flat facial profile, oblique palpebral fissures, epicanthic folds
 40% have congenital heart disease: ostium primum, atrial septal defects, AV valve
malformations, VSDs
 10-20x risk of developing acute leukemia
 Early Alzheimer's (age 40 neuropathologic changes)
 Abnormal immune response, presidpose to serious infections (lung, thyroid)
 Other Trisomies
 Trisomy 18: Edward syndrome
 Trisomy 13: Patau syndrome
 Chromosome 22q11.2 Deletion Syndrome
 Spectrum of disorders: heart defects, palate defects, facial dysmorphism, development
delays, T-cell immunodeficiency, hypocalcemia
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Schizophrenia, bipolar, ADHD
TBX1 related, PAX9
DiGeorge syndrome: thymic hypoplasia
velocardiofacial syndrome: heart outflow tracts, facial dysmorphism, dev. delays
Cytogenetic Disorders Involving Sex Chromosome
 Better tolerated vs autosomes: not a lot of genetic material on Y, inactivation of all but one X
 Lyon hypothesis: only one X chromosome is active, other X undergoes heteropyknosis
and becomes inactive, maternal or paternal inactivation occurs at random, inactivation
persists in all cells derived from each precursor cell
 Sex chromosome disorders cause subtle, chronic problems related to sexual
development/fertility.
 Difficult to diagnose at birth, most diagnosed at puberty.
 Greater number of X chromosomes > greater likelihood of mental retardation
 Klinefelter Syndrome 47,XXY
 X chromosome escapes lyonization
 Male hypogonadism, tall, long limbs, gynecomastia
 Higher risk of breast cancer, extragonadal germ cell tumors, autoimmune disease
 Turner Syndrome 45,X
 Female hypogonadism, neck webbing, swelling of nape of neck, edema of hands/feet,
heart disease, heart defects, amenorrhea (no period), short stature, broad chest
 Ovaries reduced to "streak ovaries"
 Genes involved: SHOX Xp22.33
 Hermaphroditism and Pseudohermaphroditism
 Genetic sex = presence or absence of Y chromosome
 Gonadal sex = histological characteristics of gonads
 Ductal sex = presence of mullerian or wolffian duct derivatives
 Phenotypic (genital) sex = appearance of external genitalia
 Hermaphrodite = both ovarian and testicular tissue
 Pseudohermaphrodite = disagreement between the phenotypic and gonadal sex