the bouquots and the beggs 1973. general pathology (denf 2701) fall, 2005 topic: genetic and...
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The Bouquots and the BeggsThe Bouquots and the Beggs19731973
General Pathology (DENF 2701)General Pathology (DENF 2701)Fall, 2005Fall, 2005
Topic: Genetic and Developmental DisordersTopic: Genetic and Developmental Disorders
Fall, 2005; Mondays & Wednesdays, 11:00-11:50 am; Room 132Fall, 2005; Mondays & Wednesdays, 11:00-11:50 am; Room 132Course Director: Dr. Jerry BouquotCourse Director: Dr. Jerry Bouquot
Room 3.094B; 713-500-4420; 713-745-2330 (cell)Room 3.094B; 713-500-4420; 713-745-2330 (cell)
Genetic DiseasesGenetic Diseases
30,000 genes in humans – Many capable of affecting multiple characteristics (pleiotropy) – Many characteristics have multiple genes controlling them
Common cause of diseases – 20% of pediatric in-patients have genetically related diseases
– 50% of spontaneous abortions have chromosomal aberrations
Not all inherited genes present in infancy or childhood– e.g. Huntington’s disease (Huntington’s chorea)
Not all birth defects are inherited -- e.g. congenital syphilis
Genetic TerminologyGenetic Terminology
Congenital: present at birth -- Doesn’t have to be inherited, e.g. congenital syphilis
Familial: runs in families (genetics may be unknown) Hereditary: derived from gametes of one’s own parents Polygenic (multifactorial) inheritance: multiple genes involved, multiple patterns of inheritance Polymorphism: multiple allelic forms for one gene Codominance: both alleles of a gene pair are fully expressed Pleiotropy: one gene with multiple phenotypic effects Phenotype: physical or biochemical characteristic controlled by a gene or genes Genotype: chromosomal/gene characteristics
Genetic TerminologyGenetic Terminology
Autosomal dominant (AD): only one gene is mutated -- Only one is needed for disease Autosomal recessive (AR): two genes are mutated -- One from each parent, both are needed for disease Consanguinity: child is a product of sex between close relatives
(common in AR disorders) X-linked (sex-linked): mutation is only X chromosome -- Only one is needed for disease, but only when there is no additional X chromosome to counter it (i.e. girls are unaffected) Reduced penetrance: gene does not create the clinical/biochemical characteristic it is capable of creating Variable expressivity: not all clinical/biochemical characteristics of an inherited disorder are expressed in all affected individuals
Genetic TerminologyGenetic Terminology
Heterozygous: the child has only one disease allele of the gene, from only one parent
Homozygous: the child has two disease alleles of the gene, one from each parent
Normal Male KaryotypeNormal Male Karyotype
Genetic MutationsGenetic Mutations
Permanent DNA change Only germ cell mutations can be passed on to progeny Point mutation: single nucleotide base is altered
Four basic types:
– Missense mutation
– Nonsense mutation
-- Frameshift mutation
– Trinucleotide repeat mutation
Point Mutations: Missense TypePoint Mutations: Missense Typee.g. Sickle Cell Anemia/Diseasee.g. Sickle Cell Anemia/Disease
Point Mutations: Nonsense TypePoint Mutations: Nonsense Typee.g. Sickle Cell Anemia/Diseasee.g. Sickle Cell Anemia/Disease
Stop codon replaces regular nucleotide
Point Mutations: Frameshift TypePoint Mutations: Frameshift Typee.g. Cystic Fibrosise.g. Cystic Fibrosis
-- Insert or delete 1 or 2 base pairs -- If 3 pairs: protein is created with missing amino acid
Point Mutations: Trinucleotide Repeat TypePoint Mutations: Trinucleotide Repeat Typee.g. Fragile X Syndromee.g. Fragile X Syndrome
Results in amplification
Basic Types of Genetic DisordersBasic Types of Genetic Disorders
Single gene mutation
Chromosomal aberration
Single gene mutation with nonclassical inheritance
Single Gene DisordersSingle Gene DisordersMedelian InheritanceMedelian Inheritance
5,000+ disorders; 6-8% of pediatric hospital admissions Three basic patterns: AD, AR, X-linked Examples of codominance and polymorphism:
– Histocompatibility– Blood group antigens
Pleiotropy occurs -- e.g. Marfan disease (defective fibrillin production) Mutations at different sites may produce the same phenotypic effect -- Heterogeneity When less than 50% of the normal gene is controlling: -- Clinical change, -- e.g. retinitis pigmentosa
Cytogenetic (Chromosomal) DisordersCytogenetic (Chromosomal) Disorders
Karyotype (photograph of metaphase spread of chromosomes)– Look for altered number and structure of chromosomes
Chromosomal abnormalities occur in 1/200 newborns-- Higher in stillborns
-- ½ of first trimester abortions Normal: 46 chromosomes, i.e.2n = 46 Exact multiple = euploid (3n or 4n = polyploid) Aneuploid (not an exact multiple of the normal set of chromosomes) Trisomy (2n+1): extra chromosome after meiosis Monosomy (2n-1); one less chromosome after meiosis -- Not compatible with life Mosaicism: two or more populations of cells in the same individual
(from postzygotic mitotic disjunction)
Multifactorial InheritanceMultifactorial Inheritance
Risk of expressing the disease is dependent on number of mutations inherited
Risk of new baby with the disease (2-7%) is same for all first-degree relatives (parents, siblings)
Risk of new baby with the disease depends on how many previous babies were affected– 7% risk with one affected sibling; 9% risk with two affected siblings
Concordance with identical twins is 20-40%; less for nonidentical twins
This is probably the inheritance for many common disease, e.g. diabetes mellitus, hypertension, gout, schizophrenia, bipolar disorder, certain congenital heart defects.
KaryotypeKaryotypeMetaphase ChromosomesMetaphase Chromosomes
Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995.
Nomenclature and notation Nomenclature and notation of karyotype translocation between of karyotype translocation between long arms of chromosomes 9 and 22long arms of chromosomes 9 and 22
p (petit) = short arm of chromosomeq = long arm of chromosome
t = translocation
Extra Credit QuestionExtra Credit Question
Aneuploidy is defined as:Aneuploidy is defined as:
A.A. Duplication of chromosomesDuplication of chromosomes
B.B. Abnormal number of chromosomes in Abnormal number of chromosomes in daughter celldaughter cell
C.C. Exact number of chromosomes in daughter Exact number of chromosomes in daughter cellcell
D.D. Loss of a chromosome in the daughter cellLoss of a chromosome in the daughter cell
E.E. An extra chromosome in the daughter cellAn extra chromosome in the daughter cell
General Pathology (DENF 2701)General Pathology (DENF 2701)Fall, 2005Fall, 2005
Topic: Genetic and Developmental DisordersTopic: Genetic and Developmental Disorders
Fall, 2005; Mondays & Wednesdays, 11:00-11:50 am; Room 132Fall, 2005; Mondays & Wednesdays, 11:00-11:50 am; Room 132Course Director: Dr. Jerry BouquotCourse Director: Dr. Jerry Bouquot
Room 3.094B; 713-500-4420; 713-745-2330 (cell)Room 3.094B; 713-500-4420; 713-745-2330 (cell)
Structural Changes in ChromosomesStructural Changes in ChromosomesChromosomal Breakage; Loss or Rearranged MaterialChromosomal Breakage; Loss or Rearranged Material
Usually from chromosomal breakage, with loss or rearrangement of material
Each arm is numbered from centromere outward– e.g. 2q34 = region 3, band 4 on long arm of chromosome 2
Translocations: chromosome fragments are exchanged between chromosomes
Deletion: loss of a portion of a chromosome– If not at terminal of an arm: chromosome is lost
Inversion: two breaks with reunion after pieces turn around Ring chromosome: after loss of segments from each end of
chromosome, the arms unite to form ring– Variant of deletion
Main Structural Changes of ChromosomesMain Structural Changes of Chromosomes
Photo:s Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995.
Types of Chromosomal RearrangementsTypes of Chromosomal Rearrangements
Chromosomal TranslocationChromosomal Translocation
t = translocation (transfer of part of one chromosome to another) Usually reciprocal
-- e.g. 46,XX,t(2;5)(q31;p14) = reciprocal translocation between the long arm of chromosome 2 at region 5, band 1 and the short arm of chromosome 5, region 1, band 4 If balanced: not harmful to the carrier
Centric (Robertsonian) TranslocationCentric (Robertsonian) Translocation
Break is close to centromere, short arms affected Result: one huge and one very small chromosome (which is lost) Carrier has only 45 chromosomes Compatible with survival because short arms have many redundant
genes
Isochromosome TranslocationIsochromosome Translocation
Centromere divides horizontally instead of vertically One arm is lost, remaining arm is duplicated Most common: long arm of X chromosome: i(Xq)
Trisomy DisordersTrisomy Disorders
Trisomy 21
Trisomy 13
Trisomy 18
Down SyndromeDown SyndromeTrisomy 21; MongolismTrisomy 21; Mongolism
Extra chromosome 21 (47,XX,+21)– Chromosome 21 has 225 genes
Most common of the chromosomal disorders– 1/700 births– Increased risk with increased mother’s age
(1/25 births for mothers over 45 years of age)– Age of father does not affect risk
4% are from translocation: 46,XX,der(14;21)(q10;q10),+21– Usually these are familial, with one parent a carrier for robertsonian translocation
1% are mosaic: 46,XX/47,XX,+21– From nondisjunction later in embryogenesis– Usually milder case
Trisomy 21Trisomy 21Down’s Syndrome, MongolismDown’s Syndrome, Mongolism
Facies: flat, oblique palpebral fissures, depressed nasal bridge, epicanthal folds, open mouth, macroglossia Short stature Short middle phalanx of little finger Horizontal palmar crease, -- Simian crease Short, broad hand Hyperflexibility of joints Poor muscle tone Pelvic abnormalities Congenital heart disease Mental retardation
Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995.
Down SyndromeDown SyndromeTrisomy 21; MongolismTrisomy 21; Mongolism
Epicanthic folds and antimongolian obliquity Increased risk of acute leukemia Cardiac malformations
-- Causes most childhood deaths
Live to be about 30 -- Presuming no serious cardiac malformation Susceptible to infections -- Causes many deaths If live into middle age: Alzheimer disease or dementia
Trisomy 13Trisomy 13Patau SyndromePatau Syndrome
Extra chromosome 13 (47,XX,+13) 1/15,000 births Mental retardation Polydactyly Microcephaly Rocker-bottom feet Renal and hear defects Umbilical hernia Cleft lip and palate Microphthalmia
Trisomy 18Trisomy 18Edwards SyndromeEdwards Syndrome
Extra chromosome 18 (47,XX,+18) 1/8,000 births Mental retardation Renal and heart malformations Rocker-bottom feet Overlapping fingers Short neck, low-set ears Micrognathia
Sex Chromosome DisordersSex Chromosome Disorders
Klinefelter syndrome (47,XXY)
Turner syndrome (45,XO)
XYY syndrome (47,XYY)
Usually compatible with life There is little genetic information on the Y chromosome -- Genes for male attributes are on short arm Phenotypically normal males have had 2 or 4 Y chromosomes
Lyonization of X ChromosomeLyonization of X Chromosome
Lyonization of X chromosomes: females are actually mosaics Barr body = genetically inactive X chromosome, stuck to nuclear membrane Inactivation occurs about 16 days after conception Once inactivated, all daughter cells have same kind of X chromosome Only 1 X chromosome is ever active in a cell
Photos: N. Vigneswaran, University of Texas at Houston, Houston, Texas
Klinefelter’s SyndromeKlinefelter’s SyndromeXXY MaleXXY Male
15% are mosaic >> mild cases ↑ maternal age >> ↑ risk ↑ maternal age >> ↑ risk Low serum testosterone Tall stature Long arms and legs Hypogonadism (small testes) Sterile (testicular atrophy) Small penis Mental retardation More Xs >> More MR Gynecomastia * Female pubic hair profile * High pitched voice * Reduced facial & body hair * *feminization feature
Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995.
Turner’s SyndromeTurner’s SyndromeNon-dysfunction in meiotic division of Non-dysfunction in meiotic division of
gamete formation = 45,XOgamete formation = 45,XO
50% = mosaic Infantile genitalia (even when adult) No secondary sex features Widely spaced nipples Micrognathia Prominent ears Short stature Neck webbing (distended lymphatics) Primary amenorrhea Cubitus valgus (wide carrying angle) Short fourth metacarpal bone Congenital renal anomalies Congenital aortic anomalies
Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995.
Autosomal Dominant InheritanceAutosomal Dominant InheritanceRules of InheritanceRules of Inheritance
Gender of child is not a factor Gender of parent is not a factor; usually inherit from one parent Each child has 50% risk of inheriting disease gene Only affected children can pass on the disease gene Usually anatomic/physical anomalies Homozygous inheritance may be lethal
Osteogenesis ImperfectaAD Inheritance
Autosomal Dominant InheritanceAutosomal Dominant InheritancePunnett (Genetic) SquarePunnett (Genetic) Square
Paternal GametesPaternal Gametes
Maternal Maternal GametesGametes AA aa
aaAaAa
(affected)(affected)aaaa
(normal)(normal)
aaAaAa
(affected)(affected)
aaaa
(normal)(normal)
A = disease gene a = normal gene
Therefore, 50% of children will be affected.Therefore, 50% of children will be affected.
Autosomal Dominant DisordersAutosomal Dominant Disorders
DiseaseDisease Inherited ProblemInherited Problem
AchondroplasiaAchondroplasia Dwarfism due to short limb bonesDwarfism due to short limb bones
Neurofibromatosis I & IINeurofibromatosis I & II Multiple nerve sheath tumors; acoustic Multiple nerve sheath tumors; acoustic neuromasneuromas
Adult polycystic diseaseAdult polycystic disease Enlarging cysts replacing kidneyEnlarging cysts replacing kidney
Huntington’s diseaseHuntington’s disease Progressive neural degenerationProgressive neural degeneration
Myotonic dystrophyMyotonic dystrophy Muscle weakness and wastingMuscle weakness and wasting
Familial hypercholesterolemiaFamilial hypercholesterolemia Increased cholesterol blood levelsIncreased cholesterol blood levels
Osteogenesis imperfectaOsteogenesis imperfecta Brittle bones, fractures with minimal Brittle bones, fractures with minimal traumatrauma
Marfan’s syndromeMarfan’s syndrome Abnormal elastic tissues, skeletal, Abnormal elastic tissues, skeletal, cardiovascular and ocular diseasecardiovascular and ocular disease
Ehlers Danlos syndrome (some types)Ehlers Danlos syndrome (some types) Abnormal collagen – skin, joints and Abnormal collagen – skin, joints and vascular effectsvascular effects
RetinoblastomaRetinoblastoma Malignant retinal tumorMalignant retinal tumor
Autosomal Dominant DisordersAutosomal Dominant DisordersMendelian Inheritance with Organ Systems InvolvedMendelian Inheritance with Organ Systems Involved
SystemSystem DisorderDisorder
NervousNervous Huntington diseaseHuntington disease
NeurofibromatosisNeurofibromatosis
Myotonic dystrophyMyotonic dystrophy
Tuberous sclerosisTuberous sclerosis
UrinaryUrinary Polycystic kidney diseasePolycystic kidney disease
GastrointestinalGastrointestinal Familial polyposis coliFamilial polyposis coli
HematopoieticHematopoietic Hereditary spherocytosisHereditary spherocytosis
Von Willebrand diseaseVon Willebrand disease
SkeletalSkeletal Marfan SyndromeMarfan Syndrome
Ehlers-Danlos syndromeEhlers-Danlos syndrome
Osteogenesis imperfectaOsteogenesis imperfecta
AchondroplasiaAchondroplasia
MetabolicMetabolic Familial hypercholesterolemiaFamilial hypercholesterolemia
Acute intermittent porphyriaAcute intermittent porphyria
Extra Credit QuestionExtra Credit Question
47, XXY refers to what genetic disease?47, XXY refers to what genetic disease?
A.A. Down syndromeDown syndrome
B.B. Turner syndromeTurner syndrome
C.C. Klinefelter syndromeKlinefelter syndrome
D.D. Marfan syndromeMarfan syndrome
E.E. Trisomy 13Trisomy 13
Autosomal Recessive DisordersAutosomal Recessive DisordersMendelian InheritanceMendelian Inheritance
Largest group of mendelian disorders Both alleles are mutated -- One defective gene from each parent Most persons with mutation are unaffected -- Because they are heterozygous Parents of AR child are normal in appearance -- But have the disease gene Disease is not manifested unless child has both genes -- Homozygous With only one gene: child is a carrier -- Can pass on the gene -- Does not have the disease
Autosomal Recessive DisordersAutosomal Recessive DisordersMendelian InheritanceMendelian Inheritance
Each child has a 25% chance of being affected -- Regardless of gender Consanguinity is common -- Similar genes in both parents New mutations are rare (or are rarely discovered) Usually a biochemical problem -- e.g. missing enzyme
Results:Results:-- Less end product-- Less end product-- Accumulation of garbage-- Accumulation of garbage
Autosomal Recessive InheritanceAutosomal Recessive InheritanceFamily pedigree (expression is in homozygotes)Family pedigree (expression is in homozygotes)
Rules of inheritance:Rules of inheritance: Gender of child is not a factor Gender of parent is not a factor; must inherit from both parents to be affected Risk of inheriting disease gene varies (50-100%) Affected children are homozygotes Usually enzymatic/chemical anomalies Unaffected children can pass on the disease gene
Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995.
Autosomal Recessive InheritanceAutosomal Recessive InheritancePunnett (Genetic) Square – Single Parent with GenePunnett (Genetic) Square – Single Parent with Gene
Paternal GametesPaternal Gametes
Maternal Maternal GametesGametes AA aa
aaAaAa
(heterozygote (heterozygote carrier)carrier)
aaaa(normal)(normal)
aaAaAa
(heterozygote (heterozygote carrier)carrier)
aaaa(normal)(normal)
A = disease gene a = normal gene
Therefore, 50% of children will be carriers.Therefore, 50% of children will be carriers.
Autosomal Recessive InheritanceAutosomal Recessive InheritancePunnett (Genetic) Square – Both Parents with GenePunnett (Genetic) Square – Both Parents with Gene
Paternal GametesPaternal Gametes
Maternal Maternal GametesGametes AA aa
AAAAAA
(homozygote (homozygote affected)affected)
AaAa(heterozygote (heterozygote
carrier)carrier)
aaAaAa
(heterozygote (heterozygote carrier)carrier)
aaaa(normal)(normal)
A = disease gene a = normal gene
Therefore, 50% of children will be carriers and 25% will have the disease.Therefore, 50% of children will be carriers and 25% will have the disease.
Autosomal Recessive InheritanceAutosomal Recessive InheritancePunnett (Genetic) Square – Single Parent with DiseasePunnett (Genetic) Square – Single Parent with Disease
Paternal GametesPaternal Gametes
Maternal Maternal GametesGametes AA AA
aaAaAa
(heterozygote (heterozygote carrier)carrier)
AaAa(heterozygote (heterozygote
carrier)carrier)
aaAaAa
(heterozygote (heterozygote carrier)carrier)
AaAa(heterozygote (heterozygote
carrier)carrier)
A = disease gene a = normal gene
Therefore, all children are carriers
Autosomal Recessive InheritanceAutosomal Recessive InheritancePunnett (Genetic) Square – Both Parent with DiseasePunnett (Genetic) Square – Both Parent with Disease
Paternal GametesPaternal Gametes
Maternal Maternal GametesGametes AA AA
AAAAAA
(heterozygote (heterozygote carrier)carrier)
AAAA(heterozygote (heterozygote
carrier)carrier)
AAAAAA
(heterozygote (heterozygote carrier)carrier)
AAAA(heterozygote (heterozygote
carrier)carrier)
A = disease gene a = normal gene
Therefore, all children are affected
Autosomal Recessive DisordersAutosomal Recessive Disorders
DiseaseDisease Inherited ProblemInherited Problem
Cystic fibrosisCystic fibrosis Abnormal ion-transport proteinAbnormal ion-transport protein
Sickle-cell anemiaSickle-cell anemia Abnormal hemoglobinAbnormal hemoglobin
ThalassemiaThalassemia Abnormal hemoglobinAbnormal hemoglobin
GlycogenosisGlycogenosis Enzyme deficiencyEnzyme deficiency
MucopolysaccharidosisMucopolysaccharidosis Enzyme deficiencyEnzyme deficiency
LipidosisLipidosis Enzyme deficiencyEnzyme deficiency
PhenylketonuriaPhenylketonuria Enzyme deficiencyEnzyme deficiency
AlbinismAlbinism Enzyme deficiencyEnzyme deficiency
Wilson’s diseaseWilson’s disease Copper accumulationCopper accumulation
Autosomal Recessive DisordersAutosomal Recessive DisordersMendelian Inheritance with Organ SystemsMendelian Inheritance with Organ Systems
SystemSystem DisorderDisorder
MetabolicMetabolic
Cystic fibrosisCystic fibrosis
PhenylketonuriaPhenylketonuria
GalactosemiaGalactosemia
Lysosomal storage diseaseLysosomal storage disease
αα1-antitrypsin deficiency1-antitrypsin deficiency
Wilson diseaseWilson disease
HemochromatosisHemochromatosis
Glycogen storage diseaseGlycogen storage disease
HematopoieticHematopoieticSickle cell anemiaSickle cell anemia
ThalassemiaThalassemia
EndocrineEndocrine Congenital adrenal hyperplasiaCongenital adrenal hyperplasia
SkeletalSkeletalEhlers-Danlos syndromeEhlers-Danlos syndrome
AlkaptonuriaAlkaptonuria
NervousNervous
Neurogenic muscular atrophiesNeurogenic muscular atrophies
Friedreich ataxiaFriedreich ataxia
Spinal muscular atrophySpinal muscular atrophy
X-Linked (Sex-Linked) DisordersX-Linked (Sex-Linked) DisordersMendelian InheritanceMendelian Inheritance
Very few X-linked disorders – e.g. Vitamin D resistant rickets All mutated genes are on the X-chromosome
– Only 1 Y-chromosome characteristic/disease is know: hairy ears Usually recessive -- Rarely dominant
X-Linked (Sex-Linked) DisordersX-Linked (Sex-Linked) DisordersMendelian InheritanceMendelian Inheritance
In males only one gene is needed to produce disease– Females are protected by their second X chromosome
-- Must have more than 50% of bad gene before a disease is expressed Affected males cannot pass gene to sons -- Only to daughters (50% chance) Heterozygous females almost never express phenotypical changes Mothers are typically carriers and give disease to sons (50% chance) Give disease gene, not disease, to daughters (50% chance)
X-Linked (Sex-Linked) Recessive InheritanceX-Linked (Sex-Linked) Recessive Inheritance
Rules of inheritance:Rules of inheritance: Abnormal gene is on the X chromosome Gender of child is important: only males are usually affected Transmitted from heterozygous, unaffected females Unaffected males do not carry the gene 50% of males of female carrier will be affected Both affected males and carrier females can transmit to produce unaffected heterozygous female
Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995.
X-Linked (Sex-Linked) Recessive InheritanceX-Linked (Sex-Linked) Recessive InheritancePunnett (Genetic) Square – Carrier MotherPunnett (Genetic) Square – Carrier Mother
Paternal GametesPaternal Gametes
Maternal Maternal GametesGametes
XXNN YY
XXDDXXDDXXNN
(carrier female)(carrier female)
XXDDYY(affected male)(affected male)
XXNNXXNNXXNN
(normal female)(normal female)
XXNNYY(normal male)(normal male)
Therefore, 50% of females will be carriers.
XD = disease gene XN = normal gene
X-Linked (Sex-Linked) Recessive InheritanceX-Linked (Sex-Linked) Recessive InheritancePunnett (Genetic) Square – Affected FatherPunnett (Genetic) Square – Affected Father
Paternal GametesPaternal Gametes
Maternal Maternal GametesGametes
XXDD YY
XXNNXXNNXXDD
(carrier female)(carrier female)
XXNNYY(normal male)(normal male)
XXNNXXNNXXDD
(carrier female)(carrier female)
XXNNYY(normal male)(normal male)
XD = disease gene XN = normal gene
Therefore, all females are carriers & all males are normal.
X-Linked (Sex-Linked) Recessive InheritanceX-Linked (Sex-Linked) Recessive InheritancePunnett (Genetic) Square – Carrier Mother & Affected FatherPunnett (Genetic) Square – Carrier Mother & Affected Father
Paternal GametesPaternal Gametes
Maternal Maternal GametesGametes
XXDD YY
XXDDXXDDXXDD
(affected female)(affected female)
XXDDYY(affected male)(affected male)
XXNNXXNNXXDD
(carrier female)(carrier female)
XXNNYY(normal male)(normal male)
Therefore, 50% of males and females will be affected, 50% of females will be carriers, 50% of males will be normal.
XD = disease gene XN = normal gene
X-Linked Recessive DisordersX-Linked Recessive Disorders
DiseaseDisease Inherited ProblemInherited Problem
Hemophilia AHemophilia A Bleeding tendency due to deficiency of clotting Bleeding tendency due to deficiency of clotting factor VIIIfactor VIII
Hemophilia BHemophilia B Bleeding tendency due to deficiency of clotting Bleeding tendency due to deficiency of clotting factor Xfactor X
G-6-PD deficiencyG-6-PD deficiency Attacks of hemolytic anemia after certain drugsAttacks of hemolytic anemia after certain drugs
Duchenne’s muscular Duchenne’s muscular dystrophydystrophy
Progressive muscle weakness due to dystrophin Progressive muscle weakness due to dystrophin deficiencydeficiency
Becker’s muscular Becker’s muscular dystrophydystrophy
Relative dystrophin deficiencyRelative dystrophin deficiency
X-linked (Bruton’s) X-linked (Bruton’s) agammaglobulinemiaagammaglobulinemia
Decreased gamma globulins due to B-cell Decreased gamma globulins due to B-cell maturation failurematuration failure
X-linked ichthyosisX-linked ichthyosis Permanently thick, scaly skin due to deficiency of Permanently thick, scaly skin due to deficiency of steroid sulphatasesteroid sulphatase
X-Linked Recessive DisordersX-Linked Recessive DisordersMendelian InheritanceMendelian Inheritance
SystemSystem DisorderDisorder
MusculoskeletalMusculoskeletal Duchenne muscular dystrophyDuchenne muscular dystrophy
BloodBlood Hemophilias A & BHemophilias A & B
Chronic granulomatous diseaseChronic granulomatous disease
Glucose-6-phosphate dehydrogenase Glucose-6-phosphate dehydrogenase deficiencydeficiency
ImmuneImmune AggamaglobulinemiaAggamaglobulinemia
Wiskott-Aldrich syndromeWiskott-Aldrich syndrome
MetabolicMetabolic Diabetes insipidusDiabetes insipidus
Lesch-Nyhan syndromeLesch-Nyhan syndrome
NervousNervous Fragile X syndromeFragile X syndrome
Mitochondrial InheritanceMitochondrial Inheritance
Rules of inheritance:Rules of inheritance: Inheritance is only through maternal line All children of affected mother receive a dose of abnormal mitochondria in the ovum Progeny of affected male are normal Disease severity varies with dose of abnormal mitochondria -- Heteroplasmy = mixture of normal & abnormal mitochondria
Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995.
Examples of Examples of Autosomal DominantAutosomal Dominant
DisordersDisorders
NeurofibromatosisNeurofibromatosisNF-1; von Recklinghausen DiseaseNF-1; von Recklinghausen Disease
Autosomal dominant inheritance 100,000 affected persons in US 2 types:
-- NF -1 (von Recklinghausen disease) = 90% of all cases-- NF-2 (bilateral acoustic or central neurofibromatosis)
NF-1: mutation on chromosome 17-- Poor neurofibromin (negative regulator of the RAS oncoprotein)
Multiple neurofibromas, usually on skin -- Nodular v. plexiform neurofibromas
Skin pigmentation (café-au-lait spots)-- May only have the skin spots, i.e. no neural tumors
Pigmented iris hamartomas (Lisch nodules)
NeurofibromatosisNeurofibromatosisNF-1; von Recklinghausen DiseaseNF-1; von Recklinghausen Disease
30-50% with skeletal deformities -- Scoliosis-- Erosive bone defects, bone “cysts”-- Others
3% of neurofibromas become malignant-- Neurofibrosarcoma-- Usually from plexiform types
Bilateral Acoustic or Central Neurofibromatosis NF-2NF-2
Mutation on 22q12
Poor merlin (a tumor suppressor protein)
Cafe-au-lait spots
Bilateral acoustic schwannomas and multiple meningiomas
No Lisch nodules
Marfan Syndrome (Marfan Disease)Marfan Syndrome (Marfan Disease)AD InheritanceAD Inheritance
Prevalence: 2 per 10,000 population Main problem: the glycoprotein fibrillin is defective Mutation: on FBN1 gene at 15q12, in 100% of cases – FBN1 gene has 100+ different mutations! 25% are sporadic (spontaneous) mutations Clinical features are primarily from poor connective tissue:
– Tall, slender body and thin face (like Abraham Lincoln)– Ocular problems (dislocation, subluxation)– Cardiovascular problems (aneurysm)– Skin: “stretch marks” in areas of recurring stress– Other: hypotonia (weak muscles), spontaneous pneumothorax
(air in lungs)
Ehlers-Danlos Syndromes (EDSs)Ehlers-Danlos Syndromes (EDSs)Mendelian InheritanceMendelian Inheritance
Main problem: defective collagen synthesis -- There are 18+ types of collagen, all can be affected Can be AD, AR, or X-linked: 10+ different types Clinical features are primarily from poor connective tissues:
– Skin: hyperextensibility of skin, fragility– Joints: hypermobility (“double jointed’), as seen in “rubber men”
in circus side shows– Other: ruptured colon, blood vessels; detached retina
Familial HypercholesterolemiaFamilial HypercholesterolemiaAD InheritanceAD Inheritance
Prevalence: 1 per 500 population; one of the most common mendelian disorders
Main problem: mutation of receptor protein for low-density lipoprotein (LDL) – LDL transports 70% of the cholesterol
in the blood – 75% of LDL receptors are on hepatocytes
liver makes endogenous cholesterol
Mutation impairs intracellular transport and catabolism of LDL >>LDL cholesterol accumulates in serum
IDL = intermediate-density lipoproteinVLDL = very-low-density-lipoprotein
Familial HypercholesterolemiaFamilial HypercholesterolemiaAD InheritanceAD Inheritance
With fewer liver LDL receptors: -- Elevated serum cholesterol levels
– Macrophages must work harder to break it down >> xanthomas of skin and tendon sheaths
– Endothelial cells must work harder to break it down >> atherosclerosis
Heterozygotes: 3x elevation of serum cholesterol levels– Homozygotes: 5x elevation of serum cholesterol levels
Treatment: statin drugs-- Promote synthesis of LDL receptors
Examples of Examples of Autosomal RecessiveAutosomal Recessive
DisordersDisorders
Phenylketonuria (PKU)Phenylketonuria (PKU)AR InheritanceAR Inheritance
Classic form is common in persons of Scandinavian descent, -- Uncommon in blacks and Jews
Homozygotes: severe deficiency of phenylalanine hydroxylase >> hyperphenylalaninemia & PKU
Inability to convert phenylalanine into tyrosine
Normal at birth, but in a few weeks phenylalanine levels rise >> severe mental retardation (by 6 mo.) & seizures
Intermediate metabolites excreted into urine & sweat >> strong musty or mousy odor
Phenylketonuria (PKU)Phenylketonuria (PKU)AR InheritanceAR Inheritance
100+ mutant alleles have been identified– With some mutations: minimal problem
(benign hyperphenylalaninemia), but will test positive
Some variants: disease cannot be corrected with diet
1/3 cannot walk; 2/3 cannot talk
Decreased pigmentation of hair and skin (less tyrosine to create melanin); eczema
Phenylketonuria (PKU)Phenylketonuria (PKU)AR InheritanceAR Inheritance
If diet-controlled mother stops controlling her diet, then has baby >> baby is severely mentally retarded
Most states test new babies for this (e.g. Guthrie test)
Treatment: avoid intake of phenylalanine from infancy (check food labels, e.g. aspartame)
Also: mothers with PKU tendencies must lower phenylalanine levels before having a baby
Lysosomal Storage DiseasesLysosomal Storage DiseasesAR InheritanceAR Inheritance
Inherited lack of lysosomal enzymes >> intracellular buildup of improperly degraded cell products
Abnormal storage: primarily in mononuclear phagocyte system
35 different diseases, each related to a specific enzyme deficiency
Very rare
Tay-Sachs disease
Niemann-Pick disease
Gaucher disease
Tay-Sachs Disease (GM2 Gangliosidosis)Tay-Sachs Disease (GM2 Gangliosidosis)AR InheritanceAR Inheritance
Lysosomal storage disease; hexosaminidase α-subunit deficiency Gangliosides accumulate in the brain and peripheral nerves
-- Usually within neurons and axons
Tay-Sachs Disease (GM2 Gangliosidosis)Tay-Sachs Disease (GM2 Gangliosidosis)AR InheritanceAR Inheritance
85+ mutations identified-- Most affect protein folding or intracellular transport
Most common among Ashkenazi Jews (1 of every 30)
Carriers can be detected via DNA analysis or checking level of hexosaminidase in serum
Mental retardation, blindness, severe neurologic dysfunction
Death by 3 years of age
Niemann-Pick DiseaseNiemann-Pick DiseaseAR inheritanceAR inheritance
Lysosomal storage disease; sphingomyelinase deficiencyphingomyelinase deficiency
Sphingomyelin accumulates in phagocytic cells (liver, spleen, marrow, lungs, lymph nodes), neurons
Massive visceromegaly and severe neurologic deterioration
Death within 3 years
Detection: evaluate sphingomyelinaseactivity in leukocytes or fibroblasts
-- DNA-probe analysis
Foamy HepatocytesFoamy Hepatocytes
Gaucher DiseaseGaucher DiseaseAR InheritanceAR Inheritance
Mutation of gene encoding glucocerebrosidase Accumulation of glucocerebrosides in mononuclear phagocytic cells -- From RBC breakdown Chronic non-neuropathic form: 99% of all cases, -- Hepatosplenomegaly
-- Gaucher cells in spleen, liver, lymph nodes, bone marrow >> internal bone resorption, fewer blood elements, anemia,
leukopenia >> compatible with long life
Gaucher DiseaseGaucher DiseaseAR InheritanceAR Inheritance
Most common in Ashkenazi Jews Two of the three variants are lethal in childhood
--Severe CNS damage Diagnosis for carriers: evaluated level of
glucocerebrosidase in leukocytes Treatment: enzyme replacement via infusion of purified
glucocerebrosidase
Mucopolysaccharidoses (MPSs)Mucopolysaccharidoses (MPSs)AR Inheritance (Usually)AR Inheritance (Usually)
Seven variants (MPS I - MPS VII), each with specific enzyme deficiency
Mucopolysaccharides progressively accumulate in all tissues
Course facial features, corneal clouding, joint stiffness, mental retardation
Urinary excretion of mucopolysaccharides is increased
Hurler syndrome (MPS 1 H) Hunter syndrome (MPS II)
Hurler SyndromeHurler SyndromeMPS 1 H; AR InheritanceMPS 1 H; AR Inheritance
Deficiency of L-iduronidase >> accumulation of mucopolysaccharides
Ground substance is a mess >> joint stiffness
Course facial features + deformed bones of face >> gargoylism
Severe mental retardation -- Lysosomal inclusions in neurons
Death within 6-10 years from cardiac problems -- Mucopolysaccharides in coronary arteries
Examples of Examples of X-LinkedX-LinkedDisordersDisorders
Hunter SyndromeHunter SyndromeMPS II; AR InheritanceMPS II; AR Inheritance
X-linked recessive inheritance Deficiency of L-iduronosulfate sulfatase >> accumulation of
mucopolysaccharides No corneal clouding
Developmental AnomaliesDevelopmental Anomalies
PatternPattern Definition &/or MechanismDefinition &/or Mechanism Example(s)Example(s)
AgenesisAgenesis Complete failure to develop. Early failure Complete failure to develop. Early failure of developmentof development
Renal agenesisRenal agenesis
HypoplasiaHypoplasia Incomplete development; probably due Incomplete development; probably due to teratogen during growth phase.to teratogen during growth phase.
Microcephaly (alcohol)Microcephaly (alcohol)
Phocomelia (thalidomide)Phocomelia (thalidomide)
DysplasiaDysplasia Abnormal tissue organization; failure of Abnormal tissue organization; failure of differentiation and maturationdifferentiation and maturation
Renal dysplasiaRenal dysplasia
DysraphismDysraphism Failure of embryologic fusionFailure of embryologic fusion MyelomeningoceleMyelomeningocele
Ectopia vesicaeEctopia vesicae
Failure of Failure of involutioninvolution
Temporary embryological structure Temporary embryological structure remains indefinitelyremains indefinitely
Persistent urachusPersistent urachus
Thyroglossal ductThyroglossal duct
SyndactylySyndactyly
AtresiaAtresia Failure of lumen formation (no Failure of lumen formation (no programmed cell death in solid cylinder programmed cell death in solid cylinder of cellsof cells
Esophageal atresiaEsophageal atresia
Biliary atresiaBiliary atresia
EctopiaEctopia Organ or tissue displacement; failure of Organ or tissue displacement; failure of cell migration during embryological cell migration during embryological developmentdevelopment
Maldescent of testesMaldescent of testes
Fordyce granulesFordyce granules