The Bouquots and the Beggs 1973. General Pathology (DENF 2701) Fall, 2005 Topic: Genetic and Developmental Disorders Fall, 2005; Mondays & Wednesdays,

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


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


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


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


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


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


Autosomal Recessive InheritanceAutosomal Recessive InheritancePunnett (Genetic) Square – Single Parent with GenePunnett (Genetic) Square – Single Parent with Gene



aaAaAa

(heterozygote (heterozygote carrier)carrier)

aaaa(normal)(normal)

aaAaAa




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



AAAAAA

(homozygote (homozygote affected)affected)

AaAa(heterozygote (heterozygote

carrier)carrier)

aaAaAa




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


Maternal Maternal GametesGametes AA AA

aaAaAa



carrier)carrier)

aaAaAa



carrier)carrier)


Therefore, all children are carriers

Autosomal Recessive InheritanceAutosomal Recessive InheritancePunnett (Genetic) Square – Both Parent with DiseasePunnett (Genetic) Square – Both Parent with Disease


Maternal Maternal GametesGametes AA AA

AAAAAA


AAAA(heterozygote (heterozygote

carrier)carrier)

AAAAAA


AAAA(heterozygote (heterozygote

carrier)carrier)


Therefore, all children are affected

Autosomal Recessive DisordersAutosomal Recessive Disorders


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


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


X-Linked (Sex-Linked) Recessive InheritanceX-Linked (Sex-Linked) Recessive InheritancePunnett (Genetic) Square – Carrier MotherPunnett (Genetic) Square – Carrier Mother


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



XXDD YY

XXNNXXNNXXDD



XXNNXXNNXXDD




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



XXDD YY

XXDDXXDDXXDD

(affected female)(affected female)

XXDDYY(affected male)(affected male)

XXNNXXNNXXDD



Therefore, 50% of males and females will be affected, 50% of females will be carriers, 50% of males will be normal.


X-Linked Recessive DisordersX-Linked Recessive Disorders


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


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


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


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


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

Documents

The Bouquots and the Beggs 1973. General Pathology (DENF 2701) Fall, 2005 Topic: Genetic and Developmental Disorders Fall, 2005; Mondays & Wednesdays,