Genetic Disorders. INTRODUCTION: DEFINITION OF TERMS CHROMOSOMES- cellular structures where genes are located GENES- basic units of heredity carry

Genetic DisordersGenetic Disorders

INTRODUCTION:INTRODUCTION:DEFINITION OF TERMSDEFINITION OF TERMS

CHROMOSOMES- cellular structures where genes are located

GENES- basic units of heredity carry information necessary to determine specific biologic structures & functions ex. ABO Ag in RBC membrane coded by

chromosome 9

LOCUS- position in the chr where particular gene is located; all gene loci occur in pairs except X & Y genes


ALLELES- alternative genes in a single locus ex. Kell blood group system

alleles K & k

KK- homozygous Kk- heterozygous

HOMOZYGOUS GENES- gene pair that are alike

HETEROZYGOUS GENES- gene pair that are not alike

GENOTYPE- actual gene composition that make the trait

PHENOTYPE- manifestation of the structure/ form produced by the genes


DOMINANT GENES- genes that are always expressed in the phenotype whether homozygous or heterozygous

RECESSIVE (AMORPH) GENES- genes that are masked if paired w/ a dominant gene, thereby only expressed when paired w/ another recessive gene


EUPLOIDY- multiples of the haploid # that is considered normal HAPLOID (N)= 23- OCCURS IN MEIOSIS

DIPLOID (2N)= 46- OCCURS IN MITOSIS

ANEUPLOID- not exact multiples of the haploid #; only 1 pair of chr involved, therefore, germ cells have 2 copies of the same chr or lack the affected chr entirely HYPODIPLOID 2N- 1, -2, ETC. (MONOSOMY)

HYPERDIPLOID 2N+ 1, +2, ETC. (TRISOMY)


POLYPLOID- multiples of haploid #; entire set of chrs fail to divide & all the chrs are segregated in a single daughter cell TRIPLOID (3N)= 69

TETRAPLOID (4N)= 92

Congenital Disorders

Non Genetic: Developmental defects – Malformations

Genetic Disorders Chromosomal

Gene - Mendelian

Multifactorial

Mutations:

Genome: whole set – Polyploidy 4n, 8n etc.

Chromosomal: change in chromosome Number: Trisomy, monosomy

Structure: Deletion, Translocation etc.

Gene: Submicroscopic Point mutation – single base sequence

Deletions

Insertions

Cytogenetic Abnormalities:

Abnormal # of chrs: Non-disjunction - Down’s Syndrome

Anaphase lag - Turner’s xxx

Abnormal Structure: (normal #) Deletion - 5q- Cri - du - chat syndrome

Inversion -

Translocation - Ph Chromosome - t(9:22) CML,

GENETIC PATHOLOGY:

DEFINITION: Abnormalities or disease states that may or may not be congenital, transmitted by genes or chromosomal aberrations, that may be heritable (familial) or mutational

If mutational, may give the following outcomes: Heritable

Disappear

Lethal

Sterility

Malignancy

CATEGORIES:

CHROMOSOMAL ABNORMALITIES/ MUTATIONS

GENE ABNORMALITIES/ MUTATIONS

POLYGENIC/ MULTIFACTORIAL ABNORMALITIES

I. CHROMOSOMAL ABNORMALITIES/ MUTATIONS

GENERAL CONCEPTS:

Children born to older women show more chromosomal aberrations than children born to younger women

Most major chromosomal abnormalities are incompatible w/ life

Detectable by karyotyping (chromosomal analysis) w/ or w/o banding techniques (use of stains)

I. CHROMOSOMAL ABNORMALITIES/ MUTATIONS::: TYPES:

NONDISJUNCTION (Chromosomal numerical aberration)- failure of chrs to sort themselves in equal #s into daughter cells

SUBTYPES: POLYPLOIDY- see previous definition

ANEUPLOIDY- see previous definition

MOSSAICISM/ MYXOPLOIDY

Non-disjunction:

I. ANEUPLOIDY: TRISOMY

TRISOMY- presence of 3 homologous chromosome in a cell

AUTOSOMAL TRISOMY- viable throughout pregnancy, even live born but die soon after birth except Down's syndrome TRISOMY 21- DOWN'S SYNDROME

TRISOMY 18- EDWARD'S SYNDROME

TRISOMY 13- PATAU'S SYNDROME

I. ANEUPLOIDY: TRISOMY

SEX CHR. TRISOMY- abnormal development but non lethal; # of X chr. is directly proportional to mental retardation while number of Y chr. is directly proportional to aggressive behavior

TRIPLE X

I. ANEUPLOIDY: MONOSOMY

MONOSOMY- absence of one of a pair of homologous chr AUTOSOMAL MONOSOMY- IUFD is the usual

outcome

SEX CHR. MONOSOMY- compatible w/ life only if the conserved chr is an X, if not it will be less viable

• TURNER'S SYNDROME- 45, XO

Hydrops Fetalis – Monosomy X:

I. ANEUPLOIDY: MOSSAICISM/ MYXOPLOIDY

MOSSAICISM/ MYXOPLOIDY- nondisjunction at a later cell division resulting to population of normal & trisomic or monosomic cells coexisting in an individual AUTOSOMAL MOSSAICISM- rare & lethal

SEX CHR. MOSSAICISM- common

• GONADAL DYSGENESIS- TURNER'S SYNDROME 45, XO

• KLINEFELTER'S SYNDROME 47 XXY

I. CHROMOSOMAL ABNORMALITIES/ MUTATIONS::: TYPES: I. MORPHOLOGIC/

STRUCTURAL SUBTYPES:DELETION- loss of chromosomal material

following a break in the chr arm or partial monosomy CRI DU CHAT- partial monosomy of p5

RETINOBLASTOMA- q13

WILM'S TUMOR ANIRIDIA SYNDROME- p11

I. MORPHOLOGIC/ STRUCTURAL SUBTYPES:

TRANSLOCATION- transfer of segment of chromosomal material to another chromosome leading to imbalance of material in each daughter cell between non homologous chr RECIPROCAL- acentric segments of chr exchanged for

similar segment from a heterologous chr; use banding techniques for detection

ROBERTSONIAN (CENTRIC FUSION)- 2 acrocentric chr broken near centromere, exchange 2 arms and form new large metacentric chr and a small fragment, devoid of centromere & lost during subsequent division


TRANSLOCATION BALANCED- transfer w/ no loss of genetic

material; individuals are normal except for infertility & if fertile, have a high risk of having malformed offspring

UNBALANCED- transmitted in the haploid gamete & paired w/ a new set of genes from the other parent

• MALIGNANT LYMPHOMA- between 8 & 14

• LEUKEMIAS- between 22 & 9

• DOWN'S SYNDROME- chr 21


TRANSLOCATION ISOCHROMOSOMAL- faulty division of

centromere at the transverse plane of the long axis w/ formation of a pair of isochromosome (one short arm & one long arm)

• TURNER'S SYNDROME


INVERSION- break of a chr at 2 points, followed by inversion of the intermediate segments & reunion results in the formation of a chr w/ rearranged distribution of genes PERICENTRIC- rotation occurs around the

centromere

PARACENTRIC- rotation occurs only on the acentric portion of the arm


RING CHROMOSOME- break in the telomeric ends of the chr followed by deletion of the broken acentric segments & end to end fusion of the remaining portion

II. GENE ABNORMALITIES/ MUTATIONS GENERAL CONCEPTS:

Single gene defect detectable in the phenotype

Modified by penetrance, expressivity & whether defect is dominant, intermediate, recessive or X linked

Dominant pattern of inheritance usually due to alteration of aa sequence in the gene

Recessive pattern of inheritance (inborn errors of metabolism) usually is due to manufacture of abnormal enzymes or enzyme deficiencies

Follows Mendelian patterns of inheritance

PATTERNS OF INHERITANCE: AUTOSOMAL DOMINANT

Autosome- gene location

Gene expression- both homozygous & heterozygous state

Transmission of traits in every generation unless Low penetrance or modified by gene mutations

Unaffected family members do not transmit trait to offspring; affected family members usually heterozygous & transmit trait to only half of the offspring

M = F

PATTERNS OF INHERITANCE: AUTOSOMAL DOMINANT

Pp x pp

Pp : Pp : pp : pp DIABETIS INSIPIDUS

MUSCULAR DYSTROPHY

POLYDACTYLISM

MARFAN'S SYNDROME

ACHONDROPLASTIC DWARFISM

HUNTINGTON'S CHOREA

GARDNER'S SYNDROME

GOUT

HEMOCHROMATOSIS

PATTERNS OF INHERITANCE: AUTOSOMAL RECESSIVE

Autosome- gene location

Gene expression only in the homozygous state

Both parents usually heterozygous for the trait & clinically unaffected

Symptoms appear in 25% of offspring

50% of all siblings will be heterozygous for the trait thus assymptomatic

M = F

PATTERNS OF INHERITANCE: AUTOSOMAL RECESSIVE

Nn x Nn

NN : Nn : Nn : nn

ANDROGENITAL SYNDROME

ALBINISM

ALKAPTONURIA

DEAF MUTISM

GALACTOSEMIA

PHENYLKETONURIA

FAMILIAL GOITROUS CRETINISM

CYSTIC FIBROSIS

GLYCOGEN STORAGE DISEASES

MUCOPOLYSACCHARIDOSIS

LIPID STORAGE DISEASE

WILSON'S DISEASE

TYROSINOSIS

BILIRUBIN METABOLIC ABNORMALITIES

PATTERNS OF INHERITANCE: X LINKED RECESSIVE

X chromosome - Gene location

Expression of traits

100% heterozygous male

Rare homozygous female

Partial heterozygous female if X Chromosome inactivation occurs

Transmission via asymptomatic female

Each son of heterozygous female carrier has 1 in 2 chances of having the disease

Affected males do not transmit trait to their sons, only to their daughters; Unaffected males do not transmit the gene

PATTERNS OF INHERITANCE: X LINKED RECESSIVE

FEMALE X MALE (HEMOPHILIAC)

XX x Xh Y

XXh : XY : XXh : XY

FEMALE (CARRIER) x MALE (NORMAL)

Xh X x XY

Xh X : Xh Y : XX : XY

HEMOPHILIC

COLOR BLINDNESS

G6 PD DEFICIENCY

MUSCULAR DYSTROPHY- DUCHENNE TYPE

PATTERNS OF INHERITANCE: X LINKED DOMINANT

Rare

Affected heterozygous female transmit to 50% sons & 50% daughters

Affected males transmit to 100% daughters & none to their sons VIT. D RESISTANT RICKETS

PATTERNS OF INHERITANCE: Y LINKED

Not clinically significant Hairy ears

III. POLYGENIC/ MULTIFACTORIAL ABNORMALITIES

GENERAL CONCEPTS:

Environmentally influenced interactions of a number of different gene pairs HYPERTENSION

DIABETIS MELLITUS

PEPTIC ULCER

OTHER CONGENITAL HEART DISEASES

CHROMOSOMAL DISEASES:SEX CHROMOSOMAL ABNORMALITIES

X DEFICIENCY TURNER'S SYNDROME 45, XO

• Short stature female w/ webbed neck, cubitus valgus, immature genitalia w/ small fibrotic (streak) ovaries, coarctation of aorta; mostly abort; no Barr Bodies; almost 50% are mossaics w/ less stigmata

ULLRICH NOONAN SYNDROME (46, XX or XY ::: 46, X(Xq)

• Turner like phenotype; often w/ pulmonary stenosis; giant Barr Bodies


KLINEFELTER'S SYNDROME 47, XXY Most common of X chromosomal abnormality

Tall eunuchoid male w/ gynecomastia, small testis w/o spermatogenesis (infertile)

Mossaics occur


MISCELLANEOUS SYNDROMES TRIPLE X (47 XXX)- mildly retarded; normal

female phenotype

47 XYY- tall, aggressive, mildly retarded male; increased incidence among criminal


INTERSEX STATES- HERMAPHRODITISM TRUE HERMAPHRODITE- XX or XY or both;

variable phenotype, both ovaries & testis are present

PSEUDOHERMAPHRODITES (NORMAL GENECITY)

• Male phenotypically female; testicular feminization

• Female phenotypically male; virilizing ovarian or adrenal tumors

CHROMOSOMAL DISEASES: AUTOSOMAL ABNORMALITIES

More severe effects than X chr anomalies

Monosomies more severe than trisomies

The larger chromosome involved, the more serious the phenotypic disorder


DOWN'S SYNDROME- TRISOMY 21, MONGOLISM; 47 G21+

Most common of the trisomies; maternal risks increases w/ age; incidence equal in both sexes; usually due to maternal nondisjunction

Floppy infants w/ psychomotor retardation, mongoloid facies, epicanthic folds, flat nose, cardiovascular anomalies, simian palm creases, cryptorchidism, increased incidence of leukemia

Variant - Translocation type (heritable)- occurs at any maternal age; 46 XY -D; +tDqGq

Downs Karyotype: Trisomy-21

Downs Sy.

Trisomy-21

Downs Syndrome - Trisomy-21

Downs Syndrome - Trisomy-21

Simian Crease

Downs Syndrome:

Mental retardation

Neck folds

Epicanthic folds

Flat facial profile

Simian crease

Hypotonia

Umbilical hernia

Leukemia


EDWARD'S SYNDROME (16 - 18 TRISOMY, E TRISOMY); 47, E18+ Female predilection; low set ears, epicanthic folds,

micrognathia, CVS anomalies, overlapping 2nd & 5th finger, rocker bottom feet, renal anomalies, early death

PATAU'S SYNDROME (13 - 15 TRISOMY, D TRISOMY); 47, D13+ Least common, both sexes equally affected; low set ears,

micropthalmia, brain anomalies, cleft lip & palate, overlapping 2nd & 5th finger, CVS anomalies, rocker bottom feet

Cleft Lip - Trisomy 13:

Polydactyly - Trisomy 13:


CRI DU CHAT SYNDROME, 5p- Rare, common in females, cat cry, moon faced,

retarded, micrognathia, antimongoloid slant, CVS anomalies

D13p-, D13q-, E18q-, TRIPLOIDY Severe anomalies, lethal

PHILADELPHIA CHROMOSOME, G22q- Associated w/ CML; good prognosis

Syndactyly - Triploidy

Philadelphia Chromosome (Ph)

Reciprocal translocation t(9;22)

Results in bcr/abl gene fusion c-abl (Abelson) chr 9

bcr (break point cluster region) chr 22

Protein w/ tyrosine kinase activity - plays critical role in pathogenesis

CML - t(9;22) - (Ph chr)

DISEASES DUE TO GENE ABNORMALITIES AND MUTATIONS:

AUTOSOMAL DOMINANT ABNORMALITIES ACHONDROPLASIA

Defective endocndral ossification

Most common type of dwarfism

High incidence of early death

80% sterility

HUNTINGTON'S CHOREA Progressive neurologic disorder w/ choreic movements,

seizures, dementia, death

Average onset is 35 years of age so offspring is born before parent is affected

Reproduction not impaired

DISEASES DUE TO GENE ABNORMALITIES AND MUTATIONS:

AUTOSOMAL DOMINANT ABNORMALITIES: MARFAN SYNDROME

Complex defective formation of collagen & elastin

Tall, long extremities (arachnodactyly), subluxation of lens, cystic medial necrosis of aorta w/ dissecting aneurysm

Mechanism is single gene w/ multiple effects (pleiotropy), variable expression, forme fruste expression, may skip generations

GARDNER SYNDROME Complex cyst of the skin, osteomas, lower intestinal polyps

with development of colonic ca

Pleiotropy

Cell Cycle

Mitosis

Meiosis

Reduction Division (4n-2n) Prophase-1(Synapsis, g.rec)

Metaphase-1

Anaphase-1

Telophase-1

Equatorial Division (2n-n) Prophase-2

Metaphase-2

Anaphase-2

Telophase-2

Documents

Genetic Disorders. INTRODUCTION: DEFINITION OF TERMS CHROMOSOMES- cellular structures where genes are located GENES- basic units of heredity carry