genPathGeneticDses

8/9/2019 genPathGeneticDses

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Genetic Disorders

Ma. Minda Luz M. Manuguid, M.D.


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Review of Normal Genetics

Karyotypeh the number & type ofchromosomes in an individuals cells

normal human karyotype: 46 chromosomes= 22

pairs Autosomes (44) + 1 pair Sexchromosomes (2)--- male XY; female XX Diploid no. h 2n=46in somatic cells

Haploid no. h n =23in germ cells

Euploid no. h exact multiple of the haploid no.

Petitarm h p h short arm of the chromosome

Long arm h q h long arm of the chromosome


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Other Terms

Genotypeh the chromosome complement (geneticcomposition of the chromosomes) of an individual

Phenotypeh morphologic expression of the

genotype; the appearance of a trait Alleleh an alternative form of a gene (one member

of a pair) located on a specific position on a specificchromosome; there are two for each trait, each may

be dominant/recessive Homozygous h has two identical alleles for a trait

Heterozygoushas two different alleles for a trait


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DeoxyribonucleicAcid

DNA -blueprint of life (has theinstructions for making anorganism): codes for genes

- double helix of repeating

subunits (nucleotides) asestablished by JamesWatson and Francis Crick

Gene - a segment of DNA thatcodes for a protein, which inturn codes for a trait (skintone, eye color, etc)

Nucleotide - consists of a sugar(deoxyribose), phosphateand a base


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DNA structure

Nucleotides (also called Bases) Adenine, Thymine,

Guanine, and Cytosine pair in a specific way:

the Base-Pair Rule

:Adeninealways pairs with Thymine;

Guaninealways pairs with Cytosine

* Therungs of theDNA ladder can occur in any order

as long as thebase-pair rule is followed


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DNA Replication

Replication is the process where

DNA makes a copy of itself. Cells

divide for an organism to grow or

reproduce, and every new cell needs

a copy of the DNA or instructions toknow how to be a cell. DNA

replicates right before a cell divides.

DNA replication is semi-

conservative. That means that when

it makes a copy, one half of the old

strand is always kept in the new

strand. This helps reduce the

number of copy errors.


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RibonucleicAcid

RNA brings the genetic codefrom the DNA in the nucleusto the ribosomes (whereprotein synthesis occurs) inthe cytoplasm;- compared to DNA, RNA:

has one strand rather thantwo

has ribose sugar rather thandeoxyribose

has Uracil instead ofThymine


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The Genetic Code

How the code works: For instance, a stretch of DNA

that reads AATGACCAT would code for a different

gene than a stretch that reads GGGCCATAG.

* The 4 bases have endless combinations just like the

letters of the alphabet can combine to make

different words.

Each triplet / codon represents an amino acid.

nonsense codons terminate AA sequences when the

correct protein has been formed.


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Protein Synthesis

* Transcription - mRNA ismade from DNA

* mRNA takes the messagefrom the DNA to theribosomes

*Translation - proteins are

made from AAs carried bytRNA to rRNA from themessage on the mRNA


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Genetic Disorders:

Modes of Inheritance

CYTOGENETIC - defect in the number or structureof chromosomes

MENDELIAN - defect is carried by two alleles, oneof which may be dominant over the other

MULTIFACTORIAL - environmental factors enable

a genetic tendency to be expressed NONCLASSIC all other disorders not included in

the previous categories


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Cytogenetic Disorders

Aneuploidy number of chromosomes is not an exact

multiple of 23; caused by nondisjunction or by

anaphase lag

Monosomy there is an unpaired chromosome

Trisomy there is a chromosome triplet instead of a pair

*Mosaicism there are two or more populations of

cells with different numbers of

chromosomes

Mutation change in chromosome structure


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Cytogenetic Disorders: Mutation

Deletion loss of a portion of a chromosome

Inversion rearrangement from 2 breaks within a singlechromosome & reincorporation of the inverted segment

may be paracentric orpericentric

Translocation a segment of a chromosome istransferred to another: balanced reciprocal or

Robertsonian (centric fu

sion) Isochromosome formation one arm is lost, the

remaining arm is duplicated


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Cytogenetic Disorders inAutosomes

Cri du chat Syndrome

Wolff-Hirschhorn Syndrome

Down Sydrome (Trisomy 21)

Edwards Syndrome (Trisomy 18)

Patau Syndrome (Trisomy 13)


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Cri du chat syndrome

deletion of the short arm ofchromosome 5, usually (in 80%)the paternal chromosome (5p-)

characteristic mewling cry like that

of a cat: due to an abnormallaryngeal development-becomesnormal within a few weeks to a year

1 in 50,000 live births

round facies; low birth weight;respiratory problems; microcephaly;mental retardation

most have normal life expectancy;some have a shortened life span


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Cri du chat syndrome


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Wolf-Hirschhorn

syndrome4p- (paternal chromosome)

severe growth retardation &

mental defects microcephaly

cleft lip/palate

coloboma of the eye

Greek helmet facies prominent forehead; wideseteyes; broad, beaked nose

cardiac septal defects


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Trisomy 21: Down Syndrome

most common chromosomal disorder :

extra (3rd) copy of chromosome 21

Aneuploidy (47 XX/XY +21) or

Mosaicism(46XX/47XX +21)

average: 1 in 800 live births

maternal age is significant:

20 yrs : 1 in 1550 live births

45 yrs : 1 in 25 live births

varying degrees of physical disabilities & learning

difficulties


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Down Syndrome

mongoloid facies :

eyes slanted upward +epicanthic folds ( small

folds of skin at the innercorners of the eyes); flatnasal bridge & facial

profile; broad face;

small, low-set ears

gentle, shy manner


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Down Syndrome

small mouth, poor muscle tone- tongue appears

large & protruding; simian/transverse palmar crease

short stature; small hands & feet

40% with CHD: ASD, VSD, AV mal, Ostium primum

accelerated Alzheimers

10-20fold risk of Acute Leukemia

mental retardation

predisposition to infections

prone to thyroid autoimmunity


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Trisomy 18: Edwards Syndrome

1 in 8000 live births

Aneuploidy: 47XX/XY+18 or

Mosaicism: 46XX / 47XX +18mental retardation

micrognathia; short neck;overlapping fingers; prominent

occiput; low-set ears; rocker-bottom feet

CHD; renal malformations


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Trisomy 13:

P

atau Syndrome 1 in 6000 live births

Aneuploidy: 47XX/XY +13 or

Mosaicism: 46XX/47XX/XY +13

microphthalmia, microcephaly,cleft lip &/or palate, polydactyly,rocker-bottom feet

cardiac defects, renal defects,

umbilical hernia, abnormalgenitalia

mental retardation

short life span (


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Review of Normal Genetics:

The Sex ChromosomesLyon ( X- inactivation ) Hypothesis: Only one X chromosome is genetically active (euchromatin)

Any X chromosome in excess of one normally undergoesheteropyknosis (lyonization) & becomes inactive

(heterochromatin) Inactivation of maternal/paternal X occurs at random among

all the cells of the blastocyst on or about the 16th day ofembryonic life

Inactivation of the same X persists in all cells derived from

each precursor cell X inactivation occurs so that the female, with 2 X

chromosomes, would not have twice as many gene products asthe male, who has only one X chromosome.


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Review of Normal Genetics:

The Sex Chromosomes


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The Y chromo-

some is very

small com-pared to the X

chromosome.

The pseudo-

autosomal regions at the tips

contain the genetic material

on the Y that shows

similarity to the Xchromosome. The SRY

gene is located on the p arm

of the Y.


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Normal Genetics:

The Sex Chromosomes

Barr body X chromatin adark-staining mass in contactwith the nuclear membrane;represents the inactivated Xchromosome;

Y chromosome geneticdeterminant of male gender;contains the SrY(sex-

determinating region Ygene), which dictatestesticular development, on itsdistal short arm


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Gender Determination

Genetic presence / absence of the Ychromosome = male / female

Gonadal histology of gonad :Ovary=female; Testis=male

Ductal derivatives of the primordial tubes:Mullerian= female; Wolffian= male

Genital phenotypic morphology of externalgenitalia: Penis & scrotum = male;Clitoris & Labiae = female


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Cytogenetic disorders

in Sex Chromosomes

TrueHermap roditism

Klinefelter syndrome

XYYsyndrome

Turner syndrome

Multi-X syndrome;tripleX syndrome


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Hermaphroditism

True hermaphroditism

Presence of Ovotestis or both Ovary & Testis

Usually caused by translocation of Y to the X

chromosome or to an autosome65% are genetic females (46XX)

35% are mosaics (46XX/47XXY)Pseudohermaphroditism:

Female- 46XX; ovaries; external genitalia virilized or ambiguous due

to exposure to androgenic steroids e.g. CAH

Male- 46XY; testes; internal genitalia are incompletely differentiated;

external genitalia are ambiguous or feminized due to either a defect in

androgen synthesis or a defect in the androgen receptors


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Klinefelter Syndrome

Male hypogonadism: 1 cause ofmale infertility

classic : (82%) 47XXY; 15%-mosaics

1 in 850 male live births

eunuchoid body habitus;abnormally long legs

small atrophic testes; small penis

lack of secondary malecharacteristics

testosterone levels; FSH;

Estradiol atrophy/aplasia of seminiferous

tubules - azoospermia

other lesions: cryptorchidism;hypospadias


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Turner Syndrome

female hypogonadism

monosomy of sex

chromosomes: 45 X

short stature, webbed neck,broad chest

peripheral lymphedema,

pigmented nevi

coarctation of the Aorta streak ovaries

amenorrhea, infertility


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Aneuploidy involving Sex Chromosomes

XYY syndrome

Supernumerary Y :

47XYY

1 in 1000 l male births

excessively tall; prone

to severe acne

1-2% exhibit deviantbehavior antisocial,

delinquent, acting out,

impulsive

TripleXsyndrome

Multi- X syndrome :

47XXX; 48XXXX;

49XXXXX

1 in 1200 live born

females

menstrual irregularities mental retardation if

more than three Xs


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Mendelian Disorders

Autosomal Dominant

Autosomal Recessive

X-linked


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Autosomal dominant disorders

manifested even in the heterozygous

state

onset of Sx usually in adulthood

manifestations are less uniform,modified by

Penetrance percentage of

individuals with the dominant allele

who manifest the characteristic

Variableexpressivity differences

in the expression of a trait seen in all

individuals with the dominant gene


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Autosomal dominant Disorders

Neurofibromatosis

Tuberous sclerosis

Hereditary

sp erocytosis Marfan syndrome

Ehlers Danlossyndrome

Osteogenesisimperfecta

Achondroplasia

Huntingtons disease

Myotonic dystrophy

Polycystic kidney

Familial Polyposis coli

Von Willebranddisease

Familial

hypercholesterolemia

Acute intermittentPorphyria


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Neurofibromatosis TuberousSclerosis


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Hereditary Spherocytosis


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Marfan

Syndrome


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Ehlers Danlos

Syndrome


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Osteogenesis Imperfecta

Osteogenesis imperfecta type 1 (OItype 1)is a dominantly inherited,generalized connective tissue

disorder characterized mainly bybone fragility and blue sclerae.

Osteogenesis imperfecta type 2

Osteogenesis imperfecta type 3

Osteogenesis imperfecta type 4 Osteogenesis imperfecta with

opalescent teeth


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Achondroplasia


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Achondroplasia


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AutosomalRecessive Disorders

manifested only in thehomozygous state

onset of symptoms in infancy

complete / 100% penetranceis common

more uniform manifestations

usually enzyme defects

(inborn errors of metabolism) siblings have 1 chance in 4 to

be affected


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AutosomalRecessive disorders

Sicklecell anemia

Phenylketonuria

Cysticfibrosis

Galactosemia

Homocystinuria

Wilson disease

Alkaptonur

ia

Friedrichs Ataxia

Spinal muscularatrophy

Lysosomal storage

diseases

Alpha-1 Antitrypsin

deficiency

Hemochromatosis

Glycogen storage

diseases

Thalassemias

Neurogenicmuscular

atrophies


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Sickle Cell

Disease


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Sickle Cell

Anemia


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Wilson Disease


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Hemochromatosis Thalassemia


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X-linkedRecessive Disorders

Practically only males areaffected: rarely, a female willmanifest the disease due to

atypical lyonization, X-

autosometranslocation, or a new mutation

Heterozygous females areclinically unaffected but carry thegene

There is no variation ofexpression; the disease alwaysfollows a typical course


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AutosomalRecessive Inheritance


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X-linked disorders

Color-blindness (red & green mostcommon)

HemophiliaA & B

Agammaglobulinemia

Diabetes insipidus Lesch-Nyhan syndrome

Duchennemuscular dystrophy

Chronic granulomatous disease

Wiskott-Aldrich syndrome

Glucose-6-phosphate dehydrogenase deficiency

FragileX syndrome


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Color blindness


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Color blindness


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FragileX Syndrome

***Fragile X

syndrome isthe

leading inherited

causeofdevelopmental

disabilitiesand

mental impairment

worldwide. Itaffectschildrenofallethnic

andracial

backgrounds.


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FragileXSyndrome


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Multifactorial Disorders

CleftLip &/orPalate

Diabetes mellitus type II

Pyloric stenosis

CoronaryHeart disease Gout

Hypertension

Congenital Heartdisease

heritable genetictendency is expressedonly when certainenvironmental factorsare present

concordance rate inidentical twins is 40%

rate of recurrence insubsequent siblings is2-7%


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Cleft Lip & Palate

PyloricStenosis


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Single Gene disorders

of Nonclassic Inheritance

TriplerepeatMutations h

Fragile X syndrome

Mitochond

rial geneM

utations h

Leber Hereditary Optic Neuropathy (LHON)

Genomic Imprinting h

Prader Willi syndromeAngelman syndrome


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Angelman Syndrome

loss of the normal maternal contribution to a region ofchromosome 15, most commonly by deletion of a segment ofthat chromosome.

A healthy person receives two copies of chromosome 15, one

from the mother, the other from the father. However, in theregion of the chromosome that is critical for Angelmansyndrome, the maternal and paternal contribution expresscertain genes very differently. This is due to sex-relatedepigenetic imprinting; the biochemical mechanism is DNA

methylation. if the maternal contribution is lost or mutated, the result is

Angelman syndrome. (When the paternal contribution is lost,by similar mechanisms, the result is Prader-Willi syndrome.)


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Angelman syndrome

happy puppet syndrome

Docile, obedient

Inappropriate laughter


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Prader-Willi Syndrome

seven genes (or some subset thereof) on

chromosome 15 are missing or unexpressed

(chromosome 15q partial deletion) on thepaternal

chromosome The distinction of chromosome by parental origin is

due to imprinting (maternal Angelman syndrome)

incidence is 1 in 12,000-15,000 live births

characterized by hyperphagia, food preoccupations,

hypotonia, small stature & mental retardation


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