Pathophysiology: Winter Term (Chromosomal Abnormalities)

types of chromosomal abnormalities

-changes in chromosome number (most typical)

-chromosome breaks, inversions, deletions, translocations

duplication

change to a chromosome in which part of the chromosome is repeated/inserted a second time

inversion

section of chromosome flips orientation (typically doesn't show much effect but can interrupt a gene)

substitution

section of DNA from one chromosome inserts itself into another

translocation

parts of two chromosomes break off and switch places

diploid

-the normal condition where a human cell has 2N=46 (N= # of pairs)

-23 from dad, 23 from mom

haploid

-half the number of chromosomes, 1N=23

-found in gametes after meiosis

Aneuploidy

-different number of chromosomes

-cancer cells tend to be aneuploid

-ex: trisomy, monosomy, etc.

-often due to non-disjunction

chromosome structure

-2 sister chromatids attached by a centromere

-centromere can be in different locations (location helps to identify which chromosome it is)

-long arm= p

-short arm= q

-p and q give us map locations for where to physically look for a gene

Giemsa Stain

-stains chromosomes in karyotypes and shows banding

-can read banding pattern to differentiate each chromosome

-start counting banding at centromere

-there are regions on chromosomes and specific bands are within those regions

oogenesis

-all oocytes are produced in utero

-primary oocyte arrested in prophase I before birth (after DNA replication, frozen in tetrad stage)

-meiosis I iscompleted after puberty upon selection of primary follicle

chromosomal nondisjunction

-the failure of homologous chromosomes to separate properly during cell division

-more common during first meiosis rather than 2nd

-increases with age especially in females

-can also happen during sperm development but much less common

mosaicism

-condition in which cells within the same person have different genetic makeup: "chromosomal mosaicism"

-caused by error in cell division very early in fetal development

-phenotype not typically severe as pure aneuploidy

-contrast to germline mosaicism

-nondisjunction during early embryonic development (occurs in mitosis rather than meiosis)

trisomy

-type of aneuploidy

-(2N+1)= 3 copies of one chromosome

-ex: down syndrome- trisomy 21 (47, +21)

-first number is total chromosomes in genome, second is the extra chromosome

monosomy

-type of aneuploidy

-(2N-1)= a single copy of a chromosome

-ex: turner syndrome (45, x)- monosomy x

polyploidy

-addition of complete haploid sets of chromosomes

-ex: triploidy (3N=69), tetrapoid (4N=92)

-results in spontaneous abortion

structural anomalies

-rearrangements of genetic material within or between chromosomes (translocation)

-two ways this can happen

1. genetically balance

2. genetically unbalanced

genetically balanced structural anomaly

-no change in amount of essential genetic material

-possible that expression regulation might be affected

genetically unbalanced structural anomaly

-alters amount of DNA

-gain or loss of essential chromosome segments

Robertsonian Translocation

-long arms (q) of two nonhomologous chromosomes fuse at the centromere forming a single chromosome

-confined to chromosomes 13, 1,4 15, 21, and 22

-ex: 3-5% of down syndrome cases

1. carriers at increased risk for multiple children with down syndrome

2. 10-14% if maternal carrier

3. <2% if male carrier

down syndrome

-trisomy 21 (47, +21)

-1/800 births (most common aneuploidy)

-most are due to maternal nondisjunction (highly dependent on maternal age

-most are full trisomy 21 (94%)

-rest are translocations or mosaics

down syndrome features

1. intellectual disability

2. face

-low nasal bridge

-flat low-set ears

-eyes have epicanthal folds and brushfield spots

3. transverse palmar crease

4. congenital heart defects

5. reduced life expectancy

-20% mortality before age 10

-average of remainder is about 60 years old

6. early onset Alzheimer disease (~40 years old)

7. gap between toes

Edwards Syndrome

-trisomy 18 (47, +18)

-1/5000 births

-more common in pregnancy resulting in spontaneous abortion

-most are fully trisomy 18 (95%) (doesn't do robertsonian translocation)

Edwards Syndrome features

-more significant defects compared to down syndrome, especially heart defects

-intrauterine growth retardation (low birth weight)

-reduced survival (90% die by 1 year)

-profound motor and intellectual disability in survivors

Patau Syndrome

-trisomy 13 (47, +13)

-1/20-25,000 births

-full trisomy (80%)

-translocations (20%)

Patau Syndrome features

-more significant defects compared to down syndrome, especially heart defects

-micro-ophthalmia (small eyes)

-polydactyly (Extra digits)

-reduced survival compared to edwards syndrome (95% die by 1 year)

-profound motor and intellectual disability in survivors

Turner Syndrome

-monosomy x (45, x)

-1/2500 female births

-most do not reach term

-most are due to paternal nondisjunction (not related to age)

-50% 45, x monosomy

-25% mosaic

-25% other chromosome arrangements

Turner Syndrome Features

1. poorly developed lymphatic system

-increased neck folds

-lymphadema

-hydrops

2. heart defects

-coarctation of aorta

-dilated aortic root

3. endocrine

-short

-ovarian failure

-amenorrhea (failure to menstrate)

4. CNS

-average IQ

-visual/spatial difficulties

5.other

-short 4th metacarpal

-broad shield like chest

-low posterior hairline

Klinefelter Syndrome

-47, XXY (genetically male)

-1/1000 male births

-1/100 males in institutions for the mentally disabled

-1/50 males with infertility

Klinefelter Syndrome etiology

-75% of cases result from maternal nondisjunction (increased incidence with maternal age)

-25% of cases result from paternal nondisjunction

-mosaicism occurs and results in less severe disease

-individuals with XXXY and XXXXY are rare but considered to have Klinefelter syndrome (sometimes called super males)

Klinefelter Syndrome traits

1. genito-urinary

-small testes

-infertility

-cryptorchidism (testes fail to descend)

-gynecomastia (Breast like structures)

2. CNS

-intellectual disability

-personality disturbances

-behavioral problems

3. other

-eunuchoid habitus (lack of testicular function)

-long limbs

uniparental disomy

when individual inherited BOTH copies of an allele or chromosome from ONE parent

imprinting

when gene expression is determined by whether the gene comes from mother or father

-Prader Willis vs Anglelman Syndrome (15p1113 paternal vs maternal)