Chromosomal Abnormalities (Part I)

Meiosis

- A type of cell division that results in four daughter cells each with half the number of chromosomes of the parent cel

Diploid cells give rise to what in mitosis?

- Diploid (2N) give rise to haploid (1N) gametes

Meiosis is unique to which cells?

- Germ cells → spermatocytes and oocytes

Spermatocytes

- In testes, cells divide to create spermatocytes, which undergo meiosis (sexual div - identical # produced) to form 4 haploid spermatids.

Oocytes

- Female gametes, immature eggs

How is Meiosis Broken Down?

- Meiosis I

- Meiosis II

Meiosis I: Ploidy

- Diploid 2N → Haploid 1N

*Called reductive division

Where does the original Diploid (2N) cell come from before Meiosis I occurs?

- The zygote divides by mitosis to make all the body's diploid cells; some of those diploid cells in the testes or ovaries become germ cells and enter meiosis to make sperm or eggs.

How is ploidy determined?

- The amount of centromeres

Simplified Steps of Meiosis I

1. Diploid (2N, 2C) germ cell starts with 2 chromosomes (homologous).

2. Chromosomes within diploid cell are replicated during interphase. There are still 2 homologous chromosomes, except each chromosome now has a sister chromatid. Ploidy is now (2N 4C)

3. Meiosis I begins with crossover/recombination between maternal/paternal chromosomes

4. After recombination, cell divides → generates 2 haploid cells (1N, 2C)

Why are the cells 1N, 2C after cells divide in Meiosis 1?

- N: Each cell contains 1 centromere = 1N

- C: 2 copies of each chromosome as chromatids → 2C

Simplified Steps of Meiosis II

1. Starts with cells that just divided in Meiosis I, current ploidy is (1N, 2C)

2. Sister chromatids separate, cells divide → generates 4 haploid daughter cells (1N, 1C)

Meiosis I and II: Ploidy Summary

Meiosis I:

- Diploid cell (2N, 2C)

- Diploid cell after replication (2N, 4C)

- Cell divides, becomes haploid (1N, 2C) (2 Cells)

Meiosis II:

- Haploid cells from meiosis I separate sister chromatids and divide → 4x (1N, 1C) Cells

Steps and Ploidy of Spermatogenesis

1. Spermatogonium, Diploid (2N, 2C)

2. Mitosis, creating sister chromatids → 2x 1° Spermatocytes (2N, 4C)

3. Meiosis I separates homologous chromosomes → Each 1° generates 2x 2° Spermatocytes (1N, 2C)

4. Meiosis II → Sister chromatids separate → 4x Spermatids (1N, 1C)

5. Spermatids undergo spermatogenesis → Spermatozoa

Steps and Ploidy of Oogenesis

1. 1° Oocytes (2N, 4C) are arrested in Meiosis I until puberty

2. At puberty, few 1° oocytes complete meiosis I → some form polar bodies, others form 2° Oocytes (1N, 2C)

3. In 2° Oocytes, meiosis II begins but is arrested in metaphase and is ovulated in this state

4. If ovulated 2° Oocyte is fertilized, meiosis II finishes → mature ovum (1N, 1C) + another polar body (1N, 1C)

Aneuploidy

- Abnormal number of chromosomes.

Disomy, Monosomy, Trisomy

- Disomy: Two copies of each chromosome (Normal)

- Monosomy: One copy of each chromosome

- Trisomy: Three copies of each chromosome

What causes Aneuploidy?

- Meiotic Nondisjunction: Failure of chromosome pairs to separate

When can Meiotic Nondisjunction occur?

- Can occur in either Meiosis I or II

Meiosis I Nondisjunction

- Homologous chromosomes fail to separate

- Leaves one cell with homologous chromosomes, and the other with none

What happens during Meiosis II after a Meiosis I Nondisjunction?

- 2 diploid cells (only supposed to be 1N 1C)

- 2 cells with NO chromosomes

Meiosis II Nondisjunction

- Sister chromatids fail to separate

What does a Meiosis II Nondisjunction result in?

- Successful division of chromatids → 2x Haploid (1N, 1C)

- Unsuccessful division → 1x Diploid cell (2N, 2C) and 1x Cell with NO chromosomes

Where do the genes come from in the diploid cells created from Meiosis I/II Nondisjunction?

- Meiosis I: 2 Chromosomes, one from each parent

- Meiosis II: 2 Chromosomes, from SAME PARENT

When does Monosomy occur?

- Fertilization of a 1n (normal) with a 0n gamete → not typically viable

Turner Syndrome

- Females with only 1 X chromosome (due to monosomy)

When does Trisomy Occur?

- Fertilization of a 1n (normal) with 2n gametes (abnormal)

Trisomy 21

- 3 copies of chromosome 21 → Down syndrome

Trisomy 18

- 3 copies of 18 → Edward Syndrome

Edward Syndrome: Presentation

- Clenched fist showing overlapping fingers

- Rocker bottom feet

- Congenital heart defects

- abnormally shaped head, low set ears, mental retardation

- More common heart/GI defects than DS

Edward Syndrome: Prognosis

- Usually patients die within a few years of life

- 5-10% survive first year

Trisomy 13

- Extra chromosome 13 → Patau Syndrome

Patau Syndrome: Presentation

- Severe Intellectual Disability (no separation of brain hemispheres)

- Extra fingers or toes (polydactyl)

- Cleft lip/palate

- Very small or absence of eyes

Common Cause of Trisomy

- Maternal Meiosis I Nondisjunction errors

What increases risk of trisomy?

- Advanced maternal age

Trisomy Genotype Example: Father with 21A/21B; Mother with 21C/21D

- 21ACD → Meiosis I NDJ (homologous chromosomes in mom failed to separate)

- 21ACC → Meiosis II NDJ (sister chromatids in mom failed to separate → 2 copies of same chromosome in fetus)

Uniparental Disomy

- Offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent.

Isodisomy

- Non-disjunction in meiosis II, 2 copies from father

Heterodisomy

- Non-Disjunction in Meiosis I, 2 copies from mother

Euploid

- An individual with the appropriate number of chromosomes but can lead to phenotype of recessive disease as they are inheriting both copies of chromosomes from ONE parent

*Child can inherit 2 copies of a recessive diseased gene from ONE parent*

What is the most common liveborn chromosome abnormality?

- Down Syndrome

Down Syndrome: Presentation

- Flat face/nose, low set ears, almond eyes, poor muscle tone, shorter height, palmar crease

- Heart/GI Malformations

- Intellectual disability, Early Alzheimer's

- ↑ Risk of leukemia

Is the posterior skull flat or rounded in Down syndrome?

- Flat

Brushfield Spots

- White spots in iris, found in Down syndrome

Down syndrome: Presentation found in hands and feet

- Short broad hands with large palmer crease

- Sandal gap on feet

50% of those with Down syndrome experience what?

- Congenital heart defects → most commonly endocardial cushion defects

5% of those with Down syndrome experience what?

- GI Abnormalities → duodenal atresia or stenosis

Why do those with Down syndrome often experience early alzheimer's?

- Amyloid precursor protein is found on chromosome 21 (have 3 copies)

- APP breaks down to form β-Amyloid → forms plaques → Alzheimers

Down Syndrome: Definitive Test

- Fetal Karyotype: Obtain sample of fetal cells, determining its number of chromosomes

Invasive and carries risk

Down syndrome: How is a fetal karyotype obtained?

- Chorionic Villus Sampling: Taking sample of placental tissue

- Amniocentesis: Inserting needle in amniotic cavity and taking sample of fluid which contains cells from the baby

Down syndrome: Karyogram

Down Syndrome: Noninvasive Screening

- Ultrasound

- Maternal Serum Testing

Down Syndrome: 1st Trimester Ultrasound Results

- Small, poorly-formed nasal bones

- Nuchal Translucency: Fluid under back of neck

Down Syndrome: 1st Trimester Maternal Serum Results

- ↓↓ Plasma protein-A (PAPP-A)

- ↑↑ β-hCG

Down Syndrome: 2nd Trimester Maternal Serum Results

- ↓↓ α-Fetoprotein and Estriol (uE3)

- ↑↑ β-hCG and Inhibin A

Common Features of Trisomy Disorders

- All associated w/ advanced maternal age, due to NDJ

- Intellectual disability, physical deformities, heart defects

What is the 2nd most common trisomy in live births?

- Trisomy 18 → Edward Syndrome → SEVERE intellectual disability

Edward Syndrome: Occurrences in females vs males

- 3:1 Female to male ratio

Edward Syndrome: Screening

- So many physical and congenital abnormalities → easy to identify them in womb via ULTRASOUND

Edward Syndrome: 1st Trimester Maternal Serum Results

- ↓↓ PAPP-A

- ↓↓ β-hCG

Worse down syndrome → extra down

Edward Syndrome: 2nd Trimester Maternal Serum Results

- ↓↓ AFP

- ↓↓ Estriol

- ↓↓ β-hCG

- ↓↓ Inhibin-A

Worse down syndrome → extra down

How is Patau Syndrome detected?

- Fetal ultrasound > 90% of cases

Patau Syndrome: Prognosis

- Median survival is 7 days

- 91% die within first year of life

Patau Syndrome: 1st Trimester Maternal Serum Results

- ↓↓ PAPP-A

- ↓↓ β-hCG

Similar to edwards

Klinefelter and Turner Syndromes

- Klinefelter: Male with extra X (XXY)

- Turner: Female missing X (X0)

Klinefelter and Turner Syndromes: How can they be diagnosed?

- Karyotype

Klinefelter XXY shown

When is Klinefelter less severe?

Mosaicism

- 46XY in some cells // 47XXY in others

What determines severity of Klinefelter?

- Ratio of estrogen:testosterone (↑ estrogen → more severe)

Klinefelter Syndrome: Presentation

- Small/firm testes in males with atrophy in seminiferous tubules

- Low testosterone/delayed puberty

- Gynecomastia

- Female pubic hair pattern // Reduced facial and body hair

- Micropenis

- Long legs and arms

Klinefelter Syndrome: Hormone Levels

- ↑↑ FSH

- ↑ LH

What can be found within the cells of pt's with Klinefelter's?

- Barr bodies in nucleus → inactivated X chromosome

Most common presentation of turner syndrome?

- 45XO

- Caused by sperm lacking an X Chromosome

Turner Syndrome: Presentation

- Short stature, broad chest

- Widely spaced nipples

- Webbed neck

- Swollen hands and feet

- Horse-shoe kidney (fused, sits lower in pelvis)

Turner Syndrome: Ovaries

- Non-functional → failure to menstruate → infertile

- "Streak Ovaries" Fibrous connective tissue in location of ovaries, very few follicles

Turner Syndrome: Hormones

- ↓↓ Inhibin B and Estrogen

- ↑↑ LH/FSH

Turner Syndrome: Cardiovascular Complication

- 30% Bicuspid aortic valve

- 5-19% Coarctation of aorta

- High BP

Turner Syndrome: Common associated diseases

- Osteoporosis

- TIID

- Thyroid Disease