Numerical Chromosomal Abnormalities

Question 1

________ is the most error prone step processm and chromosome nondisjunction at this stage is the most frequent mutational mechanism in humans.

Answer 1

Meiosis I

Question 2

Down Syndrome

Answer 2

Down syndrome (trisomy 21) si the most common human chromosomal disorder.

How do you detect it?

1st trimester: Ultrasound measurements of nuchal folds and B-hcg and PAPP-A (pregnancy associated plasma protein).

2dn trimester: Quad screening–> 1) B-hcg, 2) AFP, 3)unconjugated estriol (uE3), and 4) Inhibin levels.

What causes it?

a)Nondisjunction in 95% of the cases, the additional chromosome si from maternal origin, mainly from nondisjunction durign meiosis I.

–>*Parents usually have normal chromosomes

b) Robertsonian translocations in 4% of the cases
c) Mosaicism in 1% of the cases

Clinical findings:

• Down syndrome is the most common chromosomal abnormality associated with mental retardation.
• Muscle hypotonia is present at birth (floppy baby syndrome).
• Upslating of palpebral fissures, epicanthic folds, flat facial profile, and macroglossia.
• *Simian crease

-Cardiac issues in 50% of the patients (major factor affecting survival in early childhood)

Gastrointestinal abnormalities:

• Esophageal and duodenal atresia
• ****Hirschsprung disease: which refers to aganglionic segment in large bowel.

Hematologic abnormalities:

-Increased risk of leukemia and anemia.

CNS:

• Most patients develop the neurophatologic signs of Alzheimer’s disease by age 35.
• Seizures

Endocrine issues:

-**Thyroid disease (hypothyroidism most common)

-Insulin dependent diabetes

-GERD, and Celiac’s disease

ENT issues:

• Chronic ear infections
• Deafness-sensorineural and conductive
• Enlarged tonsils

Orhtopedic issues:

-Joint subluxation

-Atlantoaxial subluxation (too much movement between C1 and C2)

Question 3

Describe abnormalities in seggregation in the first meiotic division:

Answer 3

1. Nondisjunction events are related to the positioning of chiasmata; crossover events that occur too near or too far from the centromere increase chromosome nondisjunction.

Too far: Centromere-distal exchanges are less effective in ensuring appropriate spindle attachment and separation of paired homologs in meiosis I.

Too close: centromere-proximal or excessive numbers of exchanges lead to entanglement of paired homologs in MI that then undergo reductional division leading to what appears to be MII errors.

2. Nondisjunction events are also related to the frequency of crossover events. The reduction or absence of recombination events increases the likelihood of nondisjunction.

Question 4

Maternal Age effect

Answer 4

The precise cause of the maternal age effect remains controversial. One current model is referred to as the “two-hit” theory, suggesting that several events may be responsible for increased aneuploidy in the eggs of women approaching menopause.

-The first “hit” is diminished recombination, caused either by a lack of chiasma or their mislocalization, resulting in a chromosome more susceptible to possible nondisjunction. The ability of oocytes to successfully complete chromosome segregation in the presence of unfavorable recombination events is thought to diminish over time, representing the second “hit” in this model.

A second model suggests that the degradation of *cohesin complexes over the course of the extended meiosis I arrest in oocytes results in precocious separation of homologs. In meiosis, the cohesin complex has dual functions: ensuring cohesion between sister chromatids and maintaining inter-homolog associations distal to the site of crossovers. Both activities are crucial in orchestrating the segregation of homologs at the first meiotic division. It is thought that there is little or no new deposition of the proteins of the cohesin complex during the extended meiosis I arrest in females.

Question 5

Edwards syndrome (Trysomy 18)

Answer 5

It is the second most common trisomy

Clinical findings:

-Mental retardation

-Clenched fist with overlappin fingers

-Rocker-bottom feet

-VSD (valvular heart disease, posterior fossa)

Question 6

Patau Syndrome (Trisomy 13)

Answer 6

Clinical findings:

-Mental retardation

-Cleft lip and palate

-Polydactily

-Holorposencephaly