DOWN SYNDROME

non-disjunction

- the failure of homologs or sister chromatids to separate properly to opposite poles during meiosis or mitosis

aneuploidy

- a chromosome number that differs from normal (does not include situations where entire sets of chromosomes are lost or duplicated)

trisomy

- an aneuploidy with an extra chromosome of one type, producing a chromosome number of 2N+1

monosomy

- an aneuploidy in which one member of a chromosome pair is missing, producing a chromosome number of 2N-1

DOWN SYNDROME PHENOTYPE

•Epicanthic fold in eye corner

•IQ seldom above 70

•Life expectancy short, few survive to 50

•Have simian crease

•May have heart defects

•May have small heads

•May have furrowed tongues

• 20 fold increased risk of leukemia

GENERAL INFORMATION•Down caused by non-disjunction of chromosome

21, correlated with age of mother and onset of menopause.

•Down also caused by attaching chromosome 21 to 14 (translocation), referred to as familial Downs.

•Amniocentesis and chorionic villi sampling developed because of defects such as Down. Newer, not yet perfected technology, samples fetal cells from maternal circulation. Once fully developed this method will be safer because it is not invasive.

•Extra copies of human chromosomes generally not well tolerated. Chromosome 21 has only 225 functional genes.

•Trisomy for chromosomes with more genes results in more pronounced defects; e.g. trisomy for chromosome 16 is common but lethal.

Primary non-disjunction

21/21 21/21

AI

AII

• 75% of Down occur at MI• 90% of all chromosome abnormalities are MI / maternal

2nd non-disjunction

21/21 21 21

Note:

non-disjunction very unlikely to occur twice in same meiosis

Mother’s gametes

21/21 -0- 21

Father’s gametes

21

Offspring: 21/21/21 21/- 21/21

Down Lethal Normal

2N: 46+1 = 47 2N: 46-1 = 45 2N: 46

(2N+1 = 47) (2N-1 = 45)

Karyotype of Down Syndrome Individual

• extra chromosome 21 comes from mother 95% of time

• other viable individuals with extra chromosome are Patau (chromosome 13) and Edwards Syndrome (chromosome 18)…both die 3-4 months

• chromosomes 13, 18, and 21 have the fewest genes

• individuals missing one chromosome almost never seen and never viable; may unmask recessive lethal or haploinsufficient genes

Correlation Down Syndrome and Maternal Age

•probability of Down related to onset of menopause, aberrant hormone levels may affect oocyte maturation

Familial Down SyndromeFamilial Down Syndrome

• long arms of chromosomes 14 and 21 fused with one common centromere(Robertsonian translocation)

• acentric fragments lost….apparently without serious consequence for individual

• genes lost are primarily rRNA(encode RNA found in ribosomes)…..additional copieslocated elsewhere in genome

• fused centromere haschromosome 14 identity at meiosis

14 21 14 21

Offspring from Mating Between Translocation Carrier and Normal Individual

• 1/3 of surviving offspring expected to be Down

• another 1/3 surviving progeny expected tobe carriers