Down Syndrome Update2013

Tamison Jewett, MDProfessor, Department of Pediatrics

Section on Medical GeneticsWake Forest Baptist health

Down syndrome (as we know it today) has existed

since the beginning of humankind.

Down syndrome history

Pottery artifacts from the Tumaco-La Tolita culture from 2500 years ago depict individuals with features of Down syndrome (DS).DS features are evident in a terra cotta sculpture carved by the Toltecs in Mexico (500-1200 AD).Esquirol, a French psychiatrist, wrote a description of the DS facial appearance in 1838.

Down syndrome history (cont.)

First described in the medical literature by Dr. John Langdon Down in England in 1866 who coined the term “Mongoloid.”In 1956, scientists discovered that the typical human cell has 46 chromosomes.In 1958, Lejeune discovered that the cells from an individual with DS had an extra chromosome 21.In 1959, 9 people with DS were found to have an extra chromosome 21.

Syndrome:

a recognizable pattern of features, usually owing to a specific cause, e.g., Down syndrome, wherein the cause is extra

chromosome 21 material

Down syndrome features

Brachycephaly (short skull front-to back)Excess nuchal (back of neck) skinHypoplastic (underdeveloped) midfaceUpslanting palpebral fissures (eyelids)Small ears w/ over-folded helices

Down syndrome features (cont.)5th finger clinodactyly (incurving)

Wide gap between 1st and 2nd toes

Single transverse palmar crease(s) (40%)

Heart defect (45%)

Fine, soft hair

It is important to remember that individuals with DS look mainly like their families; it is the characteristic pattern of features that

causes them to resemble one another.

Typical Female Chromosomes

Typical Male Chromosomes

Ideogram of the human chromosomes

p-arm=>

q-arm=><= centromere

autosomes

Sex chromosomes

Acrocentric=>

Trisomy 21 Female Chromosomes

Trisomy 21 Male Chromosomes

Nondisjunction

Abnormal cell division leading to abnormal chromosome distribution can occur in EITHER PARENT. As women age, our risk for this to occur increases, as follows:

Maternal Age Incidence of DS at delivery 15-29 1 in 1500 30-34 1 in 800 35-39 1 in 270 40-44 1 in 100 45 and over 1 in 50

Chromosomal translocations…

…can result in Down syndrome.

Down syndromeOccurs in ~1:650 live birthsThe underlying causes:

94% due to nondisjunction (unequal cell division) resulting in 47 chromosomes with an extra #21

3.3% due to an unbalanced translocation ~2.4% are mosaic (some cells have the typical 46

chromosomes, and some have 47) <1% have a duplication of a portion of chromosome 21

Extra chromosomes mean extra genes.

DNA andchromosomesare related,but are notthe same.

The genes of chromosome 21: what do we know?

There are more than 400 genes on chromosome 21.Of these, ~170 code for proteins that are also encoded by genes in mice and other animals.When genes are conserved across species, it is typically because they are important.

Chromosome 21

Not all genes on chromosome 21 cause problems when occurring in a triple dose.

2/3 of these genes are “compensated,” meaning that the amount of their product is similar to that seen in a typical population

Chromosome 21 (cont.)

1/3 of the genes on chromosome 21 are over-expressed in people with DS and are referred to as being “dosage sensitive.”

Most of these are expressed at 1.5 x the typical amount (as expected).

Some of these actually have amplified expression (more than 1.5 x the typical amount).

Chromosome 21 (cont.)

Examples of genes on chromosome 21 that are dosage sensitive and may cause problems:

COL6A1 heart defects CRYA1 cataracts DYRK1A intellectual disability; Alzheimer disease ETS2 leukemia; skeletal anomalies IFNAR immune dysfunction SOD1 premature aging APP Alzheimer disease

What’s New?

Non-invasive Prenatal Testing Using Cell-free Fetal DNA

A new method of screening the fetus for abnormal chromosome number using the

mother’s blood

Traditional Prenatal Testing

Maternal serum screening

Amniocentesis

Chorionic villus sampling (CVS)

Definition of ScreeningTest that either increases or lowers a patient’s prior risk for certain fetal conditions

Does NOT give a diagnosis

Identifies pregnancies that may need further evaluation

Should be presented as an optional test to all patients

Maternal serum screening

Specific chemicals that are made by the fetus and cross the placenta to enter the mother’s blood are measured on a maternal blood sample

Based on the amounts of the chemicals measured as well as other factors (maternal weight, smoking status, race, age, and diabetes status), a risk is determined regarding the likelihood that the fetus has a particular condition, e.g., Down syndrome

Maternal Serum Marker

AFP (alpha feto-

protein)

hCG (human

chorionic gonadotropin)

uE3 (unconjugated

estriol)

DIA(dimeric inhibin

A)

Fetal Tissue of

OriginLiver

Placenta

Adrenals, liver, placenta

Placenta

Conc. in 2nd

trimesterIncreases 15%/wk

Decreases exponentially

Increases 20%/wk

Minor fluctuations

Ranges in 2nd

trimester20-100 ng/ml

5-70 IU/ml

0.2-5 ng/ml

~100-400 pg/ml

Down syndrome Screening

•Markers used: Maternal Serum AFP, hCG, uE3 and DIA in combination with maternal age•Detects: 75-80% of Down syndrome (using these 4 markers)•General Trend: ↓AFP, ↑hCG, ↓uE3, ↑DIA•If there is an increased Down syndrome risk, the patient should be offered options of genetic counseling, detailed ultrasound, and amniocentesis

Amniocentesis (“Amnio”)

Typically performed between 15-18 weeks of pregnancy

Fetal cells floating in the amniotic fluid are collected

Risk for complication of ANY sort is about 1/270

Allows for DIRECT analysis of fetal chromosomes

Chorionic Villus Sampling (CVS)Typically performed between 10-12 weeks of pregnancyUsing a catheter inserted through the cervix with ultrasound guidance, a sample of the placenta is obtained for studyRisk for complication of any sort is 1-2%Allows for DIRECT analysis of fetal chromosomes

Non-invasive Prenatal Testing Using Cell-free Fetal DNA

A new method of screening the fetus for abnormal chromosome number using the

mother’s blood

What is cell-free fetal DNA?

DNA that is thought to be mainly from the placenta during a pregnancy and is floating free in maternal blood along with some of mother’s own cell-free DNA

Fetal cell-free DNA is thought to be cleared from the mother’s blood within hours after childbirth

Cell-free fetal DNA

Cell-free fetal DNA testing…

Can detect trisomies 13, 18 , and 21

Can be performed as early as 10 weeks of pregnancy

Can produce results by one week after maternal blood draw

For women with increased risk of fetal aneuploidy, large

studies show…

Detection rates for trisomies 13, 18, and 21 of greater than 98%

Low false positive rates (less than 0.5%)

Low false negative rates

American College of Obstetrics and Gynecology (ACOG)

recommends considering the option of cell-free DNA screening

for…Maternal age of 35 or older at delivery

Fetal ultrasound findings suggestive of trisomy 13, 18, or 21

History of a prior pregnancy with trisomy

Positive maternal serum screen for trisomy

Parental balanced Robertsonian translocation with increased risk for trisomy 13 or 21

Noninvasive prenatal testing for fetal aneuploidy. Committee Opinion No. 545. American College of Obstetricians and Gynecologists. Obstet Gynecol 2012;120:1532–4.

NOTE!

Cell-free screening is not recommended for low-risk women or women with multiple gestations because it has not been adequately evaluated for these groups.

This test only screens for the common trisomies and does not rule out other chromosome abnormalities or birth defects.

NOTE! (cont.)

Although the test is quite good, a negative result does not ensure an unaffected pregnancy.

Women with positive results should be referred for genetic counseling and be offered amnio. or CVS for confirmation.

Down Syndrome Researchers Remove Extra Copy of

Chromsome 21

Researchers at Univ. of Washington have successfully removed an extra copy of chromosome 21 from the blood cells of a person with Down s.

The goal is to be able to treat people with Down s. who have leukemia.

Cell Stem Cell 11, 615–619, November 2, 2012 ª2012 Elsevier Inc.

Down Syndrome Researchers Remove Extra Copy of Chromsome 21 (cont.)

Immature cells can be removed from the bone marrow of the patient

Doctors remove the extra chromosome 21 from those cells

The new cells are grown and transplanted back into the patient.

Down Syndrome Researchers Remove Extra Copy of Chromsome 21 (cont.)

To do this,

A virus was used to deliver an engineered gene (TKNEO) to a targeted spot on chromosome 21.

The cells were grown in conditions that did not allow the chromosome 21 containing the TKNEO to survive.

The cells lost the chromosome 21 with the TKNEO, leaving cells with only two copies of chromosome 21.

Down Syndrome Researchers Remove Extra Copy of Chromsome 21 (cont.)

So far, this seems to be safe; it has not altered genes on other chromosomes.

Dr. Russell, co-author of the paper describing the breakthrough says,

“We are certainly not proposing that the method we describe would lead to a treatment for Down syndrome,” said study co-author Dr. David Russell, from the University of Washington’s Department of Medicine.  “What we are looking at is the possibility that medical scientists could create cell therapies for some of the blood-forming disorders that accompany Down syndrome.”

Trends in Survival Among Children with Down Syndrome

across the U.S.

Study published in Pediatrics, January 2013

Examined changes in survival by race/ethnicity in 10 regions* of the U.S.

Retrospective review of 16,506 infants delivered between 1983 and 2003*portions of Arkansas, Georgia, California, Colorado, Iowa, New York, North Carolina, Oklahoma, Texas, and Utah

Trends in Survival (cont.)

Findings: Survival of children with DS in the U.S. continues to improve over time.

Survival to one year averages 94% over 10 regions studied. Low was 92% in Arkansas High was 96% in Utah

The overall 20-year survival rate is 88%.

Racial and ethnic disparities have decreased markedly over time.

DS children with low birth weight and congenital heart disease are surviving longer than previously, but these continue to be significant risk factors.

“My child has been cured by stem cell treatment.”

“Breakthrough Stem Cell Treatment for Down Syndrome” advertised at About.com—Parenting Children with Special Needs

http://stemcellof america.com touts “Down Syndrome Breakthrough”

Stem cells (fetal undifferentiated cells) are administered IV or under the skin with “no negative side effects”

Stem cell treatment (cont.)

Web site reports that “significant positive changes” are “commonly” seen 3-4 months after treatment in “Down syndrome patients”

Video testimonial by mother of small child with Down syndrome who says he “woke up” within minutes after treatment, and with further treatments his ears and head shape have changed.

Dr. who did treatment explains on video that a “normal chromosome 21” was in the stem cell treatment

Stem cell treatment (cont.)

There is NO support for such therapy in the medical literature.

The doctor(s) reporting this therapy have not published any results; all reports are anecdotal.

Cost—likely to be exorbitant

Stem Cell of America’s disclaimer:

“When all else fails but you haven't given up hope, you may be a candidate for fetal stem cell therapy. Like all medical treatments and procedures, results may significantly vary and positive results may not be achieved.”