tamison jewett, md professor, department of pediatrics section on medical genetics wake forest...
TRANSCRIPT
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) skin
Hypoplastic (underdeveloped) midface
Upslanting 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 syndrome
Occurs in ~1:650 live births
The 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 Screening
Test 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.”