Down Syndrome and Mental Retardation

Most people with Down syndrome have IQs that fall in the mild to moderate range of mental retardation. Some are so mildly affected that they live independently and are gainfully employed.

Language development is often delayed or impaired in people with Down syndrome; they understand more than they can verbalize. Also, ordinary activities of daily living and understanding the behavior of others, as well as their own, can present challenges.

Researchers at the School of Medicine and Lucile Packard Children's Hospital have identified one possible cause of mental retardation in Down syndrome. The culprit is a gene that, when overexpressed, causes neurons responsible for attention and memory to shrivel and stop functioning normally. The finding offers the first glimmer of hope that doctors could one day interfere with or even reverse the cognitive decline that frequently affects those with Down syndrome in middle age.

"We may now have the opportunity to make a big difference in people's lives," said neurologist William Mobley, MD, PhD. "If we can decrease the expression of this gene, we may be able to provide something more than supportive care to people with Down syndrome."

Mobley, who is the John E. Cahill Family Professor and director of the hospital's Down Syndrome Center, is the senior author of the research, published in the July 6 issue of Neuron. He is also the director of Stanford's Neuroscience Institute.

More than 300,000 people nationwide have Down syndrome, which is caused by an extra copy of chromosome 21, giving them a total of three. Although it is the leading cause of mental retardation in the country, little research has been conducted at the molecular or neurological level to understand and explore potential therapies for its symptoms. In addition to dealing with early cognitive difficulties, childhood heart disease and leukemia, most people with Down syndrome develop Alzheimer's disease by the age of 40.

"Down syndrome results in an extraordinarily complex constellation of symptoms," said lead author and senior research scientist Ahmad Salehi, MD, PhD. "We've done what many people thought was impossible: We've dissected it genetically to correlate one of the most troubling symptoms—cognitive dysfunction—with one particular gene. While it's not the only gene involved, its presence in three copies makes a significant difference."

Although mutations in the gene, called App for amyloid precursor protein, can cause early-onset Alzheimer's disease in otherwise healthy people, this is the first time it has been linked directly to degeneration of a specific group of neurons in the brains of those with Down syndrome. The breakthrough confirms an idea suggested by previous research: Neuronal degradation in people with Down syndrome is the result of an interrupted conversation between nerve cells in a specific part of the brain.

Like a classroom troublemaker, a signaling neuron needs feedback to thrive. It lobs specialized compounds called neurotransmitters toward its neighbor and awaits a response to its molecular spit wads. The target cell fires back such molecules as nerve growth factor, or NGF. The NGF is engulfed by the membrane of the instigator cell and is shuttled to the cell body in a process called retrograde transport. Once there it acts on the nucleus to stimulate the expression of genes that support neuronal growth. Interrupting this intercellular tit-for-tat causes the neuron to wither away.

Salehi, Mobley and their colleagues used a mouse model of Down syndrome to follow NGF's journey from the membrane to the cell body of the signaling cell. They focused on a mouse in which only about 140 genes—including App—were present in three copies. They found that although NGF retrograde transport was severely compromised in this mouse, it was markedly increased when the third copy of App was deleted. The neurons in the brain of the mouse with two copies of App were also larger than those in the mouse with three copies. "Clearly, App influences the transport of NGF in Down syndrome," said Mobley, "and we're very suspicious that it may do something similar in Alzheimer's disease. We're now investigating ways in which we might be able to turn down App expression."

Added Salehi, "It's not even necessary to turn it off completely. All we need to do is to reduce it by one-third: From 150 percent of normal back down to 100 percent."

Although it's not clear exactly how App interferes with NGF transport, a clue can be found in the intracellular compartments called endosomes that shuttle NGF to the nucleus. Mouse cells with three copies of App have endosomes that are abnormally large, perhaps making them too unwieldy to transport NGF. A similar ballooning of neuronal endosomes has been noted in people with Down syndrome and Alzheimer's disease.

The findings are tantalizing, yet many steps remain to an effective therapy for these devastating disorders, the researchers cautioned. The fact that deleting the third copy of App didn't restore the mouse to normal indicates that other genes must also affect the timing or severity of the neuronal degeneration. But Mobley and Salehi have already embarked on an ambitious plan.

"First we need to figure out at a molecular level how App works in Down syndrome," said Mobley. "Then we need to examine other genes that might be involved and test possible compounds in mouse and human cells. If we are able to do all that, we might begin to think of helping children and adults with Down syndrome to develop and age more normally."

Stem Cell Treatments to Improve symptoms in Down Syndrome

The clinical characteristics of Down syndrome, caused by the triplication of the fragment 21q22 of chromosome 21 (trisomy 21) include mental retardation, craniofacial abnormalities, clinical defects of the heart, gut and immune system, and an increased risk of other diseases, including leukemia and Alzheimer's disease. Down syndrome is further complicated by the accumulation of toxic amyloid beta deposits in the brain and perhaps blood vessels.

A comprehensive medical program that includes
1) Eliminating infections
2) Eliminating metal toxicity
3) Providing mitochondrial support (to produce ATP energy for the cell)
4) Providing antioxidants (to reduce amyloid beta and for neuroprotection)
5) Providing growth factors for neuroprotection and neurogenesis
6) Providing umbilical cord stem cells (especially cells transfected with needed genes)

Holds promise for reducing some of the symptoms of Down syndrome. This is a new frontier for human umbilical cord stem cells and one that is very exciting. We are optimistic because some of the children with cerebral palsy have responded to cord stem cells with cognitive improvements, including improvements in comprehension, logic, increased vocabulary, learning and memory.

How to Treat Down Syndrome With Speech Therapy

Step 1:
Start early. Even before a child starts to speak, speech therapy can help her communicate through gestures, physical contact and facial expressions. This is especially important in children who start speaking late, as they will still be able to get their points across.

Step 2:
Concentrate on teaching Down syndrome children how to breathe properly. A big part of the speech problem with Down syndrome children is in the fact that they cannot find a proper way to places pauses in sentences, causing words to come out either too rushed or too slowly.

Step 3:
Talk to a therapist if you notice your child has problems swallowing. This is also directly related to the way he uses his throat and may have an impact on his reactions, his speech and the way he communicates.

Step 4:
Focus on developing vocabulary and focus on words that are easy to pronounce and don't have double meanings that may confuse the child. At an early age, a speech therapist may opt for concentrating on short sentences with simple grammatical structures and then move on to more common speech patterns as the child's abilities develop.

Step 5:
Treat hearing disabilities if they are present. Being unable to hear well is one of the reasons children with Down syndrome cannot communicate properly. By speaking slowly and clearly and by enunciating each word in a sentence, parents can help children progress faster towards appropriate speech.

Tips & Warnings

* You can further the help of speech therapy right at home through the use of educational toys that focus on speech and vocabulary.
* Children who have Down syndrome and grow up in bilingual homes may have an even harder time grasping the basics of the language. Parents should stick to one language or find a therapist who specializes in bilingual children.
* Practice speaking with your child about different topics to encourage eloquence and courage.
* Resist the urge to complete your child's sentences. Let him work out the expressions by himself, even if it takes him longer to get his thoughts across.

How is Down syndrome diagnosed?

Your doctor may suggest that you have tests during pregnancy to find out if your baby has Down syndrome. A screening test can help show if the baby (fetus) is at risk for Down syndrome. But these tests sometimes give false-positive results, meaning they show a problem when there is none.

Screening tests include:

* A blood test and a fetal ultrasound late in the first trimester. The ultrasound looks for thickness in the back of the baby’s neck (nuchal fold), which can be a sign of Down syndrome. This kind of ultrasound is not available in many areas.
* A blood test called a maternal serum triple screen or quadruple screen in the second trimester. By measuring substances in your blood, these tests can estimate the chance that your baby has Down syndrome or other health problems.

Your doctor may suggest a chromosome (karyotype) test if you have an abnormal screening test result or if you are worried about Down syndrome. A karyotype test has more risks than a screening test, but it can say for sure if your baby has Down syndrome.

Karyotype tests include:

* Chorionic villus sampling in the first trimester. For this test, the doctor takes a sample of cells from the placenta, either by putting a thin tube through your vagina or by putting a thin needle into your belly.
* Amniocentesis in the second trimester. For this test, the doctor puts a thin needle into your belly and takes a sample of the liquid (amniotic fluid) that surrounds the baby.

Sometimes a baby is only diagnosed after birth. A doctor may have a good idea that a baby has Down syndrome based on the way the baby looks and the results of a physical exam. To make sure, the baby’s blood will be tested. It may take 2 to 3 weeks to get the complete test results.

What causes Down syndrome?

Down syndrome is caused by problem with a baby’s chromosomes that happens long before the baby is born. Chromosomes are the part of your cells that contain your genetic material, or DNA. Normally, a baby has 46 chromosomes. But most people with Down syndrome have 47 chromosomes. In rare cases, other chromosome problems cause Down syndrome. Having extra or abnormal chromosomes changes the way the brain and body develop.

Experts don't really know what causes the chromosome problem. But some things are known to increase the chance that a baby will have Down syndrome. These things are called risk factors. They include having a:

* Mother who is over 35. The older the mother is, the higher her baby’s risk of Down syndrome. (But most babies with Down syndrome are born to mothers younger than 35, because younger women as a group have more babies than older women do.)
* Father who is over 40.
* Brother or sister with Down syndrome.