Drug Corrects Brain Abnormalities in Mice With Down Syndrome

Down syndrome (DS) results when human babies have three copies of chromosome 21 rather than the normal two copies. However, three copies of pieces of chromosome 21 can also cause DS, and the region of chromosome 21 called the “Down Syndrome Critical Region” can also cause the symptoms of DS. The Down Syndrome Critical Region is located 21q21–21q22.3. Within this region are several genes, that, when present in three copies, seem to be responsible for the symptoms of DS. These genes are APP or amyloid beta4 precursor protein, SOD1 or Superoxide dismutase, DYRK or Tyrosine Phosphorylation-Regulated Kinase 1A, IFNAR or Interferon, Alpha, Beta, and Omega, Receptor, DSCR1 or the Down Syndrome Critical Region Gene 1 (some sort of signaling protein), COL6A1 or Collagen, type I, alpha 1, ETS2 or Avian Erythroblastosis Virus E26 Oncogene Homolog 2, and CRYAz or alpha crystalline (a protein that makes the lens of the eye).

All of these genes have been studied in laboratory animals, and the overproduction of each one of them can produce some of the symptoms of DS. For example, APP overproduction in mice leads to the death of neurons in the brain and inadequate transport of growth factors in the brain (see A.Salehi et al., Neuron, July 6, 2006; and S.G. Dorsey et al., Neuron, July 6, 2006). Also, the overexpression of CRYA1 seems to cause the increased propensity of DS patients to suffer from cataracts. Likewise, overexpression of ETS2 leads to the head and facial abnormalities in mice that are normally seen in human DS patients (Sumarsono SH, et al. (1996). Nature 379 (6565): 534–537).

People can also have only portions of the DS Critical Region triplicated and this leads to graded types of DS that only have some but not all of the symptoms of DS.

Why all this introduction to DS? It is among the most frequent genetic causes of intellectual disability. Therefore, finding a way to improve the cognitive abilities of DS patients is a major goal. T

There is a mouse strain called Ts65Dn mice that recapitulates some major brain structural and behavioral symptoms of DS and these include reduced size and cellularity of the cerebellum and learning deficits associated with the hippocampus.

Roger Reeves at Johns Hopkins University has used a drug that activates the hedgehog signaling pathway to reverse the brain deficits of Ts65Dn mice. Yes you read that right.

A single treatment given the newborn mice of the Sonic hedgehog pathway agonist SAG 1.1 (SAG) results in normal cerebellar morphology in adults.


But wait, there’s more. SAG treatment at birth also improved the hippocampal structure and function. The hippocampus is involved in learning and memory.


SAG treatment resulted in behavioral improvements and normalized performance in a test called the “Morris water maze task for learning and memory. The Morris water maze test essentially takes a mouse from a platform in shallow water and then moves the mouse through the maze and then leave it there. The mouse has to remember how they got there and retrace their steps to get back to the platform before they get too tired from all that swimming. Normally Ts65Dn mice do very poorly at this test. However, after treating newborn Ts65Dn mice with SAG, they improved their ability to find their way back.

SAG treatment also produced other effects in the brain. For example, the ratios of different types of receptors in the brain associated with memory are skewed in Ts65Dn mice, but after treatment with SAG, these ratios became far more normal. Also, the physiology of learning and memory was also more normal in the brains of SAG-treated Ts65Dn mice.

These results are extremely exciting. They confirm an important role for the hedgehog pathway in cerebellar development. Also, they suggest that the development of the cerebellum (a small lobe at the back of the brain involved in coordination and fine motor skills, direct influences the development of the hippocampus. These results also suggest that it might be possible to provide a viable therapeutic intervention to improve cognitive function for DS patients.

This excitement must be tempered. This is an animal model and not a perfect animal model. Also, it is unclear if such a compound will work in humans. Much more work must be done, but this is a fascinating start.

Child With Missing Cerebellum Is Learning How to Walk

The inimitable Wesley Smith has blogged about a remarkable child who was born without several portions of his brain. This little boy, Chase Britton, was born prematurely. He had a MRI scan at the age of one, and this scan showed that Chase was completely missing his cerebellum, and his pons. The cerebellum is a small lobe at the back of the brain that underlies the occipital and temporal lobes of the cerebral cortex. The cerebellum accounts for approximately 10% of the brain’s volume, but it contains over 50% of the total number of neurons in the brain. The cerebellum has several functions: 1) Maintenance of balance and posture; 2) Coordination of voluntary movements; 3) Motor learning; and 4) Cognitive functions.

Those small postural adjustments that help us maintain balance are all mediated by the cerebellum. It does this by means of input from receptors in the inner ear (vestibular receptors) and in the joints that tell your brain about the orientation of your body. Consequently, patients with damage to the cerebellum suffer from balance problems.  Most movements result from different muscle groups acting together in a temporally coordinated fashion, and the cerebellum coordinates the timing and force of these different muscle groups to produce fluid limb or body movements. The cerebellum also plays a major role in adapting and fine-tuning motor movements in order to make accurate movements through a trial-and-error process. For example learning to hit a baseball, shooting a basketball, slapping a hockey puck or other types of fine motor processes. Finally, the cerebellum is involved in certain cognitive functions, especially those that require motor skills, for example, language acquisition.

The pons is a portion of the brain that lies just in front of the cerebellum. The pons contains many “vital centers.” Vital centers are clusters of neurons that control vital bodily functions such as breathing, heart beat, and other such functions.

Chase has forced neurologists to rethink how the brain works or how the brain rewires itself in response to damage or developmental abnormalities. From the story:

But instead of being unable to carry out tasks like sitting up or crawling, Chase has forced experts to rethink how the brain functions. His mother Heather Britton told AOL News: ‘We call him the Little Gremlin. He loves to play tricks on people. His goal in life is to make people smile. ‘No one had ever seen it before. And then we’d go to the neurologists and they’d say, “that’s impossible, he has the MRI of a vegetable”.’ Dr Adre du Plessis, chief of Foetal and Transitional Medicine at the Children’s National Medical Center in Washington D.C., told WGRZ: ‘There are some very bright, specialised people across the country and in Europe that have put their minds to this dilemma and are continuing to do so, and we haven’t come up with an answer.

This boy is disabled, but he is not a vegetable. If you do not believe me, see this video of him learning to walk here. However, in places like Holland, Chase would have been exterminated under the Groningen Protocol. According to the Groningen Protocol, Dutch doctors can euthanize infants with terminal and seriously disabling conditions. In Belgium too, disabled babies are murdered, and in most countries, Chase would have been done in. Even though his is not, Chase would have been classified as an “anencephalic” baby. Anencephalic babies are born without the tops of their heads and are missing their cerebral cortex. They have a brain stem and their hearts are still beating but there is no indication that they can feel pain, beyond simple reflexes. The majority of anencephalic babies are born dead (stillborn), and about one third of them live a few hours to a few days. In very rare cases, they will live a few weeks up to a few months. Anencephalic babies are also born blind, deaf, unconscious, and unable to feel pain. They still react with spinal or brainstem reactions to stimuli. They are typically given comfort care until death so that a peaceful environment for the parents, with support from chaplains, counselors, and hospital staff.

Anencephalic babies are considered a good source of organs for neonatal transplantation. The current Uniform Declaration of Death Act (UDDA) requires brain death and irreversible cessation of heart/lung function prior to organ donation. This prevents organ donation from living donors who might have some reversibility in their brain function. Unfortunately, many organs from anencephalic babies may not be usable as a result of damage from a lack of oxygen. With the shortage of fetal or neonatal organs for transplant, some have argued that anencephaly should be the exception to the UDDA requirements. However, the general consensus is that it is unethical to harvest organs from an anencephalic babies until they are “dead.”

Now, according to Smith, programs to procure organs from anencephalic babies often receive organs from babies that are not anencephalic, but from children who are disabled. Listen to these words from Smith’s excellent book, The Culture of Death: The Assault on Medical Ethics in America:

In 1988, Loma Linda University in California created an organ procurement protocol to use anencephalic babies as organ donors in which physicians from around the country were asked to transfer, with parental permission, qualified infants to the Loma Linda University Medical Center where the procurement would take place. The program only lasted eight months before it had to be suspended, in part because of the inability of Loma Linda doctors to procure usable organs in thirteen attempts. However, the primary reason for shutting down the initiative was that physicians referred non-anencephalic, disabled babies to Loma Linda for organ procurement.

Dr. Shewmon, USC bioethicist and law professor Alexander M. Capron and others, writing in the Journal of the American Medical Association described what happened:

[T]he experience at transplantation referral centers indicates that enthusiasm for using anencephalics does indeed quickly extend to other categories of dying infants. As a result of the national interest in Loma Linda’s protocol, for example, that institution received from ‘good’ physicians several referrals of infants with less severe anomalies for organ donation, such as ‘babies born with an abnormal amount of fluid around the brain or those born without kidneys but with a normal brain.’ Moreover, the referring physicians ‘couldn’t understand the difference’ between such newborns and anencephalics.” Joyce Peabody, MD, chief of neonatology there and primary drafter of the protocol, deserves much credit for her courageously candid statement: ‘I have become educated by the experience. … The slippery slope is real’ (D. Alan Shewmon, et al, “The Use of Anencephalic Infants as Organ Sources: A Critique,” Journal of the American Medical Association, Vol. 261, p. 1775).

Calling Chase Britton a vegetable is the height of absurdity and cruelty. He is a human being; a disabled one, but a human person. Thank God that his parents did not condemn him to death because of his disability. His perseverance is a testimony to his human spirit.