Perspectives for Treatment of Chromosome Disorders


Chromosomal disorders are conditions where, as a result of deletions or
duplications of some chromosomal segments, the organism experiences the excess or absence of a significant number of genes. Manifestations of chromosomal disorders include both morphological defects caused by the abnormal action of genes during embryonal development and functional abnormalities (seizures, hypotonia, aggression, hyperactivity, sleep disturbances, etc.) caused by the constant abnormal action of genes. When we use the term “treatment of chromosomal disorders” we talk about attempts to alleviate functional abnormalities and give patients a better chance to live independently. It is obvious, however, that morphological defects which occur during embryonal development cannot be restored by any drugs.

The existing attempts for treatment of patients with chromosomal
abnormalities may be subdivided into several groups. The potentially most fundamental methods have a goal to restore a normal karyotype or inactivate the action of excessive genes. One strategy involves inactivation of one of the chromosomes 21 in a trisomic patient with Down syndrome. One of the human genes – gene XIST –
inactivates one of X-chromosomes in females. The XIST gene prevents
transcription of the genes on the X-chromosome. If this gene is inserted into one of chromosomes 21 in a patient with Down syndrome, this chromosome will became inactivated, restoring the normal “disomic” condition. Currently the experiments with inactivation of excessive chromosomes are in the “embryonal” stage; if these tests provide good results in laboratory animals, this method will be tested with clinical trials. Although currently XIST-strategy is studied only for
cells with trisomy 21, the same method may be promising for other trisomies as well.

Some types of chromosomal pathology (ring chromosomes, additional
markers, dicentric chromosomes) are relatively unstable. Most patients with these abnormalities have both a clone with an abnormal chromosome and a normal clone. Generation of pluripotent stem cells from the skin cells of a patient with ring chromosome 17 has shown that reprogrammed cells lost the abnormal chromosome 17 and duplicated the wild-cell normal homologue. If this is true for other ring chromosomes and other forms of “unstable” pathology, it will provide an
opportunity to use cellular reprogramming as a way of therapy for certain chromosomal disorders.

A strategy of reprogramming as well as XIST-strategy, however, will (or
may) cause uniparental disomy – a condition when both homologues chromosomes are identical (i.e. two copies of the same maternal or paternal chromosome). If this chromosome carries an autosomal-recessive gene, the patient (or reprogrammed cells of the patient) may become homozygous for this gene.

Other methods for treatment of chromosomal pathology seem to be not so fundamental by nature but more achievable. Down syndrome for instance is a condition where several attempts for treatment of patients with this pathology have been made.

It is well known that the size of the cerebellum in persons with trisomy 21 is significantly less than in persons with a normal karyotype. As a result there is a considerable impairment of cerebellar function in patients with Down syndrome. In the experiments with a specific line of mice Ts65Dn (widely used as an animal model of Down syndrome) the newborn animals who received a stimulation by “Sonic hedgehog” – a growth factor involved in different aspects of development -show both an increase of the size of cerebellum and an improvement of its function. Mice “treated” by “Sonic hedgehog” show an ability to learn their way around a maze – an indicator of function of learning and memory. The idea of early intervention seems very plausible, but there is still a long way to go between experiments with rodents and the clinical usage of “Sonic hedgehog” (or other growth factors) in treatment of Down syndrome.

Experiments with the mice Ts65Dn show that these animals demonstrated excessive inhibitory brain activity. Release of this inhibitory effect may improve cognitive function. One way to reduce this inhibitory effect is to block the activity of GABA – the primary inhibitory neurotransmitter. There are experiments where
Ts65Dn mice were chronically treated with a negative allosteric modulator of GABA RO4938581.

It has been shown that this treatment improves the functional and neuromorphological deficit in a mouse model of Down syndrome. Currently there are some clinical trials ongoing to test this kind of treatment in adult patients with Down syndrome.

An examination of the brains in Down syndrome patients has shown a remarkable similarity between these brains and those in persons with
Alzheimer syndrome. Most Down syndrome patients develop Alzheimer-like plaques and dementia in their 40s. Persons with Down syndrome have high levels of myoinositol – a chemical related to cognitive impairment and involved in formation of plaques in the brain. There is a trial to treat patients with Down syndrome by scyllo-inositol (ELND005) – a drug originally synthesized to break up amyloid plaques in the brains of patients with Alzheimer’s syndrome. The current trial hopes to demonstrate the efficacy of this method for treatment of Down syndrome patients.

There are some publications describing possibility of “pathogenetic”
treatment in other conditions. For example many manifestations of Phelan-McDermid syndrome (deletion of 22q13.3) are caused by the loss of SHANK3 gene, which resides in this area. Neurons of Phelan-McDermid syndrome patients have reduced SHANK3 expression and defects in excitatory, but not inhibitory, synaptic transmission. Treatment of the neurons with insulin-like growth factor I (IGF1) corrects the excitatory function of these cells and shows the pathway to
correct intellectual disability and speech impairment in patients with this disorder.

The more common and more standard ways for treating chromosomal
disorders are related to the replacement of products which are not synthesized in a patient or synthesized at an unusually low level. It is similar to the usage of insulin in patients with diabetes. For example, patients with Klinefelter syndrome have very low levels of testosterone. The administration of testosterone in adolescents with Klinefelter syndrome shows good clinical efficacy in 95% of patients.
Patients with distal deletions of the long arm of chromosome 15 usually reveal significant growth delay, because this deletion involves the gene responsible for synthesis of the growth hormone. The administration of growth hormone significantly improves the growth in these patients. Treatment by growth hormone may be beneficial also for other patients with other chromosomal pathologies experiencing growth delay.

Common drugs for treatment of attention deficit hyperactivity disorder or seizures may be used also for the treatment of these manifestations in patients with chromosomal pathology, although clinical results may vary even in persons with the same chromosomal imbalance.

Dr. Iosif Lurie
Medical Geneticist
CDO Consulting Medical Advisor

Are Rare Chromosome Disorders Really All That Rare


Chromosome disorders: 2014 outlook

The whole concept of chromosomal disorders has drastically changed in the last several years. Traditionally, the examination of chromosomes under the microscope was the main (or even the only) way of diagnosing chromosomal pathology. However, even in optimal variants visual examination allows recognition of deletions or duplications not less than 5 Mb. Actually, the vast majority of patients recognized as having chromosomal anomalies had an excess of deficit of very large segments of DNA (at least 10-15 Mb). Of course, such large segments contain dozen of genes – including genes involved in mental development and numerous morphogenetic processes. Virtually all persons with unbalanced chromosomal abnormalities recognized by a “standard” cytogenetics had delayed psycho-motor development, facial dysmorphism and (in many cases) defects of the brain, eyes, heart and other organs. As a result, chromosomal disorders were considered conditions involving (as mandatory traits) dysmorphic features and delay in psycho-motor development.

Methods of molecular cytogenetics which have become a common practice over the last few years allow recognition of even the smallest imbalances. As a result it has been found that a large number of patients previously reported as having a normal karyotype, actually have small deletions or duplications. Contemporary data shows that ~25% of persons with facial dysmorphism and a various degree of psycho-motor delay have deletions or duplications of chromosomal material. Only one third of these abnormalities could have been diagnosed by “standard” cytogenetic examination.

It has been shown that several syndromes of “unknown” etiology actually are caused by small chromosomal imbalances (Williams syndrome is caused by 1.5-2 Mb deletion of 7q11.23, TAR syndrome is caused by proximal del 1q21.1). Many other syndromes can be considered as etiologically heterogeneous: in some cases these conditions are caused by a mutation of one gene, in other cases by microdeletions involving the causative genes. It may be true for Sotos syndrome, where many patients have del 5q35, for Rokitansky-Küster syndrome in patients with del 17q12, etc. Numerous new syndromes caused by chromosomal microdeletions or microduplications have been delineated over the last 4-5 years (del 1p34, del 2p15p16, del 17q21.31, etc.). These new syndromes involve all chromosomes and almost all segments of DNA. In all these conditions there are no doubts about the pathological role of the given deletion or duplication.

Molecular cytogenetics has shown that above evidently pathological microdeletions and microduplications there are 3 other classes of microanomalies: a) “presumably pathogenic” copy number variants (CNV); b) benign CNV, and c) variants of unknown significance (VOUS).

Examination of a large group of persons has shown that several forms of microdeletions and microduplications (del/dup 15q11, del/dup 15q13, del/dup 16p11, del 16p13) are relatively common and may be found even in healthy persons. However among patients with clinical abnormalities which do not seem to be characteristic for traditional “chromosomal disorders” (e.g., in patients with autism or epilepsy) these CNV have been discovered much more commonly (sometimes 10 times more commonly) than in general population. There is doubt that these variants strongly predispose to some forms of pathology although the mechanisms of the realization of these effects are not fully explained.

Special examinations has shown that up to 8% of patients with epilepsy, 6% persons with autism and 2-3% of persons with schizophrenia may have copy number variants as causative factors of afore-mentioned conditions. Epilepsy, autism and schizophrenia are very common disorders. Even if only 2-3% of the patients with these conditions are caused by chromosomal rearrangements it will considerably increase the general pool of persons with rare chromosomal disorders.

An increased frequency of copy number variants was found among persons with different forms of heart defects (tetralogy of Fallot, stenosis of pulmonary artery), among patients with cryptogenic cerebral palsy (cerebral palsy without evident acquired cause) and even among obese persons. All these facts lead to significant expansion of the general pool of “rare chromosomal anomalies”. Of course, these calculations include only definitely pathogenic or presumably pathogenic CNV. And neither developmental delay nor dysmorphism seem to be mandatory for disorders caused by excess or deficiency of chromosomal material.

If any given variant occurs in affected and healthy persons with the same frequency this variant should be considered as benign.

The largest problem is variants of unknown significance (VOUS) when (at least currently) it is not possible to determine significance of the found variant. Several factors should be considered upon analysis of each such variant.

  •   Character of the lost (or added) genes. If the list of abnormal genes includes genes known to be related to human disorders, the variant is likely pathologic. If the given variant does not involve any genes, it almost certainly has to be considered as benign.
  •   Type of variant – a deletion of the same size is ~ twice more likely to be pathologic than a duplication of the same size.
  •   Size of deletion (or duplication) – basically the larger size presumes involvement of a larger number of genes.
  •   Inheritance of the variant: the variants inherited from healthy parents are most likely benign variants, whereas sporadic deletions (or duplications) are more likely to be pathologic.

    Although the list of VOUS is shrinking (some variants became considered as benign and vice versa), the large number of VOUS remains a significant obstacle in interpretation of data obtained by molecular cytogenetics.


Dr. Iosif Lurie, Medical Geneticist, CDO Consulting Medical Advisor


Rare Chromosome Disorder Awareness Week is almost here!

Hi everyone –

It is almost here! Rare Chromosome Disorder Awareness Week (RCDAW) begins June 2nd!

Many CDO members are organizing special events this week. We would love to know what you have planned too.   Let us know and we will post to our Facebook pages.

Would you like RCDAW flyers to help spread the word and increase awareness in your neighborhood, town or city?   These can even be personalized to include your favorite photo.   Please e-mail Kelly Paulson – for the flyer and instructions on how to add your child’s photo.

There is one super easy way to increase awareness this week – just visit our website – – and download the RCDAW logo and add it to your personal websites and blogs.  We even have the logo available in different languages!

Beautiful CDO awareness t-shirts are also now available – we are offering three different designs along with many other items through our online store.

And in honor of Rare Chromosome Disorder Awareness Week, CDO is giving away free RCDA bookmarks to our members. Please simply send a stamped self-addressed envelope to the address shown below to receive your free glossy bookmark.

Individually each of these chromosome changes is still considered rare. But we are gradually now learning these disorders actually may not be as rare as once believed. Please support Chromosome Disorder Outreach Inc., RCDAW, and our goals of increasing research, education and understanding. Together we are a strong force.

Chromosome Disorder Outreach Inc. P.O. Box 724 Boca Raton FL  33429-0724

Take 5 Minutes and Recharge

At night, I’m generally pretty exhausted, but it’s not always easy for me to sleep. I lay there trying to think through all the ways my two girls could get hurt, how I could respond to each of these situations, and whether I would even be able to help them. Most of these scenarios are somehow related to their disabilities, so there may only be only a certain number of things that I can do within the realm of possibility for them. The one that keeps me up most frequently is the fear that they will fall down the stairs. You may not have the same worries as me, but you may resonate more with the fears that other moms have expressed to me:


  • Will my child ever make friends or fit into a group?
  • At what point will my child realize her or she is “different “?
  • Will I always be able to care for my child?
  • What if I see a medical issue but the medical professionals won’t or can’t do anything?
  • What if the disease progresses to a point that his or her body starts shutting down?
  • What will he or she do without me?


Lots of things to worry about, only so much time to think about that AND everything else. That can be exhausting without bringing in the day-to-day routines of actual caring for your child.

Well-meaning people (and magazines) who may not understand try to give helpful advice to help decrease our stress level. “Get some exercise,” “Meditate when you wake up,” “Grab 5 minutes by yourself to recharge,” “Go out on a date night.” This is generally great advice, but easy platitudes like this aren’t useful by themselves because they don’t address the obstacles that keep us from taking advantage of that advice. We don’t exercise because of our exhaustion. We would meditate if we could remember, which we can’t do because we’re so tired. And you’re joking if you think 5 minutes is going to help us feel better. If we could get about 3 days of just laying in bed, that may begin to help, but we also wouldn’t be able to because to be able to get away guilt-free because do you know how hard it is to get a babysitter for a couple of hours, never mind a couple of days? (Breathe!)

Every parent has their own set of worries. This is not a political piece on how our lives are so much harder than those with typical children. Instead, I want this to be a discussion on our levels of stress, and our lack of self-care. Since our kids need a bit more attention, and for longer periods, we have to figure out how to take care of ourselves somehow. We need a plan for support.

We may not be able to get a day at the spa, or even a full day at home to get stuff done, but we can take steps to help ourselves and our families. What government or community supports do you have access to? Respite? Social work? Family or friends? Start making a list of these just to be able to reference. Also, because our families tend to be high needs, it may not always be about getting a break. It may be more about making the everyday routine run smoother. Can you get groceries delivered? Can you afford an occasional cleaning lady? What about freezing dinners for those extra hectic nights? Sometimes, it may be as simple as taking a step back and remembering that these are our children. We take on so many roles (parent, therapist, body guard, nutritionist, teacher, etc.) that sometimes we need to relax, forget those roles, and just play with our child. Those are the memories that they will remember.

I don’t want to bring you down with this article. I do want to leave you with some hope. And here is that hope: as much as you worry, and go through your hard times, you are not alone. We all have, at minimum, this group. Please use us as a place of support. Some of us are lucky enough to also have family close by or the financial support of local agencies for respite or nursing services, and hopefully some of us have good relationships with our children’s therapist(s). And there are those who are just beginning our journey into the world of special needs parenting. To the new families, I urge you to start doing your research now so that you have the support system in place when you need it. Because you will, and that’s OK.

Submitted by Jacqueline Bair


The Mom Identity

I was talking with a friend yesterday morning and we were discussing how we almost can’t remember who we were before we were moms.  It seems like so much of our identity has been lost to the needs of our very young children.  And for me, this goes a step further.  I am not just a mom; I am a mom of a child with special needs.  Sometimes, it seems that 99% of my time, my thoughts, and my efforts go toward my children.  Semmes, my typical 13-month-old is in the throes of separation anxiety; not even my husband can make him happy much of the time.  He needs his mommy ALL THE TIME.  I know that this is a short season of his life and in some ways it does make me pretty happy, especially when he sees me across the room, throws his hands up in the air, and moves as fast as his little legs will let him go toward me (I would say run, but that would esteem the movement). I am conflicted with my emotions, to say the least. And with Cooper, my 3-year-old with special needs, it seems like there is always a doctor’s appointment, or a medicine to give, or his oxygen levels need to be monitored, or he’s crying for absolutely no reason, or he’s overwhelmed and needs to go off by himself and lay down.  You know, things that normally aren’t on the mind of a mom of a three and half-year-old. In many ways, being a mom will always be a big part of my identity.  Obviously.  But as my children get older and need me less and go off to school and become their own little selves, I will be less needed and will less identify that way.  Except for Cooper, who at three is the developmental equivalent of a 9-month-old, who will never be potty trained, who is tube fed. I will always be needed with Cooper.  And I will always be a mom of a special needs child as much as I am right now. And some days, this is a hard, daunting reality to face. And some days, I wouldn’t change it for the world. At book club last night, we were talking about how strange it is for us to realize that our parents were PEOPLE before they were parents.  They had relationships, opinions, lives.  And I think it takes having a child of your own to really realize that.  Because you know that you were a person before you were a mom and you know that being a mom isn’t 100% of you.  But when your children are young, it’s hard to remember that.  Some days it’s all I can do to keep my head above water. I’ve realized how important mom relationships are. Finding people who are supportive, who go on playdates, who sit with your special needs child while you change your typical child. I’ve become more choosy, but this choosiness has made the relationships with my friends more substantial. Sometimes, they’re the only way I get through a day and sometimes I’m the only reason they do. submitted by Crady Schneider