Early Developmental Stage Correction of Chromosomal Abnormalities

A few weeks ago an article appeared online on medicaldaily.com with the title: Genetic Testing Sometimes Finds Chromosomal Abnormalities In Embryos, But They May Turn Normal Before Birth. This article as written appears to give a false impression that chromosome abnormalities diagnosed prenatally may correct themselves before birth.

Dr. Iosif Lurie, medical geneticist and CDO Medical Advisor offers his comments.

Recent data (especially after invention of molecular methods in cytogenetics) shows that at the early stages of development a cell may attempt to correct some cytogenetic anomalies. Trisomic cells may “evict” the additional chromosome, cells with a structural anomaly in one chromosome may use either the same “expulsion” tactics or another rescue mechanism involving many chromosomes (chromothripsis). However, these mechanisms may be successful only at the earliest stages (maybe in the first 1-2 weeks after fertilization), and definitely before any prenatal diagnosis. A fetus at 9-10 weeks already has the same chromosomal complement as he/she will have after birth.

Moreover, sometimes a cell having, for example, two identical maternal chromosomes and one paternal expels the paternal one. A chromosomally normal embryo (child) will result but with uniparental disomy. And if this chromosome has a recessive gene this gene will be homozygous in the child. I think that rare cases of UPD5, for example, are results of such rescues at the early stages of development.

After an unfavorable prenatal diagnosis should parents decide to terminate a pregnancy, most centers will confirm the prenatal diagnosis by pathologic and/or cytogenetic examination of the fetus. Should numerous cases of a chromosomally normal fetus being mistakenly aborted after an erroneous diagnosis of chromosomal pathology we would correspondingly expect to see an increase in “wrongful death” litigation. And we have not seen this.

This article gives a false impression that in many cases chromosomal abnormalities revealed by prenatal diagnosis may be restored by themselves. This underscores the importance of always checking with your personal healthcare provider about any information you locate online or elsewhere, it may not always be complete or accurate.

Dr. Iosif Lurie, Medical Geneticist
Linda Sorg, CDO President

Applying for Social Security Disability with a Chromosomal Disorder

Applying for Social Security Disability with a Chromosomal Disorder

When it comes to finances, oftentimes people living with a disability need extra help, especially those living with a chromosomal disorder that will affect them for the entirety of their lives. The United States government encourages people with a disability to apply for Social Security Disability benefits. The monthly payments and medical benefits that the disability programs offer can greatly help their financial burdens.


What is Social Security Disability?

 The government has two different programs that can help people with a disability. The Social Security Disability Insurance program, also known as SSDI, pays benefits to people that have worked and paid social security taxes in the past. This program mostly helps individuals that have worked and paid Social Security taxes for a certain period of time and before becoming disabled. The Supplemental Security Income program, also known as SSI, is designed to help those that have little or no income and lack a sufficient work history.


Technical and Medical Requirements

 Individuals looking to apply for Social Security Disability benefits must meet certain requirements. When applying for SSDI, you must meet work history and medical eligibility requirements. On the other hand, to qualify for SSI, you must only meet the medical and income requirements and asset limits.

A person’s work history determines whether or not a person is eligible to receive Social Security Disability benefits. In order to qualify for SSDI, the applicant needs to have earned enough work credits, meaning you paid Social Security taxes, depending on your age. Work credits are earned each year that you work, and a worker can earn up to a maximum of four work credits per year.

To be eligible for SSI benefits, your household income can’t exceed $761 as an individual or $1,082 as an adult. Your household assets also can’t exceed $2,000 as an individual or $3,000 as a couple.

In addition to meeting the technical requirements of the SSI and SSDI programs, you also need to meet the medical criteria. The SSA published the “Blue Book”, which lists all of the disabling conditions that could qualify you for benefits. Each condition has its own set of criteria that must be met in order to prove that your condition is in fact disabling. http://www.disability-benefits-help.org/disabling-conditions

Chromosomal disorders are covered under Sections 10.00 (adult listing) and 110.00 (child listing) of the SSA’s Blue Book. In order to be approved for disability benefits under this section, you must be able to provide the SSA with clear evidence of:


  • A diagnosis;
  • A copy of a laboratory report of a conclusive karyotype analysis;
  • Medical records showing physical manifestations of the condition are present; and
  • Evidence that your condition interferes with your ability to function.


Applying for Social Security Disability

You can apply for Social Security Disability benefits online or in person at your local Social Security office. Applications for children must be filed in person at an office. If applying in person, you should call the SSA’s toll-free number at 1-800-772-1213 to make an appointment with the local Social Security office. This option also allows you to make an appointment to apply for Social Security Disability over the phone. Once a disability appointment has been made, you will be sent a disability starter kit in order to prepare for the interview.


What Is Needed to Apply

 When starting the application process, you will need the following information:

  • Social security number
  • Copy of the birth certificate
  • Names, addresses, and phone numbers of the doctors or hospitals that addressed the disability.
  • Complete medical record of all visits associated with disability.
  • Laboratory and test results.
  • Summary of work and the type of work completed.
  • Copy of the most recent W-2 form.

In addition to this information and the basic application, applicants will need to fill out other forms. One form will describe the medical condition and how it affects the applicant’s ability to work; the other form simply gives health care professionals the authorization to give out personal medical information. http://www.disability-benefits-help.org/content/application-process


Benefits after Approval or Denial

 Once the disability application is approved, you can expect to receive a monthly payment to help cover basic needs of living. This notice will be received two to four months after the date of the initial application. If the claim was denied, you have 60 days to appeal that denial from the date of the notice. A good number of applicants may be denied during the initial stage of the application process, but are awarded benefits as the result of an appeal.

Considering Legal Representation

 Although there’s not always a need for legal representation during the application process, having a lawyer’s help can greatly improve your ability to be approved for disability benefits. A lawyer will know how to handle all situations and can correctly fill out all necessary forms. As an expert in the field, a lawyer knows what laws affect your particular disability case and will be able to put those laws to work for you.


Lisa Giorgetti
Community Liaison
Social Security Disability Help

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