Issue 16 | April 2018
The ‘A’s have it this April – Asbestos, Ataxia, and Apraxia
Welcome back to another issue of myStrand! The first week of April is traditionally observed as Asbestos Awareness Week – a topic less well known in India, but nevertheless important to highlight. Another issue at the forefront of our editorial team’s mind is the plight of families affected by rare diseases and this month we have chosen to feature a family where neuromuscular issues have affected three of their four children before a geneticist identified the root cause of the problem. Read on and let us know if you would like us to feature a particular genetic disease or health-related issue in one of our future issues at strandlive@str The myStrand Team!
Three siblings’ ataxia symptoms explained by clinical exome test results
All parents keenly follow the developmental milestones of their children as they grow from infants to toddlers and preschoolers. Is he growing as he should, is she able to jump, roll, climb as she should for her age? Those are constant questions on their minds. When something is off, a little imbalance here or there, or sudden uncoordinated movements set alarm bells ringing and sadly for some parents this means that something’s not quite right. Unfortunately, this realization can sometimes be the start of a long and arduous journey to identify what exactly is causing these developmental problems. And what if the disorder was actually inherited from the parents?
Reaching a definitive diagnosis can be difficult
When faced with developmental delays of any kind, doctors often have to rely on being able to identify the distinguishing features from a vast array of symptoms that a young patient might suffer from to come to a definitive diagnosis and determine treatment. Add to that, the fact that many disorders known to us today can only be roughly distinguished from each other based on visible symptoms alone, yet one disorder or syndrome would respond better to a certain kind of treatment than another. How can the doctor tell the difference? Then there are the so-called spectrum disorders, for which the severity of symptoms is the primary indicator as to where on the range of known developmental challenges a patient is found and how he or she should therefore be treated. This uncertainty leads patients down an often daunting road of clinical investigations, starting from blood tests, various scans like x-rays or MRIs, or physical assessments of their abilities that can go on for years.
When things start going wrong
However, scientists and doctors have been working together to get to the root cause of many a developmental disorder. They are starting to be able to link them to specific errors in our biological make-up, genetic mutations, single spelling errors in our DNA, that mean the difference between a healthy 4-year-old and one who is not quite keeping up and starting to have difficulties with his coordination. This is exactly what happened to little Ardarferoze* in Mumbai. Around his fourth birthday, his parents started to notice that he has trouble with balance, often resulting in falls and injuries, and sometimes even uncoordinated movements of his limbs. Prior to that he had been developing just like any other infant and toddler. Incidentally, he also had developed issues with the ability to move his eyes sideways, which meant that he had to turn his whole body in order to be able to see objects to his extreme left or right, also referred to as apraxia. These changes set alarm bells ringing because two of his older siblings had developed similar symptoms in their early years and now required constant assistance and care. By now, the suspicion that this condition might actually be inherited had started to creep in and the parents sought professional help from two renowned geneticists in Mumbai.
Getting to the root cause of the problem
Seeking professional help to get to the root cause of these developmental issues of now three out of four of their children had become very important to the parents, especially since they were planning to have another child. What if that child too would suffer from the same symptoms as the Ardarferoze and his two sisters? Was there anything they could do? Those were the questions burning on their minds when they went for their first consultation. A look at their family history and the fact that now three children were affected by similar symptoms, classified as ataxia-like based on the apparent symptoms plus Adarferoze’s apparent apraxia, prompted the geneticists to order a genetic test, in this case the Strand Clinical Exome Test, to look for genetic mutations that might be to blame for his symptoms. The result would also allow the doctors to pinpoint the exact type of ataxia Adarferoze was suffering from.
The results are in
The test result revealed a genetic mutation in the APTX gene. This specific mutation had not been previously reported but was classified as pathogenic because it was found very close to other genetic mutations in the same gene that have been found in other patients with similar symptoms, and which was known to be inherited in an autosomal recessive manner. This means, that two copies of the mutated gene have to be present in an individual for symptoms to develop.
In addition, whenever a test reveals a novel mutation, the scientists working on the result use a set of tools to simulate the likely effect a particular mutation has on the function of the affected gene. In Ardarferoze’s case, those tools predicted that the gene would no longer be able to perform its proper function to create an important protein, making this particular mutation a ‘loss-of-function’ one. Based on this analysis, the doctors were able to specify that Ardarferoze was suffering from ataxia with oculomotor apraxia type 1 (AOA1).
Testing the parents
Because the parents were anxious about the likelihood of having another child suffering from the same condition, the geneticists recommended something call mutation-specific testing (MST) for them. MST confirmed what was already suspected based on Adarferoze’s test result; that both his father and his mother had just a single copy of the same mutation as their son, and were therefore unaffected. They were therefore advised by the genetic counsellor and the geneticists that the chance of having another child with the same mutation was 25%. They were also apprised of the possibility of testing a fetus via amniocentesis or chorionic villus sampling for this specific mutation.
Armed with this knowledge, Ardarferoze’s parents were finally able to understand what had happened to their children and why they were suffering from ataxia. It will also help them make better informed decisions about any future pregnancies.
*Name changed to protect patient privacy
Disclaimer: The information provided in this article is in no way intended to replace expert medical advice. Always discuss any concerns with your doctor.
About Ataxia Disorders
There are several disorders that fall under the umbrella of ataxia. They are differentiated based on the presence of specific genetic mutations as well as the range and severity of symptoms observed and determined based on traditional tests. Ataxia with oculomotor apraxia type 1 (AOA1) is a severely disabling neuromuscular disorder. Uncoordinated movement of limbs (ataxia) is usually the first manifestation of this inherited disorder. The inability to move eyes sideways (apraxia) is another symptom. Ataxia with oculomotor apraxia type 2 (AOA2) in comparison is a slow and progressively debilitating neuromuscular disease which can manifest as symptoms around the age of 15 years. Progressive degeneration of nerves can appear in both these types leading to additional disability. Other types of ataxia include ataxia telangecstasia, Friedrich’s ataxia, and ataxia with vitamin E deficiency (AVED). Treatment interventions exist only for some forms of ataxia, including AVED, where supplementation of vitamin E has been found to avert the development of ataxia symptoms completely if administered early on. This distinction makes an exact diagnosis, especially in asymptomatic family members, extremely important and relevant.
Mesothelioma: The Role of Asbestos and Precision Medicine in India
Asbestos has deep ties in the fabric of Indian industry and construction. Behind China, India is the second largest market for asbestos in the world, importing hundreds of millions of dollars worth of the material annually. The impact asbestos has on community and individual health is as vast as it is severe. As a versatile material favored by the construction and repair industries because of its heat and fire resistant properties, asbestos use saw its peak in the mid-20th century. However, people began noticing its alarming health effects only decades after exposure to the toxin.Some of the effects from exposure include certain forms of cancer. Asbestos fibers often remain in the body for years, leading to irritation and the eventual development of malignant cells. Through further research and the development of clinical trials, aggressive cancers that are difficult to treat may stand a better chance with tumor profile-based targeted therapies and experimental treatments such as gene therapy.
Asbestos Use in India
Being the largest global importer of asbestos, much of India’s industry relies on the mineral’s production and use. Asbestos-containing products are manufactured in nearly 200 factories around India. The mineral can be found in a range of products, from cement and roofing to household appliances and automotive parts.
Due to its rarity, mesothelioma can often be misdiagnosed or improperly treated. To fully understand the condition and how it develops, further clinical study and testing needs to be done. Patients may not develop symptoms of mesothelioma for upwards of 10-50 years, and these symptoms are typically only discovered in the later stages of the disease. Innovative treatment methods and solutions could prove life changing for the majority of patients who do not survive more than a year after diagnosis.
Precision Medicine and Mesothelioma
Even in its initial stages gene therapy has the potential to hugely benefit cancer patients like those suffering from mesothelioma. At its core, gene therapy works to replace mutated or cancerous cells, leading to correcting the gene completely and deactivating the mutation. In mesothelioma cases, the DNA of a cell is damaged by asbestos fibers, leading to uncontrolled growth and abnormalities.
Mesothelioma patients most often receive treatment through some form of surgery, radiation, or chemotherapy. While a combination of these three treatments sees the highest success rates, the condition’s prognosis continues to be poor. However, the advent of precision medicine has started to provide new avenues for mesothelioma patients. Targeted therapy based on the mutation profile of the tumor is starting to become a reality for some patients (eg Erlotinib for tumors that carry an EGFR mutation) with some success in extending survival beyond one year, in some cases even up to five years. Gene therapy on the other hand is still in its experimental stages for mesothelioma, but is available now to patients through clinical trials. So far, much of the results have seen limited success with notable side effects or complications.
Further implementation and testing is needed to realize the full significance of gene therapy treatments for cancers like mesothelioma. Because it is less common, mesothelioma and other rare conditions may be less likely to receive funding for research, widespread data sharing, and experimental treatments. This means every clinical trial and new treatment endeavor will go a long way to impact patients and the mesothelioma community.
The TP53 Gene
Researchers have uncovered the TP53 gene as an effective target in treating tumors through gene therapy. This gene comprises a key protein (p53) that regulates normal cell function within the body and is vital in preventing tumor growth. Almost every form of cancer linked to a poor prognosis has a mutation in this gene, making it an ideal targeted therapy.
Preclinical studies have focused on the common genetic mutation in mesothelioma which deactivates the p53 pathways. This study has been successful in restoring the pathways that prevent tumor growth, but so far researchers have not been able to use this therapy to greatly reduce tumor size.
Mesothelioma in India
On a global scale, the World Health Organization estimates asbestos was linked to an estimated 107,000 deaths in 2004 alone. Although about 60 countries have banned the use of asbestos due to its threat to human health, India’s asbestos industry continues to grow. Around 80% of mesothelioma cases in the country involve men who experienced occupational exposure or those living in proximity to production.
Yet, mesothelioma is a considerably new condition for India, with the first case being reported as recently as 2015. However, the crux of this cancer is that it will continually be diagnosed for years, even after asbestos has been fully banned. The epidemic of asbestos exposure in India will only come to a halt when the dangers associated with this mineral are fully investigated, and it has been proactively handled or disposed of.
Until this time, it is important that evolving forms of cancer treatment, like targeted and gene therapy, are studied and implemented to help save the lives of those afflicted by mesothelioma. Precision medicine has the potential to greatly impact the way cancer care is approached, especially for patients with late stage diagnoses and where other forms of treatment would be too risky or ineffective. Further study into these treatment options provides hope in the cancer research community, and gives those who may face hazardous asbestos exposure the chance at a more promising future.
Disclaimer: The information provided in this article is in no way intended to replace expert medical advice. Always discuss the best possible course of action for your situation with your doctor.
Impacting Lives with Precision Medicine
Don’t delay that follow up appointment!
It might seem obvious, but apparently it is not. Have you ever had that moment where you went for your annual health check and your test results are not quite within the normal range, but you chose to ignore it, or were to busy to make the appointment for the follow-up investigations? Well, a recent study has actually looked at patient data to find out how long people wait between a positive cancer screening result and getting the follow-up scans or tests done and what impact that had on the progression of the cancer and subsequent treatment outcome. The first finding again is obvious, the longer you wait, the worse it gets! However, you’d be surprised to hear that some people actually never follow up. And one more nugget to take away – while the researchers were reluctant to define a safe time window within which the cancer (if the screening result wasn’t a false positive) is unlikely to progress to a more advanced stage is measured in days. 60-90 days, to be exact, was the range for the four types of cancer the researchers looked at. So don’t delay that follow-up appointment – when it comes to cancer, knowing for sure as soon as possible is always the better option! Read more
Call us now to arrange a free genetic counselling session!