Canadian Doctor Making Great Strides in Predicting Scoliosis
1. Functional Scoliosis Test
Their team previously discovered that many types of cells found in idiopathic scoliosis (IS) patients exhibit a different response to transmitted melatonin ( hormone that regulates sleep and wakefulness) signals. Since melatonin receptors can be found in most types cell this response can be measured using blood cells. Their functional test measures how blood cells respond to melatonin using a blood sample. The test can be done at any age (only once) and shows the genetic likelihood of developing scoliosis. Since 3 specific responses occur among idiopathic scoliosis (IS) patients, three categories were developed.
After determining which functional subgroup the patient belongs to, they can determine:
- For asymptomatic kids: a risk-score indicating the likelihood of developing scoliosis.
- For early stage scoliotic kids: the predictive risk of progression for those with mild scoliosis. Like any genetic test, it is not 100% certain if a child will or will not develop scoliosis because the cause of IS involves other environmental influences* (i.e., trauma, postural stress, exposure to specific types of bacteria, nutritional deficiency). Children at high risk may develop a severe scoliosis if they are often exposed to specific environmental factors. Those with limited exposure to environmental factors could develop a mild scoliosis or none at all.
*Epigenetics is the study of factors that influence gene expression with respect to environment, disease, normal development and aging. Epi is the Greek prefix for “over, outside of, or around”. Epigenetics looks at cellular and physiological trait variations that are not caused by changes in the DNA sequence but by variations in the transcriptional potential of a cell that may or may not be inherited. Unlike genetics, which is based on changes to DNA sequence (the genotype), the variations in gene expression or cellular phenotype of epigenetics have other causes. As an organism grows and develops, chemical reactions activate and deactivate parts of the genome. Epigenetics is the study of these chemical reactions and the factors that influence them. It is universally accepted that scoliosis is not a Mendelian disorder (any genetic disease which follows simple mendelian patterns of inheritance), and does not occur because of a defect in a single gene. Source
- The risk of developing specific co-occurring disorders (osteoporosis, anxiety, depression, etc.) which are known to be associated with IS. They are currently researching whether some functional subgroups are at greater risk of developing early onset of osteoporosis. If this can be determined, patients could potentially prevent or delay the effects of osteoporosis by increasing their bone mass with exercise, diet and supplementation. Testing scoliotic adults could be beneficial for determining which functional subgroup they belong to. In the long run, classification will aid in the development of tailored pharmacological treatments (personalized medicine). This could reduce potential side-effects, align patients with the best treatment for a given patient to stop curve progression and eventually to prevent scoliosis when combined with an early screening using this functional test. They are conducting tests to identify potentially useful therapeutic agents, but parents and patients must be aware that these drugs won’t be tested in clinical trials anytime soon since they are just now beginning this phase research.
To illustrate the usefulness of this test, Dr Moreau compares it to cystic fibrosis (CF) diagnosis. Since CF is caused by mutations to a single gene that aids in the transport of chloride ions, a functional test is used to measure chloride ions levels in the the patient’s sweat. If it is determined the patient has CF, specific mutations are then tested after.
Biochemical scoliosis test:
The second test is biochemical test and measures two proteins, Osteopontin (OPN)† and soluble CD44 (sCD44)‡, in the blood. Their research conducted in Montreal, Milan and Hong Kong showed a connection between elevated OPN in plasma with IS onset and severity. They found high levels of OPN in all surgical cases (Cobb angle greater than 45°) compared to cases of mild scoliosis and non-scoliotic subjects they tested. They also found surgical cases to have the lowest levels of sCD44 compared to mild and non-scoliotic subjects. Since sCD44 binds with free OPN in the body it can prevent the expression of scoliosis. Dr. Moreau states that OPN “is the key player causing IS onset and it is responsible for spinal deformity progression”.
†Osteopontin is an extracellular structural protein associated with bone remodeling/strengthening. Source ‡Soluble CD44 is a cell-surface protein involved in cell–cell interactions, cell adhesion and migration. Source
What will these tests show?
Both the biochemical test and the functional test are required to predict the risk of developing scoliosis and progression. Though the functional test would only be necessary once, the biochemical test would be conducted at regular intervals to monitor:
- Risk of progression over a given period of time since plasma OPN and sCD44 levels are affected by both individual genetics and environmental factors. The test’s ability to monitor environmental impact on scoliosis progression would be a tremendous breakthrough in the field.
- Efficacy of treatment methods such as bracing, exercises or medications – If OPN triggers scoliosis onset, any treatment that decreases OPN levels would theoretically have an affect on scoliosis presentation.
- Determine the contribution of environmental factors known to trigger high OPN levels by measuring plasma OPN and sCD44 levels. OPN responds to many stimuli such as mycobacterial infections, drugs, diet, exercise, and biomechanical changes.
- Eliminating these factors or reducing exposure may reduce the risk of scoliosis progression. Dr. Moreau compares this to asthma since there is no treatment aside from rescue inhalers and medications to reduce asthma attacks, but reducing exposure to allergens (dust, pet dander, chemicals etc) is very effective in managing asthma. Regularly monitoring OPN and sCD44 blood levels would help to identify environmental factors that affect scoliosis.
Why aren’t these tests available to the public?
Originally, the tests were expected to be available by 2008-2009 but there were delays in the completion of clinical trials in Montreal, and launching clinical trials in Milan (Italy) and Hong Kong (China). These trials are essential to demonstrate that the tests could be replicated in different populations and still produce the same results. However, the future looks optimistic since the biochemical tests performed in Milan and Hong Kong were conducted by others and confirmed the results achieved in Montreal.
The tests were designed to screen large populations of children and they have the ability to do so through the use of a robotic platform in Montreal. Dr. Marco Brayda-Bruno (the head of the research team in Milan, Italy) has received a grant from the Italian government for a pilot project to screen 1200 school children for scoliosis using the tests.
Will the tests be available for infantile scoliosis?
Though the tests were confirmed for juvenile and adolescent cases, they have not been tested for infantile cases. Dr Moreau explains that since infantile scoliosis is rare in North America the trials would need to be conducted in a region where infantile scoliosis occurs are more frequently.
How can these tests improve scoliosis braces?
Dr Moreau predicts that monitoring plasma OPN and sCD44 levels could be used in the future to evaluate bracing efficacy and even treatment compliance. Since both OPN and sCD44 (OPN specifically) are affected by biomechanical forces, the tests could be used to gauge the effects of bracing and physical therapy. Through this means, the tests could determine:
- which therapies would be best suited for which patients
- which patients would benefit from early intervention
- which patients have the greatest risk of progression and are likely to require surgical intervention
- Which have low or non-existing risk of progression and don’t require bracing
“We are now, for the first time, in the exceptional position of being able to foresee the eradication of the disease in the very near future with the development of the first drugs within ten years’ time.”
– Dr. Moreau
Dr. Moreau also predicts that the functional test could be used in the near future to prevent certain co-occurring diseases such as osteoporosis or depression. For example, a third of IS patients become osteopenic and may develop osteoporosis by their thirties and the functional test could be used to identify these at risk patients at an early stage and prevent progression by initiating preventative drug therapy.