Rare diseases that aren’t really rare
90 per cent have no approved therapies
Chanelle Michelle Laflèche, 25, has cystic fibrosis (CF), a disorder that affects your lungs, digestive tract, pancreas and other organs. It’s thought to be an inherited condition.
A defective gene, more specifically mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, causes disruptions in how the CFTR protein operates. This leads to a buildup of sticky and thick mucus in your organs. Clogged airways can make it difficult to breathe. Mucus blocking the ducts in the pancreas can cause problems with digesting food.
CF is considered a rare disease.
Rare diseases are classified as diseases that affect a small percentage of the human population. Little to no research, a lack of funding, challenges in diagnosis (such as having to see multiple specialists over many years) and limited access to treatment are all common issues that go handin-hand with these health conditions.
According to Dr. Stacie Colwell, IWK Health physician in Complex Care Paediatrics, rare diseases, in fact, are not really rare.
“Individual rare disease is rare but rare diseases — plural — are not rare at all,” said the physician.
“Canada, like the WHO, defines a rare disease as one that affects less than 50 persons per 100,000 population. For comparison’s sake, true redheads are just two per cent per cent of the population, but rare diseases are half of a tenth of a per cent. Put another away, there are at least 40 times more redheads than people living with a particular rare disease. That said, there are so many rare diseases that 3.5 to six per cent of the world’s population is living with a rare disease —which means for every one redhead you meet, there are two or three times as many people living with a rare disorder.”
When it comes to pediatric rare diseases, an overwhelming majority of them (perhaps 80 per cent), are genetic conditions, said the doctor. Even though the field of genetics has seen great strides over the last decades, little is known about what individual genetic differences actually mean.
“When a patient has genetic testing, the most common abnormal finding is what we call a ‘VUS’ — a variant of unknown significance. A ‘VUS’ just means that we have found something different, a variant, but we don’t know what it means or if it means anything at all,” said Colwell.
According to Dr. Victor Martinez, clinical genomics specialist at the IWK Health Centre and assistant professor in the Department of Pathology at Dalhousie University, the IWK Clinical Genomics lab currently performs CF genetic testing for the Maritime provinces.
“Having a genetic diagnosis for CF is important for patients to access treatments and medications. It also provides families with information to make decisions about the future.”
Cystic fibrosis is one of the most common rare diseases in Atlantic Canada’s health-care system, said Martinez.
Another group of rare diseases that’s relatively common is repeat expansion disorders, or REDS.
“REDS are caused by abnormalities in certain DNA regions where short sequences are repeated multiple times. In REDS, these repetitive segments become longer through incorrect DNA copying during cell division. For example, extra repeats in the HTT gene cause Huntington’s disease, expanded repeats in the DMPK gene lead to myotonic muscular dystrophy, and fragile X syndrome originates from expanded repeats in the FMR1 gene. These conditions worsen over time as more repeats accumulate and often run in families, but the age when symptoms first appear can vary widely between generations. Unfortunately, most REDS have no cure. However, a genetic diagnosis is an important milestone for patients, families and potentially others across Canada,” said Martinez.
LIVING WITH A RARE DISEASE
For Laflèche, one of the main everyday challenges of living with CF has to do with a lack of access to medications that she needs or having to pay high costs to get them.
Having to explain to people why she doesn’t feel well, lacks energy or motivation and has stomach problems, breathing issues and headaches is not easy either.
“(These) all affect you and your daily life, making it less enjoyable on some days than others. But often people just see you as being lazy,” shared the Cornwall, Ont., resident who was diagnosed when she was seven.
Her life revolves around her daily treatments. At least, that’s how it feels to Laflèche.
“It’s not easy. I get phone calls daily from doctor offices or clinics constantly booking me appointments as if I’m not trying to live a life. They expect you to be able to show up no matter the day or time, it doesn’t matter if you have plans.”
Carrying pills — supplemental digestive enzymes — around with her wherever she goes is also part of her life. “Or I suffer from not eating or extreme stomach pain,” said Laflèche.
Having a disorder that is rare also means that there’s an average time of five to eight years between when symptoms show up and when the disease is diagnosed, said Colwell.
“That’s five to eight years of worry and wonder, of medical visits and hospitalizations, of testing and imaging, searching for a name, a label, to explain what your child has been experiencing. And I say child, not because I am a pediatrician but because twothirds of rare disease diagnoses are given to children,” said the doctor.
And if you thought your troubles were going to become fewer and far between after a diagnosis, think again. Colwell said 90 per cent of rare diseases have no approved therapies and for the 10 per cent that do have therapies, access to them, financing the treatments and insurance coverage are not clear-cut processes. There’s also the chance that treatment options aren’t even available anywhere in your country or continent.
“That’s a really different — uniquely challenging and also isolating — experience for parents of children living with rare diseases,” said the pediatrician.
WHAT PLAGUES THE HEALTH-CARE SYSTEM?
Dr. Colwell thinks that the lack of treatment for rare diseases is connected, in varying degrees, to the infancy of scientific knowledge, the physiologic limits on current abilities to intervene in any body processes, the limited research support for specific diseases that affect very few people and the limited motivation of for-profit groups to design treatments for such a small number of affected people.
“I must emphasize ... that (it is) not due to a lack of advocacy on the part of parents, who are the drivers of innovation, nor from a lack of dedication from the medical providers, the community therapists, the school teams, the researchers or the myriad of people whose passion and profession are for ‘the care of rare,’” she said.
Laflèche also wishes that health-care professionals don’t compare one rare disease with another. Each one is unique and deserves its own analysis.
“I wish people would realize that often research for rare diseases go towards a ‘majority,’ meaning the ones that are a bit more complex (such as uncommon gene mutations for CF) get left behind. And the world thinks they have a new medicine for all of CF now, but that’s not true,” added the Cornwall resident.
The word “rare” means that not all clinicians or researchers are aware of the characteristics of a given condition, said Martinez. Many of them, especially those that aren’t specialized, might never or very rarely encounter certain rare diseases.
“Somewhat related to this point, there is a shortage of specialists like geneticists and neurologists, particularly in rural areas. This results in uneven access to highly specialized professionals who can provide rare disease diagnoses,” said the clinical genomics specialist.
Even though diagnosing a specific rare disease is a huge milestone that follows years of research and the information gathered is voluminous, it’s not readily available to help diagnose similar rare diseases in Canada or world over, added Martinez.
This presents another challenge: a lack of communication and spread of valuable knowledge.
“The accumulated knowledge often resides with the diagnosing clinician but we need to find ways to share this information securely with other professionals while maintaining patient privacy. This will accelerate future rare disease diagnoses,” said the assistant professor.
Perhaps this is why The Implementation of Clinical Exomes in a Pre- and Perinatal Setting, a project Martinez is involved in, is important.
IMPLEMENTATION OF CLINICAL EXOMES IN A PRE-AND PERINATAL SETTING
The project, which is part of Genome Canada’s “All for One” initiative, has seen the implementation of a new technology known as nextgeneration sequencing that can sequence the human exome.
“‘Exomes’ are the portions of our genome containing the information for the genes and proteins our bodies need. Though exomes make up just two per cent of our genome, changes in this small portion account for around 80 per cent of disease-causing mutations ... By sequencing, we mean that we can read the sequence of the chemical block that forms our DNA and look for unexpected changes that can cause damage to our cells and, eventually, cause a disease. We plan to use this sequencing to uncover these genetic changes before birth (prenatal) or in the period from pregnancy up to one year after birth (perinatal). We hope to obtain genetic information about possible genetic variations that could lead to complications later in life, including rare diseases,” said the assistant professor.
There’s also a data-sharing component within the project. Martinez and the rest of the team are working with children’s hospitals across Canada to share clinical findings that arise from patients with rare diseases. Although it’s time-consuming, mainly because there is emphasis on patient privacy and secure data sharing, the clinical genomics specialist believes that once it’s operational, this initiative could make diagnosis of rare diseases simpler across provinces.
“This platform could allow an anonymized rare disease case diagnosed in Nova Scotia to aid the diagnosis of a similar patient located in Yukon, and vice versa. Patients affected by rare diseases everywhere will benefit from faster, more accurate diagnoses using shared data from across Canada.”