The rare disease definition, challenge and pathways of the future

I've seen data citing that more than 8,000 rare diseases comprise as many as 400,000 cases worldwide. Of those 8,000 rare diseases, 80% have a genetic origin. It seems to me that this estimation of global cases might potentially be short of the real number. I've read research citing that just the number of clinical depression cases is estimated to be around 300,000 worldwide. Moreover, we don't even know if the estimate includes a guess at unreported cases. Some countries have no reporting or information sharing. Or on the other hand, maybe the data citing the 400,000 rare disease cases doesn't consider depression a rare disease. So I'm not sure what all these numbers mean. While the jury is out, I keep seeing that ~350,000 worldwide cases number popping up in different journals and papers.

An article in the journal, Nature, used the Orphanet database to arrive at these estimates. "...conservative, evidence-based estimate for the population prevalence of rare diseases of 3.5–5.9%, which equates to 263–446 million persons affected globally at any point in time."

The rare disease diagnosis is costly, arduous and frustrating, involving years of tests by multiple specialists. A study by Delphin German Centers for Diseases determined that rare disease diagnosis took about 6 years on average, within which incorrect diagnoses were made along the way. It's common for patients to experience being written off by practitioners as if their problems were psychosomatic. The paper refers to the merry-go-round of doctor visits as an "odyssey", while the primary care physician is faced with trying to refer the patient to the right specialist. Diseases with vague symptoms that mimic numerous other etiologies are particularly challenging for practitioners. A couple areas that offer some of the greatest challenges involve the array of autoimmune and neuromuscular disorders.

In Forbes, Claire Novorol talks about the uphill battle doctors face in patient diagnostics or rare disease. She mentions a case early in her career involving what she considers a long road of exhaustive testing that was treading water for more than a year. Eventually, only after tireless research of available databases was she able to finally make any progress. As I wrote above, that's relatively short time for a rare disease diagnosis, and I'm sure the cost to the patient was still considerable.

Resources are being assembled in creative ways. In the NY Times, a section called Diagnosis: Unsolved Casesis dedicated to crowdsourcing by reaching out to the readers in order to help diagnose people with mysterious disorders. She presents rare cases and asks for reader help. It is now a Netflix series. The author refers to the patient odyssey as "bleak."

There are so many rare genetic diseases for which there is little available data about molecular processes or etiologies. Due to the rarity of some of the more obscure rare diseases in question and the limited numbers of patients, samples, research and resources are just naturally going to be scarce.

Rare disease research will make greater headway in mapping a wide range of the more "common" of the rare diseases. There are initiatives underway. One is the international, collaborative new "International Rare Diseases Consortium." From what I've read, the sharing of samples is essential for accelerated research. It only makes sense, right? One source refers to these shared samples as "biobanks."

Here's the good news part. Genome sequencing is the game-changing breakthrough that is becoming more affordable for everyone, and in the form of a one-time test, making it well worth the cost--especially in light of the "odyssey" process. It can save a patient years of dead end roads and the associated medical costs, incorrect medications and mental toll. It doesn't even require a prescription.

As per an interesting research paper in the EPMA Journal, Whole Genome Sequencing (WGS) holds the key to unlocking the mechanisms involved in rare diseases. With WGS, "...all exons and non-coding genomic sequences are covered and structural variations can also be detected. The identification of non-coding genomic variations that can act as modifier can be informative for explanation of discordant spectrum of phenotypes that is frequently observed in rare diseases."

Scientists around the world are focusing on using WGS to help identify genetic biomarkers for rare diseases. The Oxford Dictionary defines a biomarker as "a measurable substance in an organism whose presence is indicative of some phenomenon such as disease, infection, or environmental exposure." But WGS isn't plug-and-play. The human genome is vast. Scientists need to know where to look in screening for specific diseases, so expertise is crucial.

There is light at the end of the tunnel because progress is constant. In fact, there is enough genetic data already available for diagnosing a number of rare diseases. Maybe I'm using the word "diagnosing" a bit freely. Apparently, definitive diagnosis isn't exactly how this stuff works. Scientists can give probability scores for, say, a person developing a certain disease. But that is still huge progress considering the painstaking "odyssey" described above. Results might even help doctors rule things out so they don't waste time and money going down dead ends.

One paper I found on Pubmed had a unique name for the future of healthcare. With breakthroughs using WGS, future molecular biomarker diagnostics and treatment are a form of "personalized medicine."

Following is the more well-known rare diseases list I found listed where whole-genome sequencing can already be critically important:

• Age-related Macular Degeneration • Becker muscular dystrophy • Bipolar Disorder • Breast cancer • Celiac Disease • Cystic fibrosis • Duchenne muscular dystrophy • Epilepsy • Hemophilia A and B • Huntington’s disease • Major Depressive Disorder • Obsessive Compulsive Disorder • Ovarian cancer • Parkinson's Disease • Psoriasis • Schizophrenia

But that's not where it ends. I found a list of far more obscure diseases for which there are biomarkers. According to a Biomarkers in Rare Diseases on Pubmed, there has been progress in identifying biomarkers for the following rare diseases:

• Gaucher disease • Fabry disease • Hirschsprung disease • advanced anal squamous cell carcinoma • sarcoidosis • neuroinflammatory diseases of the central nervous system • Peutz–Jeghers syndrome • Rett syndrome

I have to assume that there are many others I missed in researching this topic. I'm not a scientist, so hopefully the way I understood and explained things is accurate. If you think I made any mistakes, please let me know! Anyway, whole-genome sequencing is very exciting, and I'm actually planning on doing a test one of these days. As a side note, I'm interested in its application of diagnosing various disorders in the realm of mental health. For instance, a small segment of people diagnosed with Major Depressive Disorder have been considered treatment-resistant. Maybe some of these patients would be found to actually have bipolar disorder --which is treated differently.

I've seen data citing that more than 8,000 rare diseases comprise as many as 400,000 cases worldwide. Of those 8,000 rare diseases, 80% have a genetic origin. It seems to me that this estimation of global cases might potentially be short of the real number. I've read research citing that just the number of clinical depression cases is estimated to be around 300,000 worldwide. Moreover, we don't even know if the estimate includes a guess at unreported cases. Some countries have no reporting or information sharing. Or on the other hand, maybe the data citing the 400,000 rare disease cases doesn't consider depression a rare disease. So I'm not sure what all these numbers mean. While the jury is out, I keep seeing that ~350,000 worldwide cases number popping up in different journals and papers.

The rare disease challenge and pathways of the future