Rare Diseases are, by definition, rare. They typically affect less than 1/2000th of the population. Many of them are genetic and caused by mutations in a single gene and over the last two decades, thousands of genes causing many of these disorders have been identified.
Rare Diseases are quite different from the more familiar common disorders like heart disease, diabetes, arthritis, cancer, etc. Common disorders largely result from the pressure of environmental factors acting on an individual’s genetic predispositions which, if present to a sufficient degree, tips one over into disease. In common disorders, a single causative factor is very uncommon; instead, it is the interaction of many genes of ‘small effect’ combined with many environmental factors (such as diet, drinking, smoking, exercise, occupation etc.). As a result, it is much harder to uncover individual factors, particularly genes for common disorders, even though they offer the promise of greatly enhancing our ability to improve the treatment.
Historically, drugs have been developed primarily based on the symptomatic benefit that they have on a disorder. This required good observation and, not infrequently, a degree of serendipity, as was the case with the discovery of penicillin by Alexander Fleming.
The more we understand about a disorder, the more options to target for treatment become available. This has been a stepwise process over time and generally, the initial treatments target the symptoms, symptoms such as pain and fever. Even today, this is far too often the primary treatment for many disorders. Understanding of the underlying anatomy, physiology and biochemistry of a disease allows us to target these elements more directly, e.g., the narrowed airways of asthma, awareness of hypertension and its hidden dangers or the gouty trauma and pain of uric acid. As our understanding continues to deepen, our ability to treat disorders continues to improve, and more targeted treatments have a profound impact on treating the symptoms and the underlying causes of the disorder. An important early example is Phenylketonuria or PKU, a disorder that leads to a profound and permanently low IQ, and autism. In 1934, the Norwegian physician Asbjørn Følling discovered that PKU was the result of abnormally high levels of an essential amino acid, which is found in many foods, including breast milk. A targeted dietary treatment was rapidly developed and quickly shown to prevent these severe consequences. Similarly, following the discovery that a lethal form of leukemia was caused by an abnormal fusion of two genes, Brian Druker and colleagues were able to develop a custom drug, Imatinib. This drug targets the abnormal protein formed by the gene fusion, much like a key fitting into a lock. Imatinib’s development, based on understanding the molecular basis for this form of leukemia, revolutionized the treatment and has saved the lives of many.
Our ability to find the underlying cause of single gene disorders has continued at a rapid pace and alongside, new treatments are being developed and applied. They may target the effects of the mutations or, more recently, may change the very code of the DNA and tackle the problem at its very root. Some of these ‘gene therapies’ have already been approved. For example, treatment for Spinal Muscular Atrophy, a severe neuromuscular disorder with profound weakness presenting early in life.
Research holds up the hope of a transformational improvement, and these evolving discoveries and their effects are very important for the affected people. But, for the vast majority of people, these discoveries haven’t yet had a significant impact on the type of care they can get. It is gradually beginning to change as we get a better knowledge of the molecular mechanisms and pathways underlying prevalent diseases gene by gene. Thus, for example, insights learned from those with the rare Gaucher disease are being applied to seeking new treatment targets for Parkinson disease. In fact, rare disorders are providing insights and informing treatment in every area of medicine and many aspects of life. These include, for example, (1) body systems such as the skin, cardiovascular or nervous system etc., (2) common health issues such as obesity and sleep problems, and (3) natural processes such as growth and aging.
Yet, despite intense work, identifying the genetic basis to most rare disorders remains a significant hurdle. At this time, we have identified less than half of the predicted structural genes responsible for our health, wellness, and disease. These are a large part of the missing pieces of the puzzle that slow medical advancement. The challenge remains that rare diseases are rare. We need to find them, and we need to look further than we have to date. A country like India is estimated to have tens of millions of people directly affected by rare disorders. This very large number certainly contains within it, many individuals with many disorders that have not yet been genetically characterized and for a proportion, will not even be described and remain undiscovered diseases. Population diversity in India offers unique challenges and opportunities for gene discovery. Thousands of years of cultural stratification in India has resulted in over 4500 distinct population groups with distinct and unique genetic traits.
Discovering the causative factor or gene is of great importance for the affected individual and their family, but the scale in India is such that currently many are not able to get the critical assessments that are needed. This is also an important need for the greater population for whom these insights can lead to research into new classes of drugs for the benefit of all. Within the challenges however lies opportunity for discovery, discovery that has the potential to transform medical care for everybody, those with rare disease and those with common diseases.
Alharbi SA, Wainwright M, Alahmadi TA, Salleeh HB, Faden AA, Chinnathambi A. What if Fleming had not discovered penicillin? Saudi J Biol Sci. 2014 Sep;21(4):289-93. doi: 10.1016/j.sjbs.2013.12.007. Epub 2014 Jan 8. PMID: 25183937; PMCID: PMC4150221.
Woolf LI, Adams J. The Early History of PKU. Int J Neonatal Screen. 2020 Jul 29;6(3):59. doi: 10.3390/ijns6030059. PMID: 33239585; PMCID: PMC7570064.
Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996 May;2(5):561-6. doi: 10.1038/nm0596-561. PMID: 8616716.
Druker BJ. STI571 (Gleevec) as a paradigm for cancer therapy. Trends Mol Med. 2002;8(4 Suppl):S14-8. doi: 10.1016/s1471-4914(02)02305-5. PMID: 11927282.
Rigo F, Hua Y, Krainer AR, Bennett CF. Antisense-based therapy for the treatment of spinal muscular atrophy. J Cell Biol. 2012 Oct 1;199(1):21-5. doi: 10.1083/jcb.201207087. PMID: 23027901; PMCID: PMC3461520.
Wasnik VB, Thool AR. Ocular Gene Therapy: A Literature Review With Focus on Current Clinical Trials. Cureus. 2022 Sep 24;14(9):e29533. doi: 10.7759/cureus.29533. PMID: 36312652; PMCID: PMC9590687.
Kumar M, Srikanth MP, Deleidi M, Hallett PJ, Isacson O, Feldman RA. Acid ceramidase involved in pathogenic cascade leading to accumulation of α-synuclein in iPSC model of GBA1-associated Parkinson’s disease. Hum Mol Genet. 2023 Feb 8:ddad025. doi: 10.1093/hmg/ddad025. Epub ahead of print. PMID: 36752535.
Boyden LM, Vincent NG, Zhou J, Hu R, Craiglow BG, Bayliss SJ, Rosman IS, Lucky AW, Diaz LA, Goldsmith LA, Paller AS, Lifton RP, Baserga SJ, Choate KA. Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma. Am J Hum Genet. 2017 Jun 1;100(6):978-984. doi: 10.1016/j.ajhg.2017.05.003. PMID: 28575652; PMCID: PMC5473720.
Creamer TJ, Bramel EE, MacFarlane EG. Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies. Genes (Basel). 2021 Jan 27;12(2):183. doi: 10.3390/genes12020183. PMID: 33514025; PMCID: PMC7912671.
Ward K. Rare disease gives insight into autism, epilepsy, editorial MSU today 2019 (of Malik R, et al., Nat Commun. 2019 Nov 1;10(1):4994. doi: 10.1038/s41467-019-12962-4. PMID: 31676823; PMCID: PMC6825152).
Rajasimha HK, Shirol PB, Ramamoorthy P, Hegde M, Barde S, Chandru V, Ravinandan ME, Ramchandran R, Haldar K, Lin JC, Babar IA, Girisha KM, Srinivasan S, Navaneetham D, Battu R, Devarakonda R, Kini U, Vijayachandra K, Verma IC. Organization for rare diseases India (ORDI) – addressing the challenges and opportunities for the Indian rare diseases’ community. Genet Res (Camb). 2014 Aug 13;96:e009. doi: 10.1017/S0016672314000111. PMID: 25579084; PMCID: PMC7044965.