Friday, June 27, 2014

When Rare Diseases and Common Diseases Converge to the Same Clinical Picture

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

In yesterday's blog, we discussed by a rare disease and a common disease may both have the same clinical presentation, a phenomenon that I call disease convergence. The short explanation for disease convergence is that there are a limited number of ways that the body can respond to malfunctions.

Here is an excerpt from Chapter 10, in which disease convergence is discussed:

Hypertension is another excellent example of convergence toward a common phenotype. As discussed in Section 5.4, there are numerous genetic and environmental causes of hypertension. The causes of hypertension may include overactivity of the renin–angiotensin system, or channel defects at various sites of the renal tubule, or arterial wall pathology, or increased salt consumption. Regardless of the underlying cause of hypertension, all inherited and acquired forms of the disease converge onto one physiologic pathway: increased net salt balance leading to increased intravascular volume, leading to augmented cardiac output, leading to elevated blood pressure [8]. Regardless of the underlying mechanism leading to an individual’s hypertension, diuretics such as hydrochlorothiazide or furosemide, which reduce the reabsorption of sodium in the kidneys, will almost always lower blood pressure. We see a similar phenomenon with rare and common causes of diabetes. Extremely rare single gene diabetes, including HNF1A MODY and permanent neonatal diabetes associated with the KCNJ11 and ABCC8 genes, is controlled with sulfonylurea, the same drug used to treat common type 2 diabetes. The cause of monogenic diabetes is quite different from the cause of common type 2 diabetes, but their pathways converge; and all these diseases respond to the same treatment [9].

Some of the rare diseases exhibit convergence with one another. For example, epidermolysis bullosa is an inherited disease characterized by blistering of the skin and mucosal membranes (e.g., mouth). It is always caused by a defect in the mechanism whereby the epidermis is anchored onto the underlying dermis. Blisters are formed in locations where the epidermis lifts off the dermis, usually at sites of friction. Over 300 gene defects can result in epidermolysis bullosa. Depending on the variant form of the disease, any of several different genes may serve as the underlying cause (e.g., COL, PLEC, Desmoplakin genes). There is also an autoimmune form of epidermolysis bullosa acquisita, wherein antibodies target Type VII collagen, a component of the basement membrane glue that lies between the epidermis and the dermis. Regardless of the underlying cause, all variants of epidermolysis bullosa converge to a blistering phenotype.

10.1.3 Rule—A large set of cellular defects accounts for a relatively small number of possible pathologic conditions. Brief Rationale—In any complex system, there are a limited number of functional parts, but each functional part can break down due to a vast number of possible defects.

We can see that nothing in the universe is ever as chaotic as we might expect from the complexity of the individual elements of the system. Despite the enormous number of atoms in the universe, there seem to be just a few dozen types of cosmological bodies (e.g., stars, planets, black holes). These bodies assemble into galaxies that seem to have a relatively narrow array of shapes and sizes. In the case of biological systems, complex processes settle for a limited number of outcome categories.

10.1.4 Rule—Regardless of the complexity of a system, the outcomes are typically repeatable and stable.
Brief Rationale—All existing biological systems, despite their complexity, converge toward stability. If a biological system were unstable, it would cease to exist.

The phenomenon of convergence may explain some of the genetic complexity that seems to characterize many, if not all, of the common diseases. When there are hundreds or thousands of gene variations that are associated with one disease, it is likely that all these different genes contribute to a limited range of available disease pathways. In diseases that have a complex genetic etiology, it makes sense to examine the pathways that converge to a final clinical phenotype, rather than to try to understand the individual contribution from each variant gene.

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy for your library or reading room.

- Jules J. Berman, Ph.D., M.D.

tags: convergence, disease convergence, orphan diseases, orphan drugs, drug development, common diseases, complex diseases, rare disease models of common diseases, disease pathway, complex diseases, common diseases, disease phenotype, pathogenesis, disease pathway