Wednesday, February 17, 2016

The Rarity of the Rare Diseases

"If I didn't believe it, I would never have seen it." -Anon

The difference in rates of occurrence of the rare diseases compared with the common diseases is profound, often on the order of a thousand-fold or more. You need to wonder, is there some biological factor that keeps the incidence of the monogenic diseases low, and the incidence of polygenic diseases high? Darwinian selection keeps the incidence of life-threatening monogenic diseasese low; individuals with serious childhood diseases will be less likely to procreate and to pass disease genes onto others.

In the case of the polygenic diseases [which happens to include most of the common diseases], there is no natural process of selection that would cull disease genes from the general population. If a disease occurs in late in adulthood, as is often the case for polygenic diseases, Darwinian selection many not apply; affected individuals will have an opportunity to procreate. More importantly, though, Darwinian selection cannot operate efficiently on a set of polygenic disease genes. If the variant genes that cause a polygenic disease are common poymorphisms (i.e., naturally occurring gene variants observed in populations), then the variants may serve a useful purpose in concert with other genes, in some subset of cells, or under certain sets of conditions. For example, a gene that downregulates the number of mitochondria contained in cells may be useful under anoxic conditions, when mitochondrial oxygenic respiration is low, and useful in red cell differentiation, when mitochondria are normally eliminated. If such a gene were somehow removed, its absence may reduce susceptibility to a particular disease while simultaneously introducing a new cellular defect. When dealing with a polygenic disease, selecting against the variant genes may have adverse consequences. As the number of genes involved in a polygenic disease increases, the overall effect of selecting against individual variant genes becomes unpredictable and chaotic.

Rule - Every common disease was, at some point, a rare disease.
Brief Rationale - Every epidemic begins with a solitary case. Common diseases are equivalent to epidemics that settle in to stay.

There is an inherited immunodeficiency of cattle caused by a deficiency of leukocyte adhesion factor. Affected cattle are homozygous for a gene allele that codes for a substitution in a a single amino acid in its protein product. Heterozygotes (i.e., cattle with an unpaired mutant allele) are common in the U.S., with a carrier rate of about 10%. Every cattle with a mutant allele is a descendant from one bull, whose sperm was used to artificially inseminate cows in the 1950s and 1960s (1). A disease that was essentially non-existent in 1950 became a common scourge of the dairy industry within a half-century, all due to the founder effect amplified by modern animal husbandry.

In the past century, we have seen many rare diseases of humans become commonplace. Environmental factors can raise the incidence of some rare diseases to the point that they become common. Here are some examples.

Heart disease. Increased availability of cheap fatty and sweet foods, combined with social factors that favor a sedentary life-style, raised the heart attack from a collection of rare, hereditary conditions to one of the most common causes of death in industrialized societies.

Colon cancer. Common in the United States, colon cancer has an incidence of 40/100,000. In Africa and some parts of Asia, colon cancer is a rare disease, with an incidence under 5/100,000 (2). Speculation abounds to explain why this is so, but the the issue of diet looms large. The low-fiber, low-vegetable, high-meat diet preferred in high-incidence societies, contrasted with the high-fiber, high-vegetable, low-meat diet in the low incidence societies provides a credible, if unproven, explanation.

AIDS. Late in 1981, a Haitian man presented at Jackson Memorial Hospital in Miami with a constellation of infectious diseases, a strange rash, and mouth lesions of an unfamiliar type. At the time, the attending physicians were baffled. Eventually, after a desperate review of the newest literature, a diagnosis of an extremely rare diseases tentatively named GRIDS (gay-related immune disease syndrome), was rendered. Today, GRIDS, now known as AIDS, is a diagnosis that can be rendered, without hesitation or error, by a first-year medical student. In 1981, there were about a dozen well-document cases in the U.S. In 2011, 1.7 million people died of AIDS worldwide (3).

Lung cancer. Prior to the popularization of cigarette smoking, lung cancer was extremely rare. Today, lung cancer is the leading cause of cancer deaths in every country where smoking is common.

Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.

- Jules Berman (copyrighted material)

key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, disease complexity, common diseases, jules j berman


[1] Kehrli ME, Ackermann MR, Shuster DE, van der Maaten MJ, Schmalstieg FC, Anderson DC, et al. Bovine leukocyte adhesion deficiency: beta(2) integrin deficiency in young Holstein cattle. Am J Path 140:1489-1492, 1992.

[2] World Cancer Research Fund and American Institute for Cancer Research Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective. Washington, DC, American Institute for Cancer Research, 2007. Available at:, viewed August 13, 2015.

[3] Global Health Observatory. HIV/AIDS. World Health Organization. Available from, viewed July 27, 2013.