Friday, February 26, 2016

Rare Disease Versions of Common Diseases

"Mille viae ducunt homines per saecula Romam" (A thousand roads lead men forever to Rome) - Alain de Lille in Liber Parabolarum, circa 1175

It is almost impossible to study a rare disease without uncovering some fundamental cellular mechanism underlying a common disease (1). The reason is simple: there are a finite number of mechanisms whereby cells can malfunction, and most of these mechanisms are encountered, in pure form, in one or another rare disease. Furthermore, the best way to understand a complex disease often involves understanding the rare diseases that reproduce the common disease phenotype.

Rule - We know more about the pathogenesis of rare diseases than we know about the pathogenesis of common diseases.
Brief Rationale - Each common disease has many causes and many pathways that contribute to the fully developed clinical phenotype. Because many cellular events are happening at once, there really is no way to design a controlled experiment that can determine the consequences of altering a single component of the system. Hence, the common diseases are all somewhat inscrutable.

For example, consider the pathologic complexity of cancer. Every measured pathway, organelle, and biochemical process is altered in cancer cells. The history of cancer research is littered by theories of carcinogenesis based on observations of malfunctioning cellular components. Here is a small sampling of paraphrased hypotheses:

"Cancer cells have unchecked proliferation, accounting for the malignant phenotype."

"Cancer cells preferentially employ anaerobic metabolism, which accounts for the malignant phenotype."

"Cancer cells have dysfunctional mitochondria, accounting for the malignant phenotype."

"Cancer cells have lost programmed senescence; hence the non-dying cells account for the malignant phenotype."

"Cancer cells have lost cellular junctions cell membrane processes that control transmembrane homeostasis, giving rise to a malignant phenotype."

"The epigenome is ultimately responsible for the normal control of the genome; when the epigenome is sufficiently altered, cells cannot behave normally, and cancer results.

"Cancer cells are genetically unstable, resulting in the selection of cells with a malignant phenotype."

These theories and many others have helped fund generations of cancer researchers. All of these theories were based on valid observations. The problem has been that when everything is changed from normal in a cell, as it is in cancer, it becomes impossible to select those changes that are the underlying causes of disease (2).

What is true for cancer is true for every complex disease. We cannot determine the effects of one variable on another variable when all the variables are changing, all of the time. Under such circumstances, the most we can do is to describe the phenotype of the diseases during its development, and make a reasonable guess as to what seems to be the most important events that arise as the disease progresses. The monogenic rare diseases are much easier to study; one gene changes, and one disease phenotype emerges. A monogenic disease is something that scientists can understand.

Rule - Common diseases are aggregates of the individual pathogenic pathways that account for the rare diseases.
Brief Rationale - Because every pathway is a product of gene expression, and because virtually every gene of functional importance is a candidate for a rare disease, it is reasonable to assume that each of the many pathways that participate in the phenotypic expression of a common disease will be expressed, in one or more of the 7,000+ rare diseases.

The set of rare diseases covers all the bases, so that every pathological expression of every pathway is presumably represented by a rare disease. If this is the case, you might expect similarities between the clinical phenotypes of common diseases and of rare diseases.

Rule - Any polygenic disease can be replicated by a monogenic disease.
Brief Rationale - The phenotype associated with a polygenic disease converges toward a physiologically permissible outcome. Because there is a monogenic disease affecting virtually every pathway available to cells, it is likely that each common disease will be replicated by at least one monogenic disease that converges to the same clinical phenotype.

We have observed that there are few common diseases, and that there are many different causes for the common diseases. If many different causes lead to a limited number of common phenotypes, can we not infer that many pathways lead to the common diseases, including the pathways found in rare diseases (3), (4)?

In point of fact, there are monogenic forms of most, if not all, of the common diseases.

- MODY (Maturity onset diabetes of the young), also known as monogenic diabetes, refers to any of several hereditary forms of the disease. Despite its name, MODY develops in children, like most other rare diseases. The "Maturity onset" in its name refers to its common disease counterpart.

- Fragile X syndrome (FXS), also known as Martin-Bell syndrome, is a monogenic cause of autism.

- McKusick-Kaufman syndrome and Bardet-Biedl syndrome-6 are both diseases that include a monogenic form, that causes obesity.

- Monogenic emphysema due to alpha-1-antitrypsin deficiency (5).

- Monogenic gallstone disease due to a mutation in the ABCB4 gene.

- Monogenic cardiomyopathy due to a mutation in the ABCC9 gene.

- Monogenic cardiac arrhythmia due to monogenic mutations in ion channel genes

- Monogenic cause of migraine in familial hemiplegic migraine type 2 and familial basilar migraine, due to mutations in the gene encoding the alpha-2 subunit of the sodium/potassium pump.

- Monogenic osteoarthritis, as a component of familial osteochondritis dissecans, due to mutation in the ACAN gene.

- Familial Alzheimer disease type 1 due to a mutation in the gene encoding the amyloid precursor protein.

- Monogenic, Mendelian forms of hypertension associated with proteins involved, in one way or another, with the transport of electrolytes in the renal tubules. Changes in electrolyte transport result in increased retention of sodium and to an increased volume of body fluid (6), (7), (8).

- Auto-inflammatory syndromes with monogenic subtypes, including familial Mediterranean fever caused by a mutation in the MEFV gene, encoding pyrin (9).

In at least one polygenic disease, Williams-Beuren syndrome, a gene associated with the disease has been assigned a specific trait, essentially establishing a monogenic disease within a polygenic disease. Williams-Beuren syndrome is a microdeletion disorder caused by a deletion of about 26 genes on the long arm of chromosome 7. It is characterized by a striking facial morphism described as "elfin", developmental delays, transient hypercalcemia, and cardiovascular abnormalities. One gene, of the 26 deleted genes, seems to account for all of the cardiovascular abnormalities (10). Other feature of the syndrome are seem to arise collectively from the other deleted genes.

If common diseases are puzzles, then rare diseases are the pieces of the puzzle.

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, phenocopy disease, phenocopies jules j berman


[1] Jiang X, Liu B, Jiang J, Zhao H, Fan M, Zhang J, et al. Modularity in the genetic disease-phenotype network. FEBS Letters 582 (2008) 2549-2554, 2008.

[2] Berman JJ. Neoplasms: principles of development and diversity. Jones & Bartlett, Sudbury, 2009.

[3] Rennard SI, Vestbo J. The many "small COPDs", COPD should be an orphan disease. Chest 134:623-627, 2008.

[4] Crow YJ. Lupus: how much "complexity" is really (just) genetic heterogeneity? Arthritis and Rheumatism 63:3661-3664, 2011.

[5] Stoller JK, Aboussouan LS. Alpha1-antitrypsin deficiency. Lancet 365:2225-2236, 2005.

[6] Lifton RP. Molecular genetics of human blood pressure variation. Science 272:676-680, 1996.

[7] Wilson FH, Kahle KT, Sabath E, Lalioti MD, Rapson AK, Hoover RS, et al. Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4. Proc Natl Acad Sci USA. 2003 100:680-684, 2003.

[8] Bahr V, Oelkers W, Diederich S. Monogenic hypertension. Journal Med Klin (Munich) 98:208-217, 2003.

[9] Glaser RL, Goldbach-Mansky R. The spectrum of monogenic autoinflammatory syndromes: understanding disease mechanisms and use of targeted therapies. Curr Allergy Asthma Rep 8:288-298, 2008.

[10] Pober BR. Williams-Beuren syndrome. New England Journal of Medicine 362:239-252, 2010.