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.

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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

References:

[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.

Phenocopy Mimics of Rare Diseases: Lessons for the Common Diseases

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.

The topic of phenocopy diseases was introduced in yesterday's blog post. Phenocopy diseases are medical conditions that closely mimic a genetic disease, but are caused or triggered by an environmental factor. In many cases, phenocopy diseases are non-hereditary and acute. In some cases, the phenocopy disease is reversible when the environmental trigger is removed or when an appropriate treatment is applied.

Here is just one example of phenocopy disease (from my book):

Acquired von Willebrand disease [the phenocopy disease] and inherited von Willebrand disease [the genetic disease]

Von Willebrand factor is a complex protein, the largest protein found in plasma, and is required for platelet adhesion. Reduction in von Willebrand factor results in a clotting disorder. Von Willebrand disease can result from inherited deficiency or it can be acquired through several mechanisms. In an autoimmune variant of the disease, antibodies reacting with the factor produce a protein complex that is rapidly cleared, effectively producing a deficiency. As a large, complex molecule, von Willebrand factor is particularly vulnerable to mechanical disruption. Artificial heart valves have been observed to produce von Willebrand disease. In cases of thrombocythemia (i.e., increased numbers of platelets in blood), excess platelets can absorb the von Willebrand factor to produce a functional deficiency.

From observations of many phenocopy diseases, we can make the following generalization, discussed in Chapter 9 of my book:

9.5.1 Rule—Phenocopy diseases are typically mimics of rare diseases, not common diseases. Brief Rationale—The prototypical phenocopy disease involves a single agent having a specific effect on a single pathway in a limited number of cell types.

In theory, any pathway can be altered by a drug to produce a phenotype that mimics a monogenic disease. A simple interruption of normal cellular function of a gene or a pathway is consistent with what we see in rare diseases and in phenocopy diseases, and lacks the cumulative acquisition of multiple genetic or cellular aberrations that typically characterize the common diseases. Phenocopy diseases provide important clues to the pathogenesis of rare and common diseases for the following reasons:

1. There is usually one pathway involved, often found in a limited number of cell types, and the phenocopy disease teaches us how this pathway operates and how it can be disrupted.

2. The pathway disrupted in the phenocopy disease is almost always the same pathway that is disrupted in the rare genetic disease. Hence, the phenocopy tells us how the rare disease expresses itself, and this is something that we can seldom infer from our knowledge of the gene mutation associated with the rare disease.

3. When the genetic cause of the rare disease is unknown, the careful study of its phenocopy will always yield a set of candidate genes that may operate in the rare disease.

4. Pharmacologic treatments for the phenocopy disease may apply to pathways operative in the genetic form of the disease or in the common diseases.

5. The pathway involved in a phenocopy disease can contribute to the pathogenesis of a common disease. Hence, understanding the phenocopy diseases brings us a little closer to understanding common diseases [60]. This topic will be discussed further in Chapter 10.

6. Recognizing the cause of a phenocopy disease may curtail potential environmental catastrophes.

The phenocopy diseases help us to focus on the cellular pathways leading to disease. If you exclusively study the genetics of disease, you will likely miss the cellular pathways that link rare diseases with common diseases.

The phenocopy diseases remind us that you can have a disease without a causal gene, but you cannot have a disease without a causal pathway.

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 of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D. tags: rare disease, common disease, orphan disease, orphan drugs, phenocopy disease, mimics of disease, principles of pathology, complex disease, disease biology, pathogenesis

Phenocopy Diseases: Their Relationship to Rare Diseases and Common Diseases

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.

Phenocopy diseases are medical conditions that closely mimic a genetic disease, but are caused or triggered by an environmental factor. In many cases, phenocopy diseases are non-hereditary and acute. In some cases, the phenocopy disease is reversible when the environmental trigger is removed or when an appropriate treatment is applied.

Here is just one example of phenocopy disease (from my book):

Acquired conduction defect [the phenocopy disease] and inherited conduction defect [the rare, genetic disease that is copied by the phenocopy disease]

Disorders of ion flux across membranes are known as channelopathies. The inherited cardiac conduction channelopathies were discussed in Section 5.3.

Because the anti-arrhythmogenic and anti-epileptic drugs typically target ion channels, they are the drugs most likely to produce, as an adverse side effect, disorders of cardiac conduction. For example, rufinamide, an oral antiepileptic drug, has been reported to cause QT-interval shortening [44]. Quinidine, disopyramide, and procainamide have been reported to produce QT prolongation [45].

Several channelopathies can be acquired as autoimmune diseases, in which antibodies react with ion channels, or related cellular components upon which the ion channels depend (e.g., myasthenia gravis, Lambert–Eaton myasthenic syndrome, cerebellar ataxia associated with VGCC antibodies, acquired neuromyotonia, Morvan fibrillary chorea, limbic encephalitis) [46].

Progressive familial heart block type IA is a genetic disorder of the cardiac conduction system. Clinically similar conditions can be acquired when the tissues of the conduction systems are damaged, as in: myocardial infarct, conduction system ischemia (i.e., lack of blood flow to components of the conduction system, particularly the His–Purkinje conduction tissue), age-related degeneration of conduction system, and complications of procedures (i.e., insertion of wires or lines into the heart chambers) [47].

The importance of the phenocopy diseases to our general understanding of disease processes, and to the development of successful treatments for rare diseases and common diseases, will be discussed in the next few blogs.

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 of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D. tags: rare disease, common disease, orphan disease, orphan drugs, phenocopy disease, complex disease, heart block, arrhythmia, disease biology, pathogenesis