Friday, July 18, 2014

Rare Diseases Hiding Among 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.



Here is an excerpt from Chapter 12:
It is easy to find cases wherein a rare disease accounts for a somewhat uncommon clinical presentation of a common disease.
12.1.2 Rule—Uncommon presentations of common diseases are sometimes rare diseases, camouflaged by a common clinical phenotype.
Brief Rationale—Common diseases tend to occur with a characteristic clinical phenotype and a characteristic history (e.g., risk factors, underlying causes). Deviations from the normal phenotype and history are occasionally significant.
Rare diseases may produce a disease that approximates the common disease; the differences being subtle findings revealed to the most astute observers. Here is some pithy wisdom that senior physicians love to impart to junior colleagues: “When you see hoof prints, look for horses, not zebras.” The message warns young doctors that most clinical findings can be accounted for by common diseases. Nonetheless, physicians must understand that zebras, unlike unicorns and griffins, actually exist. Occasionally, a rare disease will present with the clinical phenotype of a common disease.

For example, mutations of the JAK2 gene are involved in several myeloproliferative conditions, including myelofibrosis, polycythemia vera (see Glossary item, Polycythemia), and at least one form of hereditary thrombocythemia (i.e., increased blood platelets) [9–11]. Surprisingly, somatic blood cells with JAK2 mutations are found in 10% of apparently healthy individuals [12]. The high incidence of JAK2 mutations in the general population, and the known propensity for JAK2 mutations to cause thrombocythemia and thrombosis, should alert physicians to the possibility that some cases of idiopathic thrombosis may be caused by a platelet disorder caused by undiagnosed JAK2 mutation of blood cells. As it happens, it has been shown that a JAK2 mutation can be found in 41% of patients who present with idiopathic chronic portal, splenic and mesenteric venous thrombosis [13]. Such thrombotic events are uncommon in otherwise healthy patients. The search for a zebra, in this case a cryptic myeloproliferative disorder caused by a JAK2 mutation, pays off (see Glossary item, Myeloproliferative disorder).

Zebras can hide among the horses. Consider lung cancer, the number one cause of cancer deaths in the U.S. When lung cancer occurs in a young person, you might wonder if this is a rare disease cloaked as a common disease. Midline carcinoma of children and young adults is an extremely rare type of lung cancer. It is characterized by a NUT gene mutation, not typically found in commonly occurring lung cancers of adults [14]. Hence, midline carcinoma of children and young adults is an example of a rare disease hidden in a common disease. Secretory carcinoma, formerly known as juvenile breast cancer, is a rare form of breast cancer. It has a less aggressive clinical course than commonly occurring breast cancer, and occurs at a younger median age (i.e., about 25 years) than the median age of occurrence of common breast cancer (i.e., 61 years). In 2002, it was discovered that the expression of the ETV6-NTRK3 gene fusion is a primary event in the carcinogenesis of secretory breast carcinoma [15]. Once again, an uncommon presentation of a common tumor was found to hide a rare disease with its own characteristic genetic mutation.

Myelodysplastic syndrome, formerly known as preleukemia, is a rare blood disorder occurring almost exclusively in older individuals. The specific gene causing myelodysplastic syndrome is unknown, but recurrent cytogenetic alterations have been found in bone marrow cells, particularly losses of the long arm of chromosome 5 (i.e., 5q-) and of chromosome 7 (i.e., monosomy 7). Myelodysplastic syndrome occurs in very young children, with extreme rarity. Virtually all such childhood cases involve monosomy 7. An inherited predisposition to lose one copy of chromosome 7 in somatic cells has been reported in kindreds whose children have a high likelihood of developing myelodysplastic syndrome, or of acute leukemia. Hence, it seems that a somatic chromosomal abnormality associated with a rare disease occurring in adults is also associated with an even more rare childhood form of the disease. The childhood disease may occur when an inherited mutation predisposes children to the equivalent somatic chromosomal abnormality observed in the adult form of the disease [16,17].

As a final example, there are two recognized types of acute myelogenous leukemia (AML): AML following myelodysplasia, a preleukemia, and de novo AML, which develops in the absence of an observed preleukemic condition [18]. De novo AML can occur in children or in adults. The de novo AML cases in children have a different set of cytogenetic markers than those observed in adult de novo AML [19].

I urge you to read more about my 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: common disease, orphan disease, orphan drugs, rare disease, subsets of disease, disease genetics, genetics of complex disease, genetics of common diseases, cryptic disease

Thursday, July 17, 2014

Pareto's Principle and Long-Tailed Distribution Curves

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 book has an extensive glossary, that explains the meaning and relevance of medical terms appearing throughout the chapters. The glossary can be read as a stand-along document. Here is an example of one term, "Pareto's Principle", excerpted from the glossary.
Pareto’s principle - Also known as the 80/20 rule, Pareto’s principle holds that a small number of items account for the vast majority of observations. For example, a small number of rich people account for the majority of wealth. Just two countries, India plus China, account for 37% of the world population. Within most countries, a small number of provinces or geographic areas contain the majority of the population of a country (e.g., east and west coastlines of the U.S.). A small number of books, compared with the total number of published books, account for the majority of book sales.

Likewise, a small number of diseases account for the bulk of human morbidity and mortality. For example, two common types of cancer, basal cell carcinoma of skin and squamous cell carcinoma of skin, account for about 1 million new cases of cancer each year in the U.S. This is approximately the sum total for all other types of cancer combined. We see a similar phenomenon when we count causes of death. About 2.6 million people die each year in the U.S. [98]. The top two causes of death account for 1,171,652 deaths (596,339 deaths from heart disease and 575,313 deaths from cancer [99]), or about 45% of all U.S. deaths. All of the remaining deaths are accounted for by more than 7000 conditions.

Sets of data that follow Pareto’s principle are often said to follow a Zipf distribution, or a power law distribution. These types of distributions are not tractable by standard statistical descriptors because they do not produce a symmetric bell-shaped curve. Simple measurements such as average and standard deviation have virtually no practical meaning when applied to Zipf distributions. Furthermore, the Gaussian distribution does not apply, and none of the statistical inferences built upon an assumption of a Gaussian distribution will hold on data sets that observe Pareto’s principle.

I urge you to read more about my 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: 80/20 rule, common disease, data analysis, glossary, orphan disease, orphan drugs, rare disease, statistics

Tuesday, July 15, 2014

Relationship between Hamartoma and Cancer

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 book has an extensive glossary, that explains the meaning and relevance of medical terms appearing throughout the chapters. The glossary can be read as a stand-along document. Here is an example of one term, "hamartoma", excerpted from the glossary.
Hamartoma - Hamartomas are benign tumors that occupy a peculiar zone lying between neoplasia (i.e., a clonal expansion of an abnormal cell) and hyperplasia (i.e., the localized overgrowth of a tissue). Some hamartomas are composed of tissues derived from several embryonic lineages (e.g., ectodermal tissues mixed with mesenchymal tissue). This is almost never the case in cancers, which are clonally derived neoplasms wherein every cell is derived from a single embryonic lineage. Tuberous sclerosis is an inherited hamartoma syndrome. The pathognomonic lesion in tuberous sclerosis is the brain tuber, from which the syndrome takes its name. Tubers of the brain consist of localized but poorly demarcated malformations of neuronal and glial cells. Like other hamartoma syndromes, the germline mutation in tuberous sclerosis produces benign hamartomas as well as carcinomas, indicating that hamartomas and cancers are biologically related. Hamartomas and cancers associated with tuberous sclerosis include cortical tubers of brain, retinal astrocytoma, cardiac rhabdomyoma, lymphangiomyomatosis (very rarely), facial angiofibroma, white ash leaf-shaped macules, subcutaneous nodules, cafe-au-lait spots, subungual fibromata, myocardial rhabdomyoma, multiple bilateral renal angiomyolipoma, ependymoma, renal carcinoma, subependymal giant cell astrocytoma [62].

Another genetic condition associated with hamartomas is Cowden syndrome, also known as multiple hamartoma syndrome. Cowden syndrome is associated with a loss of function mutation in PTEN, a tumor suppressor gene. Features that may be encountered are macrocephaly, intestinal hamartomatous polyps, benign hamartomatous skin tumors (multiple trichilemmomas, papillomatous papules, and acral keratoses), dysplastic gangliocytoma of the cerebellum, and a predisposition to cancers of the breast, thyroid and endometrium.

I urge you to read more about my 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, types of cancer, cancer types, tumor types, tumor biology, rare cancers, common cancers, hyperplasia, tissue overgrowth, disease genes, genetic disease, carcinogenesis, glossary

Aneuploidy and Carcinogenesis

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 book has an extensive glossary, that explains the meaning and relevance of medical terms appearing throughout the chapters. The glossary can be read as a stand-along document. Here is an example of one term, "aneuploidy", excerpted from the glossary.
Aneuploidy - The presence of an abnormal number of chromosomes (for the species) in a cell. Most cancers contain aneuploid cells; an observation that holds true for virtually every poorly differentiated cancer. Aneuploidy is seen less often in benign tumors and well-differentiated tumors. Aneuploidy is also found in epithelial precancers and other growing lesions that can sometimes regress spontaneously (e.g., keratoacanthoma). These observations have prompted speculation that chromosomal instability and the acquisition of aneuploidy is an underlying cause of the cancer phenotype (i.e., tumor growth, invasion into surrounding tissues, and metastases).

Such causal associations invite skepticism, particularly in the realm of cancer biology, as virtually every cellular process and constituent of cancer cells has been shown to deviate from the norm. Nonetheless, there is good reason to suspect that aneuploidy is at least a factor in tumor development, as mutations that cause aneuploidy are associated with a heightened risk of cancer (e.g., Brca1 gene mutations [13] and mutations of mitotic checkpoint genes [14]). Cancer researchers have warned that aneuploidy, by itself, may not cause cancer [15]. Aneuploidy may need to be accompanied by other factors associated with genetic instability, such as the accumulation of DNA damage, specific cancer-causing mutations, epigenomic and cytogenetic abnormalities, and reduced cell death [15].

As usual, a rare disease helps to clarify the role of aneuploidy in carcinogenesis. Mosaic variegated aneuploidy syndrome-1 (MVA1) is caused by a homozygous or compound heterozygous mutation in the BUB1B gene, which encodes a key protein in the mitotic spindle check point. This disease is characterized by widespread aneuploidy in more than 25% of the cells of the body, and a heightened risk of developing childhood cancers (e.g., rhabdomyosarcoma, Wilms tumor, and leukemia). Because the underlying cause of mosaic variegated aneuploidy syndrome-1 is a gene that produces aneuploidy, and because such aneuploidy is an early event (i.e., congenital) that precedes the development of cancer and that is found in the developed cancer cells, then it is reasonable to infer that aneuploidy is closely associated with events that lead to cancer. See Mutator phenotype, Carcinogenesis, Cytogenetics, and Karyotype.

I urge you to read more about my 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, types of cancer, cancer types, tumor types, tumor biology, rare cancers, common cancers, aneuploidy, cytogenetics, euploidy, carcinogenesis, glossary

Monday, July 14, 2014

Most Types of Cancer are Rare Cancers

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.



Here is an excerpt from Chapter 8:
There are about 6000 types of cancer that have been assigned names by pathologists [4–6]. About a dozen of these cancers are common diseases. The remaining cancers (i.e., about 6000 entities) comfortably qualify as “rare” under U.S. Public Law 107-280, the Rare Diseases Act of 2002 [7]. Consequently, healthcare workers must somehow come to grips with 6000 types of rare cancers.

Moreover, the variety of rare cancers is increasing rapidly. As we learn more and more about the genetics of cancers, we find that the common cancers can be subtyped into genetically distinct groups. Furthermore, we are finding an increasing number of alternate alleles and heterogeneous genes that account for rare diseases.

Hence, the trend is leading us to divide the common cancers into genetically distinct subtypes that qualify as rare cancers, and to divide the known rare cancers into ultra-rare subtypes.

I urge you to read more about my 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, types of cancer, cancer types, tumor types, tumor biology, rare cancers, common cancers

Sunday, July 13, 2014

Clinical trial failures: help from the Rare 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.



For a variety of reasons, clinical trials for rare diseases tend to have much greater likelihood of success than clinical trials on common diseases. Moreover, treatments developed for the rare diseases will almost always find some value in the treatment of one or more common diseases [a major theme discussed developed in the book]. Here is a short excerpt from Chapter 14.
It can be difficult or impossible to enroll all the patients required for a clinical trial. In an analysis of 500 planned cancer trials, 40% of trials failed to accrue the minimum necessary number of patients. Of cancer trials that have passed through preclinical, phase I clinical, and phase II clinical trials, three out of five failed to achieve the necessary patient enrollment to move into the final phase III clinical trial [12]. Most clinical trials for cardiovascular disease, diabetes, or depression are designed to be even larger than cancer trials [12].

Overall, about 95% of drugs that move through the clinical trial gauntlet will fail [13]. Of the 5% of drugs that pass, their value may be minimal. To pass a clinical trial, a drug must have proven efficacy. It need not be curative; only effective. Of the drugs that pass clinical trials, some will have negligible or incremental benefits. After a drug has reached market, its value to the general population might be less than anyone had anticipated. Clinical trials, like any human endeavor, are subject to error [14–16]. Like any human endeavor, clinical trials need to be validated in clinical practice [10]. It may take years or decades to determine whether a treatment that demonstrated a small but statistically significant effect in a clinical trial will have equivalent value in everyday practice.

Funders of medical research are slowly learning that there simply is not enough money or time to conduct all of the clinical trials that are needed to advance medical science at a pace that is remotely comparable to the pace of medical progress in the first half of the twentieth century.
14.2.2 Rule—Clinical trials for common diseases have limited value if the test population is heterogeneous; as is often the case.
Brief Rationale—Abundant evidence suggests that most common diseases are heterogeneous, composed of genotypically and phenotypically distinct disease populations, with each population responding differently with the clinical trial.

The population affected by a common disease often consists of many distinct genetic and phenotypic subtypes of the disease; essentially many different diseases. A successful clinical trial for a common disease would require a drug that is effective against different diseases that happen to have a somewhat similar phenotype. One-size-fits-all therapies seldom work as well as anticipated, and more than 95% of the clinical trials for common diseases fail [13].
14.2.3 Rule—Clinical trials for the rare diseases are less expensive, can be performed with less money, and provide more definitive results than clinical trials on common diseases. Brief Rationale—Common diseases are heterogeneous and produce a mixed set of results on subpopulations. This in turn dilutes the effect of a treatment and enlarges the required number of trial participants. Rare diseases are homogeneous, thus producing a uniform effect in the trial population, and thus lowering the number of trial participants required to produce a statistically convincing result.

Rare diseases often have a single genetic aberration, driving a single metabolic pathway that results in the expression of a rather uniform clinical phenotype. This means that a drug that succeeds in one patient will likely succeed in every patient who has the same disease. Likewise, a drug that fails in one patient will fail in all the other patients. This phenomenon has enormous consequences for the design of clinical trials. When the effects of drugs are consistent, the number of patients enrolled in clinical trials can be reduced, compared with the size of clinical trials wherein the effects of drugs are highly variable among the treated population. In general, clinical trials targeted on rare diseases or on genotypically distinct subsets of common diseases require fewer enrolled participants than trials conducted on heterogeneous populations that have a common disease [13].

It is wrong to assume that because rare diseases affect fewer individuals than do the common diseases, it would be difficult to recruit a sufficient number of patients into an orphan drug trial. Due to the energetic and successful activities of rare disease organizations, registries of patients have been collected for hundreds of different conditions. For the most part, patients with rare diseases are eager to enroll in clinical trials. The rare disease registries, made available to clinical trialists, eliminate the hit-or-miss accrual activities that characterize clinical trials for common diseases.

I urge you to read more about my 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, clinical trials, complex disease, ancillary studies, trial design, statistical significance, reproducibility,

Treating precancers reduces breast cancer deaths

Breast cancer deaths rose through the '70s and '80s, but declined in the '90s. For nearly the past 20 years, American women have had about a 2% annual drop in the breast cancer death rate.

Here is the mortality graph provided by the National Cancer Institutes SEER (Surveillance, Epidemiology and End Results) program.



Though nobody wants to take the blame for the rise in breast cancer deaths in the '70s and '80s, lots of people want credit for the fall of breast cancer deaths that began in the '90s. Was it due to a reduction to the exposure of carcinogens, or to better treatment, or to earlier diagnosis?

The fall in breast cancer deaths does not seem to be due to cancer prevention. While the deaths from breast cancer were falling, there was an apparent rise in the incidence of breast cancer cases. Here is the SEER graph for the incidence in breast cancer in the U.S.



Since the breast cancer incidence rose while the deaths from breast cancer dropped, it seemed as though the benefit must have come from better treatment or earlier detection.

A major study, attempting to resolve this issue, was published in the New England Journal of Medicine, in 2005:

Effect of screening and adjuvant therapy on mortality from breast cancer.
Berry DA, Cronin KA, Plevritis SK, Fryback DG, Clarke L, Zelen M, Mandelblatt JS, Yakovlev AY, Habbema JD, Feuer EJ; Cancer Intervention and Surveillance Modeling Network (CISNET) Collaborators. N Engl J Med 353:1784-1792, 2005.


They concluded that that 28 to 65 percent of the sharp decrease in breast cancer
deaths from 1990 to 2000 was due to mammograms. The remainder of the improvement was was attributed improved breast cancer treatment.

The study did not take into account the great contribution of precancer treatment to the reduction of breast cancer deaths.

Let's review this SEER data, this time taking into account the diagnosis of DCIS (ductal carcinoma in situ) a precancer that precedes the development of invasive breast cancer. Here is the SEER data for the incidence of all breast cancer and of DCIS (the precancer for breast cancer).



In the past few decades, there has been a huge rise in the number of diagnosed cases of breast precancers. This is due largely to the use of mammography, which can detect lesions that cannot be found by palpation. When a precancer is detected and removed, the patient does not develop invasive cancer.

The total number of breast cancer cases includes cases of DCIS. If we subtract the number of breast precancer cases (DCIS) from the total number of breast cancer cases, we get the incidence of invasive breast cancer cases. Here is the SEER data.



The middle bars in the graph represent the incidence of invasive breast cancers. The graph shows that incidence of invasive breast cancers has actually dropped since the early '90s, as the diagnosis and treatment of DCIS has risen.

Much of the decrease in breast cancer mortality can be accounted for by the diagnosis and treatment of breast precancers. In fact the drop in breast cancer deaths follows the same slope, and has about the same magnitude, as the drop in invasive breast cancers that follows the increase in breast precancer treatments.

- © 2010 Jules Berman

Friday, July 11, 2014

Causality: Single Gene Disorders Can be Biologically Complex

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.



One of the points discussed in the book is disease causation, and how we often fool ourselves into thinking that we understand how a disease develops, simply because we can name the gene or agent that precipitates the disease.

A gene may code for a single protein, but complex genetic and epigenetic conditions will effect the individual's response to a specific gene defect. Hence, different individuals, each with their own unique genome and epigenome, will respond differently to the same genetic aberration. Here is an excerpt from Chapter 9:
If a disease were truly caused by an aberration of a single gene, then all of the consequences of the genetic aberration would be identical in every person with the gene. In fact, some monogenic diseases have remarkably uniform clinical phenotypes in affected populations (e.g., sickle cell disease). What would happen if the same genetic aberration were recapitulated in a mouse? If the mouse homologue served the same purpose as the human gene, and if the gene were the sole cause of the disease, then you might expect the disease to be the same in man and mouse.

Lesch–Nyhan disease is a rare syndrome caused by a deficiency of HGPRT (hypoxanthine-guanine phosphoribosyl transferase), an enzyme involved in purine metabolism. In humans, HGPRT deficiency results in high levels of uric acid, with resultant renal disease and gout. A vast array of neurologic and psychologic signs accompanies the syndrome, including self-mutilation. Neurologic features tend to increase as the affected child ages. The same HGPRT deficiency of humans can be produced in mice. Mice with HGPRT deficiency do not have disease. As far as anyone can tell, mice with HGPRT deficiency are totally normal [18]. How can this be?

A single gene cannot cause a disease all by itself. Every monogenic disease is expressed in a complex system wherein the defective gene is a participant in various pathways that eventually lead to a disease. The mouse, evidently, has a set of pathways that compensates for the deficiency in HGPRT.

Diabetes is usually a common polygenic disease. There are rare subtypes of type 2 diabetes that have a monogenic origin. As you would expect, these rare subtypes arise in children, and have a Mendelian pattern of inheritance. One such monogenic form of diabetes is MODY-8 (maturity-onset diabetes of the young), caused by a mutation in the carboxyl-ester lipase gene. This same mutation was delivered to a transgenic mouse, intended as an animal model for MODY (see Glossary item, Transgenic). Mice carrying the same altered gene as the human failed to develop any signs of diabetes, or pancreatic damage, or any dysfunction caused by the mutated gene [19].

I urge you to read more about my 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, monogenic disease, complex disease, causality, disease causation, cause of disease, pathogenesis

Thursday, July 10, 2014

Causality versus Pathogenesis

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.



One of the points discussed in the book is disease causation, and how we often fool ourselves into thinking that we understand how a disease develops, simply because we can name the gene or agent that precipitates the disease.

Here is an excerpt from Chapter 8 [Note: Pathogenesis is the sequence of cellular events that eventually leads to the clinical expression of a disease]:
In the field of medicine, we often cannot assign a specific cause to a particular disease without seriously misleading ourselves. For example, what is the cause of rheumatic fever? Rheumatic fever is an autoimmune process that targets the heart. Rheumatic fever occurs in people who have been infected with a Group A strain of Streptococcus pyogenes. The infection, which usually presents as a pharyngitis, elicits an immune response against a bacterial antigen. The antibody species that target the bacterial antigen happen to cross-react with proteins in normal heart and vessels. These cross-reacting antibodies damage the heart and vessels to produce rheumatic fever.

Rheumatic fever is one of the most thoroughly studied and best understood diseases known to man. Knowing all that we know about the pathogenesis, pathology, and clinical features of rheumatic fever, it should be easy to specify the cause of the disease. Alas, this is not the case. For example, we cannot assert that rheumatic fever is caused by Streptococcus pyogenes because not all cases of infection lead to rheumatic fever, and because the clinical features of the disease are not actually caused by the infection. Likewise, we cannot assert that rheumatic fever is an autoimmune disease because it does not result from a defect in the autoimmune response. Basically, rheumatic fever involves a normal immune response to a foreign antigen (i.e., a protein of Streptococcus pyogenes bacteria) that happens to cross-react with the heart proteins. Furthermore, we cannot claim that rheumatic fever is caused by a heart defect; the heart is an innocent bystander in a process that evolved over time in tissues other than the heart (i.e., the pharynx and other tissues in which immunocytes reside). The more we know about the pathogenesis of rheumatic fever, the more difficult it becomes to specify its cause.

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, rheumatic fever, rheumatic heart disease, heart disease, immune disease, strep infection, causality, disease causation, cause of disease, pathogenesis

Wednesday, July 9, 2014

Rare Cancer are Subsets of Common Cancers

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.



One of the key ideas developed in the book is that each common diseases is actually an aggregate of cellular processes that are present, individually, in rare diseases. In the case of the common cancers, we can find specific rare diseases that are subsets of the common diseases.

Here is an excerpt from Chapter 8:

8.3.3 Inherited syndromes that cause rare cancers are often associated with increased risk for developing common cancers; hence, the causes of rare cancers are related to the causes of common cancers. Many of the greatest advances in our understanding of common cancers have come through the study of rare familial cancer syndromes in which common types of cancer occur. Here are a few common cancers and the familial syndromes that account for a small percentage of cases.

Colon tumors (benign and malignant)
- Colorectal cancer hereditary non-polyposis
- Polyposis syndrome, mixed hereditary
- Turcot syndrome (central nervous system cancer and familial polyposis of the colon)
- Mismatch repair gene pmsl1 colorectal cancer hereditary, non-polyposis type 3 included
- Checkpoint kinase 2 S. pombe homologue of breast and colorectal cancer susceptibility
- Colorectal adenomatous polyposis autosomal recessive
- Oligodontia–colorectal cancer syndrome
- Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome
- Adenomatous polyposis of the colon (APC)
- Peutz–Jeghers syndrome
- Colorectal cancer hereditary non-polyposis type 2
- Colorectal cancer susceptibility on chromosome 9
Lung cancer
- Lung cancer 1
- Lung cancer, alveolar cell carcinoma included
Breast cancer
- Brca1 breast cancer type 1
- Breast cancer 11–22 translocation associated
- Brca2 breast cancer type 2
- Brca3 breast cancer type 3
Basal cell carcinoma of skin (see Glossary item, Basal cell carcinoma)
- Basal cell carcinomas with milia and coarse sparse hair
- Basal cell nevus syndrome
- Basal cell carcinoma, multiple
- Basaloid follicular hamartoma syndrome (see Glossary item, Hamartoma)
- Basal cell carcinoma with follicular differentiation
- Xeroderma pigmentosum complementation group b
- Xeroderma pigmentosum 1
Renal cell carcinoma
- Renal carcinoma, familial associated 1 included
- Renal cell carcinoma, papillary
- Non-papillary renal carcinoma 1
- Renal cell carcinoma, papillary 3
- Leiomyomatosis and renal cell cancer hereditary
Thyroid cancer
- Thyroid carcinoma, familial medullary
- Familial non-medullary thyroid cancer
- Papillary thyroid microcarcinoma
- Thyroid carcinoma, papillary with papillary renal neoplasia
- Thyroid carcinoma, non-medullary 1
- Thyroid carcinoma, Hürthle cell
- Thyroid carcinoma, follicular
Ovarian cancer
- Epithelial ovarian cancer
- Ovarian cancer, epithelial, susceptibility to
Melanoma
- Melanoma, cutaneous malignant 4
- Melanoma, cutaneous malignant 3
- Familial atypical multiple mole melanoma-pancreatic carcinoma syndrome
- Dysplastic nevus syndrome, hereditary b-k mole syndrome
Prostate cancer
- Prostate cancer, hereditary x-linked
- Prostate cancer, hereditary 1
- Prostate cancer, hereditary 20
- Prostate cancer, hereditary 7
- Prostate cancer, hereditary 3
- Prostate cancer/brain cancer, susceptibility
When we look at individual inherited cancer syndromes, we see that both rare and common cancers may result. Here is the list of different types of cancer associated with the Li–Fraumeni syndrome [15]. The syndrome-associated cancers are divided into common and rare cancers.

Common tumors associated with Li-Fraumeni syndrome
- Breast cancer
- Lung adenocarcinoma
- Colon cancer
- Pancreatic cancer
- Prostate cancer
Rare tumors associated with Li-Fraumeni syndrome
- Soft tissue sarcomas
- Osteosarcomas
- Brain tumors
- Acute leukemias
- Adrenocortical carcinomas
- Wilms tumor
- Phyllodes tumor of breast
It is worth noting that the common cancers associated with rare cancer syndromes have a similar morphologic appearance as their sporadic counterparts. This suggests that regardless of underlying genetic cause, the pathogenesis of each named common cancer tends to converge to its characteristic phenotype.

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, carcinogenesis, common cancers, rare cancers, cancer syndromes, familial cancer syndromes

Tuesday, July 8, 2014

Direct Assault on Advanced Stage Common Cancers Has Not Yielded Cures

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.



Here is a short excerpt from Chapter 8:
Though there are thousands of types of human cancer, the bulk of cancer cases in humans are accounted for by just a few, under a dozen, types of cancer. The two most commonly occurring cancers of humans are basal cell carcinoma of skin and squamous cell carcinoma of skin. Together, these two tumors account for about 1.2 million new cancers each year in the U.S., nearly equal to the number of all the other types of cancers combined. These tumors are so common that, frequently, more than one basal cell carcinoma or squamous cell carcinoma will occur in the same individual. Fortunately for us, these two tumors seldom cause deaths; most cases are cured by simple excision. Cancer registries do not bother to collect records on these two cancers, and the published data on cancer incidence, compiled from registries and surveillance databases, typically ignores these two tumors. Nonetheless, we will see later in this chapter that basal cell carcinoma of skin and squamous cell carcinoma of skin tell us much about the biology of cancer in humans.

In Section 2.1, we discussed Pareto’s principle, wherein a few common items account for the majority of instances of any collection. Cancer obeys Pareto’s principle: a few cancers account for most cases of cancer occurring in humans. Collected U.S. data for the year 2008 indicate that, after excluding basal cell carcinomas and squamous cell carcinomas of skin, there were 1,437,180 new cancers. In the same year, there were 565,650 cancer deaths, of which 161,840 individuals died of lung cancer [1]. The percentage of U.S. cancer deaths from lung cancer was 28.6% (161,840/565,650). Also in 2008, there were 49,960 deaths from colorectal cancer, accounting for 8.8% of U.S. cancer deaths (49,960/565,650). Just two cancers (lung and colorectal) accounted for 37.4% of deaths from cancer in the U.S. When age-adjusted data are examined, the top five cancer killers (lung, colon, breast, pancreas, and prostate) account for 57% of all cancer deaths [1] (see Glossary item, Age-adjusted).

Observing that a few types of cancers account for the bulk of human cancer deaths, funding agencies have concentrated their efforts on finding cures for the most common cancers. Just seven types of common cancer, out of about 6000 known cancers, account for over 36% of cancer funding [2]. The justification for distributing cancer research funding toward research in the common cancers is simple. If cures can be found for the most common cancers, we could drastically reduce the number of cancer deaths in the U.S. and in the world. Curing a rare cancer that might affect a few hundred people worldwide would seem to be an ill-advised investment of our limited resources. Hence the rare cancers receive relatively little cancer funding compared with the common cancers.

The drawback to this straightforward approach is that it has failed. Despite decades of funding, we still do not know how to cure common cancers when they are diagnosed at an advanced disease stage. New discoveries in cancer genetics have highlighted the incredible complexity of the commonly occurring cancers. The complexity of the common cancers has been a seemingly insurmountable barrier blocking the development of simple and effective cures. Despite the long-term efforts of an army of cancer researchers, the age-adjusted death rate from cancers in the year 2000 was about the same as it was in 1975. A significant drop in the cancer death rate since the year 2000 is largely attributed to smoking cessation and other preventive measures; not due to effective new cures for the advanced stage common cancers[3].
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, advanced stage cancer, cures for advanced stage cancers, cancer priorities, cancer funding, cancer research funding

Monday, July 7, 2014

Rare Diseases and Orphan Drugs: Recent Blogs

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.



Over the past several weeks, I've been posting to several different blogs on the subject of rare diseases.

Here is the list of my rare disease posts, with links:

Developing Diagnostic Tests for Common Diseases: Role of the Rare Diseases

Rare Diseases Account for Subsets of Common Diseases

Phenocopy Mimics of Rare Diseases: Lessons for the Common Diseases

Phenocopy Diseases: Their Relationship to Rare Diseases and Common Diseases

What Rare Diseases Teach Us About the Cellular Basis of Aging

What is the Fundamental Biological Process that Causes Aging?

Wrinkling and Sagging are Chronic Toxic Processes Not Directly Caused by Aging

Disease Complexity: Rare Diseases and Common Diseases

Case Reports of Rare Diseases Have General Value

When Rare Diseases and Common Diseases Converge to Same Clinical Picture

Rare Diseases and Common Diseases can Converge to the Same Clinical Conditions

Rare Disease Legislation in the U.S.

Definition of Rare Disease

Developing Diagnostic Tests for Common Diseases: Role of the Rare Diseases

Rare Diseases Account for Subsets of Common Diseases

Improving Clinical Trials by Focusing on Rare Diseases

Rare Diseases of Unknown Origin

Rare Diseases are Sentinels for the Common Diseases

Biological Differences between Rare Cancers and Common Cancers

Rare Diseases are Biologically Different from Common Diseases

Rare Cancers are Biologically Different from Common Cancers

Rare Cancers

Clinical Trials and Rare Diseases

Rules for the Rare Diseases

The Rationale for Funding Rare Disease Research

New Book Explains the Importance of Rare Disease Research

I urge you to read more about this book. There's a good preview of the book at the Google Books site. If you think that you and your colleagues may benefit from reading this 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 diseases, orphan diseases, orphan drugs, funding opportunities, rare cancers, common diseases, complex diseases, clinical trials, rare disease organizations, disease advocates

Sunday, July 6, 2014

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

Saturday, July 5, 2014

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 the electrical systems in humans that defects 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

Friday, July 4, 2014

What Rare Diseases Teach Us About the Cellular Basis of Aging

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.



Chapter 4 explains that much what we think we know about the aging process comes from studying rare diseases of premature aging, such as Hutchinson–Gilford progeria syndrome, Bloom syndrome, Werner syndrome, Cockayne syndrome, dyskeratosis congenita, Fanconi anemia, Wolfram syndrome, and xeroderma pigmentosum. Lessons learned from these rare diseases are summarized in Chapter 4.

From Chapter 4:
4.4.3 Rule—On a cellular basis, aging is a process confined to non-renewable cell populations. Brief Rationale—Long-lived cells that cannot replace themselves, such as fully differentiated neurons, muscle cells, and cartilage cells, have no biological destiny other than degeneration and death.
As non-dividing cells undergo wear and tear, or suffer damage that cannot be repaired, they will die. The tissues in which these damaged cells reside will function with diminished capacity. For example, osteoarthritis is a chronic disease that occurs from repeated episodes of bone crunching on its cartilage cushion within joints. Osteoarthritis occurs primarily in weight-bearing joints, such as knees and hips. Over a lifetime, the cartilage is frayed and eroded. Injured chondrocytes do not divide, or they divide with insufficient zest to restore a normal cartilaginous cushion. As erosion of the cartilaginous lining continues, an inflammatory reaction develops in the joint. The inflammatory reaction produces pain, swelling, and associated clinical symptoms.

Consider oocytes. All of the oocytes that a woman will produce are present in utero, reaching a peak of about 7 million cells at 5 months’ gestation. After the peak is reached, about 3 months before birth, the oocytes begin to die; they are not replaced. The number of live oocytes declines until the number falls below a threshold of 1000, triggering menopause [28]. In this instance, as in every other example of human tissues undergoing aging, the process involves cells that cannot regenerate.

Frailty is a universal feature of old age. After the age of about 50, muscle mass gradually declines. The frailty associated with extreme aging is due, in part, to progressive sarcopenia. Muscle cells atrophy (i.e., reduce their size), die, and are not renewed. Frailty occurs because muscle cells were not designed to renew themselves continuously and indefinitely.

It was once thought that the brain cells you were born with are the same cells that you will die with; that brain cells do not divide. It is now known that regeneration (i.e., the growth of new neurons) occurs throughout life. This may be so, but new growth comes from reserve cells, not from fully differentiated neurons. Cell division cannot occur in a cell that becomes very large, like a neuron, and has appendages (i.e., an axon and dendrites) extending to and from other cells, sometimes over great distances (up to several feet in the case of motor neurons innervating foot muscles). Axons are ensheathed by a dependent network of periaxonal cells (i.e., oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system). Neurons are transfixed anatomically, and cannot round up to divide. Hence, the fully mature neuron has little or no regenerative opportunity. Consequently, many of the cellular changes that we associate with aging take place in neurons. The dementia that accompanies aging is due to the inability of injured neurons to repair or replace

The tauopathies are disorders wherein tau protein accumulates within neurons. Tau proteins are involved in the stabilization of microtubules in every cell throughout the body, but they accumulate to the greatest extent in the neurons of the central nervous system. If a fully differentiated neuron cannot clear its tau proteins, it will suffer progressive damage, leading to cell death. Though tau proteins are ubiquitous, the tauopathies always develop as neurodegenerative disorders. Examples of diseases in which tau proteins are found include: Alzheimer’s disease, progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, dementia pugilistica, a form of Parkinsonism known as Lytico–Bodig disease or as Parkinson–dementia complex of Guam, a form of Parkinsonism linked to chromosome 17, frontotemporal dementia, frontotemporal lobar degeneration, Hallervorden–Spatz disease, lipofuscinosis, meningioangiomatosis, Pick’s disease, a rare tumor of neurons known as ganglioglioma [29], subacute sclerosing panencephalitis, lead encephalopathy, tangle-predominant dementia, and tuberous sclerosis.

Agin The prion diseases are another example of disorders that target non-dividing neurons. The term prion was introduced in 1982 by Stanley Prusiner [30]. Prions are the only infectious agent that contains neither DNA nor RNA. A prion is a misfolded protein that can serve as a template for proteins of the same type to misfold, producing globs of non-functioning protein, causing cells to degenerate. The site of greatest accumulation of prion protein is in brain cells. Though few scientists would consider prions to be organisms, living or otherwise, they are undoubtedly transmissible infectious agents. The most common mode of transmission of prion disease is through the consumption of brains of infected animals.

The cells of the body that are most vulnerable to prion disease are the neurons of the brain. The reason for the particular sensitivity of neurons to prion disease relates to the limited ability of neurons to replicate (i.e., to replace damaged neurons with new neurons), reconnect (to replace damaged connections between a neuron and other cells), and to remove degenerated cells and debris. There are five known prion diseases of humans, and all of them produce encephalopathies characterized by decreasing cognitive ability and impaired motor coordination. They are: Kuru, Creutzfeldt–Jakob disease, bovine spongiform encephalopathy (known in humans as new variant Creutzfeldt–Jakob disease), Gerstmann–Straussler–Scheinker syndrome, and fatal familial insomnia. At present, all of the prion diseases are progressive and fatal. Prions have been observed in fungi, where their accumulation does not seem to produce any deleterious effect, and may even be advantageous to the organism [31].

In Section 4.3, we listed the many causative mechanisms underlying the rare diseases of premature aging. Without exception, every disease of premature aging creates a defect in the normal process of cellular renewal. If we understood how to control and maintain stem cell renewal, a feat that nematodes seem to have mastered, then we might understand how to defeat the aging process. In Chapter 7, we will be discussing cancer, another disorder of cell renewal. Whereas aging is a disease of cells that cannot divide, cancer is a disease of cells that cannot stop dividing.
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, aging, ageing, cell renewal, cancer, cause of aging, biology of aging, orphan disease, orphan drugs