Why do Common Diseases Typically Occur in Adults, while Rare Diseases occur in Children?

The rare diseases are often inherited monogenic diseases. Consequently every cell in the body contains the causal gene, and the gene has the opportunity to exert its effect throughout the period of embryonic development, and into childhood. Hence, the rare diseases tend to occur in childhood. The common diseases are caused by multiple factors that accumulate throughout life. Hence, the common diseases tend occur in adults. In general, the incidence of common diseases steadily increases with age

Rule - When you graph the frequency of occurrence of a rare disease against the age of the individuals that develop the disease, there is usually one clear peak.
Brief Rationale - Rare diseases often result from a single mutation that enters the germline at the time of conception. The process by which the gene mutation leads to a clinical disease will require roughly the same length of time, in most affected individuals, producing a smooth, single peak, when disease occurrences are graphed against age of occurrence.

There are exceptions to the "one peak" rule. Some diseases have a bimodal distribution (i.e., two peaks). Distributions with more than two peaks are likely to occur, but the peaks in polymodal graphs run into one another and cannot, in general, be distinguished with certainty. Our ability to tease out polymodal data peaks may be improved, somewhat, as we become more adept at collecting information on large number of individuals, with verified, detailed quantitative feature data (i.e., age of occurrence of disease, gene mutations present in lesions, gene expression profiles)

Rule - Bimodality, when it occurs, is more often observed in the rare diseases, than the common diseases.
Brief Rationale - Because there are many occurrences of a common disease, second peaks (i.e. subpopulations with separate peak occurrence with age), are likely to be masked by the large number of occurrences of the larger peak. Because the total number of individuals with a rare disease is small, a relatively small subpopulation, with its own specific age of disease occurrence, is likely to produce a visible second peak, when the data is graphed.

For example, Hodgkin lymphoma, a rare tumor, has two peaks of disease occurrence

Graph showing incidence of Hodgkin Lymphoma, by age of occurrence of disease. There are two peaks in the graph. The first peak occurs in the early 20s. After the first peak, there is a trough, in the mid 40s, after which incidence increases steadily with age, toward a second peak. The graph was generated at the National Cancer Institute's Surveillance, Epidemiology and End Results "Fast Stats" query site.
http://seer.cancer.gov/faststats/selections.php?series=cancer

What does it mean when a rare disease breaks the "one peak" rule and demonstrates a bimodal age distribution? Here are a few possibilities:

1. Two different diseases, presumably with overlapping phenotypes, occur in two peak age groups, and are mistakenly assigned the same name.

2. A population is exposed to two environmental disease-causing agents, one working slower than the other.

3. A subpopulation is exposed to a different concentration of disease-causing agent, or at a different age, either resulting in disease occurring at a different average age, for the subpopulation.

4. Two genetic causes for the same disease have different latencies (i.e., lengths of time for the disease to develop)

5. Two sub-populations have different disease modifiers (i.e., sets of genes that alter the pathogenesis of the disease).

6. Faulty or insufficient data. Bimodality may be a distortion due to poor data that does not adequately conform to the naturally occurring (unimodal) distribution.

7. False conclusions based on accurate data. The second peak may be caused by valid by "noisy" data. Scientists should not assume that statistical conclusions, based on a single set of data, are correct. All conclusions must be constantly re-examined in light of new findings.

8. Combinations of examples 1 through 7.

Occasionally, we can determine the biological mechanism that accounts for a bimodal age distribution. For example, Kaposi sarcoma, caused by human herpesvirus-8, has two peaks in occurrence. The first peak, in young people, occurs in individuals with AIDS-related Kaposi sarcoma. The second peak occurs in older men, was a recognized disease entity prior to the AIDS epidemic (i.e., prior to 1980s), and is often referred to as "classic" Kaposi sarcoma. Classic Kaposi sarcoma is slow-growing, arises on the skin, often on the leg, and does not metastasize. It tends to occur in individuals of Mediterranean descent.

Once you begin to think about diseases in terms of multimodality, there is a short leap to thinking that the common, complex diseases are composite entities, composed of small sets of separate diseases that share a clinical phenotype.

Rule - A disease that can be separated into biological subsets, based on a quantifiable trait, such as age, can be interpreted as an aggregate of separate diseases, each with a smaller occurrence rate than the original disease.
Brief Rationale - By definition, a disease is a pathological condition that is biologically distinct from other pathologic conditions.

In a provocative journal article entitled,"The many 'small COPDs', COPD should be an orphan disease," Stephen Rennard argued that many chronic diseases are actually heterogenous groups of diseases that we are just now learning to distinguish from one another (1). When we begin the process of separating diseases into related but distinguishable subsets of disease, we can begin to see why the common diseases may be aggregates of less common diseases. For example, mutation in the BRCA2 gene account for some cases of breast cancer, but the percentage is small. In fact, all of the known breast cancer risk genes, in aggregate, account for under 10% of the incidence of breast cancer. The remaining 90% would qualify today as sporadic tumors.

Interestingly, the same BRCA2 gene that accounts for a subset of cases of breast cancer, also accounts for a miniscule subset of a rare disease: Fanconi anemia. Most cases of Fanconi anemia are caused by mutations in genes coding for protein components of the Fanconi anemia protein complex which, along with BRCA2, helps coordinate DNA repair (2). A small percentage of Fanconi anemia patients are caused by homozygous mutations in the BRCA2 gene.

Rule - Single gene mutations may account for small subsets of common diseases, but they do not account for large subsets of common diseases.
Brief Rationale - All the single gene disease mutations are rare. If this were not so, we would expect to see Mendelian inheritance, typical for monogenic diseases, among the common diseases; but we do not.

Though a rare disease hidden within a common disease accounts for only a small proportion of the total number of disease cases, the genetic cause of the rare disease subset may be much easier to find than the genetic cause of the so-called sporadic cases (3). When one mutated gene fully accounts for a subset of cases of a disease, its statistical association with with the disease can be demonstrated with a relatively small number of cases (3).

Rule - Rare diseases that are subsets of common diseases often occur in a younger population than the cases occurring in the larger set of individuals with so-called sporadic disease.
Brief Rationale - Rare diseases are typically germline, monogenic diseases that occur in young individuals.

A rare subset of lung cancers is caused by a rearrangement in the NUT gene. As in so many other rare diseases that have a germline, monogenic cause, these cancers tend to occur in a much younger age group than cancers caused by an environmental factor (i.e., smoking, in this case) (4). The same observation holds for secretory breast carcinoma, formerly known as juvenile carcinoma of breast, which occurs in a younger age group than classic ductal breast carcinoma, and which is characterized by a specific fusion gene (5). Similarly, myelodysplastic syndrome, a preleukemic condition for which the preponderance of casses occur in elderly individuals, is known to occur in children who inherit a predisposition to losing chromosome 7 in somatic blood forming cells (6), (7).

Rule - In a bimodal disease wherein the disease occurs in two age groups: young and old, the strongest likelihood of finding an effective treatment resides in the younger age group.
Brief Rationale - The younger age group is more likely to have a monogenic or oligogenic cause of the disease, and this often translates into a targeted cure. The older age group is likely to develop disease after the accumulation of multiple epigenetic, genetic, and environmental alterations, making it difficult to find an effective treatment.

Every type of cancer that is curable at an advanced stage (i.e., having multiple and widespread metastases) is a cancer of childhood. All of the cancers that typically occur late in life are incurable when they progress to an advanced stage.

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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, monogenic disease, disease genetics, jules j berman

References:

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

[2] D'Andrea AD.Susceptibility pathways in Fanconi's anemia and breast cancer. N Engl J Med 362(20):1909-1919, 2010.

[3] Li B, Leal SM. Discovery of Rare Variants via Sequencing: Implications for the Design of Complex Trait Association Studies. PLoS Genet 5:e1000481, 2009.

[4] French CA, Kutok JL, Faquin WC, Toretsky JA, Antonescu CR, Griffin CA, et al. Midline Carcinoma of Children and Young Adults With NUT Rearrangement. J Clin Oncol 22:4135-4139, 2004.

[5] Tognon C, Knezevich SR, Huntsman D, Roskelley CD, Melnyk N, Mathers JA, et al. Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell 2:367-376, 2002.

[6] Lizcova L, Zemanova Z, Malinova E, Jarosova M, Mejstrikova E, Smisek P, et al. A novel recurrent chromosomal aberration involving chromosome 7 in childhood myelodysplastic syndrome. Cancer Genet Cytogenet 201:52-56, 2010.

[7] Shannon KM, Turhan AG, Chang SS, Bowcock AM, Rogers PC, Carroll WL, et al. Familial bone marrow monosomy 7. Evidence that the predisposing locus is not on the long arm of chromosome 7. J Clin Invest 84:984-989, 1989.

More on the Complexity of Rare Monogenic Diseases

In yesterday's blog, we saw how one gene can cause several phenotypically distinctive diseases. In this section, we shall review the mechanisms whereby one disease can be caused by any one of several different genes. When one clinical phenotype is caused by any one of several different genes, the phenomenon is referred to locus heterogeneity.

Here are a few examples wherein rare, monogenic diseases can be caused by errors in any one of several different genes:

- Tuberous sclerosis is an inherited monogenic rare syndrome that produces multiple benign hamartomas, as well as certain types of cancers. The genetic basis of tuberous sclerosis involves bi-allelic inactivation of either of two unlinked genes that seem to have equivalent pathogenic roles. The genes are TSC1 (encoding hamartin) and TSC2 (encoding tuberin). In this disease, the hamartin and tuberin genes lock together in a protein complex. A defect in either gene disrupts the same pathway (1).

- Bardet-Biedl syndrome is characterized by rod-cone dystrophy, obesity, polydactyly, and a variety of organ abnormalities. The various forms of Bardet-Biedl syndrome are accounted for by mutations in one of at least 14 different genes. Although the underlying pathogenesis of Bardet-Biedl syndrome is yet to be clarified, there is evidence to suggest that each of the gene mutations known to cause Bardet-Biedl produce a defect in the basal body of ciliated cells (2). Such defects produce the pleiotropic phenotype that characterizes Bardet-Biedl syndrome.

- Li-Fraumeni syndrome is an inherited cancer syndrome characterized by an increased risk of developing such common cancers as breast cancer, lung cancer, colon cancer, pancreatic cancer, and prostate cancer. Various types of rare cancers associated with the Li-Fraumeni syndrome include soft tissue sarcomas, osteosarcomas, brain tumors, acute leukemias, adrenocortical carcinomas, Wilms tumor, and phyllodes tumor of breast. The observation that common cancers and rare cancers having a common underlying genetic cause would seem to indicate that a rare genetic cause of a common disease can sometimes occur within a gene that is known to cause a rare disease.

Li-Fraumeni syndrome was originally believed to be caused exclusively by mutations in the TP53 gene encoding protein p53. TP53 is an example of a tumor suppressor gene. The absence of a tumor suppressor reduces the cell's normal ability to suppress cellular events that increase the susceptibility of cells to cancer. In the case of the p53 gene, loss of activity reduces the ability of cells to undergo apoptosis, a process by which cells commit suicide following DNA damage. By continuing to survive and divide, damaged cells contribute to a subpopulation of cells at risk for progressing through the stages of carcinogenesis. As it turns out, mutations in genes other than TP53 can produce a syndrome similar to, if not indistinguishable from, Li-Fraumeni syndrome. In addition to TP53, the genes that produce forms of Li-Fraumeni syndrome include CHEK2 and BRCA1 (3). In all three cases, the resulting syndrome results in a very high risk for breast cancer (4). All three genes have similar functions: controlling whether cells live or die following DNA damage.

- Retinitis pigmentosa is a group of inherited conditions characterized by the progressive loss of photoreceptor cells in the retina. Rhodopsin consists of the protein moiety opsin and a reversibly covalently bound cofactor, retinal (5). More than 100 mutations in the rhodopsin gene account for about 25% of cases. About 150 mutations have been reported in the opsin gene. Other mutated genes causing variants of retinitis pigmenotosa involve pre-mRNA splicing factors, as well as post-translational errors in protein folding and other errors of chaperone proteins. Mutations in any one of more than 35 different genes can cause variant forms of retinitis pigmentosa. Retinitis pigmentosa is unusual for being a disease that can be inherited as an autosomal dominant, autosomal recessive, or X-linked disorder. Digenic and mitochondrial forms of retinitis pigmentosa have been described, and the disease can appear as a solitary disorder or as part of a multi-organ syndrome (e.g., NARP syndrome of neuropathy, ataxia, and retinitis pigmentosa caused by a mutation in the mitochondrial DNA gene MT-ATP6).

Why there are so many forms of retinitis, with such a large repertoire of disease-causing genes, is somewhat of a mystery. Most of the genes causing various forms of retinitis pigmentosa express constituents of specialized photoreceptors found exclusively in retinal photoreceptor cells (e.g., rhodopsin). Other genes that cause retinitis pigmentosa are active in many different cells (e.g., splicing factors). The outer segment of rod photoreceptors are continuously shed from the tips of cells and replaced by new segments. Rods are extraordinarily dependent on maintaining a high rate of self-renewal, and small deficiencies in cell synthesis may precipitate the loss of these cells (6), (7), (8).

- 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 causing the epidermis to be poorly anchored to the underlying dermis. 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 helps bind epidermis with dermis.

There are also instances in which a rare phenotypic condition occurs as a component of multiple syndromes, each caused by a different genetic mutation. For example, inherited hemophagocytic lymphohistocytosis is a component of Chediak-Higashi syndrome and of Griscelli syndrome. Hemophagocytosis is the pathological phagocytosis (i.e., engulfment) of red blood cells by macrophages. Acquired hemophagocytic lymphohistocytosis can occur in Letterer-Siwe disease (9). In all cases, the final pathogenetic steps of these phenotypically related diseases involves the hypersecretion of cytokines by lymphocytes and macrophages, precipitating a severe, and life-threatening, inflammatory response, that includes hemophagocytosis.

In instances where a combined gene deficiency is found, the root cause may be a microdeletion, that deletes multiple genes, at once. Alternately, a combined deficiency may be caused by a pleiotropic gene that controls the synthesis of several different proteins. In combined factor V and factor VIII clotting factor deficiency, a defect in either the LMAN1 OR MCFD2 genes results in deminished transport of factor V and factor VIII from the endoplasmic reticulum to the Golgi apparatus. Hence, the post-translational processing of both these factors is incomplete, and a combined deficiency results. The gene products of MCFD2 and LMAN1 form a cargo receptor complex that acts on a similar set of proteins. Hence, mutations in either gene can produce the same combined deficiency of factor V and factor VIII (10).

The number of rare genetic syndromes that can be caused by any one of several different genes is quite long. A few additional examples are listed here.

- Autosomal dominant cutis laxa can be caused by a mutation of the elastin gene or the fibulin-5 gene.

- Hypotrichosis simplex of the scalp can be caused by mutation in the CDSN gene or the KRT74 gene.

- Oguchi disease can be caused by a mutation oin the arrestin gene or the rhodopsin kinase gene.

- Autosomal dominant form of throbocytopenia can be caused by a mutation in the ANKRD26 gene, or the cytochrome c gene.

The diseases discussed in this section are examples of disease convergence, in which different underlying processes eventually converge to a common phenotype.

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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, monogenic disease, disease genetics, jules j berman

References:

[1] van Slegtenhorst M, Nellist M, Nagelkerken B, Cheadle J, Snell R, van den Ouweland A, et al. Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum Mol Genet 7:1053-1057, 1998.

[2] Ansley SJ, Badano JL, Blacque OE, Hill J, Hoskins BE, Leitch CC, et al. Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome. Nature 425:628-633, 2003.

[3] Silva AG, Ewald IP, Sapienza M, Pinheiro M, Peixoto A, de N brega AF, et al. Li-Fraumeni-like syndrome associated with a large BRCA1 intragenic deletion. BMC Cancer 12:237, 2012.

[4] Walsh T, Casadei S, Coats KH, Swisher E, Stray SM, Higgins J, et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA 295:1379-1388, 2006.

[5] Hubbard R, Wald G. The mechanism of rhodopsin synthesis. Proc Natl Acad Sci USA.37:69-79, 1951.

[6] Faustino NA, Cooper TA. Pre-mRNA splicing and human disease. Genes and Dev 17:419-437, 2003.

[7] Korenbrot JI, Fernald RD. Circadian rhythm and light regulate opsin mRNA in rod photoreceptors. Nature 337:454-457, 1989.

[8] Tanackovic G, Ransijn A, Thibault P, Abou Elela S, Klinck R, Berson EL, et al. PRPF mutations are associated with generalized defects in spliceosome formation and pre-mRNA splicing in patients with retinitis pigmentosa. Hum Mol Genet 20:2116-2130, 2011.

[9] Dufourcq-Lagelouse R, Pastural E, Barrat FJ, Feldmann J, Le Deist F, Fischer A, et al. Genetic basis of hemophagocytic lymphohistiocytosis syndrome (Review). Int J Mol Med 4:127-133, 1999.

[10] Zhang B, McGee B, Yamaoka JS, Guglielmone H, Downes KA, Minoldo S, et al. Combined deficiency of factor V and factor VIII is due to mutations in either LMAN1 or MCFD2. Blood 107:1903-1907, 2006.

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 an aberration of a single gene were the only cause of a disease, then all of the consequences of the genetic aberration would be identical in every affected person. The is seldom the case, but sickle cell disease is a rare exception to the rule (i.e., sickle cell disease has a remarkably uniform clinical phenotype in affected individuals).

What would happen if a genetic aberration, known to produce disease in humans, 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

DISEASE COMPLEXITY: 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.

In most cases, rare genetic diseases are produced by a single mutation in a single gene, to produce a rare disease that typically develops early in life, often with a rather uniform clinical presentation. In Chapter 7, some of the complexities of single-gene disorders are discussed. Here is an excerpt:

A single gene may produce a protein product whose function varies depending on the specific site and type of mutation in the gene. Hence, variations in a gene can produce different diseases. For example, different mutations of the same gene, desmoplakin, cause the following diseases:

- Arrhythmogenic right ventricular dysplasia-8

- Dilated cardiomyopathy with woolly hair and keratoderma

- Lethal acantholytic epidermolysis bullosa

- Keratosis palmoplantaris striata II

- Skin fragility-woolly hair syndrome

In some cases, variation in the sites of mutations in a gene does not produce different diseases, but may account for one disease with different levels of severity. For example, in the case of Wiskott–Aldrich syndrome, discussed in Section 7.1, mutations that truncate the protein product of the WAS gene will produce severe disease, while mutations that produce changes in single amino acids, without changing the length of the protein, will tend to produce mild disease [14].

In other cases, the [epigenetic] gain or loss of methylation at a gene site may produce disorders of nearly opposite clinical features. For example, the H19 differentially methylated region is a site on chromosome 11p15.5 in which microdeletions occur in some cases of Beckwith–Wiedemann syndrome and Russell–Silver syndrome. Opposite methylation patterns in the H19 differentially methylated region will cause Beckwith–Wiedemann syndrome when there is gain-of-methylation and Russell–Silver syndrome when there is loss-of-methylation (see Glossary item, Gain-of-function) [15]. Beckwith–Wiedemann syndrome is characterized by tissue overgrowth and tumor formation [16]. Russell–Silver syndrome is characterized by dwarfism. The role of methylation in epigenetic regulation will be described in further detail in Chapter 10.

If single-gene disorders can be complex, try to imagine the biological complexity of common diseases, which typically have a polygenic origin (i.e., multiple genes involved), with multiple environmental influences, with symptoms developing in steps, sometimes extending over decades! The difficulty understanding the biology of the common diseases, in contrast with the relative ease of understanding the rare diseases, is a topic that is explored in depth in the book.

I urge you to read more about this book. There's a good preview of the book at the Google Books site.

- Jules J. Berman, Ph.D., M.D. tags: rare disease, common disease, disease complexity, complex diseases, genetics of disease, monogenic disease, polygenic disease, orphan disease, orphan drugs, Beckwith-Wiedemann, Wiskott-Aldrich