"While a rare disease is rare, rare diseases are common."

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The final essay comes from Jeremy Reid, a fifth year medical student from the University of Birmingham. Like Nicholas Heng in our previous post, Jeremy also addressed the question:

How might rare genetic diseases be fundamental to our understanding of medicine as a whole?

A ‘rare’ disease is defined, according to the European Union, as one which affects five or fewer individuals per 10,000 of the population, resulting in 5000-8000 ‘rare’ diseases.

The majority of rare diseases are a consequence of mutations to a single gene, transmitted according to a Mendelian pattern of inheritance. These can therefore be termed ‘Mendelian’ diseases, and are also known as ‘orphan’ diseases.

By contrast, most common diseases, often termed ‘complex’ diseases, tend to have a multifactorial aetiology, with many genetic variants and environmental factors influencing risk of disease development.

Research into rare genetic diseases is challenging for at least two reasons. Firstly, by definition, there are fewer patients who have the condition than for common diseases meaning that, in general, it is harder to coordinate statistically robust studies.

Rare diseases tend not to attract investment from funding bodies to the same degree as common diseases.

Secondly, rare diseases tend not to attract investment from funding bodies to the same degree as common diseases. This may at first glance make sense; why devote precious finite resources to studying a rare disease, the results of which will only affect a few, when your investment could be directed at the study of a common disease in which your findings are relevant to many?

It is my intention in this article to challenge this thinking by putting forward a case for the broader benefits of rare disease research and how it impacts on our understanding of medicine as a whole.

Rare genetic diseases reveal biochemical pathways

In a Mendelian disorder, we approach the isolation of a single gene’s phenotypic contribution, thus simplifying the many genetic influences found in complex disorders. Furthermore, a rare disease with an underlying monogenic pathology indicates that the genetic variant in question is important enough to cause sufficient physiological disruption to cause clinical disease, but that it is compatible with life, therefore essentially self-selecting genes worthy of study.

On the basis of observed differences between the affected individual and the unaffected population (with wildtype alleles), it is possible to hypothesize how the gene and its protein product contribute to biochemical pathways and physiological processes.

On the basis of observed differences between the affected individual and the unaffected population (with wildtype alleles), it is possible to hypothesize how the gene and its protein product contribute to biochemical pathways and physiological processes.

Further investigations can be made by studying the biological parameters of affected individuals. The knowledge gleaned can inform our understanding of biochemical pathways within the body, enhancing our understanding of normal physiology and of pathology.

An example of an area in which rare genetic diseases have significantly contributed to our understanding of how the body works is energy balance. Congenital Leptin Deficiency is a very rare disorder in which individuals are unable to produce the adipokine leptin due to missense or frameshift mutations in the leptin encoding gene (the ob gene).

The condition has an autosomal recessive inheritance pattern and a phenotype of severe obesity secondary to excessive food consumption with severe insulin resistance and endocrine abnormalities.

The ob gene was first studied in a severely obese strain of mice, termed ob/ob, with the murine gene and human homologue being cloned in 1994. Further analysis revealed that leptin acts on the hypothalamus to inhibit the production of neuropeptide Y, an important neurotransmitter in the neural appetite circuitry which acts to promote feeding behavior.

The first human cases with confirmed mutation to the ob gene were reported in 1997 with a very similar phenotype to ob/ob mice. The administration of exogenous leptin produces a dramatic reversal in clinical features; appetite is reduced, fat mass falls, sensitivity to insulin is increased, and endocrine abnormalities are corrected.

The story of leptin has led to an efficacious therapy in the form of leptin replacement for the handful of individuals with Congenital Leptin Deficiency. While exogenous leptin is not an example of an effective weight loss intervention in the obese population at large, the study of leptin, and indeed many other Mendelian obesity disorders, have taught us much about the underlying processes of overweight and obesity, which affect an estimated 2.1 billion individuals worldwide.

Mendelian conditions often appear phenotypically as a severe form of a complex disease, and often share underlying pathophysiological mechanisms. This means that the Mendelian condition can act as a model of simplified aetiology for the pathophysiology of the more complex condition.

This information will be vital in the continued search for solutions to the obesity crisis. Note however that the study of some Mendelian diseases has led to specific drug targets that are very effective in the general population.

Perhaps the best example is Familial Hypercholesterolaemia, the study of which led to the development of statins, a class of drugs which inhibit the enzyme HMG-CoA reductase to lower levels of cholesterol in the blood. Statins are now some of the most widely prescribed drugs in modern medicine.

Mendelian conditions often appear phenotypically as a severe form of a complex disease, and often share underlying pathophysiological mechanisms. This means that the Mendelian condition can act as a model of simplified aetiology for the pathophysiology of the more complex condition.

It also may mean that reproducing the Mendelian condition in animals can produce useful animal models of the complex condition. This permits close biological investigation with methods that may be inappropriate for human subjects, and the screening of compounds for therapeutic efficacy, facilitating systems pharmacology research.

For example, the aforementioned ob/ob mouse is in widespread use as a model for the metabolic syndrome. And the overexpression of genes associated with Early Onset Familial Alzheimer’s Disease (Presenelin-1, Amyloid Precursor Protein and MAPT, which encodes tau) in mice has resulted in a useful model with similar features to the common human form of Alzheimer’s disease; intracellular neurofibrillary tangles, extracellular plaques and memory deficits.

Rare genetic diseases reveal the principles of genetics

The mechanisms by which both mutations to the genetic code and non-coded control of gene expression can cause disease are fundamental to our understanding of all conditions which have a genetic influence, and indeed biology in general.

Through the study of Mendelian disorders, much about genetics has been revealed, and it is likely that this will continue to be the case.

Due to the monogenic nature of Mendelian disorders, they simplify the complex genetic picture, facilitating the study of genetics. Through the study of Mendelian disorders, much about genetics has been revealed, and it is likely that this will continue to be the case.

One of the key questions that Mendelian disorders have posed is how phenotypic variations can occur between individuals with the same defective gene, or even the same mutation. A good disease to study for the investigation of this question is Cystic Fibrosis, due to its relative prevalence compared to most other monogenic disorders.

Blackman and colleagues investigated the incidence of the development of diabetes as a complication of Cystic Fibrosis amongst a cohort with the disease, and found that concordance was 0.73 amongst monozygotic twins, but only 0.18 amongst dizygotic twins.

This demonstrates that other parts of the genome have a significant influence on the phenotype of what is supposedly a single gene disorder. Furthermore, the level of concordance among the monozygotic twins is not identical, pointing to factors outside the genome that come into play.

As monozygotic twins share an identical genome at the start of life, this must represent new changes to the genome or non-genomic influences affecting phenotype.

This is further indicated by the dozens of case reports in the literature for monozygotic twins, in which only one twin exhibits a Mendelian disorder. As monozygotic twins share an identical genome at the start of life, this must represent new changes to the genome or non-genomic influences affecting phenotype.

The study of Mendelian disorders has been helpful in elucidating the complexities of various genetic mechanisms, such as X-inactivation, repeat instability and epigenetics, amongst others.

These discoveries call into question the validity of the classical division of genetic disorders as monogenic Mendelian or polygenic complex, with calls for genetic disease to be viewed as a continuum from simple to complex disease.

New discoveries about genetic principles may have very wide ramifications. This will be of ever increasing importance as personalized medicine becomes a routine part of clinical practice, and as we continue to unravel the genetic complexities behind complex disorders. Having an accurate understanding of how genetic variations are expressed and ultimately affect phenotype is essential if therapies based on the analysis of an individual’s genome are to be safe and efficacious.

Conclusion

The prevalence of a disease is of no consolation to those afflicted.

Throughout this article I have tried to show that what we learn from research into rare genetic diseases is applicable to the whole of medicine, not just to the specific disease of study. Despite this being the thrust of this article, I would like to end by emphasizing how life transforming research can be for patients with the rare genetic disease in question, and that this should not be forgotten in this discussion.

While a rare disease is rare, rare diseases are common. And the prevalence of a disease is of no consolation to those afflicted. It is therefore important to prioritize research into rare genetic diseases, both for the individuals affected by the disease in question, and for the broader insights relevant to the practice of medicine as a whole.

Read more about rare diseases on our webpage.