The Medical butterfly effect; how a discovery in a rare disease can have large effects elsewhere.

Sophie E M Raby, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Road, Cambridge, CB2 0SP

The study of rare diseases is incredibly common in scientific research. Scientists justify this by claiming that understanding these rare conditions can provide insight into common disorders.

However, since funding is limited and must be prioritized, is this really the case? Or are researchers simply stating this on grant applications to obtain funding in order to satisfy their own intellectual interests? In short, what are the arguments for and against the study of rare diseases?

A rare disease is defined as a disease that occurs infrequently in the general population, in Europe affecting less than 1 in 2000 of the population [1]. This includes diseases that you are likely to have heard of such as Huntington’s disease, amyotrophic lateral sclerosis and cystic fibrosis. However, at the other end of the spectrum, ‘very rare diseases’ such as progeria, ‘FOP’ (fibrodysplasia ossificans progressiva) and Fanconi’s anaemia may only affect a few hundred (or even a single family) [1].

There are estimated to be around 7000 rare diseases, with 80% having a genetic basis. Others are the result of infections, allergies (such as eosinophilis oesophagitis and Churg Strauss syndrome) and environmental causes. Paradoxically, despite being individually rare, it is not uncommon to have a rare disease, and it is estimated that about 6% of the population suffer from a rare disease. It is also worth considering that a relatively common condition may mask an underlying rare disease. For example, Shokeir syndrome, Feigenbaum Bergron Richardson syndrome and Dravet syndrome may all present with epilepsy [2]. In a recent study of 17 common chronic adult diseases, 188 Mendelian disorders were identified in the OMIM database that featured one of these chronic diseases presenting in adulthood [3] (Table 1).

The proportion that Mendelian disorders contribute to common conditions is unknown and it should always be considered in an unusual presentation or if there is a strong family history of a disease. Patients may have to deal with delays in diagnosis (as the symptoms may not be recognized), a sense of isolation (as there are so few patients with the disease) and inequality in access to treatment [4]. Clearly it is important to study these conditions in their own right. Considering that many have a monogenic basis, sometimes even small discoveries can have a huge impact on the patient. For example, the recent introduction of screening newborns for MCAD (medium chain acyl CoA dehydrogenase deficiency), an autosomal recessive disease resulting from a disorder of fatty acid oxidation, allows avoidance of the serious and potentially fatal outcomes that this disease may present with in undiagnosed children [5,6]. In a few patients with severe early onset obesity, identification of mutations resulting in a loss of function in the gene encoding leptin has been found. Treatment of these children with recombinant human leptin has resulted in complete reversal of the phenotype [7]. This amazing result for the few children with this problem is analogous to the dramatic increase in survival of giving insulin to children with type1 diabetes. Of course, funding will always be easier to obtain for research that concentrates on a rare inherited form of a chronic disease, but when discoveries like this herald such life-changing outcomes, surely it could be argued that studying rare diseases should be the primary aim of research and not necessarily a precursor to advances in other conditions?

Table adapted from Scheuner, 2004 [3].
Mendelian disorder Chronic disease presenting in adulthood
Bardet-Biedl syndrome Diabetes Mellitus
Homocystinuria Coronary artery disease
Cowden syndrome Breast cancer, endometrial cancer
Li-Fraumeni syndrome Breast cancer
Tuberous sclerosis Kidney cancer


Several organizations have been set up to promote the rights of patients with rare diseases. There is even a national rare disease day (held in the UK on the last day of February every year). Whilst there is a special status to safeguard the research and development of orphan drugs, this does not correspond to a special status in their availability. The majority of ultra orphan drugs are invariably cost-ineffective when assessed using current criteria. In the past, funding has been secured on the basis of equity, that ‘patients suffering from rare conditions should be entitled to the same quality of treatment as other patients.’ [6,8]. However, with ever increasing numbers of orphan drugs reaching the market (about 2 each year), there is criticism that this principal has been wrongly applied. It is argued that rarity is not in itself a factor that should be taken into account when assessing a new drug; that a patient’s quality of life should not be valued less because the condition is not rare [9].
Perhaps as well as applying this argument to the availability of orphan drugs, it should also be applied to research of the rare disease in the first place. Studying rare diseases may not be in itself justifiable.

Utilitarianism therefore is a principle which seems to underlie research in an environment limited by funding. If rare diseases cannot be studied in their own right, is it justifiable to study them if the discoveries made can contribute on a much wider scale than the rare disease can itself?
There are many examples of where this has been the case. To illustrate this, I will describe a few examples from cancer research.


Retinoblastoma is a childhood cancer of the retinal cells that can be either sporadic or inherited. In the inherited form, only one wild type allele of the retinoblastoma (Rb) gene is present, such that loss of this copy is the primary event underlying the development of the tumour. Rb is a tumour suppressor gene that is frequently mutated in cancer. It is critical in regulating the G1-S phase transition in the cell cycle. Patients with the inherited mutation also have an increased frequency of tumours elsewhere in the body. In contrast, the sporadic form of the disease tends to occur in an older age group and is not associated with an increased risk of tumours elsewhere. It was whilst studying this disease that Knudsen formulated his ‘2 hit hypothesis,’ that inactivation of both alleles of a tumour suppressor gene (which are almost always recessive in nature), are required for tumour development. Hence in the sporadic form of Retinoblastoma both mutations occur in somatic cells whilst in the familial form, only one does – the other is inherited via the germ line [10,11]. This hypothesis now serves as a basis for understanding how mutations in many different tumour suppressor genes cause cancer.


Fanconi’s anaemia is an autosomal recessive disorder which is estimated to affect 1000 people worldwide. Patients have a greatly increased predisposition to cancer, particularly the haematological malignancies, such as AML, as well as abnormalities in development and bone marrow failure. It is genetically heterogeneous in that there are 13 complementation groups, each of which is associated with a particular disease gene. Research into these genes has defined a pathway of DNA repair. Recently some of the proteins involved in this pathway have been found to correlate with those that confer susceptibility to breast cancer, for example BRCA2 is the same as the Fanconi’s anaemia D1 protein. Whilst this is not the case for BRCA1, it does interact with components of the Fanconi’s anaemia pathway as well as with BRCA2 itself [12].

Patients with heterozygous mutations in BRCA1 and 2 are at increased risk of developing breast and ovarian cancer as well as cancers of the pancreas and the prostate. Both BRCA proteins interact with other Fanconi’s anaemia proteins within the homologous recombination pathway necessary for error-free repair of double stranded breaks within the DNA. Loss of the wild-type allele results in defective repair of these double strand breaks and hence results in chromosomal genetic instability, producing a cell that successively accumulates mutations at a much higher rate than normal [13].

Knowledge of the BRCA-Fanconi’s anaemia DNA repair pathway has contributed to the development of a new drug specifically targeting this pathway in patients with heterozygous BRCA mutations. PARP (Poly (ADP) ribose polymerase) inhibitors inhibit the action of the single strand break repair protein PARP. Single strand breaks, when not repaired give rise to double strand breaks at replication forks, which are normally repaired by the error free process of homologous recombination. However, in tumour cells where the remaining BRCA allele has been lost, an alternative error prone pathway must now repair the dsDNA break. This is effectively cytotoxic for the tumour cells, but since normal cells retain a wild type BRCA allele, they remain largely unaffected (Figure 1). A phase 1 trial with PARP (poly (ADP-Ribose) polymerase) inhibitors have shown promising early results in that they did not have the toxic side effect profile that would normally be expected with conventional chemotherapy [14]. Targeting a specific molecular pathway that is defective only in the tumour is a novel rationale towards designing drugs and there is hope that this could be extended to patients with sporadic cancers that are also found to have non-BRCA defects in the homologous recombination pathway [15]. The development of PARP inhibitors illustrates that knowledge of a specific genetic defect allows the development of specific small molecules. However, in the more common diseases, the multiplicity of pathways makes it hard for one small molecule to knock out the key molecular pathway and so ameliorate the disease.


There has been much interest recently into the prospect of targeting the Hedgehog signaling pathway for the development of new cancer therapies. The hedgehog pathway is crucial for development in embryogenesis, and whilst it is thought to be inactive in adults, it is reactivated in a number of cancers. Insight into the activity of the pathway in cancer came about through the study of the rare autosomal dominant disease, Gorlin’s syndrome. Patients with this condition suffer from an increased susceptibility to medulloblastomas, multiple basal cell carcinomas, and skeletal deformities [16]. Hedgehog pathway inhibitors have been tested in patients with (sporadic) locally advanced basal cell carcinoma and in a patient with medulloblastoma. In both, there was a remarkable initial response to the drug [17,18]. Whilst medulloblastoma and locally advanced basal cell carcinoma are comparatively rare forms of cancer (basal cell carcinoma is usually curable by resection), this work is now being extended to more common tumours. For example, in a mouse model of pancreatic cancer, treatment with a hedgehog inhibitor has been found to improve the response to conventional chemotherapy [19].

Studying rare diseases can therefore be informative out of proportion to the initial result. However, this is not always the case. Whilst rare genetic diseases tend to be caused by monogenic mutations with a more robust link between cause and effect, many genetic and environmental factors contribute towards the pathogenesis of common disorders. This makes it difficult to dissect cause and effect and therefore to obtain a molecular handle that allows research to evaluate the problem. Therefore, for a rare disease to be of direct value, its mutated gene should be the same (or act in the same pathway) as that which confers an increased risk of an associated common sporadic disease. For example, whilst the study of rare inherited forms of Alzheimer’s disease has led to great advances in understanding the mechanisms of neurodegeneration in the disease, the genes underlying these rare forms are not the same as those that have been found to confer an increased susceptibility to the sporadic form [20,21]. Caution should always therefore be applied when generalizing from a rare disease to its more common counterpart.

The final argument supporting research into rare diseases is the purest; that experiments should be conducted out of interest for the sake of science itself and should not necessarily aim towards a more beneficial goal. That “science should be illuminating as well as fruitful,” was the viewpoint of Sir Edward Appleton, a Nobel prizewinner in physics, who thought that ‘knowledge and insight should be sufficient reward in themselves’ [22]. Although this ideal is not really applicable in terms of modern day medical research, it should perhaps be kept in mind, especially when an experiment fails to achieve a particular positive outcome.


As the pathways involved in both rare and genetic disorders tend to be the same, the potential rewards are often immediately obvious. However, it should always be kept in mind that this research may benefit patients with the rare condition themselves, as limited funding means that their condition is rarely studied as a primary aim in itself.

With the underlying basis of many monogenic disorders yet to be determined, and the advent of fast, cheap whole genome sequencing [23], studying rare diseases holds great promise for illuminating aspects of many more complex common disorders in the future.


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