Using rare genetic diseases to understand medicine

Earlier this year, Findacure, in conjunction with Orphanet Journal of Rare Diseases, announced the winner of its student essay competition on rare diseases (The Student Voice). European medical and biological undergraduate students gave their rare disease opinions, experience, and knowledge, in response to one of three topic choices. While the overall winning essay by Roberta Garau is set for publication in Orphanet Journal of Rare Diseases, we are proud to bring you some of our top choices in this week leading up to Rare Disease Day.

The second essay comes from Nicholas Heng, a second year medical student from the University of Dundee. Nicholas’s essay answered the topic question:

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

Introduction

Rare diseases play a key role in healthcare today, with far-reaching implications that have shaped medicine in the past few decades. Interestingly, the sheer volume of diseases (>5000) mean that cumulatively, there could be as many as 30 million Europeans and 25 million Americans affected.

Out of that, 80% are of genetic origin. Nevertheless, the actual burden of these diseases remain elusive due to scant or overall lack of epidemiological data, making diagnosis and management all the more difficult.

Current research into pathophysiological mechanisms has not only shed light on normal and abnormal physiology, but also helped to elucidate underlying pathology behind common disorders. Besides that, the development of more efficacious diagnostic tools have broadened clinical perspectives and led to diverse applications in the treatment of other diseases too.

These would not have been possible if not for the immense collaborative partnerships formed between academia, pharmaceutical establishments, patient-driven organizations and regulatory authorities, underscoring the importance of cooperation. Undoubtedly, delving deeper into rare genetic diseases can provide valuable insights into our current understanding of medicine.

Shoring up the science

Rare genetic diseases serve as crucial gateways in understanding fundamental physiological processes and how disruptions result in aberrant pathology and the disease process.

Unravelling the intricacies of the mechanisms leading to abnormal pathology holds the potential to understanding the opposite – the normal physiology of the body. They provide immense opportunities to decipher the multifarious complexities of the human body, through learning about the extremes of human pathology.

Take for example, the study of congenital leptin deficiency, which has led to great strides in current understanding of energy homeostasis. The subsequent discovery of the hormone, leptin, not only precipitated the elucidation of its function and associated pathway, but also provided valuable insights into obesity via defects in fat oxidation and energy expenditure, and how eating behaviors and appetite are biologically related.

This also holds true in abetalipoproteinaemia, where its pathogenesis helped to elucidate the workings of lipoprotein assembly and vitamin E metabolism in the absorption of dietary fats, cholesterol and fat-soluble vitamins. These show that rare genetic diseases serve as crucial gateways in understanding fundamental physiological processes and how disruptions result in aberrant pathology and the disease process.

The link to common disorders

Besides that, learning about rare genetic diseases can also broaden present knowledge on the pathogenesis of other common disorders. This is seen in alkaptonuria, which is characterized by inability to metabolize homogentisic acid (HGA) due to a deficiency in the enzyme, homogentisate 1,2-dioxygenase.

The accumulation of HGA in connective tissue is implicated in ochronotic arthropathy, resulting in degenerative osteoarthritis associated with extra-articular manifestations. This has led to the development of alkaptonuria as a disease model for osteoarthritis, supplementing current understanding of osteoarthritis, the most common form of joint disease.

Additionally, congenital generalized lipodystrophy (CGL), a rare disease characterized by lack of subcutaneous fat, hypertriglyceridemia and hepatic steatosis, is extensively used as a model to study type II diabetes.

Being able to decipher how such diseases work, has not only augmented current perspectives on other common conditions, but also enhanced future efforts to maximize the effectiveness of diagnosis, investigations and management.

Although obesity is a known risk factor, it is not the only reason for insulin resistance, as evidenced by lack of subcutaneous fats in CGL. Instead, the markedly reduced leptin and adiponectin levels in such patients, both hormones synthesized by adipose tissue, have been implicated in the pathophysiology of metabolic dysfunction. Through intensive research and expanding the clinical knowledge base on type II diabetes, it is hoped that appropriate treatment and management can be established and undertaken.

All these point towards research into rare genetic diseases as playing key roles in today’s ever-changing and rapidly advancing fields of science and medicine. Being able to decipher how such diseases work, has not only augmented current perspectives on other common conditions, but also enhanced future efforts to maximize the effectiveness of diagnosis, investigations and management.

Diagnostic precision and efficiency

With the advent of genetic testing, the diagnosis of rare genetic diseases has experienced a paradigm shift. This is exemplified by cystic fibrosis, where intensive research coupled with genetic testing has led to the identification of pathogenic mutations in genes, and correlation to other signs and symptoms that were previously unknown to the disease process such as male infertility and foetal bowel hyperechogenicity. This broadening of clinical knowledge has aided the overall diagnostic process hugely in differentiating various pathologic phenotypes, especially those involved in multisystem disorders.

Expanding and applying present understanding to improve diagnostic precision, has directly resulted in recognition of smaller subgroups within disease populations, not only leading to the classification of several common diseases as rare (subsets of cancers), but also identifying progressively smaller subgroups within rare genetic diseases themselves (over 23 pathogenic mutation subsets in cystic fibrosis accounting for 85% of patient population). However, as many mutations have unknown effects or are influenced by modifier genes, more still needs to be done to minimize these limitations and improve diagnostic efficiency.

Treatment and management

On the other hand, understanding disease pathogenesis has paved the way for development of more efficacious treatment and management, with wide-ranging applications. This can be seen in primary human immunodeficiency diseases, where identification of associated genes has led to rigorous research into the physiology of innate and adaptive immunity, eventually culminating in the novel treatment of severe combined immunodeficiency (SCID) more than four decades ago via gene therapy.

As of 2012, there has been more than 1800 clinical trials completed, accentuating the importance and relevance of gene therapy in medicine today.

Since then, gene therapy has begun to play a greater role in treatment and alleviation of various other genetic disorders, such as cancer, infectious diseases, and other immunological disorders. As of 2012, there has been more than 1800 clinical trials completed, accentuating the importance and relevance of gene therapy in medicine today.

In more recent times, there has been increasing attention focused on tuberous sclerosis, a rare disorder characterized by benign tumour growths, where mutations in either TSC1 or TSC2 tumor suppressor genes have been implicated [21].

As both genes encode proteins that inhibit the mammalian target of rapamycin complex 1 (mTORC1) signalling, there is inhibition of autophagy and accumulation of dysfunctional protein aggregates. Interestingly, this is similarly seen in tumorigenesis, where the mTORC1 pathway is constitutively active.

Therefore, understanding tuberous sclerosis can play a crucial role in decoding cancer. In fact, encouraging data from clinical trials involving mTOR inhibitors indicate their potential to play a more prominent role in the treatment of cancer in the near future.

In this aspect, the progress in discovery of novel and modified therapeutic options has unexpectedly precipitated far wider applications in treatment of other diseases than was previously envisioned. Armed with a greater repertoire, there lies much hope in the development of more effective management in the future.

Expanding clinical perspectives

With increasing public awareness of rare genetic diseases, there has been greater recognition of the extensive difficulties patients face. Being able to empathize with the current situation can broaden healthcare professionals’ perspectives on what diagnosis, management and patient-centred care really encompasses.

Regardless of whether the person on the receiving end is a physician, nurse or allied health professional, it is important to understand that diseases, no matter how rare, should not be dismissed or neglected.

Regardless of whether the person on the receiving end is a physician, nurse or allied health professional, it is important to understand that diseases, no matter how rare, should not be dismissed or neglected, but be actively considered in the context of the patient. This not only allows one to appreciate the complexities of medicine, but also is essential in the drive towards greater efficiency in diagnosis and management.

Forging collaborative partnerships

Aside from that, the rapid progress of today’s research into rare diseases also underscores the importance of collaboration between different parties involved in medicine. The close partnerships between patient advocacy groups, pharmaceutical companies and academic institutions have played a key role in research and development.

Patient driven organizations such as the National Organisation for Rare Disorders (NORD) and the Genetic Alliance in the United States prove instrumental in not only raising awareness about such diseases, but also in facilitating research through database creations and providing financial incentives.

Implementation of the Orphan Drug Act further served to benefit patients through reducing barriers to and incentivising drug research and development.

Additionally, the European Organisation for Rare Diseases (EURORDIS), a patient-driven alliance of organizations, has established closer links with European regulatory authorities, and established a critical role for patient voices in the devising of policies, especially with the Committee for Orphan Medicinal Products (COMP).

In these aspects, such collaborations can significantly improve patient outcomes through sharing of expertise and knowledge amongst healthcare professionals, while also maximising cost-effectiveness and improving access to treatments requiring specific resources.

This stresses the tremendous value of collaboration efforts in medicine, not only pertaining to rare genetic diseases, but also to every other disease afflicting the human body.

Conclusion

Research has gained much traction, with increasing recognition of not only their importance in the understanding of medicine, but also the need to tackle them.

Undeniably, rare genetic diseases will continue to play an essential role in medicine. Research has gained much traction, with increasing recognition of not only their importance in the understanding of medicine, but also the need to tackle them.

Nonetheless, effective diagnosis, treatment and management still remain a distant reality today, despite rapid advances in characterizing these diseases. With limited expertise and resources, depending solely on local or national capabilities will indubitably prove inadequate.

Therefore, maintaining the momentum on rare genetic diseases relies upon building up robust collaborations between international organizations, regulatory authorities, academic institutions and pharmaceutical companies in the drive towards establishing concrete objectives, realistic goals and consensus plans of action.


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