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Rare diseases: low numbers, high impact

Updated Friday, 26th February 2021

Rare Diseases Day is celebrated annually on the last day of February. This ‘rare day’ which occurs on the 28th February, or once every 4 years, the 29th of February was an apt choice for Rare Diseases Day. Many people do not fully appreciate what a ‘Rare Disease’ is, as they are so uncommon. The article aims to explain rare diseases and raise awareness of these fascinating and devastating conditions.

What is a rare disease?

Definitions vary between countries, but most commonly accepted is that a rare disease is a disease that affects fewer than 50 out of 100,000 individuals in a population at any time (or 1 individual in 2,000). The value stating how many individuals in a population show a certain characteristic at a given time (e.g. are affected by a disease) is called prevalence.  

Some rare diseases only affect one or a handful of individuals worldwide, meaning that they are extremely rare. However, diseases like Huntington’s Disease (HD) or Cystic Fibrosis (CF) are also classed as rare diseases, despite being far more well known.

How many rare diseases are known?

At the time of writing, around 7,000 rare diseases have been described. Over 80% of those affect less than 1 in 1 million people (so they are very rare). However, new rare diseases are constantly being described, so this number is continuously increasing.

In the UK, around 3.5 million individuals have a rare disease. It is estimated that over the whole lifetime, around 1 in 17 people will be affected by a rare disease

Why are rare diseases important to study?

As there are so many rare diseases, around 300 million people worldwide are diagnosed with a rare disease. In the UK, around 3.5 million individuals have a rare disease. It is estimated that over the whole lifetime, around 1 in 17 people will be affected by a rare disease, which is much higher than the name implies.

Raising awareness of rare diseases is also important because in many cases they can take years to diagnose (healthcare professionals do not come across them very often), and this delay can cause anguish for the families and reduced quality of life for the patients.

Rare diseases can affect individuals of all ages, however, over 50% of rare diseases have a childhood-onset, so children are more likely to be affected by a rare disease. These are often terminal illnesses, and only 35% of children with a rare disease will live beyond their 5th birthday.

In addition, only a few treatments for rare diseases are available and as it is often easier to slow progression than to reverse symptoms, so it is critical to begin treatment as soon as possible. Increased awareness of rare diseases can help to improve diagnosis, support for families, research into the causes of the diseases, and development of treatments. It is often small charities and patient associations that tirelessly campaign to educate clinicians, research scientists, and the public, on these diseases.

What causes rare diseases?

Most rare diseases (thought to be around 80%) have an inheritable genetic origin. These include HD and CF, mentioned above, and also a group of rare diseases collectively called Neuronal Ceroid Lipofuscinoses (NCLs). The NCLs include CLN3 disease (the juvenile onset form of the NCLs), which we are researching at The Open University.

Like most inherited rare diseases, CLN3 disease is passed on in a recessive manner, through genes carrying mutations. Our cells contain pairs of chromosomes, one inherited from each parent. One chromosome holds a full set of genes, so we have two copies of each gene in total.

Someone with one normal CLN3 gene and one mutant copy of the CLN3 gene would be a carrier of CLN3 disease. A carrier would not have symptoms but could pass the disease on to children with another carrier; the child would have a 1 in 4 chance of inheriting both mutant copies of the CLN3 gene and being affected by CLN3 disease.

Diagram - Inheritance of CLN3 disease Copyrighted  image Icon Copyright: Emily Coode, PhD student in LHCS, The Open University. Inheritance of CLN3 disease. The child inherits one chromosome from each parent. If both parents are carriers, there is a 25% chance that the child inherits two mutated copies of the gene and will develop the disease.

However, not all rare diseases are inherited. For example, based on their prevalence and small numbers, all childhood cancers are classified as rare diseases. In some cases, environmental influences, like alcohol during pregnancy, can cause a rare disease. And finally, some infectious diseases are classified as rare diseases.  

Infectious diseases as rare diseases?

It was mentioned above that a rare disease is defined by its prevalence and the commonly accepted threshold is fewer than 1 in 2,000 people being affected. For many infectious diseases, even this low threshold will never be reached. However, for highly infectious diseases like Ebola, it is important to see that during an outbreak a disease can change from being rare to common in a certain region, and then become rare again.

Can we treat rare diseases?

Very few specific treatments for rare diseases are currently available. The first examples of treatments were to replace a missing enzyme by supplying it to the body (enzyme replacement therapy for Gaucher disease in 1991). However, many of the treatments only alleviate the disease symptoms and do not treat the cause of the disease. Still, by providing better support, the life span of individuals with CF has increased from 10 years in 1962 to 37 years in 2013, showing the importance of supportive treatments.

Modern techniques permitting the modification of genetic material and introducing it into the human body allow for the exploration of new avenues in the treatment of rare diseases. For example, gene therapy for CLN3 disease is currently in development to give patients a normal copy of the CLN3 gene; using a modified virus injected into the spinal fluid, to reach the brain1. This type of therapy aims to incorporate a normal gene that can function in place of the mutant CLN3 genes the patient already has.

What incentivises the research and development of treatments for rare diseases?

The first major incentive to increase the development of treatments for rare diseases was the ‘Orphan Drug Act’ passed in 1983 by the US government, which provided incentives to the pharmaceutical industry to develop therapies for rare diseases. It was followed in 2002 by the Rare Disease Act. Similar European Legislation, stimulating the development of Orphan Medical Products, was passed in 2000. Both legislations use the term ‘orphan’, which refers to the underlying diseases being orphaned, or neglected when it comes to the development of treatments. Since the introduction of the incentives, the number of drugs for treating rare diseases has continuously increased, as has the number of publications on rare diseases.

The UK government has a Strategy for rare diseases with the aim to ensure no one gets left behind just because they have a rare disease'. It is aiming to ensure the best quality of life and support for the ~3.5 million individuals with a rare disease that live in the UK.

How do we contribute to rare diseases research at The Open University?

In our lab, we study the effects of CLN3 disease (also called Batten Disease) on basic cell models and the more complex cardiac myocytes. We started by looking at critical cell processes which might be affected in the disease, especially those important in sensitive cells like cardiac myocytes. This work is aimed to understand the causes of the heart dysfunction observed in later life in individuals with CLN3 Disease (read about Broken Hearts in Batten Disease).

Other groups in the School of Life, Health and Chemical Sciences at The Open University also incorporate the study of rare diseases into their research. As one of the many diseases they study, the Blood Brain Barrier group research a rare disease affecting women of childbearing age (read about Idiopatic Intracranial Hypertension). The Cancer Epigenetics group is working on a project to understand the pathogenesis of a rare paediatric brain cancer called Diffuse Intrinsic Pontine Glioma (DIPG). DIPG is currently incurable and associated with a dire prognosis. The charity Abbie’s Army is supporting this research.

Where can I find more information on rare diseases?

Many charities focus their work on rare diseases. As previously mentioned, they are often responsible for campaigns such as raising awareness among healthcare professionals, the government, and researchers. They also have an important role in research; raising funding and bringing providing venues for meetings of the scientific community, clinicians, and patients or their families to facilitate a greater understanding of the disease. Research is aimed not only at understanding the causes of the diseases and at improving prognosis and quality of life through treatment, but also to fast track diagnosis through the development of simplified tests for unique disease markers (called biomarkers).

Further information

1) clinicaltrials.gov (2018) NCT03770572 'Gene Therapy for Children with CLN3 Batten Disease’, accessed 25th February 2021.

 

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