What Are Rare Diseases?

Up to 80% of rare diseases have a hereditary component of a genetic nature, but this isn't the case in all cases- far from it.

Written and verified by el biólogo Samuel Antonio Sánchez Amador.

Last update: 05 April, 2021

As indicated by the Orpha.net portal (the database on rare pathologies par excellence), a rare disease is a condition that affects a small percentage of the population compared to the rest of healthy people. In general, this criterion is met when the condition affects 1 in 2,000 people or fewer.

In Europe, the prevalence threshold for a disease to be considered rare is set at 5 cases per 10,000 inhabitants. In addition, most patients are detected in pediatric age, since 80% of them are the product of genetic inheritance. However, other conditions are infectious, oncological, degenerative, or gestational in origin.

After the investment of more than one billion US dollars in the last 15 years, the majority of rare diseases still lack a correct diagnosis and intervention method. Join us as we look at some of the most interesting and representative examples.

Rare diseases in the world

Although the vast majority of rare diseases are detected during childhood, the prevalence is much higher in adulthood, as indicated by the journal Anales del Sistema Sanitario de Navarra. This is because, unfortunately, many of the children with these diseases die as soon as they are born or within a few days of delivery.

As a curiosity, it should be noted that the definition of rare disease varies depending on the country. To exemplify this range of discrepancies, have a look at the following data:

1. In the European community, a rare disease is one that affects 5 out of 10,000 people or less.
2. However, a very different global figure is used in the US: fewer than 200,000 cases for the entire country.
3. In Japan, a rare disease affects 4 or fewer patients per 10,000 inhabitants.
4. Australia draws the limit of rare pathology in less than 2 000 sick people in the country.
5. In other areas, the figure drops to 2 or fewer patients per 10,000 inhabitants.

Despite the fact that the European Union set the aforementioned limit in 1999, countries such as Denmark, Sweden, and the United Kingdom maintain different criteria. Thus, it’s impossible to give an exact definition of the term, as what’s considered a rare disease in one country may not be so in another.

Furthermore, even though these data appear to represent a very low pathological burden, nothing is further from the truth. As CHEST magazine indicates, approximately 25 million Americans require treatment for their rare pathological conditions.

An estimated 300 million people worldwide have rare diseases.

How many rare diseases are there?

It’s estimated that there are thousands of rare diseases around the world. Currently, the figure ranges between 6,000 – 8,000, but this number keeps on growing, due to the large number of medical publications that address the subject. In any case, the “official” amount varies according to the qualifying criteria imposed.

Unfortunately, only 400 of all these conditions have effective treatments available. 75% of them occur with symptoms in childhood, and 30% of the patients are under 5 years of age. The genetic and/or biochemical abnormalities in most of these clinical pictures have not yet been described.

The vast majority of rare diseases have no cure.

Some examples

As you’ll have seen, we’re facing a wide-ranging term that’s quite difficult to classify at times. In order to go into a bit more detail regarding these figures, here are some of the characteristics of certain of these rare diseases.

1. Acquired hemophilia

Acquired hemophilia (HA) is a very rare autoimmune disorder that occurs in patients with a family history of bleeding tendencies. In this condition, the patient’s immune system produces antibodies against blood clotting factors (generally factor VIII), which encourages excessive bleeding with or without stimuli.

As indicated by the Science Direct portal, the incidence of this pathology is 1 to 3 cases per million inhabitants per year. The mortality rate ranges between 9% and 33% depending on the information consulted, as hemorrhages in muscles, soft tissues, and organs can complicate the survival of the patient.

The treatment of this pathology consists of 2 phases: stopping the bleeding and eliminating the autoantibodies. In order to do this, bridging coagulants and immunosuppressive treatments are used simultaneously. However, due to its rarity, there is no standardized approach and each case must be evaluated individually.

2. Amyloidosis

Amyloidosis includes a number of rare clinical entities. However, they all have something in common: an abnormally folded protein (amyloid) accumulates in tissues and organs and interferes with the normal functioning of the body.

Primary amyloidosis (AL) is the most common variant of all, and yet only 0.9 patients are affected per 100,000 inhabitants per year. The average age is 65, and 2/3 of those affected are men. The most affected organ is almost always the kidney, an essential organ for life. Without proper treatment, the average survival period is 12 months.

As the Mayo Clinic indicates, amyloidosis has no cure. Chemotherapy, targeted therapies, autologous stem cell transplants, and whole organ replacement can save a patient’s life, but not all are suitable for these approaches. Again, the prognosis and treatment depends on each case.

3. Kabuki syndrome

This syndrome is rare, as it’s estimated to affect only 1 in 32,000 newborns. It’s a very interesting pathology at a genetic level, as it’s associated with a de novo mutation. This means that the parents aren’t carriers of defective genes, but the patient’s gene undergoes changes during fetal development.

In any case, from here on, the pathology follows a normal Mendelian pattern, as parents with mutated genes pass them on to their children. To date, 2 sections of the genome associated with Kabuki syndrome have been detected: KMT2D and KDM6A. However, 30% of patients don’t have a specific causative agent.

Children with Kabuki syndrome show unusual facial and physical features, but these aren’t the only symptoms. Many suffer from heart defects, hearing loss, kidney failure, and other organic dysfunctions. Treatment is based on monitoring and surgery of the affected parts if necessary, as this disease has no cure.

4. Rabies

You didn’t expect this disease on the list, did you? Rabies is a perfect example that rare diseases can also be infectious. In India (considered a risk region), there are about 2 cases per 100,000 inhabitants per year, while in Africa this value increases to 4 per 100,000.

With these figures, it’s surprising to learn that some 59,000 people die each year from rabies. As would be expected, almost all cases occur in low-income rural areas, where contact with wild mammals is high and treatment and/or vaccination are conspicuous by their absence.

However, thanks to vaccination, more than 300,000 deaths a year are prevented worldwide.

As indicated by the World Health Organization (WHO), rabies is a zoonotic viral disease, that is, it’s transmitted from other animals to humans. Infected dog bites account for 99% of deaths from this rare disease.

The best treatment is vaccination. If a patient is bitten by a wild animal, rapid-acting injections and rabies vaccines can save their life.

5. Thyroid cancer

Another of the diseases that fall under the category of a “rare disease”. In general, when we think about these pathologies, we associate them with genetic mutations, but these tests show that it doesn’t have to always be the case. Thyroid cancer is rare, accounting for less than 1% of malignant neoplasms.

Based on this percentage, it isn’t surprising to learn that only between 2 and 20 cases arise per 100,000 inhabitants per year. As its name suggests, thyroid cancer grows in the thyroid gland, a butterfly-shaped tissue at the base of the neck.

Fortunately, some histological subtypes have a good prognosis. The 5-year survival rate after diagnosis is 98%, as indicated by Cancer.net. Most of the cases are solved with a surgical removal before things get too advanced, although radiation therapy, chemo or targeted therapies may also be necessary.

6. Examples of inherited diseases

As we’ve said, up to 8 out of 10 rare diseases have a hereditary genetic basis. As it’s impossible to cover them all, here’s a list with some representative classifications:

1. Monogenic diseases: These are caused by the mutation in the sequence of a single gene. More than 6,000 monogenic diseases are known, many of them rare. They can follow an autosomal dominant or recessive pattern, or be linked to the X sex chromosome.
2. Oligogenic diseases: These are encoded by changes and interactions in more than one gene.
3. Polygenic diseases: Their presentation depends on genetic mutations and environmental factors. Finding a specific cause for them is very difficult.

A complex and indefinite term

As you’ll have seen, not all rare diseases are directly associated with specific genetic mutations. We remind you that up to 80% of them do respond to certain inheritance patterns, but with the large number of clinical conditions that this term encompasses, there’s room for cancer, acquired disorders, and infectious events.

After this final reflection, we can only ask ourselves the following: does the term “rare disease” really exist? With more than 300 million people affected by a pathology of this nature and with no established criteria, it’s clear that this medical classification gives little or no information about the nature of the illness itself.