The 10 Rarest Diseases in the World

The term "rare disease" is much less homogeneous than it may seem at first, since this pathological group affects millions of human beings. Here are 10 rare conditions.

Written and verified by el biólogo Samuel Antonio Sánchez Amador.

Last update: 12 July, 2023

Making a list of the 10 rarest diseases in the world is a very complex task, since the definition of the term itself varies according to the region consulted, the social health system, the number of inhabitants and many more factors. Despite being called “rare”, this group of pathologies affects 300 million people worldwide, as indicated by Rare Diseases International.

A rare disease in Japan may not be so in Europe, and vice versa. What is clear is that this group of conditions represents an inescapable medical reality that shouldn’t be ignored, since approximately 4% of the world’s population suffers from a “rare” clinical picture that hasn’t yet been sufficiently studied. If you want to get to know the 10 rarest diseases in the world, read on.

What are the rarest diseases in the world?

According to the specialized portal Orpha.net, a rare disease is any condition that affects a small number of inhabitants compared to the general population. Some definitions include only the percentage of affected patients, while others also take into account the level of knowledge that exists about the pathology and the availability of tools to treat it.

The problem with this term is that there is no general consensus. In the following list, we’re going to show you what requirements a disease must meet in order to be classified as “rare” according to the countries consulted:

• In the United States, a rare disease is one that affects fewer than 200,000 people nationwide. This would correspond to 1 case in every 1500 inhabitants.
• On the other hand, in Japan, such a condition should affect fewer than 50,000 people. This is equivalent to 1 in every 2,500 inhabitants in the region.
• In Australia, the number of patients must be less than 2000 individuals in all cases.
• In Taiwan, the figure is placed at 1 patient per 10,000 inhabitants.

As you can see, the definition of this group of diseases differs greatly depending on the country in question, and doesn’t respond to a standardized criterion. Furthermore, to designate a group of pathologies that affect 300 million people in the world as “rare”, is, to say the least, a little strange.

In the following lines, we’re going to bring you the 10 diseases that could be the rarest in the world, but keep in mind that the list varies depending on the place and the definition that is applied to the term. Now that this issue is clarified, let’s take a look at them.

1. Progeria

Progeria, also known as Hutchinson-Gilford syndrome, is an extremely rare genetic disease that accelerates the aging of neonates, especially between their first and second year of life. The prevalence is low to exceptional levels, since it’s estimated that this disease appears in 1 in every 7,000,000 newborns.

This rare disease is an autosomal dominant condition that results from a sporadic mutation in the germ line, specifically affecting the LMNA gene, vital for the synthesis of the membrane of the nucleus of cells. Some of the symptoms of this pathology are the following:

• Short stature
• Dry skin, premature baldness, and the presence of gray hair
• Prominent eyes, prominent cranial veins, and exceptionally sized skull
• Narrow chest with marked ribs
• Osteolysis, osteoporosis, and atherosclerosis
• Spots on the skin similar to those that occur with senescence, due to poor metabolism of the pigment melanin

In short, a young child has the characteristics of an elderly person when suffering from this condition. There’s no cure for this genetic disorder and most patients die before the age of 13, exceptionally reaching the age of 20.

2. Kuru

If the term “kuru” isn’t familiar to you, the position of this pathology in the list of the 10 rarest diseases in the world is self-explanatory. As indicated by the United States National Library of Medicine, this condition is caused by an infectious protein (prion) that is located in contaminated human brain tissue.

Kuru was first discovered in the 20th century in New Guinea and began to be studied medically in the 1950s. Although it sounds grotesque, today it is known that the disease was transmitted by the cannibalistic rituals of the tribes of the region, since they ate the brains of dead people as part of a funeral ritual.

After very long incubation times (up to 13 years), the prion (or misfolded protein) could eventually “transmit” its three-dimensional misfolding to other proteins, leading to the following symptoms:

1. Phase 1: the infected person has tremors, unstable posture, coordination problems and great difficulty in forming words properly.
2. Stage 2: the individual loses the ability to move without support and presents drastic emotional fluctuations.
3. Phase 3: the patient has severe swallowing difficulties (dysphagia), which causes him to lose weight drastically. It also develops ulcers that don’t heal and which cause infection.

All people with kuru died between 3 months and 2 years after the start of phase 1. Because cannibalism has been eliminated from any region where the behavior was present, there have been no infections in recent decades. The last patient is believed to have died between 2006 and 2009, due to the prion’s long incubation times.

3. Fibrodysplasia ossificans progressiva (FOP)

As in the case of Progeria, fibrodysplasia ossificans progressiva (FOP) is an inherited autosomal dominant disease. This condition causes the progressive ossification of the skeletal (voluntary) muscles, tendons, fasciae, and ligaments, structures that should be elastic to a greater or lesser extent.

This disease finds its cause in the mutation of the ACVR1 gene, responsible for developing and repairing the skeletal system. According to the journal Organogenesis, FOP affects 0.5 people per million inhabitants. It’s one of the rarest diseases in the world, with only about 800 cases diagnosed throughout history.

4. Morgellons disease

Morgellons disease is atypical even within this list, as it’s a medically inexplicable condition. The patient who presents it feels incessant itching, in addition to the appearance of small sores and particles on the skin. People with this disorder tend to develop skin lesions of many types, scratching and biting themselves because of the itch.

Despite the fact that this novel term has been coined to describe the condition, most professionals consider it to be a manifestation of the parasitic dermatozoal delusion. Therefore, it is usually categorized in the section of “unspecified delusional disorders” in the psychiatric setting, although infectious triggers are not ruled out.

Patients often experience formication, or what is the same, a sensation that insects and other organisms crawl under their skin. This horrible clinical picture is usually addressed through cognitive therapy and psychotropic medications, but people who suffer from the disease argue that “their feelings are not taken seriously” and demand medical, not psychological, approaches.

5. Methemoglobinemia

Methemoglobinemia is one of the rarest diseases in the world. In this condition, the patient’s body produces an abnormal amount of methemoglobin in the blood, a modified form of hemoglobin that is unable to transport oxygen to the tissues properly. There are 2 types:

• Congenital methemoglobinemia: This is due to a deficiency of the enzyme diaphorase I, which increases the levels of methemoglobin in the blood and reduces the amount of oxygen that is transported to the tissues.
• Acquired methemoglobinemia: The use of certain drugs can greatly increase the rate of methemoglobin formation (up to 1000 times).

This condition is diagnosed when the levels of methemoglobin in the blood are greater than 1%, as indicated by the medical portal Medscape. When the values of this compound increase above 15%, cardiac and neurological symptoms appear in the patient, as a consequence of hypoxia or a lack of oxygen in the tissues.

Fortunately, this rare disease can be treated with the administration of oxygen and drugs. The use of methylene blue is vital to save the lives of these patients, since the compound returns methemoglobin to its state capable of receiving oxygen (normal hemoglobin).

6. Microcephaly

The term “microcephaly” is used to designate children who have a smaller head diameter than expected for their age, ethnicity, and gender. This condition can present at birth or develop over the years, but due to its relationship to brain size, it is almost always accompanied by intellectual disability, limited motor function, and difficulty communicating.

This is one of the rarest diseases in the world, but its epidemiological figures vary greatly depending on the region consulted. For example, the Centers for Disease Control and Prevention (CDC) indicates that 1 in 800 to 1 in 5,000 children are born with microcephaly in the United States. The following causes are considered:

• Infections during maternal pregnancy: Cytomegalovirus and toxoplasmosis can lead to neonatal microcephaly.
• Severe malnutrition.
• Fetal exposure to harmful substances, such as alcohol and chemicals.
• Interruption of blood flow to the baby during pregnancy.

There is no treatment for microcephaly and only drugs are prescribed to relieve symptoms. When this condition is associated with chromosomal failures, life expectancy is less than 1 year in almost all cases.

7. Progressive hemifacial atrophy

Also known as Parry-Romberg syndrome, this disease affects the skin, facial muscles, and bony structures of the face. It usually involves only one of the planes of the head (hence its name, hemifacial), but sometimes it affects the entire face and can even extend to the arms and trunk.

Unilateral atrophy gives the patient a very strange appearance, as if half of their face is in the process of decomposition. In addition, it can promote problems with the development of the dentition, the palate and even favor the appearance of epileptic episodes. There is no treatment for this condition, but cosmetic surgery allows the face to regain some symmetry.

8. Verruciform epidermodysplasia

Verruciform epidermodysplasia is another of the rarest diseases in the world, but it has certain very distinctive features. The problem is not caused by the pathology itself, but is derived from an abnormal susceptibility to infection by the human papillomavirus (HPV), which belongs to a group of more than 100 viral agents that manifest in various ways in human beings.

The disease is characterized by the appearance of superficial formations throughout the life of the patient: macules, pustules and “horn” shaped lesions are common. In addition, it’s also associated with an increased risk of skin carcinomas, which greatly complicates the clinical picture.

Although there’s no standard treatment for the disease, acitretin is often used for its antiproliferative properties. Unfortunately, 30-60% of patients over the age of 40-50 end up developing non-melanoma skin cancer.

9. RPI deficiency

As we search for increasingly rare diseases, the availability of information becomes more and more limited. Very little is known about RPI deficiency, but many media consider it the rarest pathology in the world, perhaps only surpassed by Field’s disease.

According to studies, ribose 5-phosphate isomerase (RPI) deficiency is an enzymopathy due to a mutation. Some of its most notable symptoms are the following:

• Optic atrophy and nystagmus (a type of abnormal eye movement).
• Cerebellar ataxia.
• Spasms and seizures
• Psychomotor retardation.
• Leukoencephalopathy (breakdown of the white matter of the brain).
• Delay in general development.

As you can imagine, there is no type of treatment for this condition. It should be noted that it is an exceptionally rare disease, since only 4 cases have been detected in 30 years, so its knowledge is very limited.

10. Fields disease

We close the space in the most emphatic way possible, since it can be assured that Fields disease is the rarest pathology in the world. This condition has only been recorded in 2 people throughout history: twins Kirstie and Catherine Fields.

It is a neuromuscular disease that affects the nerve fibers responsible for carrying out the movements of the skeletal muscles. It is believed to be congenital and appears to have a progressive developmental pattern, but with only 2 patients in the world, it is very difficult to establish a prognosis and treatment.

The world of rare diseases is vast

As we have said, more than 300 million people are affected by one or more of the 7000 rare diseases that are known medically today.

Be that as it may, with this list we have collected some of the rarest diseases in the world, with RPI deficiency and Fields disease being the rarest of all. Certainly, more exposure and investigation of all the cited conditions is required so that no patient feels permanently neglected.