The definition of a rare disease varies by country and health agency, but the National Institutes of Health in the United States currently defines “rare disease” as one affecting less than 200,000 Americans. The agency estimates that there are approximately 7,000 rare diseases affecting 25 million Americans. The rarest diseases tend to be genetic in nature because of their inability to spread among the population outside of reproduction, though acquired neurological conditions are also often rare.
Pinpointing the rarest diseases in the world is a tough task as it implies that the disease occurs often enough to be known and recorded, but so rarely that other diseases easily outshine it in reports. The rarest disease is likely one that is already eradicated. The last known natural case of smallpox was recorded in Somalia in 1977. Prior to that time it ravaged the human population, killing roughly a third of all it infected. The virus that causes the disease now only exists as laboratory samples.
In 1998, 4-year-old Welsh twins Catherine and Kirstie Fields began showing the symptoms of a deteriorating muscular disease that stumped doctors. The neuromuscular condition was so rare that doctors were certain they are the only people in the world who have it and named it after them – Fields condition or Fields’ disease.
Hutchinson-Gilford Progeria Syndrome, known simply as progeria, is a condition in which a child prematurely ages. First described in the late 1800s, the disease has been reported across the globe but only affects 1 in 4 million to 1 in 8 million children. Individuals with the condition rarely make it to the second decade of life. The disease is currently thought to be a defect in genes encoding lamins, cytoskeletal proteins involved in a number of cellular processes and tissues, coinciding with the systemic symptoms and problems encountered in these patients.
Human prion diseases
Among the infectious diseases, prion diseases are among the most rare. The pathogens in these diseases are proteins that undergo a conformational change and disrupt the working structure of the brain. Because they are transmissible, they can cause an acquired neurological disease, though some variants may be due to genetic abnormalities. Among the human forms of prion diseases are Creutzfeldt-Jakob disease and Kuru. Kuru is transmitted via cannibalism, specifically by the Fore people of New Guinea. The practice was halted in 1960, leaving very few carriers of the disease and no new transmission events into the 21st century. However, the long incubation period of the disease leaves the chance for new manifestations among remaining carriers, the number of which is unknown. In contrast, Creutzfeldt-Jakob is thought to possibly be genetic (classical CJD, occurring in an estimated 1 out of every 1 million people) or related to mad cow disease (variant CJD, diagnosed in less than 200 people worldwide, none in the United States).
Fibrodysplasia ossificans progressive
Affecting an estimated 1 in 2 million people worldwide, fibrodysplasia ossificans progressive (FOP) has only been diagnosed in a few hundred people. The disorder involves the ossification of connective tissue – the ligaments and tendons are transformed into bone as the person ages. The most characteristic features are a large big toe and the shoulders and neck slumping into the upper torso in late childhood. The condition is thought to be the result of autosomal dominant mutations in the ACVR1 gene.
A sporadic genetic condition affecting the cranial nerves, particularly the sixth and seventh, Moebius syndrome results in facial deformities that are present at birth. Skeletal anomalies are also often seen and about a third of children with the disorder have autism. Only 300 cases have been described in the English literature according to Medscape, and about 2000 cases are thought to exist currently worldwide, affecting approximately 1 in 50,000 births.
Porphyria is a group of disorders in the production of heme, the protein in red blood cells that bind oxygen for transport. As a result, sufferers have pale skin, anemia, and historical comparisons to vampires, in addition to potential neurological issues. However, many people with the genetic mutations underlying the disorder do not exhibit symptoms. The National Institutes of Health Genetics Home Reference estimates the prevalence as 1 in 500 to 1 in 50,000. Like so many other rare diseases, the real prevalence of the disorder uncertain.