Top Rarest Diseases

Also called orphan diseases, rare diseases are those that are extremely uncommon and often have such low prevalence that a common doctor would not run into more than one case of that disease over a course of years, if ever. The most uncommon diseases that human kind faced are usually of genetic type. There are more than 6,000 rare diseases listed in the US Office of Rare Diseases today. There is no single definition accepted yet to define the term rare disease, but in the United States, a certain disease can be considered rare if affects less than 200,000 people and less than 1 in 2,000 people in European Union Countries.
Here is the list of 15 most uncommon illnesses ever, that affect humans:
1. Ribose-5-phosphate isomerase deficiency

Ribose-5-phosphate isomerase deficiency (RPI deficiency) is a human disorder caused by mutations in the pentose phosphate pathway enzyme ribose-5-phosphate isomerase. With a single diagnosed patient, RPI deficiency is currently considered to be the rarest disease in the world.
The affected person was a boy born in 1984 and diagnosed by MRI as suffering from a white matter disease (leukoencephalopathy) . Analysis of SPECT profiles indicated an increase in the polyols arabitol, ribitol and erithrol. This discovery later led to the identification of the disease-causing mutations, a premature stop codon and a missense mutation in the RPI gene. Since the report of this first case in 1999, no further patients have been diagnosed. In the search for an explanation for this rarity, it has been found that the patient suffers from a seldom-seen allelic combination. One allele is a non-functional null allele, while the other encodes for a partially-active enzyme. Furthermore, the partially-functional allele has expression deficits that depend on the cell type in which it is expressed. Therefore, some of the patient’s cells have a considerable amount of RPI activity, whereas others do not. The molecular cause of the pathology is not fully understood. One hypothesis is that ribose-5-phosphate may lack for RNA synthesis; another possibility is that the accumulation of D-ribitol and D-arabitol may be toxic.
2. Carpenter syndrome

Also called acrocephalopolysyndactyly type II, is an extremely rare autosomal recessive congenital disorder characterized by craniofacial malformations, obesity, and syndactyly.
Carpenter syndrome presents several features: tower-shaped skull (craniosynostosis); additional or fused digits (fingers and toes); obesity; reduced height. Mental deficiency is also common with the disorder, although some patients may have average intellectual capacity.
Carpenter Syndrome belongs to a group of rare genetic disorders known as acrocephalopolysyndactyly, abbreviated ACPS (RN, 2007). There were originally five types of ACPS, but this number has been decreased because they have been found to be closely related to one another or to other disorders (Paul A. Johnson, 2002). The most common physical manifestation of Carpenter Syndrome is early fusing of the fibrous cranial sutures which results in an abnormally pointed head. The fusion of the skull bones is evident from birth (National Organization for Rare Disorders, Inc., 2008). Babies’ mobile cranial bones form a cone shape as the pass through the birth canal and soon thereafter return to a normal shape; however, a baby affected by carpenter syndrome maintains a cone shaped head.
A baby affected by Carpenter Syndrome will also display malformations of the face. An individual affected by the syndrome may have broad cheeks, a flat nasal bridge, and a wide upturned nose with abnormally large nasal openings.
3. Progressive Multifocal Leukoencephalopathy (PML)

Progressive multifocal leukoencephalopathy (PML) is a neurological disorder characterized by destruction of the myelin, an oily substance that helps protect nerve cells in the brain and spinal cord, also known as central nervous system (CNS) white matter. It is caused by a virus called JC virus (JCV), named after the initials of the patient in whom it was first discovered. The virus is widespread, found in at least 85% of the general adult population. It remains inactive in healthy individuals and causes disease only when the immune system has been severely weakened, such as in people with HIV/AIDS, or hematological malignancies, and in organ transplant recipients who receive immuno- suppressant medications to avoid rejection of the transplanted organ. Altogether, PML occurs in approximately one in 250,000 people.
The term “progressive” in PML means that the disease continues to get worse and often leads to serious brain damage. The term “multifocal” means that JCV causes disease in multiple parts of the brain. However, it is possible for an individual with PML to have only one brain lesion instead of several lesions. The term “leukoencephalopathy” means that the disease affects mainly the white matter of the brain or myelin, although there are some rare cases in which the gray matter neurons is also involved.
4. Zimmermann-Laband syndrome (ZLS)

Also known as Laband Zimmermann syndrome, and Laband’s Syndrome, is an extremely rare autosomal dominant congenital disorder.
Symptoms include gingival fibromatosis, associated with hypoplasia of the distal phalanges, nail dysplasia, joint hypermobility, and sometimes hepatosplenomegaly. The nose and pinnae are usually large and poorly developed, which gives the individuals with the syndrome abnormal facial characteristics. Mental retardation may also occur. Both males and females are equally affected. Gingival fibromatosis is usually present at birth or appears short after. The term Zimmermann-Laband was coined by Carl Jacob Witkop in 1971. Zimmerman-Laband syndrome is inherited in an autosomal dominant pattern. This means the defective gene is located on an autosome, and only one copy of the gene is sufficient to cause the disorder, when inherited from a parent who has the disorder.
5. Paraneoplastic Neurologic Syndromes (PNS)

Paraneoplastic neurologic syndromes (PNS) are a group of conditions that affect the nervous system (brain, spinal cord, nerves and/or muscles) in patients with cancer. The term “paraneoplastic” means that the neurological syndrome is not caused by the tumor itself, but by the immunological reactions that the tumor produces. It is believed that the body’s normal immunological system interprets the tumor as an invasion. When this occurs, the immunological system mounts an immune response, utilizing antibodies and lymphocytes to fight the tumor. The end result is that the patient’s own immune system can cause collateral damage to the nervous system, which can sometimes be severe. In many patients, the immune response can cause nervous system damage that far exceeds the damage done to the tumor. The effects of PNS can remit entirely, although there can also be permanent effects.
6. Pfeiffer syndrome

It is a genetic disorder characterized by the premature fusion of certain bones of the skull (craniosynostosis), which prevents further growth of the skull and affects the shape of the head and face. It is named after Rudolf Arthur Pfeiffer who, in 1964, described a list of features that included a coronal synostosis, turribachycephaly (high prominent forehead) and maxillary hypoplasia (eyes that appear to bulge, but are actually due to small underlying cheek bones). Pfeiffer syndrome affects about 1 in 130,000 births.
7. Dercum’s Disease

Dercum’s disease is an extremely rare disorder characterized by multiple, painful growths consisting of fatty tissue (lipomas). These growths mainly occur on the trunk, the upper arms and upper legs and are found just below the skin (subcutaneously). Pain associated with Dercum’s disease can often be severe. Pain may be caused by these growths pressing on nearby nerves. Dercum’s disease mainly occurs in adults and more women are affected than men. In some cases, affected individuals may also experience weight gain, depression, lethargy, and/or confusion. The exact cause of Dercum’s disease is unknown.
8. Winchester syndrome

Is a rare congenital connective tissue disease described in 1969, of which the main characteristics are short stature, marked contractures of joints, opacities in the cornea, a coarse face, dissolution of the carpal and tarsal bones (in the hands and feet respectively) and osteoporosis. Appearances resembled rheumatoid arthritis. Increased uronic acid was demonstrated in cultured fibroblasts from the skin and to a lesser degree in both parents. Despite initial tests not showing increased mucopolysaccharide excretion, the disease was regarded as a mucopolysaccharidosis.
In 2005 a patient with Winchester syndrome was shown to have mutations in the matrix metalloproteinase 2 (MMP2) gene. A 2006 study showed other mutations in the same gene, and observed that Winchester syndrome is probably part of a continuum that also includes Torg syndrome and nodulosis-arthropathy-osteolysis syndrome (NAO).
9. Meleda disease (MDM)

Also called “mal de Meleda”, also called Mljet disease, keratosis palmoplantaris and transgradiens of siemens, (also known as “Acral keratoderma,” “Mutilating palmoplantar keratoderma of the Gamborg-Nielsen type,” “Palmoplantar ectodermal dysplasia type VIII”, and “Palmoplantar keratoderma of the Norrbotten type”) is an extremely rare autosomal recessive congenital skin disorder in which dry, thick patches of skin develop on the soles of the hands and feet, a condition known as palmoplantar hyperkeratosis. MDM is most common on the Dalmatian island of Mljet (or Meleda), thought to be because of a founder effect. It is of autosomal recessive inheritance. It may be caused by a mutation on the SLURP1 gene, located on chromosome 8.
10. Familial Idiopathic Basal Ganglia Calcifications (Fahr’s Disease)

Fahr’s Disease is a rare degenerative neurological disorder characterized by the presence of abnormal calcium deposits (calcifications) and associated cell loss in certain areas of the brain (e.g., basal ganglia). The condition is often referred to as idiopathic basal ganglia calcification or IBGC because there is no apparent explanation for such calcification in these brain regions (idiopathic). Associated symptoms include progressive deterioration of cognitive abilities (dementia) and loss of acquired motor skills. As the condition progresses, paralysis may develop that is associated with increased muscle stiffness (rigidity) and restricted movements (spastic paralysis). Additional abnormalities may include relatively slow, involuntary, continual writhing movements (athetosis) or chorea, a related condition characterized by irregular, rapid, jerky movements. In some affected individuals, there may also be gradual deterioration of the nerve fibers that transmit impulses from the retinas to the brain (optic atrophy), a condition associated with partial or near complete visual impairment.
According to reports in the medical literature, Fahr’s Disease is often familial. Familial Fahr’s Disease may be transmitted as an autosomal recessive trait or, in other affected families (kindreds), may have autosomal dominant inheritance. In other instances, the condition appears to occur randomly for unknown reasons (sporadically). Some experts suggest that the condition may sometimes result from an unidentified infection during pregnancy affecting the developing fetus (intrauterine infection).
11. Neuromyelitis Optica (Devic’s disease)

Neuromyelitis optica, also known as Devic disease (DD), is a chronic disorder of nerve tissue characterized by inflammation of the optic nerve (optic neuritis) and inflammation of the spinal cord (myelitis). There appear to be two forms of this disease. In the classical, but less common type, there is a series of attacks over a short period of time (days or weeks) but, after the initial outburst, there are seldom repeat incidents. The second form is more common and is characterized by repeated attacks separated by periods of remission. In this form, the interval between attacks may be weeks, months or years. In its early stages, Devic disease may be confused with multiple sclerosis.
12. Esthesioneuroblastoma

Esthesioneuroblastoma is a rare form of cancer involving nasal cavity and believed to arise from the olfactory epithelium. It can cause loss of vision, sight and taste. It is often considered synonymous with “olfactory neuroblastoma”, but the tissue of origin is not yet well characterized. Associated with Trisomy 8. It was first characterized in 1924. According to the BBC, only 200 cases of the disease have been recorded worldwide in the past two decades. A 1997 medical publications search identified 1,457 cases in the published literature since its discovery in 1924, however 487 were cited in more than one paper, bringing the total of reported cases to 945.
Several surgical approaches have been described, but post-excision recurrence rates have remained very high. The disease was brought into prominence by the case of Chantal Sébire, who was suffering from the disease and ended her life after being denied euthanasia.
13. Landau Kleffner Syndrome

Landau–Kleffner syndrome (LKS), also called infantile acquired aphasia, acquired epileptic aphasia or aphasia with convulsive disorder, is a very rare, childhood neurological syndrome.
It is named for William Landau and Frank Kleffner, who characterized it in 1957. Landau Kleffner syndrome (LKS) is also characterized by the loss of comprehension and expression of verbal language (aphasia) in association with severely abnormal electroencephalic (EEG) findings that often result in seizures. LKS affects the parts of the brain that control comprehension and speech (Broca’s area and Wernicke’s area). The disorder usually occurs in children between the ages of 5 and 7 years. Typically, children with LKS develop normally but then lose their language skills. While many of the affected individuals have clinical seizures, some only have electrographic seizures, including electrographic status epilepticus of sleep (ESES).
14. Alpha-1-Antitrypsin Deficiency (A1AD)

Alpha-1 Antitrypsin Deficiency (A1AD) is a hereditary disorder characterized by low levels of a protein called alpha-1 antitrypsin (A1AT) which is found circulating in the blood. This inherited deficiency blocks A1AT primarily produced in the Liver, from release to the blood stream and predisposes an individual to several symptomatic illnesses, but most commonly appears as emphysema, often progressive liver cirrhosis and rarely, as a skin condition called panniculitis. A deficiency of A1AT allows substances that break down protein (proteolytic enzymes) to attack various tissues of the body. This results in destructive changes in the lungs (emphysema). The primary build up of unreleased A1AT in the liver may lead to cirrhosis and affect the skin. Alpha-1 Antitrypsin is produced in the liver ordinarily released by specialized, granular white blood cells (neutrophils) in response to infection or inflammation. A deficiency of Alpha-1 Antitrypsin in the blood stream results in unbalanced (relatively unopposed) rapid breakdown of proteins (protease activity), especially in the supporting elastic structures of the lungs.
This destruction over many years leads to emphysema and is accelerated by smoking and air pollution, often in occupational exposures. The inherited disease is often undiagnosed as environmental triggered COPD the #4 cause of death in the United States. The inherited lung diseases progression, when diagnosed is often treatable using a protein replacement therapy.
15. Cyclic Vomiting Syndrome (CVS)

Cyclic vomiting syndrome (CVS) is a rare disorder characterized by recurrent episodes of severe nausea and vomiting. An episode may last for a few hours to several days and then is followed by a period of time during which affected individuals are free of severe nausea and vomiting. This alternating pattern of disease and disease-free periods distinguishes cyclic vomiting syndrome from other similar disorders. The associated nausea and vomiting can be severe enough to be incapacitating (e.g., individuals may be unable to walk or talk and/or be bedridden). Additional symptoms that are often present during an episode including paleness of the skin (pallor), lack of energy (lethargy), abdominal pain and headaches. In some cases as children grow older, they may outgrow these episodes, although many of these children eventually develop migraines. Cyclic vomiting syndrome affects children more often than adults. In adults, episodes occur less frequently, but may last longer. The exact cause of cyclic vomiting syndrome is unknown.