Neurological disorders affecting the brain represent some of medicine’s most perplexing mysteries. These disorders often challenge our understanding of neuroscience and highlight the incredible complexity of the human brain. Here’s a closer look at ten of the world’s rarest neurological diseases, their discovery, interesting facts and impact on those affected.
| Diseases | Year of discovery | Approximately affected |
|---|---|---|
| Kleine-Levin Syndrome | 1925 | One in a million people worldwide |
| RPI Deficiency | 1999 | Only about four documented cases worldwide |
| Cantu Syndrome | 1982 | Fewer than 100 cases documented till date |
| Bobble-head Doll Syndrome | 1966 | Only about 34 cases have been documented worldwide |
| Kuru Disease | 1950s | Affected about 1% of the population in certain villages |
| Rett Syndrome | 1966 | Affects approximately 1 in 8,500 females worldwide |
| Creutzfeldt-Jakob Disease | 1920s | One in a million people annually worldwide |
| Microcephaly | 19th century | Global prevalence varies widely, from 1.3 to 150 per 100,000 live births |
| Angelman Syndrome | 1965 | Affects approximately 1 in 12,000 to 20,000 people worldwide |
| Batten Disease | 1903 | Affects approximately 2 to 4 per 100,000 births in the United States |
10. Kleine-Levin Syndrome (KLS)
Year of discovery: 1925
Approximately affected: One in a million people worldwide
KLS manifests as recurring episodes where patients sleep up to 20 hours daily for days or weeks at a time. During their brief waking periods, they often display altered behavior including hyperphagia (excessive eating), hypersexuality, and profound confusion. Patients may experience vivid hallucinations and complete disorientation, often having little memory of these episodes afterward.
The cause remains largely unknown, though researchers suspect autoimmune or genetic factors may play a role. Episodes typically recur every few months and may persist for years, though many patients experience decreasing severity and frequency as they age. While stimulants like modafinil may help manage excessive sleepiness and mood stabilizers such as lithium have shown some promise in reducing episode frequency, there is currently no definitive cure for KLS.
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9. Ribose-5-Phosphate Isomerase Deficiency (RPI Deficiency)
Year of discovery: 1999
Approximately affected: Only about four documented cases worldwide
RPI Deficiency manifests as progressive leukoencephalopathy (white matter disease in the brain), developmental delays, seizures, and eventual optic atrophy leading to vision loss. The extreme rarity of this condition has hampered research efforts, and there is currently no effective treatment. Management focuses on supportive care and symptom control.
The disease is caused by mutations in the RPIA gene, which affects an enzyme necessary for carbohydrate metabolism. The extremely low prevalence—essentially one in two billion people—makes this condition particularly challenging to study and understand.
8. Cantu Syndrome
Year of discovery: 1982
Approximately affected: Fewer than 100 cases documented till date
Cantu Syndrome is immediately recognizable by its characteristic hypertrichosis (excessive hair growth), distinctive coarse facial features, cardiac anomalies, and skeletal abnormalities. Patients often have enlarged hearts, patent ductus arteriosus, and other cardiac defects that require ongoing monitoring.
The syndrome results from mutations in the ABCC9 gene, which encodes a protein that forms potassium channels important for regulating cellular electrical activity. These mutations cause the channels to remain open inappropriately, disrupting cellular function. Treatment approaches are largely supportive, addressing specific symptoms as they arise.
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7. Bobble-head Doll Syndrome
Year of discovery: 1966
Approximately affected: Only about 34 cases have been documented worldwide
Bobble-head Doll Syndrome typically affects children around age three and is characterized by involuntary, rhythmic nodding or bobbling movements of the head at 2-3 Hz frequency. These movements temporarily cease during sleep or when the child focuses intently on a task. The syndrome results from cysts in the third ventricle of the brain causing pressure and hydrocephalus, which disrupts normal motor control.
Early diagnosis and treatment are critical, as surgical interventions such as ventriculoperitoneal shunting or endoscopic procedures to relieve pressure can lead to complete resolution of symptoms. Delays in treatment, however, can result in permanent neurological damage.
6. Kuru Disease
Year of discovery: 1950s
Approximately affected: Affected about 1% of the population in certain villages, but is now virtually extinct
Kuru belongs to a class of diseases called transmissible spongiform encephalopathies, caused by infectious proteins called prions. Patients developed progressive cerebellar ataxia, tremors, emotional instability, and eventual death, typically within one year of symptom onset.
The disease spread through the Fore tribe’s funeral practices, which involved ritual consumption of deceased relatives’ brain tissue. When these practices ceased in the late 1950s, the incidence of Kuru declined dramatically. No treatment was ever developed, but research on Kuru provided crucial insights into prion diseases like Creutzfeldt-Jakob Disease.
5. Rett Syndrome
Year of discovery: 1966
Approximately affected: Affects approximately 1 in 8,500 females worldwide
Rett Syndrome almost exclusively affects girls, as the responsible gene (MECP2) is located on the X chromosome, and males with the mutation typically do not survive to birth.
The condition presents with apparently normal early development followed by regression between 6-18 months of age. Children lose acquired motor and communication skills, develop distinctive repetitive hand movements (hand wringing or washing motions), and may experience seizures, breathing irregularities, and intellectual disability.
While there is no cure, research into gene therapy is promising. Current management includes anticonvulsants for seizures, physical therapy to maintain mobility, and supportive care to improve quality of life.
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4. Creutzfeldt-Jakob Disease (CJD)
Year of discovery: 1920s
Approximately affected: One in a million people annually worldwide
Like Kuru, CJD is a prion disease, causing proteins in the brain to fold abnormally and cluster together, creating holes in brain tissue. It manifests as rapidly progressive dementia alongside muscle stiffness, involuntary movements, and visual disturbances. Most patients die within a year of symptom onset.
CJD can occur spontaneously (sporadic CJD, accounting for 85% of cases), be inherited through genetic mutations (familial CJD, about 10-15% of cases), or be acquired through exposure to infected tissue (acquired CJD, less than 1% of cases). The variant form (vCJD) is linked to consumption of beef from cattle infected with bovine spongiform encephalopathy (“mad cow disease”).
No cure exists, and treatment focuses on supportive care. The disease’s rapid progression and invariably fatal outcome make it one of the most devastating neurological disorders.
3. Microcephaly
Year of discovery: 19th century
Approximately affected: Global prevalence varies widely, from 1.3 to 150 per 100,000 live births
Microcephaly is characterized by an abnormally small head circumference, reflecting inadequate brain development. The condition can result from hundreds of different genetic mutations or environmental factors like prenatal infections (including Zika, rubella, and cytomegalovirus), toxic exposures, or severe maternal malnutrition.
Children with microcephaly frequently experience developmental delays, intellectual disabilities, seizures, and motor function impairments, though the severity varies considerably. While there is no cure, early intervention with physical, occupational, and speech therapies can significantly improve outcomes and quality of life.
2. Angelman Syndrome
Year of discovery: 1965
Approximately affected: Affects approximately 1 in 12,000 to 20,000 people worldwide
Angelman Syndrome results from the loss of function of the UBE3A gene on the maternal chromosome 15. Patients typically have severe developmental delays, minimal speech, movement and balance disorders, and a notably happy demeanor with frequent smiling and laughter. Seizures affect 80-90% of individuals with the syndrome.
Though there is no cure, advances in understanding the genetic mechanisms have led to promising research into targeted therapies. Current management includes anticonvulsant medications for seizure control, physical therapy to improve mobility, and communication therapies.
1. Batten Disease
Year of discovery: 1903
Approximately affected: Affects approximately 2 to 4 per 100,000 births in the United States, with varying numbers worldwide
Batten disease results from mutations in several different genes that affect the body’s ability to dispose of cellular waste, leading to abnormal buildup of proteins and lipids in neurons. Children with Batten disease typically develop normally before showing symptoms, which include progressive vision loss, seizures, cognitive decline, and motor dysfunction.
In 2017, the FDA approved the first treatment for a specific form of Batten disease—Brineura (cerliponase alfa) for CLN2 disease. This enzyme replacement therapy can slow the progression of symptoms when started early. For other forms, treatment remains supportive, though numerous gene therapy approaches are in clinical trials, offering hope for this devastating condition.
Conclusion
These rare neurological brain disorders highlight how intricate and vulnerable the human brain really is. Each condition comes with its own set of challenges, often leaving patients and families searching for answers. While treatments are limited, growing research and awareness offer hope for better care and, one day, possible cures.
