Top 10 Rare Diseases in the World you’ve Never Heard Of

Rare diseases are the most dangerous, uncurable, or may take longer to heal. Health is the primary goal of every individual to be maintained. Everyone tries to protect their health. Even though thousands of diseases are prevalent and curable within hours to days, some rare diseases are uncurable. These are rare and affect one in every million.

These rare diseases are generally autoimmune diseases, bone diseases, etc. Some of these rare diseases can be cured, some are not. If you are not sensitive and eager to know what the top 10 rare diseases in the world are that you have never heard of, please read this article. Here we have listed some of the top rare diseases, causes, and symptoms. Read on!

What are Rare Diseases?

Not every disease is rare. There is a criterion to declare a rare disease. In general terms, lack of knowledge, scientifically not proven, difficult to diagnose, no proper tests to confirm, and zero equipment to treat come under rare diseases. So these diseases throw challenges at health workers, doctors, and patients. These orphan diseases are medical conditions that occur in specific groups of people. A rare disease is seen in fewer than 1 in 2000 people. So these rare diseases are mostly uncommon, but the new world after 2010 is seeing more cases. 

List of the Top 10 Rare Diseases in the World:

1. Hutchinson-Gilford Progeria Syndrome
2. Fibrodysplasia Ossificans Progressiva (FOP)
3. Hereditary hyperekplexia
4. Von Hippel-Lindau Disease (VHL)
5. Harlequin ichthyosis
6. Autosomal recessive primary microcephaly
7. McCune-Albright syndrome
8. Lesch-Nyhan syndrome
9. Nail-patella syndrome
10. Paroxysmal extreme pain disorder

Let’s see what the top rare diseases in the world What You Need to Know About Their Causes and Symptoms.

1. Hutchinson-Gilford Progeria Syndrome:

Other names: HGPS, Hutchinson-Gilford syndrome, progeria, progeria of childhood.

Symptoms of HGPS:

• People appear aged at the age of 2-3 years. They are born normally, but their rate of weight gain isn’t up to par with age compared to the other children of the same age. They grow slowly.

• Their facial appearance is a bit different. Nose with a sharp tip, thin skin like in older people, thin lips, large eyes, ears are wide. They look like aliens. 

• They face alopecia. Almost all hair is gone at a young age. 

• They don’t have subcutaneous fat. This means the fat under the skin required for sitting, standing, etc. is not developed in them. This causes joint pain in them.

• Their arteries are hard in childhood itself. So they are prone to heart attacks at an early age.

Causes of HGPS:

• This is a genetic disorder. Mutations in the LMNA gene cause it. 

• A protein called ‘Lamin A’ decides the shape of the nucleus around cells. So this LMNA gene makes this protein, Lamin A. When this protein’s structure changes, the nucleus’ shape also differs. 
• These alterations can cause cells to be damaged at a very young age. So this condition is called progeria.

Frequency:

One in 4 million people. A total of 130 people have been affected by this disease since 1886. It is one of the rarest diseases in the world.

Inheritance:

There is no history of inheritance. It can affect people with no family history of this disease.

2. Fibrodysplasia Ossificans Progressiva (FOP):

Other names: FOP, Myositis ossificans, Myositis ossificans progressiva, Progressive myositis ossificans, Progressive ossifying myositis.

Symptoms of FOP:

• Fibrodysplasia Ossificans Progressiva is a bone disorder. Our body has muscle over the bones. Also, ligaments and tendons connect muscles. So in this disease, these muscles will be replaced by bone. This is called ‘Ossification’.

• People suffer by having extra skeletal bones, which limits basic movements such as sitting, standing, etc.

• This disease limits the full opening of the mouth, making it difficult to speak and eat. And causes malnutrition.

• May face breathing difficulties due to extra growth of bone in the rib area. So lungs can not expand properly.

• Stiffness and inflammation in joints occur. This condition is also called ‘Myositis’.

• People are born with malformed big toes. This symptom helps doctors to distinguish between FOP and other skeletal-related problems. 
• Short thumbs and other skeletal abnormalities. 

Causes of FOP:

1. Our body needs BMP – Bone morphogenetic protein type I receptors to form bones. So a gene named ACVR 1 instructs these receptors.
2. It controls the growth of bones such as how much length and size.
3. Mutations in this ACVR 1 gene cause abnormal control of the receptor activity. So this makes extra growth of bones which replaces muscles. This is called ‘ossification’. 
4. So in childhood, bone growth will be like in adults, because receptors malfunction gives false information to muscle tissue, allowing the bone to grow extra skeletal. 

Frequency:

One in 1 million people. Only a few hundred cases have been reported. It is also one of the rare diseases in the world.

Inheritance:

As mutations vary time and again, inheritance is not involved. However, one cell from the affected person’s gene is enough to cause the new baby to be affected.

3. Hereditary hyperekplexia:

Other names: Congenital stiff-man syndrome, Congenital, stiff-person syndrome, Familial hyperekplexia, Hyperekplexia, Startle syndrome, STHE, and Stiff-baby syndrome.

Symptoms of Hereditary Hyperekplexia:

• This is mostly seen in infants. Infants are ‘hypertonic’. This means when they hear loud noise they get into shock. They startle. This is called ‘Hypertonia’. 

• So when infants hear loud noises they become rigid. So sometimes they stop breathing, and if it is prolonged they become fatal. 

• Muscle Twitches – infants continuously move their arms and legs even when they fall asleep. This is called ‘Hypnagogic myoclonus’.

• When you tap their nose, they lift their head forward which causes spasms in their next muscles.

• These symptoms may fade over some time. But these symptoms may reoccur again in old age. In older age also they may get symptoms of hypnagogic myoclonus. 

• So muscles become rigid and older people may fall. 

• Older people will be less able to listen to loud noises.

• Some injuries will be prolonged and recurrent seizures may occur. This is called ‘Epilepsy’.

• This syndrome sometimes leads to SIDS – Sudden Infant Death Syndrome. Sudden death of babies less than 1 year of age has been reported.

Causes of Hereditary Hyperekplexia:

• Multiple gene mutations have been found. These genes are involved in making proteins found in neurons. These proteins transmit neuron response to a molecule named ‘Glycin’. It is an amino acid and neurotransmitter. It acts as a chemical messenger that transmits signals between neurons. 

• So these mutations may send false signals and disrupt normal nervous system functioning. So these will make infants do abnormal movements, and exaggerated startle reactions.

• Mutations in the GLRA 1 gene are the prime reason for Hereditary hyperekplexia. Glycin receptor protein has an Alpha 1 subunit, made by following instructions given by the GLRA 1 gene. So mutations in this gene will send wrong or zero signals to the brainstem through spinal cords. So when signals stop suddenly, it causes startling conditions in the infants. So this results in Hereditary hyperekplexia.

Frequency:

Studies are still in progress to define how frequently this disease occurs. But a total of 150 people have been affected by Hereditary hyperekplexia. It is a rare diseases in the world.

Inheritance:

There are two types of inheritance in Hereditary hyperekplexia.

• Autosomal Dominant Pattern: In this pattern, one of the parents of the affected infant has altered the GLRA 1 gene. So this one altered gene is enough to get Hereditary hyperekplexia. Some cases may have mutations in the gene that came from one parent.

• Autosomal Recessive Pattern: In this pattern, both parents of the affected infant contribute two altered mutations of the GLRA 1 gene. But parents don’t show any symptoms The infant born to these parents shows signs of Hereditary hyperekplexia.

4. Von Hippel-Lindau Disease (VHL):

Other names: angiomatosis retinae, cerebelloretinal angiomatosis, familial, Hippel-Lindau disease, VHL syndrome, Von Hippel-Lindau disease.

Symptoms of VHL syndrome:

• This disease forms tumours and cysts in different body parts and continues to grow throughout life. These tumours may be cancerous or non-cancerous. These tumours are named hemangioblastomas.

• These tumours may form in the brain, spinal cords, or blood vessels and cause serious health issues. These are non-cancerous tumours that are still dangerous. Symptoms may include vomiting, headaches, and weakness.

• Tumours form at the back of the Retina (Retinal Angiomas) and may cause vision loss.

• Symptoms may include cysts in the Kidneys (Clear cell renal carcinoma), Pancreatic cancer (Pancreatic Neuroendocrine Tumor)  and Genital tract cysts.

• Adrenal gland cysts called Pheochromocytoma associated with Von Hippel-Lindau Disease may cause severe headaches, panic attacks and excessive sweating. It also causes high blood pressure and the patient may not respond to medicines.

• Almost 10 per cent of people affected by Von Hippel-Lindau disease may have Endo Lymphatic Sac Tumors, which are tumours formed in inner ear canals. These may cause hearing loss and complete deafness.

• Some patients may develop tumours in the liver and lungs but show no symptoms.

Causes of VHL syndrome:

• Mutations in the VHL gene cause Von Hippel-Lindau disease.

• This VHL gene controls abnormal cell growth. This is a tumour suppressor. 

• The abnormal or altered VHL gene causes cells to grow uncontrollably as it doesn’t regulate the production of VHL protein.

Frequency:

Von Hippel-Lindau disease may occur in one in every 36,000 people. It is one of the rare diseases in the world.

Inheritance:

This disease is inherited in the form of Autosomal Dominant Pattern. So a single altered gene from one of the parents is enough to form cysts. 20 percent may have a mutation in the VHL gene. However, this disease needs different copies of the VHL gene to form tumours. 2 copies of the VHL gene don’t allow the body to form VHL protein and cause cysts.

5. Harlequin ichthyosis:

Other names: Autosomal recessive congenital ichthyosis 4B, Harlequin baby syndrome, HI, Ichthyosis congenital, Harlequin fetus type.

Symptoms of Harlequin ichthyosis:

• This is a genetic skin disorder. Infants are born with thick and hard skin.

• The skin has diamond-shaped plates with cracks in between. These are large in shape and very hard. 

• These plates on the skin cause abnormal growth of eyes, nose, ears, etc.

• Hard skin on the chest may cause breathing difficulties.

• Abnormal skin may also fail to face environmental changes. Symptoms may include dehydration, fighting infections, balancing body temperature, etc.

• It becomes difficult for newborn babies to survive with the hard skin. However, certain medical treatments can cause the infant to survive.

Causes of Harlequin ichthyosis:

• Mutations in ABCA 12 lead to Harlequin ichthyosis.

• This gene forms a protein that helps the skin cells to grow healthy. This gene transfers lipid fats and enzymes to layers under the skin.

• So mutations in this ABCA 12 gene don’t produce ABCA 12 protein which abrupts transfer of lipid fats to the skin. So this causes abnormal Epidermis in infants.

Frequency:

It is a rare diseases. The correct number of cases affected is still unknown.

Inheritance:

This may be caused by an Autosomal Recessive Pattern. Parents of the infant carry 2 different copies of the gene, each individually. However, parents may not show any symptoms.

6. Autosomal Recessive Primary Microcephaly:

Other names: MCPH, Microcephaly primary hereditary, Primary autosomal recessive microcephaly, True microcephaly.

Symptoms of MCPH:

• Microcephaly in Greek means ‘small head’. This disease is called MCPH, in which infants are born and grow with small heads.

• The circumference of infants is small compared to infants of the same age. Their brain is also small. 

• The infants may have smaller brain volume, although they don’t normally show any abnormalities in brain structure.

• But they grow with smaller heads than normal.

• Symptoms may worsen with age as it does not allow proper functioning of joints. 

• Some other symptoms include delayed speech and language skills. 

• Few infants don’t show attention. Small structures, a sloping forehead, and seizures are some of the other symptoms. However, this disease doesn’t affect the organs of the body.

Causes of MCPH: 

• Mutations in 7 different genes can cause microcephaly. 

• Half of the cases detected are due to mutations in the ASPM gene. This gene generates a protein that helps in making early development of brain cells. This decides the size of the brain.

• Mutations in this gene may stop the formation of neurons in the brain, and stop the early development of the brain. This reduces brain size and head size as well.
• As this causes fewer neurons, infants show delayed speech and learning skills.

Frequency:

It varies from one in 30000 to one in 250000. Over 200 families have been affected till now. Most of this disease is seen in northern Pakistan, where the frequency is one in 10,000. 

Inheritance:

This may be caused by an Autosomal Recessive Pattern. Parents of the infant carry 2 different copies of the gene, each individually. However, parents may not show any symptoms. It is considered one of the rare diseases in the world.

7. McCune Albright Syndrome:

Other names: Albright syndrome, Albright’s disease, Albright’s disease of bone, Albright’s syndrome, Albright’s syndrome with precocious puberty, Albright-McCune-Sternberg syndrome, Albright-Sternberg syndrome, Fibrous dysplasia with pigmentary skin changes and precocious puberty, MAS, Osteitis fibrosa disseminata, PFD, POFD, Polyostotic fibrous dysplasia.

Symptoms of McCune Albright Syndrome:

• This disorder affects the bones, the skin and the Endocrine tissues.

• People affected show symptoms of  Polyostotic fibrous dysplasia. Polyostotic means abnormal tissues in bones and fibrous means fibre tissues will replace bone areas. This leads to weakened bones and the chances of getting multiple fractures are high. 

• The replacement of bones with fibrous tissues in all parts of the body leads to uneven growth of body parts. Face structure may be different to others. Tissues in leg bones may cause the uneven length of the leg, which makes a patient limp.

• Less than 1% of the people affected are prone to bone cancer.

• Light brown patches on the skin may appear in some cases. These are called café-au-lait spots. These may have smooth borders and only appear on one side of the body.

• Due to cysts forming in ovaries, girls start menstruating at the age of 2. Early puberty is due to excess estrogen produced by these ovarian cysts.

• This disease affects mostly endocrine functionalities. 50 per cent of people affected by McCune-Albright syndrome may experience hyperthyroidism. This is due to cysts forming in the neck, like Goitre which releases excessive thyroid hormone. So these nodules formed at the thyroid glands will lead to high BP, increased heart rate, sweating and tremors. 

• An increase in the growth hormone released by the pituitary glands results in longer feet and palms. Some may have distinct facial structures called ‘coarse’.

• Some infants below age 2 may experience increased levels of ‘Cortisol’ produced by the adrenal glands. This leads to Cushing syndrome. This syndrome increases weight gain in the head and upper body. Other symptoms may include fragile skin, delayed growth, and fatigue.
• Few may develop polyps in the gastrointestinal tract, which are usually benign.

Causes of McCune Albright Syndrome:

• Mutations in the GNAS gene cause McCune-Albright syndrome. 

• This gene makes a protein complex called guanine nucleotide-binding protein simply a G protein. 

• This protein complex influences cell functions and their activity.

• This protein complex also controls adenylate cyclase, an enzyme.

• The mutations in the GNAS gene lead to overproduction of the enzyme and excessive hormone production.

• This excessive hormone production results in abnormal cell functionalities. 

Frequency:

One in 100000 to one in 1000000. It is considered one of the rare diseases in the world.

Inheritance:

This syndrome is not inherited. Parents may have normal GNAS genes but children may have mutations. Also, one individual may have cells with a normal GNAS gene and some cells with a mutation of this gene. So severity depends on the location of the cells and their reproduction rate. So this condition is not passed on to the next generation. It is also one of the rare diseases in the world.

8. Lesch Nyhan syndrome:

Other names: Choreoathetosis self-mutilation syndrome, Complete HPRT deficiency, Complete hypoxanthine-guanine phosphoribosyltransferase deficiency, Deficiency of guanine phosphoribosyltransferase, Deficiency of hypoxanthine phosphoribosyltransferase HGPRT deficiency, Hypoxanthine guanine phosphoribosyltransferase deficiency, Hypoxanthine phosphoribosyltransferase deficiency, Juvenile gout, choreoathetosis, mental retardation syndrome, Juvenile hyperuricemia syndrome, Lesch-Nyhan disease, LND, LNS, Primary hyperuricemia syndrome, Total HPRT deficiency, Total hypoxanthine-guanine phosphoribosyl transferase deficiency, X-linked hyperuricemia, X-linked primary hyperuricemia, and X-linked uric aciduria enzyme defect.

Symptoms of Lesch Nyhan syndrome:

• This syndrome is exclusively seen in Males. Males may have neuralgia and behavioural disorders.

• Excessive production of Uric acid. Uric acid is a waste by-product present in blood and urine.

• This leads to uric acid deposits under the skin and joints. This condition is called goiter Arthritis.

• Also, excessive production of uric acid will form stones in the kidneys and gallbladder.

• Neuralgia leads to Dystonia (tensing of muscles), chorea-jerking movements), and Ballismus (failing of limbs). 

• People affected by this syndrome cannot walk, or sit and need a wheelchair. 

• Self-injuries like sudden falling, biting and head banging have been seen in some people.

Causes of Lesch Nyhan Syndrome:

• Mutations in the HPRT-1 gene cause Lesch-Nyhan syndrome. This gene makes an enzyme called hypoxanthine phosphoribosyltransferase 1.

• This enzyme recycles purines, which are the building blocks of DNA and RNA. Recycling of purines ensures quality production of building blocks in DNA and RNA.

• Deficiency in this enzyme due to mutations in the HPRT-1 gene causes Lesch-Nyhan syndrome. When the body lacks this enzyme, the recycling of purines doesn’t occur, resulting in excessive uric acid formation in the body.

• The enzyme somehow controls the production of dopamine, a chemical messenger produced in the brain that controls physical movements and emotions. Research is still going on to identify how this syndrome is associated with dopamine production.

• A shortage of dopamine causes neuralgia and other behavioural problems.

Frequency:

One in 380000 individuals. It is widespread in all parts of the world. This is one of the rare diseases in the world.

Inheritance:

This is inherited in the form of an X-linked recessive pattern. Males have one X chromosome and females have 2 X-chromosome. So a mutation in male X-chromosome is enough to get this syndrome. In females, mutations should be in 2 X-chromosomes to get this disease. So mutations in both chromosomes are impossible so this syndrome doesn’t appear in females. Only males are affected.

9. Nail Patella Syndrome:

Other names: Fong disease, Hereditary onycho-osteodysplasia, Hereditary osteo-onychodysplasia, Osterreicher syndrome, Pelvic horn syndrome, Turner-Kieser syndrome.

Symptoms of Nail Patella Syndrome:

• Abnormalities in the nails, elbows, knees and pelvis. The symptoms may vary from person to person in the same family.

• Nails may be underdeveloped, discoloured, pitted and ridged. The skin under the nail is a triangular shape rather than a crescent shape. 

• Fingernails are more affected than toenails. Thumb fingernails are the most affected.

• Skeletal abnormalities in elbow, knee and pelvis. Some people with this syndrome may not have kneecaps or are small and irregular. Some may have dislocated kneecaps. 

• People can’t stretch their arms wide as they may have abnormal webbing in the elbow area. Bones are bent outwards which stops full stretching of elbows.

• Outgrowths of iliac bones in the pelvic region. These are called iliac horns. These are not harmful and can be identified only through X-rays. It is rare to have iliac horns without having Nail-patella syndrome.

• Kidney failure and glaucoma are some other symptoms of this syndrome.

Causes of Nail Patella Syndrome:

• Mutations in the LMX1B gene cause this syndrome. This gene is responsible for the proper functioning of other genes.

• It binds some regions of DNA, and it is called a transcription factor. 

• This gene is important during the embryonic formation of the limbs, kidneys, and pelvis. 

• Mutations in the LMX1B gene lead to abnormal elbows, kidneys, knees and pelvis. 

• It is still a mystery how mutations in LMX1B are associated with Nail-patella syndrome.

Frequency:

One in 50000 individuals. It is one of the rare diseases in the world.

Inheritance:

This is inherited in the form Autosomal Dominant Pattern. One copy of the altered gene from one of the parents is enough to get this disorder. Some may get affected due to other mutations with parents showing no symptoms of this disorder.

10. Paroxysmal Extreme Pain Disorder:

Other names: Familial rectal pain, PEPD, PEXPD, Submandibular, ocular, and rectal pain with flushing.

Symptoms of PEPD:

• Skin redness and flushing. Sharp pains last a few seconds to minutes in several parts.

• These pains may last for longer periods. 

• The lower part of the body is mostly affected like around the rectum.

• Irregular bowel movements can cause pain in the rectum.

• Constipation, apnea, slower heartbeat and seizures are some other symptoms.

• Pain starts in the lower part at an early age and with age, the area of pain shifts towards the upper part of the body including the face and jaw.

• Pain triggers with temperature differences, spicy food and cold drinks. Cold wind alleviates sharp pain.

• This disorder mainly affects the peripheral nervous system which connects the brain and spine to peripheral nerve cells that detect sensations like touch, pain and smell.

Causes of PEPD:

• Mutations in the SCN9A gene cause this disorder. This gene makes one of the subunits of the sodium channel named NaV1.7. 

• Sodium channels send sodium ions to cells to generate and transmit electrical signals. 

• These are found in nociceptors which transmit pain signals to the brain through the spinal cord.

• Mutations in the SCN9A gene send abnormal sodium ions to the nociceptors. Increased sodium ions lead to sharp pain attacks. 

• Proper research is still pending to know how these pain signals change their position with age, changes in breathing, and seizures.

Frequency:

Paroxysmal extreme pain disorder is a rare disease, and only 80 people have been affected till now.

Inheritance:

Paroxysmal extreme pain disorder is inherited in the form of an autosomal dominant pattern. One copy of the altered gene from one of the parents is enough to cause this disorder. Some may get affected due to other mutations, with parents showing no symptoms of this disorder.

Conclusion:

Rare diseases affect one individual in every lakh people. These are non-treatable, as these diseases may not have proper medical research. Medicines are unknown. The treatment equipment has been uninvented. Some rare diseases may not have tests to identify them. When anyone is affected by these rare diseases, the chance of survival is less than 10 per cent. Most of these rare conditions are due to genetic disorders. Mutations in various genes cause rare diseases. So this article gives you the top 10 rare diseases that you have never heard of. There are a lot more rare diseases you can search for on Google to get details. 

Feb 29th of every year is considered World Rare Disease Day. The National Organization for Rare Disorders (NORD) is a voice for affected people. The theme of World Rare Diseases Day 2024 is ‘Share your colours’.