Rare Diseases: Listing the Unknown

 The world is definitely a strange place. On every look and corner, one can find innumerable undiscovered aspects of life. From unknown animal species to untraced diseases in humans, one can gain an abundant and unending knowledge. The rarity of disease is indeed measurable, however, what lies unmeasurable is the extent of its knowledge to humans. In many cases, a disease that may be rare in a certain geographical terrain may not be unexplored in another. Therefore, this piece of knowledge and information would only talk about diseases that are largely rare or are rare at the global economic scale.

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Before enlisting the rare diseases, let us discuss more about the concept. A rare disease is generally a health issue/ condition that only affects a small group of the population and has a low prevalence rate. On a global scientific level, around 6000-8000 rare diseases exist, with the rarity increasing at a regular and consistent rate. According to Orphan Drug Act, a disease can be termed as a rare one if and only if it affects less than 2,00,000 people in the United States. Congress in the U.S., enacted the Orphan Drug Act in 1983 to encourage the production of medicines to treat uncommon and rare disorders. Companies and other drug researchers can ask the FDA to designate a drug as an orphan if the medication satisfies certain requirements.

Over 30 million Americans suffer from one of the over 7,000 uncommon diseases. There are no known treatments for the majority of rare illnesses, many of which are fatal. The complex biology and incomplete knowledge of the natural history of many rare diseases make developing drugs, biologics, and medical devices for use in treating uncommon diseases difficult for various reasons. Conducting clinical trials can be challenging due to the rare disease's naturally limited patient pool. Although the FDA has authorized hundreds of medications for rare diseases since the Orphan Drug Act was passed into law in 1983, the majority of rare diseases still lack FDA-approved treatments. To assist the development of products for rare diseases, the FDA collaborates with a variety of individuals and organizations, including patients and manufacturers of drugs and devices. The study of uncommon diseases is complicated, varied, ever-evolving, and there is a knowledge gap in both medicine and medical science. There are now 450 uncommon diseases known to exist in India. Both internationally and domestically, rare diseases present a significant challenge to public health systems in terms of the difficulty in gathering epidemiological data, which hinders the development of burden of disease and cost estimations, the difficulty in research and development, the difficulty in making an accurate and timely diagnosis, the complexity of tertiary level management involving long-term care and rehabilitation, and the unavailability and prohibitive cost of treatment.

According to the World Health Organization (WHO), a rare disease is one that affects no more than one person out of every 1000. Various nations have developed their own definitions to meet their unique needs and in light of their population, healthcare system, and resources. A disease or ailment affecting fewer than 200,000 patients nationwide is considered rare in the US (6.4 in 10,000 people). A rare disease affects no more than 5 persons in 10,000 and can be fatal or very debilitating. In Japan, uncommon diseases are defined as those that have less than 50,000 prevalent cases (0.4%) nationwide.

Table. 1: Definition of rare diseases in different countries

Source: The I.C. Verma Sub-Committee Report' Guidelines for Therapy and Management'

While almost all rare diseases are hereditary, not all rare diseases are. There are also highly uncommon varieties of infectious diseases, such as rare malignancies and autoimmune diseases. Many rare diseases still have unidentified causes. Rare diseases are severe, frequently chronic, and degenerative illnesses. Many uncommon disorders, such as proximal spinal muscular atrophy, neurofibromatosis, osteogenesis imperfecta, chondrodysplasia, and Rett syndrome, have symptoms that can be seen at birth or in infancy. However, more than 50% of rare diseases, such as Kaposi's sarcoma, thyroid cancer, amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, Crohn's disease, and Huntington's diseases, develop throughout adulthood.

Table. 2: Global percentage and stats related to rare diseases

Source: World Economic Forum

Finding methods to identify, treat, and even prevent several uncommon diseases has seen significant advancement in recent years. However, since there are no cures for the great majority of rare diseases, much more needs to be done. Drug firms are encouraged to create therapies for uncommon diseases by the Orphan Drug Act of 1983. More than 340 treatments have received FDA approval in the 25 years after the Act was made a federal law in the United States. The Therapeutics for Rare and Neglected Diseases (TRND) program was recently formed by the National Institutes of Health (NIH) in an effort to build an integrated research pipeline and accelerate the creation of novel therapies for rare and neglected diseases. Of course, not every rare disease is as uncommon. In actuality, rare diseases can be simply grouped into various orders of magnitude. There is no agreed-upon terminology to distinguish between rare diseases that are more prevalent and those that are so uncommon they only affect a small number of people globally. Rarity is a spectrum, and the word "rare" is relative. Below is the discussion for some of the rare diseases prevalent in the world:

Fig.1: A list of top rare diseases in the world

Alice in Wonderland Syndrome (AIWS)

An assortment of symptoms with a change in body image is referred to as the "Alice in Wonderland Syndrome" (AIWS). The inaccurate perception of body part sizes or the sizes of external objects is attributed to a change in visual perception. Nighttime perceptions are the most frequent. The prevalence of Alice in Wonderland syndrome is estimated to be between 10 and 20 percent of the population, and most affected people are thought to experience it only a few times throughout their lifetimes. In 1955, British psychiatrist Dr. John Todd first described AIWS. Todd chose Lewis Carroll's well-known classic as the inspiration for the name because the sickness is similar to what Alice went through. Some interesting facts about this disease are:

• Things look bigger or smaller than they actually are. Other person with Alice in Wonderland syndrome may view their bodily parts in a distorted fashion, either much bigger or much smaller. In some circumstances, it's not simply an external object that seems to alter the size. Naturally, while experiencing AIWS for the first time, people may feel some concern and fear about what is creating these impressions. It depends on the person, but for those who experience recurrent incidents, it may eventually be more mysterious than terrifying.
• The author of Alice's Adventures in Wonderland, Lewis Carroll (real name Charles Lutwidge Dodgson), may have drawn inspiration from his migraines while creating the novel. When Alice drinks from a bottle with the message "Drink me," she shrinks to a height of less than a foot in the story. She eats a cake shortly after that, which makes her exceedingly tall and causes her head to strike the ceiling. In fact, based on some of his journal entries, it appears that novelist Lewis Carroll most likely suffered from migraines. It's been hypothesized that he may have personally had Alice in Wonderland syndrome, which may have contributed to the development of some of those odd passages in those writings.
• What causes Alice in wonderland syndrome is uncertain, according to experts. The parieto-occipital region of the brain may be the source of Alice in Wonderland syndrome when it occurs along with migraine. The occipital area controls vision, whereas the parietal area controls how the body and space are perceived. Although it seems to start in the frontal lobe when AIWS is connected to epilepsy, there is still much to understand about that.
• Alice in Wonderland syndrome is so uncommon that many professionals may never experience it throughout their careers. Although specialists concur that it's uncommon, it's unknown how common it actually is. No epidemiological studies that would demonstrate the prevalence of AIWS in the general population have been conducted as of yet. In addition, according to a review written in June 2016 and published in Neurology Clinical Practice, there is no established method for diagnosing the illness. When two people present with the same symptoms, one may be diagnosed with AIWS, and the other may not. The absence of diagnosis may also be a result of some people's reluctance to discuss their symptoms for fear that others may mistake them for having a mental condition or hallucinations.
• The syndrome known as Alice in Wonderland is not specifically treatable. In the event that a migraine is to blame, we would prescribe migraine medication as a remedy. If you frequently experience migraines, taking preventive medicine and treating acute migraine attacks as needed. Seizure medication would be necessary if Alice in Wonderland syndrome is linked to seizures.

OTHER SYMPTOMS:

Some other symptoms of this rare disease include distorted time perception (time moving too quickly or slowly), distorted touch perception (sensation received by touching a surface is entirely wrong and unreal), and distorted sound perception.

Laughing Death

Only the indigenous Fore people of New Guinea were home to Laughing Death, also known as Kuru. In the 1950s, the illness, which was marked by sudden fits of maniacal laughter, made headlines and attracted medical professionals worldwide. American and Australian doctors saw men and women with trembling limbs that went away with rest, but a month to three months later, the patients would start to wobble and stumble, lose their ability to stand, develop cross eyes, and lose the capacity to speak coherently before passing away. According to the National Institute of Neurological Disorders and Stroke, testing on the deceased's brain revealed that the death had been brought on by developing "swiss-cheesing" holes in the brain. Eventually, American doctor Carleton Gajdusek discovered that the sickness was being spread by the tribal custom of eating deceased family members. The epidemic ended after cannibalism was eradicated. Gajdusek received the Nobel Prize for his contributions in 1976. If you enjoy cannibalism, you might pass out from laughter. This occurred to an indigenous tribe in Papua New Guinea when the disorder, known as the "laughing death" nearly wiped off the entire tribe. This illness is a direct effect of cannibalism, which was widespread among an indigenous group in Papua New Guinea. Some interesting facts about this disease are:

• You can genuinely laugh until you're dead if you have a rare and untreatable neurological illness. This illness, sometimes known as Kuru, was widespread among the Fore people of Papua New Guinea.
• Uncontrollable trembling and pathological laughter are common side effects. Essentially, this illness is a sort of transmissible spongiform encephalopathy (TSE).
• Prion proteins or improperly folded proteins are the cause. This illness cannot be brought on by bacterial, viral, or fungal diseases. After consuming a tainted brain, a person often passes away within a year.
• A patient with this illness will undoubtedly pass away because it is incurable. Fortunately, there haven't been any documented occurrences in almost a decade. This illness may have vanished from the planet; we can only hope.

CAUSE OF THE DISEASE:

According to experts, cannibalism in funeral rites may be to blame. In this culture, family members who had passed away were cooked and consumed to release their spirits. Typically, females and young children eat the brain, which contains infectious prions. This condition might take anywhere between 10 and 50 years to develop fully. As a result, even though cannibalism in this society ended in the early 1960s, the illness continued to spread until 2009. After that, the cases stopped.

Hutchinson-Gilford Progeria Syndrome (HGPS)

Since 1896, more than 130 cases have been reported in scientific literature globally. The prevalence rate of this rare disease is 1 in 8 million. Currently, there is no cure for this disease. The symptoms of HGPS, an extremely rare genetic condition, reflect features of ageing at a relatively young age. One in eight million live births are affected by the illness, and those born with it often live into their mid-teens or early twenties. Due to this hereditary disease, aging begins to rapidly and dramatically manifest in childhood. Prominent eyes, a thin beaky nose, thin lips, a tiny chin, and projecting ears are among the traits of the typical face. Some interesting facts about this disease are:

• Most progeria-affected children eventually pass away from heart issues or strokes. A progeria-affected child should expect to live for roughly 13 years on average. Some people with the condition may pass away sooner, while others may survive longer—up to 20 years—than others.
• Progeria is typically discovered during infancy or early childhood years, frequently during routine examinations, when a baby first displays the premature aging indications.
• There are no known risk factors for progeria, such as a person's lifestyle or the environment in which they live, or for developing progeria while pregnant. Progeria is incredibly uncommon. The likelihood of having a second progenie is between 2 and 3 percent for parents who already have one progenie.
• Progerian children typically experience substantial arterial stiffening (atherosclerosis). This disorder is where the artery walls stiffen and thicken, frequently limiting blood flow. Arteries are blood channels that transport nutrients and oxygen from the heart to the rest of the body. Most progerian children pass away from complications brought on by atherosclerosis.
• Common signs and symptoms of this rare disease are slowed growth, below-average height and weight, hair loss, including eyelashes and eyebrows, narrowed face, small lower jaw, thin lips and beaked nose, head disproportionately large for the face, high-pitched voice, visible veins, prominent eyes and incomplete closure of the eyelids, thinning, spotty, Some hearing loss, loss of fat under the skin and loss of muscle mass, hip dislocation, insulin resistance, and wrinkled skin.

CAUSE OF THE DISEASE:

A single gene mutation brings on progeria. The lamin A (LMNA) gene produces a protein required for binding the cell's nucleus together. A progerin-like variant of the lamin A protein, which is produced when this gene is defective (mutated), causes cells to become unstable. This seems to accelerate the aging process in progeria. Progeria is an uncommon genetic abnormality that isn't frequently handed down through families. In most instances, the gene mutation is a rare, random event.

Stoneman Syndrome

Stoneman Syndrome, also known as fibrodysplasia ossificans progressive (FOP), is a condition that gradually transforms connective tissue such as tendons, muscles, and ligaments into bone. The diseases gradually advance from the neck to the shoulders, then go down the lower body before reaching the legs. As the condition progresses, it will gradually restrict how much the body can move. The patient has problems opening their mouth, which makes eating and speaking difficult. Heterotopic ossification (HO), a permanent process in which a second skeleton develops over the first, can result in enormous bone growth as a result of surgical attempts to remove the bone development. After a slight accident or fall, people with this syndrome may become less mobile because the stimulation of bone formation causes this. Due to the rarity of this disorder's occurrence, fibrosis or cancer may be misdiagnosed as this disorder's symptoms. The patient will be put in even greater danger if a misdiagnosis results in a biopsy. There are presently no treatments for this ailment because it only affects one in every 2 million people. Some interesting facts about this disease are:

• When many soft tissue sites experience irregular episodic bone growth, it typically causes stiffness, restricted motion, and eventually ankylosis (fusion) of the afflicted joints (neck, back, shoulders, elbows, hips, knees, wrists, ankles, and mouth - frequently in that order).
• The first clinical manifestations of this illness are these alterations in the skeleton, which are congenital (existing at birth). A shortened great toe, a deformed distal first metatarsal, a missing or aberrant first phalanx, and/or an irregular interphalangeal joint are typical skeletal abnormalities linked to FOP.
• A typical physical trait of people with FOP is chronic swelling in numerous body areas. When newly produced bone presses on lymphatic capillaries, impeding the flow of tissue fluid, swelling may happen in conjunction with the unusual bone growth that characterizes FOP. It may also happen independently. A lack of pumping motion within the ossified (hardened) muscle can also contribute to swelling by causing blood and tissue fluids to collect in a limb (such as the arms and/or legs).
• In about 50% of those affected, hearing impairment is present. People who have more severe variant FOP may experience hair loss or a modest cognitive delay.
• The first case of FOP, an extremely rare inherited connective tissue condition, was discovered in the 18th century. There are about 900 confirmed patients worldwide out of an estimated 4000 affected people. All racial groups and both sexes are equally affected by this illness.

CAUSE OF THE DISEASE:

It is not predisposed to either race or gender. The first 10 years of life are when the disease postnatally develops. Autosomal dominant genetic inheritance patterns can be acquired from either parent. Mutations in the activin receptor 1a/activin kinase 2 (ACVR1/ALK2) are the genetic etiology of FOP.

Porphyria

Porphyria is notorious for its purple urine and faeces as well as the possibility that it affected the "crazy" English King George III in the 18th century. The epidermis and neurological system are both impacted by porphyria, which causes problems with the generation of "heme," a protein necessary for red blood cells. Attacks cause nausea, vomiting, constipation, abdominal pain, and stomach cramps. Other signs include swelling, irritation, and a heightened sensitivity to the sun. Also possible is increased hair growth on the forehead. The toxins left over from failed heme synthesis can impact the color of other places, especially after exposure to sunshine. The teeth and fingernails can occasionally take on a crimson hue. These poisons cause black urine and faeces, respectively. This illness may have affected Mary Queen of Scots, Vincent Van Gogh, and King Nebuchadnezzar of Babylon, per some publications. Some interesting facts about this disease are:

• Porphyria falls into one of two broad categories: cutaneous (which primarily affects the skin) and acute (which primarily affects the neurological system). Skin and neurological system symptoms coexist in some forms of porphyria.
• The precise type and severity of porphyria determine the individual signs and symptoms. Usually, one or both parents convey an aberrant gene to their offspring, causing the youngster to develop porphyria.
• Although porphyria cannot be cured, you may be able to manage it if you make specific lifestyle adjustments to minimize precipitating symptoms. The sort of porphyria you have will determine how your symptoms are treated.
• Porphyrias that manifest suddenly and can have severe symptoms in the neurological system are referred to as acute porphyrias. After the attack, symptoms typically get better progressively over days to weeks. The most prevalent type of acute porphyria is acute intermittent porphyria. Cutaneous porphyrias are types of the disease that manifest as skin symptoms when sunlight exposure, but they typically have no effect on your neural system. Of all the porphyria types, porphyria cutanea tarda (PCT) is the most prevalent.
• Some common signs and symptoms of the disease include severe abdominal pain, sensitivity to the sun and sometimes artificial light, causing burning pain, sudden painful skin redness (erythema) and swelling, urination problems, rapid or irregular heartbeats you can feel (palpitations), high blood pressure, blisters on exposed skin, usually the hands, arms and face, fragile thin skin with changes in skin color (pigment), pain in your chest, legs or back, constipation or diarrhea, nausea and vomiting, muscle pain, tingling, numbness, weakness or paralysis, red or brown urine, seizures, mental changes, such as anxiety, confusion, hallucinations, disorientation or paranoia and breathing problems.

CAUSE OF THE DISEASE:

There is an issue with heme production in all forms of porphyria. Heme is a portion of haemoglobin, a protein found in red blood cells that transports oxygen from the lungs to every cell in your body. Eight separate enzymes are required for the formation of heme, which takes place in the liver and bone marrow; the lack of a particular enzyme determines the kind of porphyria. In cutaneous porphyria, the porphyrins accumulate in the skin and produce symptoms when they are exposed to sunlight. The accumulation harms the nerve system in acute porphyrias.

This article enlists 5 rare diseases prevalent in the society. Since there are innumerable rare diseases, knowledge about few does no harm. Knowledge must be grabbed from anywhere and everywhere possible.

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