Rarest Diseases in The World

Rarest Diseases in The World:

This year, EPSA is acknowledging February 29 as Rare Diseases day. As a crucial part of healthcare system, we believe we should be more informed about such diseases as well as more common ones. We are all very aware and of knowledgeable in cold, flu, allergies, asthma, AIDS, Crohn’s, cancer and many more that are seen frequently across the globe. But what about The Rarest Diseases İn The World?  Even though these diseases are very rare. It is a fact that they have occurred in a certain point and there is no guarantee that they will not be seen again. If and when that happens, it is crucial that all aspects of healthcare are ready and providing the best service. Treatment plan is just as important as diagnosing these diseases. This can be challenging for a few reasons

Time and Money management: Many researchers might opt to study frequent occurring diseases than rare ones because their resources and time will be of use to more patients- therefore saving more lives.

Lack of knowledge: As future pharmacists, we are taught almost none of these rare diseases therefore took no interest in researching any of them.

Limited Data: Because these diseases are so rare, there is very little one can work with. This might cause a research to not be ideally inclusive and well-rounded. It can be extremely challenging to work with minimal data found in reports from the past.

The Pathology of Rare Diseases: As you will see further in this blog, almost all rare diseases occur because of genetic mutations. Approaching mutations is different than approaching a pneumonia- per se. Because the pathology is encoded deep in cellular basis, it is extremely challenging to treat it. We know that CRISPR- CAS9 and many genetic therapeutics are proven to work, but are very expensive and not widely available in the world. This causes the treatments to genetic diseases to be symptomatic rather than treating the source of the pathology.

Here, we have gathered the rarest diseases in the world. And yes, there is one that is “the rarest”

Hutchinson-Gilford Progeria Syndrome:

Shortly referred as just “progeria”, HGPS can simply be described as aging way faster than normal. This aging process is so fast, that the average life span is 14.5 without treatment. It might sound a little odd, but it is literally aging prematurely. Think about all the symptoms that we might come across older patients. Coronary conditions, wrinkly skin, hearing and eyesight loss, skeletal issues. Your typical geriatric case.

The cause is- you guessed it- genetic mutations. Heterozygous pathologic variants of LMNA cause this disease as well as 500 other pathological mutations. The mutation causes abnormal production of the protein progerin. The production of progerin is the parameter for the diagnosis.

Contrary to its rare occurrence, HGPS is highly researched and there is an FDA approved drug for its treatment. Lonafarnib inhibits post-translational farnesylation of progerin therefore making the symptoms less intense. It comes with its toxicities such as diarrhoea, GIS discomfort, appetite loss. Lonafarnib increases the lifespan about 2-3 years on average.

The treatment plan also includes lifestyle managements such ass no intense activities, conjunctive hydration, regular ECGs, joint and dental care and staying away from crowds.

Werner Syndrome:

Werner syndrome is similar to HGPS on the surface. Apart from complete different pathophysiology, the main difference is that Werner syndrome is an accelerated aging process that occurs after the ages 30 on average. After a person with WS hits their third decade in life, complications in relations to aging start to surface. This can be listed as: diabetes mellitus type 2, osteoporosis, atherosclerosis, deep ulcerations in tendons leading to amputations, truncal obesity, malignancies, early loss of fertility and many more.

The root cause of this syndrome is also genetic mutations. WRN gene mutations are responsible for classical WS cases. 1,432- amino acid bearing WRN protein is seen to mutate more than 70 different ways, causing classical WS, around the globe.

The diagnosis is usually given by the characteristic foundings in early aging such as cataracts, dermatological abnormalities, thin and grey hair. If the features are not definitive, molecular genetic testing can be done in order to identify the pathogenic WRN mutations.

Treatment plan is for managing the symptoms and preventing complications WS might cause. This can be done by lifestyle managements, maintaining a healthy level of cholesterol, blood sugars, bone density and abstaining from smoking. Regular check-ups for overall health and especially for coronary heart diseases are crucial since the average lifespan for WS is 54, death cause by myocard infarctus, as known as heart attack. Patients should be encouraged to stay away from direct sun exposure since it might cause melanoma.


Methemoglobinemia is a disorder that causes the iron in our hemoglobins to form the oxidized ferric state FE3+, rather than the normal and health ferrous state Fe2+. Ferric iron cannot bind to and transport the oxygen to tissues. This leads to hypoxia. But because there are no associations with the hemoglobin counts, this circumstance is called “Functional Anemia”. Referring to its name, hemoglobins exist and enough by count, but the iron is not in the ideal state to carry the oxygen.

This disorder can be caused by congenital abnormalities or acquired later in life by faulty processes. Congenital methemoglobinemia is cause by the cytochrome b5 reductase (CYB5R) coding gene mutations. Or mutations in genes that code globin proteins. The CYB5R enzyme utilizes NADH to reduce the very little amount of normally occurring ferric state during oxygen transportation. Acquired methemoglobinemia can occur from a side effect of drugs or toxication. Benzocaine, Lidocaine, Sulphonamide are among these causes. Food preservative nitrites can be the root cause as well.

Methylene blue is vastly used treatment. It uses an alternative way for the methemoglobin to be reduced. The NADPH-MetHb is a less effective way to reduce the methemoglobin, but oxidative stress and exogenous electron donors- in this case methylene blue- can increase the efficiency. Methylene blue treatment is a very complicated and crucial process. The dosage and applications may vary. Methylene blue can be contraindicating for some circumstances, therefore it is utterly important that the treatment is done by experts and professionals in this field. Treatment requires multidisciplinary work and caution.

Ascorbic acid, as known as Vitamin-C is also proven to improve the reduction, but it does not have the ideal reaction rate. This makes it the secondary choice of treatment when Methylene Blue is not available for treatment. N-acetylcysteine is also suggested to enhance the treatment from in vitro study gatherings. High flow or hyperbaric oxygen deliveries to the patient are also in use.

Stone man syndrome:

Often referred as stone man syndrome, Fibrodysplasia ossificans progressiva is also a genetic disorder. This rare condition can simply be described as ossification of soft tissues. Although that might be true to some degree it is a sneaky condition that presents itself at usually the third decade of life. The ossification occurs in tissues such as ligaments, tendons and muscles. Newly formed hard tissue resembles bone formation because osteoblasts take part in the process.

The condition is usually not noticeable at birth, but most patients are seen to have malformations at their great toes.  Later in life, FOP surfaces with inflammation at soft tissues. Especially joints are the main discomfort in most cases. Neck, shoulder and spine are the most problematic parts then followed by ankles, elbows, knees, hips and jaw approaching towards the fourth decade in life.

After the condition surfaces, patients gradually start needing assistance with their Daily needs eventually leading to the need of a wheelchair. The average lifespan for FOP patients is 40 years. Death occurs mostly from thoracic insufficiency syndrome and its complications.

The mutation that causes FOP, happens in the ACVR1/ALK2 gene. These genes code the receptor ALK2 which binds with Bone Morphogenic Proteins (BMP) pathway in the bone matrix. The BMP’s takes role in bone formation in skeletal muscles.  Muscular trauma and invasive procedures such as injections or surgeries can also induce acute bone formation in patients.

The treatment for the condition is managing the symptoms. There are drugs that are in clinical trials and may be available in the future. As of now, NSAIDs, muscle relaxants, corticosteroids, amino bisphosphonates and COX-2 inhibitors are in use.

Menkes disease:

Menkes disease is X-linked recessive genetic condition that causes copper deficiency. Beside from being rare it is also fatal if not diagnosed in early childhood.  Copper metabolism abnormalities are caused by the mutation in the ATP7A gene. Over 300 mutations have been reported regarding this gene. Because the mutation is X-linked and recessive, most patients are male.

ATP7A is an active Cu transporter. Cu is essential for Cu-dependent enzymes. ATP7A transfers copper from cytoplasm to the Golgi complex to be used for metalation of cuproenzymez. If Cu levels are high, it effluxes out from the cell. The abnormality of ATP7A causes the excess copper to pile in the enterocytes and cannot efflux out from the cell. This causes copper deficiency. There are many crucial enzymes that need copper. Dysfunction of these enzymes can occur due to lack of copper and are life threatening. There are many neurological threats caused by copper deficiency such as glial cells and neurons being deprived of copper. Neuronal damage, ischemia, infarction and seizures occur in relations to neurological abnormalities.

The main factor in order to manage this condition is early diagnosis. It is utterly important that even at infancy, the diagnosis should be given.  The reason being is death can occur even as early as 6 months. Therefore, early treatment should be provided.

Treatment strategies come with its challenges. Copper should be given without the block of gastrointestinal system. Therefore, oral treatment is not an option. Subcutaneous or intravenous route is more effective. If the diagnosis and the treatment is done early in life, most of neurological damage can be prevented. Copper-histidine makes recognizable changes in appearance of the patient.

Multidisciplinary work is essential especially for this disorder. Because the patient may have seizures, nutrition issues, surgical procedures and many more complications.

RPI deficiency:

Now, onto the rarest disease in the world. Ribose-5-phosphate isomerase deficiency. This disease has only one case, ever. This specific patient was suffering from leukoencephalopathy. Ribitol and D-arabitol polyols were found in high concentrations in the brain and body fluid. RPI is a pentose phosphate pathway enzyme. The cDNA encoding RPI had two different mutations. One inherited from their mother and a missense mutation. This caused the PPP abnormalities. Because the polyol metabolism knowledge is very little at the moment. It is hard to determine the complex process that caused this case. Pentose and polyol metabolisms need to be enlightened for these cases to be studied ideally.

Gordon, L. B., Brown, W. T., & Collins, F. S. (2003). Hutchinson-Gilford Progeria Syndrome. In M. P. Adam (Eds.) et. al., GeneReviews®. University of Washington, Seattle.

Batista, N. J., Desai, S. G., Perez, A. M., Finkelstein, A., Radigan, R., Singh, M., Landman, A., Drittel, B., Abramov, D., Ahsan, M., Cornwell, S., & Zhang, D. (2023). The Molecular and Cellular Basis of Hutchinson-Gilford Progeria Syndrome and Potential Treatments. Genes14(3), 602. https://doi.org/10.3390/genes14030602

Gordon LB, Brown WT, Collins FS. Hutchinson-Gilford Progeria Syndrome. 2003 Dec 12 [Updated 2023 Oct 19]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1121/

Oshima, J., Sidorova, J. M., & Monnat, R. J., Jr (2017). Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions. Ageing research reviews33, 105–114. https://doi.org/10.1016/j.arr.2016.03.002

Oshima, J., Martin, G. M., & Hisama, F. M. (2002). Werner Syndrome. In M. P. Adam (Eds.) et. al., GeneReviews®. University of Washington, Seattle.

Ludlow JT, Wilkerson RG, Nappe TM. Methemoglobinemia. [Updated 2023 Aug 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537317/

Agrawal U, Tiwari V. Fibrodysplasia Ossificans Progressiva. [Updated 2023 Aug 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK576373/

Ramani PK, Parayil Sankaran B. Menkes Disease. [Updated 2023 Nov 14]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560917/

Wamelink, M.M.C., Grüning, NM., Jansen, E.E.W. et al. The difference between rare and exceptionally rare: molecular characterization of ribose 5-phosphate isomerase deficiency. J Mol Med 88, 931–939 (2010). https://doi.org/10.1007/s00109-010-0634-1

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