Abstract

This paper conducts a thorough investigation into both congenital and acquired anosmia, incorporating in-depth analysis, patient interviews, and smell tests to understand their distinct impacts and management strategies. Two case studies—one congenital, one acquired — provide personal insights into living with anosmia. The congenital case, a lifelong condition often due to suspected genetic factors, reveals adaptations in daily routines, safety strategies, and social interactions, highlighting the ingrained coping mechanisms developed from birth. The acquired case, exemplified by a long COVID patient, illustrates the abrupt sensory loss and its profound effects on quality of life, including altered food perception, emotional distress, and changes in social roles.

Diagnostic approaches and treatments are extensively discussed. For congenital anosmia, options focus on adaptation and include emerging treatments like olfactory training and gene therapy. Diagnostic imaging such as MRI and CT scans are crucial for uncovering structural anomalies. In contrast, treatments for acquired anosmia offer potential for recovery. Olfactory training, medications, and alternative therapies are evaluated for their efficacy in restoring smell. Also, the paper alludes to a societal problem—that some people in the world lack modern testing or scanning because of inequality.

Introduction

Motivated by a close friend's experience with congenital anosmia and his inability to seek medical diagnosis due to financial constraints, I am conducting a study on anosmia. I aim to uncover the underlying causes of this condition and determine if any olfactory function remains. Additionally, I am interested in the potential of developing perfumes specifically designed for individuals with anosmia. Anosmia, derived from the Greek words “an” (without) and “osme” (smell), refers to the total loss or absence of the sense of smell.[1] This olfactory disorder can be congenital or acquired later in life.[2] On a molecular level, anosmia is linked to disruptions in the development and function of the olfactory system, which depends on numerous molecular signals and pathways.[3] Genetic factors, such as mutations in specific genes, can result in structural and functional abnormalities in the olfactory system, leading to anosmia.[4] Examining the genetic basis of anosmia offers insights into the complexities of olfactory system development and the broader clinical implications of the condition. The objective of this paper is twofold:

The primary objective of this paper is to delve into the neurobiological underpinnings and enduring ramifications of anosmia precipitated by genetic determinants. Individuals afflicted with congenital anosmia, stemming from genetic anomalies, navigate life devoid of olfactory capabilities, influencing their cognitive and emotional frameworks. Concurrently, this research seeks to elucidate the etiology and neural mechanisms behind the acquired anosmia observed in recent COVID-19 cases. The sudden onset of this symptom in the context of the pandemic offers a distinctive lens to examine the adaptability and resilience of the olfactory neural pathways, further underscoring the multifaceted nature of olfactory disruptions in society.

By comparing long-term genetic anosmia with acquired anosmia, this paper seeks to offer a thorough understanding of the neural mechanisms underlying these conditions and their wider effects on an individual's neurocognitive and emotional well-being.

Epidemiology of Anosmia

In the United States, anosmia afflicts 3% of the adult population older than the age of 40.[5] The prevalence of impaired olfaction increases with age. In 2016, the National Health and Nutrition Examination Survey (NHANES) measured olfactory dysfunction, which involved 1818 participants. Data showed that olfactory dysfunction was 4% at ages 40 to 49 years of age, 10% at 50 to 59, 13% at 60 to 69, 25% at 70 to 79, and 39% for those over 80 years of age. Anosmia affected 14% to 22% of those over 60 years of age. [6][7]

However, there are several epidemiological factors that have to be taken into account.

1. Race:

The prevalence of anosmia varies across populations. Within the scope of anosmia's racial prevalence, a distinct disparity was observed. In the USA, Blacks exhibited a prevalence of 22.3%, nearly double the 10.4% found in whites.[8] Age and gender adjustments revealed that blacks were significantly more susceptible, with older black males being the most affected. Conversely, younger white females had the lowest incidence. Several factors, including education, cognitive health, and certain genetic markers, influenced anosmia prevalence.[9] However, even after accounting for these, the racial difference remained pronounced.

2. Region & Age-Related Variations:

The risk of developing anosmia tends to increase with age, and differs from country to country.

• The U.S.-based Epidemiology of Hearing Loss Study (EHLS) found a 24.5% prevalence among those aged 53-97.[10]
• Australia's Blue Mountain Eye Study (BMES) reported a 27% prevalence in individuals aged 60 and above.[11]
• The Beaver Dam Offspring Study (BOSS) in the U.S. indicated a 13.9% prevalence for those aged 65 and above.[12]
• A U.S. population analysis revealed a 22.3% prevalence among those aged 57-85, with 3.5% being anosmic and 18.8% hyposmic.[13]
• German studies reported anosmia rates ranging from 6% to 12% in those over 65, with gender variations.[14]
• A Spanish study found that about 61% of participants aged 60 or older had olfactory dysfunction.[15]

3. Gender Disparities:

While it's commonly believed that women have superior olfactory abilities compared to men, a comprehensive meta-analysis of various studies suggests otherwise. Analyzing data from thousands of participants across different olfactory tests, the study found that although women might slightly outperform men in olfactory tasks, the effect sizes were notably small, ranging between g[16] = 0.08 and g = 0.30. Thus, the difference in olfactory abilities between genders is minimal and may not be significant in the context of anosmia.[17]

Anatomy and Physiology of the Olfactory System

The olfactory system, important for our sense of smell, has several roles in our daily lives. Apart from helping us detect dangers like smoke or spoiled food, it is crucial for understanding flavors. It works with our taste system to influence what foods we like and what we eat.[18] The olfactory system is closely connected to the parts of our brain that handle emotions and memories.[19] Direct neural links connect the olfactory bulb to areas like the amygdala and hippocampus. Certain smells can trigger strong emotional reactions and vivid memories of past events.[20] Smell also plays a subtle but important role in social interactions, providing information about a person's health, emotions, and even genetic compatibility.[21]

To delve deeper into the mechanics of smell perception, as pictured in Figure 1, when an odorant molecule is airborne, it navigates through the nasal passages to the nasal cavity. Here, olfactory receptor neurons, extensions of the olfactory bulb situated atop the cribriform plate of the brain, come into play. Each nasal cavity is home to approximately 100 million receptor cells.[22] These cells boast between 500 to 1000 distinct odor-binding proteins on their surfaces.[23] Intriguingly, each olfactory receptor cell expresses a singular type of binding protein.[24] These afferent olfactory neurons, constituting cranial nerve I, are responsible for converting a chemical signal (airborne particles) into an electrical one, which is then relayed and ultimately interpreted by the brain. The olfactory bulb then processes this signal, which is further refined by various brain structures, including the piriform cortex, entorhinal cortex, amygdala, and hippocampus. Any obstruction or damage to the pathway through which the olfactory signal is relayed and processed can lead to anosmia, a loss of the sense of smell. Such impediments can arise from inflammatory conditions like simple infections that produce mucus plugs or nasal polyps.[25] Neurological factors encompass disruptions to the sensory nerves of the olfactory bulb or any segment of the pathway that transmits the olfactory signal to the brain.[26]

Figure: Human olfactory system; Illustration by Patrick J. Lynch, medical illustrator https://www.biocycle.net/odor-monitoring-and-detection-tools/

Etiology of Anosmia

Congenital anosmia, denoting an absence of olfactory perception from birth, is an infrequent diagnosis. Notably, while 5% of the general population exhibits a complete loss of olfactory function, only 0.01% manifest this absence congenitally.[27] Congenital anosmia is in association with four conditions or diseases:

1. Kallmann Syndrome
2. Congenital Insensitivity to Pain (CIP)
3. Ciliary Dysfunction
4. Holoprosencephaly[28]

Congenital Anosmia can be caused by:

Genetic Cases

Kallmann Syndrome: Kallmann syndrome results from an isolated defect in the secretion or action of gonadotropin-releasing hormone (GnRH) and is associated with reproductive anomalies like infertility.[29] GnRH-producing neurons are situated in the hypothalamus but undergo a unique migration during embryonic life.[30] While several genes have been identified that affect this migration and the development of the GnRH neurons, the complete genetic framework of KS remains not completely understood.[31] The genes that can mutate to make someone be diagnosed with Kallman’s Syndrome are: ANOS1 (KAL1), TENM1, FGFR1, FGF8, PROK2, PROKR2, and SEMA3A.[32][33]

• ANOS1 (KAL1) Gene:

ANOS1, previously termed KAL1, is intimately linked with Kallmann syndrome. In fact, the earlier nomenclature, “KAL1,” draws its name directly from the syndrome.[34] The ANOS1 gene provides the instructions for producing a protein called anosmin-1. This protein plays a critical role during the embryonic development of the olfactory system and the hypothalamus, which are central to the sense of smell and the regulation of reproductive hormones, respectively.[35]

• • Location and Product: Located on the X-chromosome, the ANOS1 gene encodes a protein called anosmin-1. This protein has roles in several developmental processes before birth.[36]
    • Function in the Developing Brain: In the embryonic brain, anosmin-1 is vital for:
      • Neuronal Migration: The protein aids in the movement of nerve cells to their appropriate locations during development.
      • Axonal Outgrowth: Anosmin-1 is involved in the development of axons, the long threadlike part of a nerve cell that sends out impulses.
      • Cell Adhesion: The protein assists in regulating the contact between nerve cells, which is essential for communication and organization within the brain.[37]
    • Olfactory System Involvement: One of the most noted roles of anosmin-1 is its involvement in the development of the olfactory system:
      • Olfactory Neurons: Anosmin-1 helps guide the migration of olfactory neurons. These neurons originate in the developing nose and travel to the olfactory bulb in the brain, where the sense of smell is processed.[38]
      • Olfactory Bulb: The olfactory bulb is a structure in the front of the brain that is pivotal for the perception of odors. Any disruption in the development or function of this structure can lead to anosmia.[39]
    • Gonadotropin-Releasing Hormone (GnRH) Production: Another significant role of anosmin-1 is its influence on neurons that produce GnRH. These neurons also migrate during development and are responsible for the release of hormones affecting puberty and fertility.[40]

Mutations in the ANOS1 gene can lead to a deficiency or dysfunction of the anosmin-1 protein.[41] This protein plays a pivotal role in guiding the early movement of GnRH neurons (as illustrated in Figure 2). When the normal function of anosmin-1 is compromised, it can hinder the appropriate migration of the olfactory nerve axons and the gonadotropin-releasing hormone (GnRH) neurons during embryogenesis. This disturbed migration process results in the abnormal development or complete absence of the olfactory bulbs, leading to anosmia or hyposmia. Simultaneously, the affected migration of GnRH neurons can cause hypogonadotropic hypogonadism due to the reduced secretion or absence of GnRH, a pivotal hormone for triggering puberty and maintaining reproductive functions.[42]

The connection between the KAL1 (ANOS1) gene and Kallmann syndrome (KS) became apparent when researchers studied a 19-week-old male KS fetus with a full deletion of the KAL1 gene. This deletion resulted in the halted movement of the GnRH and olfactory axons' central projections at the cribriform plate, creating a complex network of neurons. Such findings indicate that KAL1 mutations can disrupt the proper movement of both olfactory and GnRH neurons, leading to a lack of smell sensation (anosmia) and Isolated Hypogonadotropic Hypogonadism (IHH).[43] While the exact function of anosmin-1 in the development of the olfactory bulb remains uncertain, it is known that anosmin-1 is present in the bulb's outer layers and interacts with cells that produce FGFR1.[44]

Figure: Schematic drawing depicting anosmin-1 (green star), FGFR1 (blue star), and GnRH (red circle) immunoreactivity in the olfactory system and rostral forebrain during human embryogenesis after 53–54 days (CS21). Red circles with blue stars at their centre represent GnRH cells that co-express FGFR1. Link

• FGFR1 (Fibroblast Growth Factor Receptor 1)

The FGFR1 gene codes for the protein fibroblast growth factor receptor 1, which belongs to a family of receptors pivotal in the transduction of cellular signals. These signals are responsible for regulating various biological processes, including cell growth, differentiation, and tissue repair.[45] The protein product of FGFR1 primarily acts as a receptor for specific molecules called fibroblast growth factors (FGFs). Upon binding to its ligand, FGFR1 activates intracellular signaling cascades, which further dictate cellular responses like proliferation or migration.[46] When mutations occur in this gene, it can impede the proper migration and development of neurons responsible for producing the gonadotropin-releasing hormone (GnRH).[47] Furthermore, it can disrupt the formation of the olfactory bulbs, which are critical for the sense of smell. Both these factors combined can manifest as the clinical features seen in KS.[48]

____ Please refer the report for further details ____

Acquired Cases:

• Traumatic Brain Injury:

Traumas, especially those targeting the cranial region, can inflict damage on the olfactory nerve or associated structures, leading to post-traumatic anosmia. The severity and permanence of the anosmia are contingent on the extent of neural damage. Olfactory dysfunction (OD) is a disorder associated with traumatic brain injury (TBI), which is prevalent in up to 20% of patients suffering from TBI. [61]

• Neurodegenerative Afflictions:

Diseases such as Alzheimer's and Parkinson's have been correlated with olfactory deficits, with anosmia often serving as an early clinical harbinger of these neurodegenerative processes.[62]

• Chronic Toxin or Chemical Exposure:

Exposures to toxic chemicals are believed to be responsible for approximately 1–5% of all olfactory dysfunctions. Given their anatomically exposed positions, both olfactory neurons and taste buds are directly exposed to environmental agents. This direct exposure renders them vulnerable to both acute and chronic toxic insults.[63]

• Neoplastic and Surgical Considerations:

Tumors, especially those in proximity to the olfactory structures, can impede olfactory function. For example, a 67-year-old woman reported a 2-year history of anosmia. Sinuscopic examination revealed no nasal or sinus abnormalities, and rhinomanometry confirmed normal nasal airway resistance. Despite no history of trauma, smoking, or decongestant overdose, an olfactory test indicated a complete loss of smell. A head CT scan revealed a sizable brain tumor at the anterior skull base, which was further characterized by T1-weighted MRI as a large extra-axial mass at the anterior skull base, impacting the cribriform plate.[64]

• Viral Infections:

Certain pathogens, most notably the recent SARS-CoV-2, have been identified as causative agents of anosmia. The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has presented a unique and alarming symptom in a significant number of patients: anosmia, or the loss of the sense of smell. This symptom, observed in approximately 52.73% of COVID-19 patients, has raised questions about the underlying mechanisms.[65] This review delves into the potential pathways and cellular interactions that lead to anosmia in COVID-19 patients, focusing on the role of the olfactory epithelium, support cells, and the virus's interaction with the olfactory system.[66]

____ Please refer the report for further details ___

Methodology

1. Study Participants

Two individuals will be the focus of this study: one, 21, with congenital anosmia, and another, a 75-year-old woman, who experienced temporary anosmia due to COVID-19.

2. Algorithm-Based Diagnosis

Based on Figure 3, taken from the Clinical assessment of patients with smell and taste disorders - PMC, a diagnostic algorithm will be developed by transforming the symptoms and factors listed in the figure into a series of questions. The patient with congenital anosmia will be assessed using this algorithm, and the responses will be integrated into a diagram to determine the specific type of anosmia they have and how they acquired it.

These questions provided here have already been asked to the patient based on the scheme in Figure 4. The reason they are more personalized is because the patient also answered since it’s an interview.

1. Has anybody ever mentioned that you have an unpleasant smell? Like mouth or body odor?
2. Can you taste or have you tasted anything in your life?
3. And can you tell when something is too salty, too sugary, or has gone bad?
4. Do you have any olfactory abilities whatsoever?
5. Can you describe olfactory status prior to dysfunction or loss?
6. Do you, or your parents, recount any significant events that may have caused your loss of smell?
7. And when they realized, or even in recent years, have you received any testing associated with Anosmia? Such as imaging of nasal cavities, olfactory bulbs, or a brain CT or MRI?
8. Okay, now let’s get on with the test…
9. (After the test) Do you feel okay? Do you need a break?
10. From the test, it showed that your olfactory sense is absent since you couldn’t smell any of the 35 smells that I provided you with. I am at least happy that you could identify the bubble gum flavor after you chewed it. (It was bubble gum flavored). So, let’s continue with the questions. Are your nasal airways blocked? Do you often use Olynth?
11. Have you ever had olfaction in your life?
12. Have you lost your smell after an upper respiratory infection?
13. Have you experienced severe head trauma as a child?
14. Have you ever experienced any toxin exposure?
15. Okay, thank you. As you know, I am not a doctor. I am just a student performing research on Anosmia, and you are my patient for this experiment. So, I cannot provide you with a clear answer and solution as to why you have anosmia or how to cure it. But from what the questions that I have used tell me, you are recommended to go to the endocrinologist. Can I ask you a few more questions?
16. Have you encountered any situations where not being able to smell might have put you in danger, such as not detecting smoke?
17. Has the inability to smell affected your social interactions or relationships in any way?
18. Have you noticed hypogonadism in yourself?
19. Okay, that’s all. Thank you for your time.

3. Smell Test

The University of Pennsylvania Smell Identification Test (UPSIT) is an integral tool in assessing olfactory function, particularly in anosmia research. It's recognized for its efficacy in diagnosing and determining the severity of smell disorders. The UPSIT involves a series of microencapsulated scratchable patches, each containing a different odorant. During the test, the patient scratches each patch to release the scent and then chooses the corresponding odor from a list of four options. This methodical approach ensures a comprehensive evaluation of the patient's ability to recognize and differentiate a wide array of common scents.

Figure of self-made questions scheme test. It is used to determine the type of anosmia the patient has.

Following the diagnostic algorithm, better described in Figure 4, the patient will be asked questions in a flow-chart order. In addition to this, in the scheme, a 40-element smell test was integrated from the UPSIT test, and will be performed in the experiment. This test will include Bubble Gum, Menthol, Mint, Banana, Leather, Coconut, Cinnamon, Gingerbread, Pineapple, Orange, Watermelon, Grass, Smoke, Soap, Natural Gas, Rose, Onion, Chocolate, Lilac, Peach, Root Beer, Pine, Lime, Clove, Liquorice, Gasoline, Strawberry, Peanut, Pizza, Cherry, Motor Oil, Fruit Punch, Cheddar Cheese, Cedar, Dill Pickle, Lemon, Wintergreen, Thinner, Grape, Turpentine. From all of these elements, 5 couldn’t be gathered, more specifically, Natural Gas, Liquorice, Motor Oil, Wintergreen, and Turpentine. So, a 35-element test will be performed. The manner this experiment will be performed is relatively simple. The elements will be gathered by the researcher, and then would be given to the patient to smell, but the patient will have no other senses except olfactory; meaning that the patient will be blindfolded, will not be allowed to touch, taste, or look at the elements. This test will help evaluate how anosmia impacts the patient's life, particularly in terms of flavor perception and dietary choices. A recording with the experiment can be provided at request.

The design of the UPSIT ensures that it comprehensively covers various scent categories, from fruits and spices to environmental and industrial odors. Such a broad range in the test aids in precisely assessing the extent of olfactory impairment across different odor types. The results of the UPSIT, especially in a modified form as in this study, are invaluable in quantifying the degree of smell loss and can be indicative of the underlying cause of anosmia. The outcomes from this test, in conjunction with other diagnostic measures, provide a thorough understanding of the patient’s olfactory dysfunction, guiding subsequent treatment and management approaches.

4. Interview with Temporary Anosmia Patient

An interview will be conducted with a patient who experienced temporary anosmia due to COVID-19. The patient is a 75-year-old woman. The interview will explore the patient’s experience with long COVID and the impact of anosmia on neurocognitive and emotional well-being. Also, the same 35-elements UPSIT smell test will be performed on the patient with Acquired Anosmia, in the same manner. The questions are inspired by this report: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0256998 and they are listed down. They are more personalized because the questions have already been asked to the patient in an interview and they are a conversation with the patient.

1. Can you determine the exact date that you got diagnosed with COVID-19?
2. Can you list some smells that you can’t smell now, but you usually could?
3. And what about ones that you can smell?
4. You also don’t have the taste sense?
5. Do you have any other symptoms?
6. How have the nausea and tiredness affected your life?
7. And how has your smell deficiency affected your life?
8. If you don’t mind me asking, is it a significant amount?
9. When is the last time you went out?
10. Oh… I am sorry for you. Although I have to say… you are not contagious anymore. You can go out whenever you want. Okay, a last question, do you feel like is there anything else you want to mention about having long COVID?
11. I am sorry, but I am not a doctor, but from my research, I’ve noticed that it should go away soon… hopefully. And I am sorry for your weakness… It must be horrible. Thank you for your time! Are you ready for the 35-element UPSITsmell test?
12. (After the test). There are some good news! You could guess some of the smells, although only 6 out of the 35! That means you are on the right track and are soon to be recovered! Thank you for your time!

5. Data Analysis

The data collected from the algorithm-based diagnosis, UPSIT smell test, and interview will be analyzed to compare the neurobiological foundations and lifelong consequences of congenital anosmia with the acquired anosmia experienced by COVID-19 patients.

6. Ethical Considerations

All participants will provide informed consent, and the study will adhere to ethical guidelines to ensure the privacy and well-being of the participants. (Appendix)

In the context of this study, it's pertinent to note that the subject, diagnosed with congenital anosmia, had never undergone magnetic resonance imaging (MRI) or computed tomography (CT) scanning. This is primarily attributable to the limited accessibility and affordability of these advanced imaging services in the subject's healthcare environment. Consequently, the potential presence of any underlying structural anomalies or abnormalities in the brain remains unascertained. Given this limitation, the experimental phase of the research will omit the “Olfactory testing of individual or combined nostrils and imaging of nasal cavities, olfactory bulbs, and brain with CT/MRI”.

This methodology will allow for a thorough understanding of the neural mechanisms underlying different types of anosmia and their wider effects on an individual's life, behaviors, emotions, and interactions.

Results of Patient with Congenital Anosmia:

The responses of the 21-year-old patient with congenital anosmia are as follows:

1. Yes, I, in fact, always ask my sister if my mouth smells, especially when I go on dates. But as for body odor, not so much, I shower twice a day just because of the fear of smelling rotten, and I use a lot of perfume.
2. Yes, I can taste anything with no problem.
3. Yes, I can quickly tell which food tastes good, and even the specific flavors. It would be sad if I couldn’t taste… I love food. I am even in culinary school. What would I do without taste? Hahaha!
4. No. Nothing. I’ve never felt any smell in my life.
5. I can’t. I don’t remember anything regarding my “olfactory status” ever since I was born.
6. The only thing that my parents can remember was the specific day that they discovered I couldn’t smell. We were in our garden, and my dad was cutting the grass, and my mom was planting flowers, and they asked me what they smelled like, and I said, “the same.” Hahahaha. So they discovered then that I can’t differentiate between smells because I don’t have a smell whatsoever.
7. No, we never had the funds to do that. Maybe in the future, when I get my own money.
8. Okay.
9. I feel good. Let’s continue.
10. No, they are never congested, only when I get sick, and I don’t really use olynth, only in severe exceptions, when I am sick. I don’t think my Anosmia is caused by my nose being congested, hahaha!
11. No.
12. No, I was born without smell.
13. Not that me or my parents can remember of… or at least none of them admit anything happened to me when I was a child.
14. Except for the thinner now, I have been exposed to paint and other thinners, but nothing as severe as acids or anything like that.
15. Okay, thank you! When I have my own money I will hopefully be treated and researched by real doctors too… and yes, you can ask me some more questions.
16. I mean I always try to be as cautious as possible when cooking or working with gas or fire, but it hasn’t happened to me that I can’t smell something dangerous because I’m always surrounded by my friends or family.
17. No, not at all negatively. Positively, maybe yes, because everybody is so curious about the fact that I can’t smell.
18. No.
19. Sure. Thank you!

Questions, answers, and specific analysis for patients with congenital anosmia.

• Questions for a Congenital Anosmia Patient: Has anybody ever mentioned that you have an unpleasant smell? Like mouth or body odor?
• Responses of Congenital Anosmia Patient: Yes, I, in fact, always ask my sister if my mouth smells, especially when I go on dates. But as for body odor, not so much, I shower twice a day just because of the fear of smelling rotten and I use a lot of perfume.
• Analysis of responses of Congenital Anosmia patients: The patient's response to the question about personal odor due to anosmia shows a significant level of self-awareness and precaution. The subject is very conscious about potential body or mouth odor, a common concern for people with anosmia, as the subject cannot detect these smells themselves. The sister is regularly asked by the patient for feedback on the subject’s breath, especially in social situations like dating, indicating a reliance on others to fill the gap left by the subject’s condition.

The fact that the patient showers twice a day and uses a lot of perfume suggests an approach to overcompensate for inability to self-monitor odors. This behavior highlights the impact of anosmia on daily life, particularly in social contexts. The fear of having an unpleasant smell and the inability to detect it themselves can lead to anxiety in social interactions, driving them to take extra measures to ensure the subject does not have an offensive odor. Thus, the patient's response illustrates how anosmia affects not just the subject’s sense of smell but also the subject’s social interactions and personal habits.

• Question: Can you taste or have you tasted anything in your life?
• Response: Yes, I can taste anything with no problem.
• Analysis: Anosmia often impacts the sense of taste because these two senses are closely linked. However, the patient's experience highlights an important distinction. Taste and smell, while interconnected, are distinct sensory processes. Basic taste sensations like sweet, salty, sour, bitter, and umami are detected by the taste buds on the tongue. In contrast, the sense of smell contributes to the perception of the flavor of food, which is a combination of taste and smell sensations. It's common for individuals with anosmia to experience a reduced ability to perceive flavors, but the subject’s basic taste sensations often remain intact.

The patient's response indicates that the subject’s taste buds function normally, allowing them to experience basic tastes. What they might miss is the flavor complexity that arises from the combination of taste and olfactory cues.

• Question: And can you tell when something is too salty, too sugary, or has gone bad?
• Response: Yes, I can quickly tell which food tastes good, and even the specific flavors. It would be sad if I couldn’t taste… I love food. I am even in culinary school. What would I do without taste? Hahaha!
• Analysis: The patient's ability to discern varying levels of saltiness, sweetness, and the quality of food, despite the subject’s anosmia, is an important aspect to consider in this research. This ability suggests that the subject’s taste perception, particularly for basic taste qualities, remains unaffected by the lack of smell. The subject’s enthusiasm for food and culinary arts underscores the adaptability of individuals with sensory deficits and the subject’s ability to find joy and passion in activities that might seem challenging given the subject’s condition. This positive attitude and the ability to engage fully in culinary arts, relying on the sense of taste and other sensory inputs like texture and temperature, reflect remarkable adaptability.
• Question: Do you have any olfactory abilities whatsoever?
• Response: No. Nothing. I’ve never felt any smell in my life.
• Analysis: The patient's statement that they have “never felt any smell in my life” points to congenital anosmia, suggesting the subject was born without the sense of smell. It necessitates careful consideration of the patient's safety, as the subject cannot detect hazardous odors, and adjustments in lifestyle to accommodate this sensory deficit. The subject’s lack of distress suggests the subject has effectively adapted to the subject’s condition, potentially through a heightened reliance on other senses and a robust support system. However, this is not enough to tell as the subject might have had trauma as a child, maybe from toxin exposure or from physical head trauma, or a tumor.
• Question: Can you describe olfactory status prior to dysfunction or loss?
• Response: I can’t. I don’t remember anything regarding my “olfactory status” ever since I was born.
• Analysis: The patient's inability to describe any olfactory status prior to dysfunction or loss, stating, “I can’t. I don’t remember anything regarding my 'olfactory status' ever since I was born,” reinforces the diagnosis of congenital anosmia. This implies that there has been no prior functioning level of smell to reference, which is consistent with the condition where the olfactory system has never been operational. It doesn’t eliminate the possibility of acquired anosmia, just yet, where the sense of smell is lost after birth due to injury, illness, or other factors.
• Question: Do you, or your parents, recount any significant events that may have caused your loss of smell?
• Response: The only thing that my parents can remember was the specific day that they discovered I couldn’t smell. We were in our garden, and my dad was cutting the grass, and my mom was planting flowers, and they asked me what they smelled like, and I said, “the same.” Hahahaha. So they discovered then that I can’t differentiate between smells because I don’t have a smell whatsoever.
• Analysis: The anecdote shared by the patient about the subject’s parents' discovery of the anosmia during childhood suggests a scenario where the lack of smell was identified through everyday activities rather than as a result of a significant medical event or trauma. The patient's response to the scents in the garden as “the same” indicates an absence of olfactory discrimination, which is a hallmark of anosmia. The lighthearted recollection of the event with laughter (“Hahahaha”) may reflect a degree of acceptance and normalization of the subject’s condition within the subject’s family context.

There is no mention of any illness, injury, or other event that could have led to the loss of smell, which supports the classification of the anosmia as congenital rather than acquired. This absence of a causative event aligns with the earlier responses and reinforces the understanding that the patient has always been without the sense of smell. Such a realization during a routine family activity highlights how anosmia can often go unnoticed until specific situations bring the condition to light. It also underscores the importance of familial observation and engagement in the identification of sensory deficits in children.

• Question: Hahaha! And when they realized, or even in recent years, have you received any testing associated with Anosmia? Such as imaging of nasal cavities, olfactory bulbs, or a brain CT or MRI?
• Response: No, we never had the funds to do that. Maybe in the future, when I get my own money.
• Analysis: The patient's lack of access to diagnostic imaging for the subject’s congenital anosmia due to financial constraints is a significant point of consideration. This economic barrier to healthcare has prevented the acquisition of potentially valuable clinical data that could offer insights into the anatomical and functional aspects of the olfactory system. The absence of imaging tests such as MRIs or CT scans means that any structural irregularities or developmental abnormalities in the nasal cavities, olfactory bulbs, or associated brain regions have not been documented for this individual. The patient's lighthearted response and the subject’s hope to afford such diagnostic procedures in the future suggest a recognition of the importance and potential value of these tests. It also implies a proactive attitude toward understanding the subject’s condition more comprehensively when personal circumstances allow.

From a research perspective, this underscores a gap in the full clinical picture of the patient's anosmia. The reliance on self-reported symptoms and history, without the support of imaging, may limit the depth of understanding of the condition's etiology and its potential neurological basis. It also highlights a broader issue within the healthcare system related to the accessibility of diagnostic resources for individuals from lower socioeconomic backgrounds.

• Question: Okay, now let’s get on with the smell test…
• Response: Okay.
• Analysis: The patient's readiness to proceed with the UPSIT smell test, despite acknowledging a complete lack of olfactory sensation, may indicate a willingness to engage with the diagnostic process and a hope to contribute to a better understanding of the subject’s condition.

(After the test)

• Question: The test showed that your olfactory sense is absent since you couldn’t smell any of the 35 smells that I provided you with. I am at least happy that you could identify the bubble gum flavor after you chewed it. (It was bubble gum flavored). So, let’s continue with the questions. Are your nasal airways blocked? Do you often use Olynth?
• Response: No, they are never congested, only when I get sick, and I don’t really use olynth, only in severe exceptions, when I am sick. I don’t think my Anosmia is caused by my nose being congested, hahaha!
• Analysis: The patient's response after the UPSIT smell test, which confirmed the subject’s anosmia, reveals that the subject’s nasal airways are typically clear and not a contributing factor to the subject’s condition. The absence of chronic nasal congestion rules out obstructive causes for the subject’s lack of smell. the subject’s limited use of nasal decongestants like Olynth, only during illness, further supports this.

The ability to identify the flavor of bubble gum after chewing it, despite the inability to smell any of the provided scents, are consistent with the functional taste perception the patient previously reported. This ability to taste, despite the absence of smell, differentiates the subject’s condition from disorders where both taste and smell are affected.

Please refer to the report for complete details of the test conducted.

Results of Acquired / Temporary Anosmia Patient:

The responses of the 75-year-old patient with Acquired Anosmia are as follows:

1. Yes, it was, uh, about 2 months ago, on September 5th, or 6th. Since then, I haven’t felt any type of smell. Or actually, I can smell some but very faintly, and they almost don’t seem to have the smells that they should have…
2. Yes. Some of the smells have got to be… uh… I can’t smell my favorite linen laundry softener now… hahaha! Ok, and I also can’t smell I don’t know… oranges, peppers, cheese, butter, any of the food I cook, wood, my perfumes…
3. I can smell and taste very hot peppers… that’s it, and also pickled watermelons…
4. No, I don’t… Whatever I can’t smell, I can’t taste either.
5. Yes, I get nauseated, and I am usually very tired, way more tired than I was before.
6. Well, I can’t cook for my granddaughter anymore that much because I am usually too tired.
7. I can’t really make food as flavorful as I could before, and I usually need my husband’s help to determine the right taste. Hahaha. But other than this, my appetite has also decreased a lot, and I’ve lost weight. All food appears so bland right now… it seems as if nothing has taste anymore. Whenever I feel like I’m full, I have no more drive to eat since nothing has taste… I like eating very spicy and cold peppers! I like that sensation!
8. 4 kilograms, but for me, that’s quite a lot, especially at my height… I don’t really do that much sports, and I don’t go out anymore because I’m scared of infecting others, and my muscles have started to disappear.
9. The day I started getting COVID-19 symptoms, after that maybe I’ve gone out on the balcony to get some fresh air. I don’t really think I have the strength to go out of my house anymore either way…
10. No, that’s all. One more thing, actually, when do you think my smell is going to come back? I really miss it. And also, I have to mention I have gotten a bit sick recently, and I think it is associated with Long COVID, because I always feel tired and weak.
11. Of course.
12. Oh, thank you, dear! I can’t wait to be able to smell all 35 again!

Questions, answers, and specific analysis for patient with acquired anosmia as a result from COVID-19.

• Question for Acquired Anosmia Patient: Can you determine the exact date that you got diagnosed with COVID-19?
• Response of Acquired Anosmia Patient: Yes, it was, uh, about 2 months ago, on September 5th, or 6th. Since then, I haven’t felt any type of smell. Actually, I can smell some but very faintly, and they almost don’t seem to have the smells that they should have…
• Analysis of response of Acquired Anosmia patient: The patient's ability to pinpoint the diagnosis of COVID-19 to approximately two months ago suggests a clear onset of the subject’s anosmia, aligning with the timeframe of the subject’s infection. The subsequent loss of smell, a known symptom associated with COVID-19, appears to have persisted, indicating a case of long-term olfactory dysfunction post-infection. The description of faint olfactory sensations, where smells do not match the subject’s expected odors, is indicative of a condition known as parosmia, which is a distortion of olfactory perception. This can be a part of the recovery process, where the sense of smell may gradually return, albeit altered. It's a significant detail because it shows that the olfactory system is not entirely non-functional, and there may be potential for recovery.

For a 75-year-old, the impact of such sensory loss can be profound, affecting nutritional intake, enjoyment of food, and overall quality of life, while also posing safety concerns. The specific mention of altered smell rather than complete anosmia could be a hopeful sign for eventual, partial, or complete recovery of the sense of smell, which can sometimes occur after such viral infections.

• Question: Can you list some smells that you can’t smell now, but you usually could?
• Response: Yes. Some of the smells have got to be… uh… I can’t smell my favorite linen laundry softener now… hahaha! Ok, and I also can’t smell I don’t know… oranges, peppers, cheese, butter, any of the food I cook, wood, my perfumes…
• Analysis: The patient lists a variety of scents that they are unable to detect since contracting COVID-19, ranging from household items like laundry softener to various food items and personal perfumes. This indicates a broad spectrum of olfactory dysfunction, affecting both the ability to detect everyday non-food items as well as a wide array of food-related scents. The inability to smell these specific items suggests a significant change in the patient's sensory environment and daily experiences. The loss of scent from foods can affect appetite and the pleasure associated with eating, which is particularly concerning for the elderly due to the risk of nutritional deficiencies.

Moreover, the inability to enjoy familiar comforts, such as the smell of one's own home or personal scent from perfumes, can be disheartening and disorienting.

The patient's laughter when mentioning the inability to smell the subject’s favorite linen laundry softener hints at a resilient attitude towards the subject’s condition. Despite the challenges posed by the loss of smell, this response may indicate an effort to maintain a positive outlook, which can be an important aspect of coping with the sudden change in the subject’s quality of life.

____ Please refer the report for further details ____

Compare & Contrasts of Answers:

The patient with congenital anosmia has never experienced the sense of smell. This lifelong absence means the subject has developed and adapted to a world without olfactory cues from the beginning. Their adaptations, like regular checks for personal odor and reliance on others for feedback, are ingrained and normalized parts of the subject’s life. The subject has never known the sensations they are missing, which shapes the subject’s relationship with food, social interactions, and safety precautions in a unique way. The congenital nature of the subject’s condition has led to a life built around the absence of smell, with strategies and support systems in place to compensate for this deficit.

In contrast, the patient with acquired anosmia due to long COVID has experienced a drastic change in the subject’s sensory world. Previously accustomed to the nuances of smell, the sudden loss has led to a significant alteration in the subject’s quality of life. This patient's anosmia has led to a decrease in appetite, weight loss, and reliance on others for taste confirmation, indicating a disruption to the subject’s previously established routines and pleasures. The impact is more pronounced because it represents a loss of an integral part of the subject’s sensory experience, affecting the subject’s enjoyment of food, social roles, and emotional well-being. The subject’s longing for the return of smell and the joy at detecting even a few scents during the UPSIT smell test reflect a deep sense of loss and hope for recovery.

This contrast highlights how the timing and nature of the onset of anosmia (congenital versus acquired) can lead to significantly different experiences and coping mechanisms. The congenital anosmia patient has a lifetime of adaptation without ever knowing the sense, while the acquired anosmia patient experiences a profound sense of loss and adjustment to a new way of sensing the world. This difference is crucial for understanding the psychological and emotional ramifications of anosmia and the support needed for individuals facing either form of this condition. ____ Please refer the report for further details ____

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Impact Statement

My name is Matei Mihai Serban, and I chose to write about Anosmia because of a dear friend of mine's struggle with it their entire life. My paper conducted a thorough investigation into both congenital and acquired anosmia, incorporating in-depth analysis, patient interviews, and smell tests to understand their distinct impacts and management strategies. Also, I wrote an in-depth review of everything Anosmia consists of. Elio's neuroscience research program was a key turning point for me. It gave me hands-on experience in neuroscience research, showing me that I have a real passion for this field. The program was challenging, but it taught me valuable skills in scientific research and critical thinking. It also confirmed my desire to keep doing research in the future and contribute to the science community. Overall, the program was a great learning experience that helped shape my career goals.

References

[1] “Anosmia Definition & Meaning.” Merriam-Webster, Merriam-Webster, www.merriam-webster.com/dictionary/anosmia.

[2] Cleveland Clinic medical. “Anosmia.” Cleveland Clinic, my.clevelandclinic.org/health/diseases/21859-anosmia-loss-of-sense-of-smell.

[3] Karimian, Ali, et al. “Molecular Mechanisms Involved in Anosmia Induced by SARS-COV-2, with a Focus on the Transmembrane Serine Protease TMPRSS2.” Archives of Virology, U.S. National Library of Medicine, Oct. 2022, www.ncbi.nlm.nih.gov/pmc/articles/PMC9358639/.

[4] Alkelai, Anna, et al. “Next-Generation Sequencing of Patients with Congenital Anosmia.” European Journal of Human Genetics : EJHG, U.S. National Library of Medicine, Dec. 2017, www.ncbi.nlm.nih.gov/pmc/articles/PMC5865213/.

[5] Anosmia - StatPearls - NCBI Bookshelf www.ncbi.nlm.nih.gov/books/NBK482152/.

[6] Anosmia - StatPearls - NCBI Bookshelf www.ncbi.nlm.nih.gov/books/NBK482152/.

[7] VB;, Hoffman HJ;Rawal S;Li CM;Duffy. “New Chemosensory Component in the U.S. National Health and Nutrition Examination Survey (NHANES): First-Year Results for Measured Olfactory Dysfunction.” Reviews in Endocrine & Metabolic Disorders, U.S. National Library of Medicine, pubmed.ncbi.nlm.nih.gov/27287364/.

[8] Dong, Jing, et al. “The Prevalence of Anosmia and Associated Factors among U.S. Black and White Older Adults.” The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, U.S. National Library of Medicine, 1 Aug. 2017, www.ncbi.nlm.nih.gov/pmc/articles/PMC5861899/.

[9] Dong, Jing, et al. “The Prevalence of Anosmia and Associated Factors among U.S. Black and White Older Adults.” The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, U.S. National Library of Medicine, 1 Aug. 2017, www.ncbi.nlm.nih.gov/pmc/articles/PMC5861899/.

[10] Murphy C, Schubert CR, Cruickshanks KJ, Klein BE, Klein R, Nondahl DM. Prevalence of olfactory impairment in older adults. JAMA. 2002;288:2307–2312.

[11] Schubert CR, Cruickshanks KJ, Fischer ME, et al. Olfactory impairment in an adult population: The Beaver Dam Offspring Study. Chem Senses. 2012;37:325–334. doi:10.1093/chemse/bjr102.

[12] Karpa MJ, Gopinath B, Rochtchina E, et al. Prevalence and neurodegenerative or other associations with olfactory impairment in an older community. J Aging Health. 2010;22:154–168. doi:10.1177/0898264309353066

[13] Pinto JM, Schumm LP, Wroblewski KE, Kern DW, McClintock MK. Racial disparities in olfactory loss among older adults in the United States. J Gerontol A Biol Sci Med Sci. 2014;69:323–329. doi:10.1093/gerona/glt063

[14] Landis BN, Konnerth CG, Hummel T. A study on the frequency of olfactory dysfunction. Laryngoscope. 2004;114:1764–1769. doi:10.1097/00005537-200410000-00017.

[15] Mullol J, Alobid I, Marino-Sanchez F, et al. Furthering the understanding of olfaction, prevalence of loss of smell and risk factors: A population-based survey (OLFACAT study). BMJ open. 2012;2(6).

____ Please refer the report for complete list of references ____

Appendix

Sample Patient Experimentation Agreement Form

The research project entitled “Deep Dive in Anosmia; Case Studies of Congenital & Acquired Anosmia” supports the practice of protection of human participants in research. The following will provide you with information about the experiment that will help you in deciding whether or not you wish to participate. If you agree to participate, please be aware that you are free to withdraw at any point throughout the duration of the experiment without any penalty.

In this study I will ask you to smell 40 different scents (Bubble Gum, Menthol, Mint, Banana, Leather, Coconut, Cinnamon, Ginger bread, Pine Apple, Orange, Watermelon, Grass, Smoke, Soap, Natural Gas, Rose, Onion, Chocolate, Lilac, Peach, Root Beer, Pine, Lime, Clove, Liquorice, Gasoline, Strawberry, Peanut, Pizza, Cherry, Motor Oil, Fruit Punch, Cheddar Cheese, Cedar, Dill Pickle, Lemon, Wintergreen, Thinner, Grape, Turpentine) and try to identify them. Also, you will be asked questions about your Anosmia with the “Algorithm of evaluation of the patient who has olfactory loss” method.* If you have any discomfort with discussing Anosmia, or if any scents give you displeasure, please inform the experimenter, and the study will end now. All information you provide will remain confidential and will not be associated with your name. If, for any reason during this study, you do not feel comfortable, you may leave the laboratory and receive credit for the time you participated, and your information will be discarded. Your participation in this study will require approximately 40 minutes. When this study is complete, you will be provided with the results of the experiment if you request them, and you will be free to ask any questions. If you have any further questions concerning this study, please feel free to contact me by phone or email: Serban Matei Mihai at matei**@gmail.com (+Phone number). Please indicate with your signature in the space below that you understand your rights and agree to participate in the experiment.

Your participation is solicited, yet strictly voluntary. All information will be kept confidential, and your name will not be associated with any research findings.

__________ __________
Signature of Participant NAME, Investigator

__________

Print Name

_By: Serban Matei Mihai_

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of Elio Academy.