BEYOND THE USUAL SUSPECTS: REVIEW ON EXPLORING RARE, EMERGING AND ENVIRONMENTALLY INFLUENCED METABOLIC DISORDERS

Mostafa Essam Eissa

Independent Researcher and Consultant, Cairo, Egypt.

Abstract

This review highlights the multifaceted landscape of metabolic disorders, focusing on often overlooked or understudied conditions. These disorders were categorized based on potential etiology, including rare inherited, disorders of unknown origin, emerging conditions and those influenced by other diseases, environmental factors, or immune dysfunction. Additionally, we explore the impact of personalized metabolic variations and the intricate relationship between metabolism and mental health. By exploring specific examples such as maple syrup urine disease, non-alcoholic fatty liver disease, bile acid malabsorption and mitochondrial disorders, we emphasize the diverse spectrum of metabolic challenges. This overview underscores the need for continued research to unravel the complexities of these conditions, leading to improved diagnosis, treatment and prevention strategies. This is an interesting area for pharmaceutical field that need attention and extensive research to find promising treatments for the underestimated populations impacted by these diseases.

Keywords: Metabolic complications, metabolic disorders, mental health, mitochondrial disorders, personalized medicine, immune dysfunction.

INTRODUCTION

The domain of metabolic medicine is experiencing an epoch of rapid advancement, characterized by a ceaseless influx of novel insights and discoveries. Notwithstanding substantial progress in comprehending and managing prevalent metabolic disorders, a considerable subset of conditions remains under-investigated and often neglected, disproport-ionately impacting a marginalized patient population. This manuscript endeavors to illuminate these understudied domains within the complex tapestry of metabolic diseases. By directing the scientific community's attention to these overlooked pathologies, we aim to galvanize concerted efforts towards developing effective interventions^1-3. The often-limited awareness of these conditions among healthcare providers underscores the critical need for enhanced diagnostic acumen and therapeutic strategies.

The intricate landscape of human metabolism, a complex interplay of biochemical processes, continues to reveal a spectrum of disorders that challenge our understanding. While advancements in medical research have shed light on numerous metabolic conditions, a significant subset remains understudied. This article demonstrates the diverse spectrum of these underexplored metabolic disorders, categorized by their underlying etiology, clinical presentation, and emerging research trends. By examining rare inherited conditions, disorders of unknown origin and those arising from secondary complications, environmental factors or immune dysfunctions, we aim to illuminate the breadth and complexity of this field^4-6. A comprehensive understanding of these disorders is essential for advancing diagnostic capabilities, developing targeted therapies and improving patient outcomes.

Because medical research is ongoing, the discovery and study of previously unknown metabolic diseases continues to grow. However, there are several types and examples of circumstances that are frequently regarded underexplored:

1. Rare inherited metabolic disorders

These are genetic conditions caused by mutations in genes that encode enzymes or proteins crucial for specific metabolic pathways. Due to their rarity, they can be challenging to diagnose and may not have well-established treatment options. Examples:

• Maple Syrup Urine Disease (MSUD): This affects the breakdown of certain amino acids, leading to a characteristic maple syrup-like odor in urine and neurological problems⁷.
• Phenylketonuria (PKU): This affects the processing of the amino acid phenylalanine, if untreated, it can lead to intellectual disability⁸.
• Galactosemia: This affects the breakdown of the sugar galactose from milk, causing various symptoms including vomiting, diarrhea, and liver problems⁹.

2. Disorders of unknown etiology (cause)

These disorders manifest with metabolic abnormalities, but the underlying genetic or environmental triggers remain unclear. Examples:

• Non-Alcoholic Fatty Liver Disease (NAFLD): This is a buildup of fat in the liver that is not caused by excessive alcohol consumption. While risk factors are identified, the exact cause is not fully understood¹⁰.
• Fibromyalgia: This chronic condition is characterized by widespread pain, fatigue, and sleep disturbances. The cause of fibromyalgia is still under investigation, with some theories suggesting metabolic abnormalities might be involved¹¹.

3. Emerging metabolic disorders

These are recently identified or newly defined conditions with ongoing research to understand their full scope and impact. Examples:

• Bile Acid Malabsorption (BAM): This recently defined disorder shares symptoms with irritable bowel syndrome (IBS), making diagnosis difficult. It involves problems with reabsorbing bile acids in the intestine¹².
• Fabkin deficiency: This recently discovered protein plays a role in insulin production and blood sugar regulation. Research is ongoing to understand how Fabkin deficiency affects metabolism and develop potential treatment strategies¹³.

4. Metabolic complications of other diseases

Some established diseases can present with metabolic abnormalities as secondary complications. Examples:

• Metabolic complications of HIV/AIDS: HIV infection can disrupt metabolism, leading to weight loss, muscle wasting, and insulin resistance¹⁴.
• Metabolic complications of chronic inflammatory diseases: Chronic inflammation can lead to changes in how the body uses nutrients and can contribute to insulin resistance or fatty liver disease¹⁵.

5. Personalized and sub-phenotypic variations in metabolism

This emerging area explores the individual differences in how people process nutrients and respond to dietary changes. The goal is to understand how factors like genetics, gut microbiome, and lifestyle influence metabolism to personalize dietary and treatment approaches¹⁶.

6. Disorders of nutrient transport

These disorders involve issues with the absorption or transport of specific nutrients across the gut lining or within the bloodstream. Examples:

• Carnitine deficiency disorders: Carnitine is crucial for transporting fatty acids into cells for energy production. Deficiencies can lead to muscle weakness, fatigue, and heart problems¹⁷.
• Iron overload disorders: These disorders involve excessive iron accumulation in the body, often due to problems with iron regulation or absorption¹⁸.

7. Mitochondrial disorders:

Mitochondria are the "powerhouses" of cells, responsible for energy production.

Mitochondrial disorders arise from mutations in genes related to mitochondrial function, leading to impaired energy production and a variety of symptoms. Examples:

• Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS): This affects multiple organ systems due to mitochondrial dysfunction, causing muscle weakness, neurological problems, and stroke-like episodes¹⁹.
• Leber Hereditary Optic Neuropathy (LHON): This is a leading cause of inherited vision loss in young adults, caused by mutations in mitochondrial genes specifically affecting the optic nerve²⁰.

8. Metabolic consequences of environmental exposures

This emerging area explores how environmental factors like toxins, pollutants, or medications can disrupt metabolic processes. Examples:

• Metabolic effects of bisphenol A (BPA): BPA is a chemical found in some plastics and has been linked to changes in glucose and lipid metabolism in some studies²¹.
• Metabolic effects of certain medications: Some medications can have unintended consequences on metabolism, such as weight gain or changes in blood sugar control^22,23.

9. Inborn Errors of Immunity with Metabolic Features

These are a relatively new class of disorders where immune system dysfunction interacts with metabolic processes, causing a variety of symptoms²⁴. Examples:

• Autoimmune Lymphoproliferative Syndrome (ALPS): This rare disorder involves abnormal immune cell growth and can manifest with metabolic abnormalities like low blood sugar²⁵.
• Common Variable Immunodeficiency (CVID) with autoimmune features: Some individuals with CVID may also experience metabolic problems like autoimmune hepatitis or Sjogren's syndrome, which can affect metabolism²⁶.

10. Metabolic imbalances and mental health

This is a growing area of research investigating the potential link between metabolic disruptions and mental health conditions. Examples:

• The role of gut microbiome in mood disorders: Studies suggest that the gut microbiome composition might influence neurotransmitter production and contribute to depression or anxiety²⁷.
• Metabolic changes in schizophrenia: Some research suggests that people with schizophrenia may have altered glucose metabolism, highlighting a potential metabolic link to the mental health condition²⁸.

Pharmaceutical opportunities in understudied metabolic disorders

The realm of metabolic medicine presents a rich tapestry of understudied disorders, each offering unique opportunities for pharmaceutical research and development. These conditions, often characterized by their rarity, complexity or lack of definitive understanding, represent a significant unmet medical need. Rare Inherited Metabolic Disorders offer potential for orphan drug designation and gene therapy approaches^29,30. Tailored treatment strategies based on specific genetic mutations can improve outcomes for these patients. Disorders of Unknown Etiology require mechanistic studies to identify therapeutic targets and develop disease-modifying drugs. Biomarkers can aid in early diagnosis and monitoring of disease progression^31,32. Emerging Metabolic Disorders present opportunities for first-in-class therapies, clinical trials and patient registries to advance understanding and treatment^33,34. Metabolic Complications of Other Diseases often necessitate combination therapies or disease-modifying approaches to address both the primary condition and its metabolic consequences^35,36. Personalized and Sub-Phenotypic Variations in Metabolism emphasize the need for precision medicine and interventions targeting the gut microbiome^37,38. Disorders of Nutrient Transport require strategies for nutrient replacement and targeted therapies^39,40. Mitochondrial Disorders can benefit from mitochondrial therapeutics and gene therapy approaches^41,42. Metabolic Consequences of Environmental Exposures necessitate prevention, mitigation and detoxification strategies^43,44.

Inborn Errors of Immunity with Metabolic Features may benefit from immunomodulatory therapies and combination approaches⁴⁵. Finally, Metabolic Imbalances and Mental Health require dual-action therapies and personalized approaches⁴⁶. By comprehensively addressing these understudied metabolic disorders, pharmaceutical research can contribute to improving patient outcomes and advancing our understanding of human health.

CONCLUSIONS

The intricate tapestry of metabolic disorders reveals a complex interplay between genetics, environment, and lifestyle. This categorization underscores the diverse etiologies and clinical presentations within this spectrum. Rare inherited disorders like MSUD and MASD highlight the fragility of metabolic pathways, while acquired conditions such as NAFLD and metabolic complications of chronic diseases emphasize the impact of environmental and lifestyle factors. Emerging disorders like BAM and the potential metabolic implications of environmental exposures expand the boundaries of our understanding. Moreover, the intricate connections between metabolism and other systems, as seen in disorders like PANDAS/PANS and the gut-brain axis, necessitate a holistic approach. Ultimately, this analysis emphasizes the need for continued research to unravel the complexities of these disorders, leading to improved diagnosis, treatment, and prevention strategies. Exploring the pharmaceutical treatment role should not be underestimated and must be actively engaged in improving the life of those impacted population by these diseases.

AUTHOR'S CONTRIBUTIONS 

Eissa ME: conceived the idea, writing the manuscript, literature survey, formal analysis, critical review. 

DATA AVAILABILITY 

This article is available to anyone upon request from the corresponding authors.

CONFLICT OF INTEREST 

None to declare.

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