Very Long-Chain Fatty Acids (VLCFAs) X-ALD and Spinal Muscular Atrophy (SMA): Exploring the Connection

Update Oct 28th 2024:

A Novel Mouse Model for Cerebral Inflammatory Demyelination in X-Linked Adrenoleukodystrophy: Insights into Pathogenesis and Potential Therapeutic Targets
https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.27117

Very Long-Chain Fatty Acids (VLCFAs) are types of fatty acids that are metabolized by peroxisomes in the body. Peroxisomes are cellular structures that break down these fatty acids to maintain metabolic balance. When this process is impaired, VLCFAs accumulate, leading to a range of metabolic and neurological disorders. Elevated VLCFA levels are commonly associated with peroxisomal disorders, such as X-linked Adrenoleukodystrophy (X-ALD) and Zellweger Syndrome. Although VLCFAs are not directly linked to Spinal Muscular Atrophy (SMA), both conditions share some overlapping symptoms, particularly in how disturbances in metabolism and energy production affect muscle function and nutrition.

This article will explore how elevated VLCFAs impact the body, their associated symptoms, and the overlap with SMA symptoms, particularly in terms of nutrition and muscle health.

VLCFA-Related Symptoms

1. Muscle Weakness and Fatigue

One of the hallmark symptoms of elevated VLCFAs, especially in peroxisomal disorders, is progressive muscle weakness. In these disorders, VLCFAs disrupt the normal function of muscle cells by impairing cellular energy metabolism. This leads to muscle wasting and fatigue, which is a common symptom in X-ALD and Zellweger Syndrome, similar to what is observed in SMA.

Overlap with SMA: In SMA, muscle weakness is caused by the degeneration of motor neurons that control voluntary muscle movement. While the cause differs (neuronal versus metabolic), both conditions result in reduced muscle strength and early fatigue.

2. Neurological Impairment

High levels of VLCFAs can lead to demyelination, a process where the protective covering of nerve cells (myelin) is damaged. This causes various neurological symptoms, such as:

Difficulty walking
Poor motor coordination (ataxia)
Spasticity (stiff muscles)
Numbness or tingling in the limbs

These neurological impairments mirror the motor dysfunction seen in SMA, where loss of motor neurons results in impaired movement and muscle control.

3. Seizures

Certain peroxisomal disorders that involve elevated VLCFAs, such as Zellweger Syndrome, can lead to seizures. This adds to the neurological burden in affected individuals, as seizures further complicate the management of the disease.

4. Developmental Delays

Children with peroxisomal disorders often experience delays in reaching developmental milestones, including walking, sitting, and speech. These delays are due to the disruption of normal nerve and muscle function, which can resemble the motor developmental challenges seen in SMA.

5. Vision and Hearing Loss

VLCFA accumulation can damage the optic and auditory nerves, leading to progressive vision and hearing loss. This is common in X-ALD and other peroxisomal disorders, and can also be seen in some forms of neurodegenerative diseases that affect sensory pathways.

6. Liver Dysfunction

Peroxisomal disorders involving VLCFAs often lead to hepatomegaly (enlarged liver) and liver dysfunction, which can result in symptoms like jaundice, poor appetite, and malnutrition. This further exacerbates feeding and nutritional challenges, which are also seen in SMA.

7. Adrenal Insufficiency (Specific to X-ALD)

Adrenal insufficiency is a key feature of X-ALD, where elevated VLCFAs damage the adrenal glands. This leads to symptoms such as fatigue, low blood pressure, and hyperpigmentation. Fatigue and muscle weakness, common in SMA, are also present in adrenal insufficiency, compounding the difficulty in diagnosing and managing both conditions.

Very Long-Chain Fatty Acid (VLCFA) disorders are typically linked to defects in peroxisomal function, as VLCFAs are broken down within peroxisomes.
Several genes are associated with VLCFA disorders, particularly those involved in peroxisomal biogenesis and function. Below are key genes related to VLCFA metabolism and the associated disorders:

1. ABCD1 (ATP-Binding Cassette Subfamily D Member 1)

Disorder: X-linked Adrenoleukodystrophy (X-ALD)
Function: This gene encodes a protein involved in the transport of VLCFAs into peroxisomes for degradation. Mutations in this gene lead to the accumulation of VLCFAs in cells, causing the neurological and adrenal symptoms seen in X-ALD.
Gene Reference on NCBI

2. PEX Genes (PEX1, PEX2, PEX3, PEX6, etc.)

Disorder: Zellweger Spectrum Disorders (Zellweger Syndrome, Neonatal Adrenoleukodystrophy, Infantile Refsum Disease)
Function: These genes are involved in the biogenesis of peroxisomes. Mutations in any of the PEX genes can lead to defective peroxisomal assembly and function, causing an accumulation of VLCFAs and other metabolic issues.
Gene Reference on NCBI (PEX1)

3. ACOX1 (Acyl-CoA Oxidase 1)

Disorder: Pseudo-Zellweger Syndrome
Function: ACOX1 encodes an enzyme that catalyzes the first step in the β-oxidation of VLCFAs within peroxisomes. Mutations in this gene lead to defective fatty acid degradation.
Gene Reference on NCBI

4. SCP2 (Sterol Carrier Protein 2)

Disorder: Peroxisomal Acyl-CoA Oxidase Deficiency
Function: SCP2 encodes a protein involved in the transport of VLCFAs and other lipids to peroxisomes. Mutations in this gene can disrupt VLCFA metabolism and peroxisomal function.
Gene Reference on NCBI

5. ACSL1 (Acyl-CoA Synthetase Long-Chain Family Member 1)

Disorder: VLCFA-related lipid metabolism disorders
Function: This gene is responsible for converting free fatty acids, including VLCFAs, into fatty acyl-CoA, a substrate for β-oxidation. Mutations can impair the metabolism of long-chain fatty acids.
Gene Reference on NCBI

6. PHARC Genes (ABHD12)

Disorder: PHARC Syndrome (Polyneuropathy, Hearing Loss, Ataxia, Retinitis Pigmentosa, Cataract)
Function: ABHD12 encodes a protein involved in lipid metabolism and the regulation of VLCFA levels. Mutations cause an accumulation of abnormal lipids, contributing to neurological symptoms.
Gene Reference on NCBI

7. GNPAT (Glyceronephosphate O-Acyltransferase)

Disorder: Rhizomelic Chondrodysplasia Punctata Type 2
Function: This gene encodes an enzyme involved in plasmalogen biosynthesis, which is essential for peroxisomal function. Mutations lead to abnormal VLCFA processing and skeletal abnormalities.
Gene Reference on NCBI

These genes are critical for normal peroxisomal function and VLCFA metabolism. Mutations in any of these genes can lead to the accumulation of VLCFAs, causing various metabolic and neurological disorders.

Overlap Between VLCFA-Related Disorders and SMA Symptoms

1. Muscle Weakness and Fatigue

Both SMA and VLCFA-related disorders cause progressive muscle weakness, though for different reasons. In SMA, motor neurons degenerate, leading to muscle atrophy. In VLCFA-related disorders, metabolic dysfunction impairs muscle cell function, leading to similar outcomes.

2. Feeding Difficulties

In advanced SMA, muscle weakness affects swallowing and feeding, which can lead to malnutrition. Similarly, in peroxisomal disorders, disrupted energy metabolism, liver dysfunction, and muscle weakness contribute to feeding difficulties and weight loss.

3. Growth and Development

Children with both SMA and elevated VLCFAs may experience delayed growth and motor development. In SMA, this results from muscle degeneration and motor neuron loss, while in VLCFA-related disorders, it is due to disrupted cellular metabolism and nerve function.

4. Respiratory Weakness

Both conditions can lead to respiratory muscle involvement, increasing the risk of breathing difficulties and infections. In SMA, this is due to weakened muscles controlling breathing, while in VLCFA disorders, energy metabolism disruptions and muscle weakness impair respiratory function.

Very long-chain fatty acids (VLCFAs) have been implicated in certain types of cardiovascular damage, although their role is complex and often depends on specific genetic or metabolic conditions.

Peroxisomal Disorders: VLCFAs are primarily broken down in peroxisomes, a type of organelle in cells. In certain genetic disorders, like X-linked adrenoleukodystrophy (X-ALD) and Zellweger syndrome, there is a defect in the metabolism of VLCFAs. As a result, VLCFAs accumulate in various tissues, including the heart. The accumulation of VLCFAs can contribute to cardiac dysfunction, which can manifest as heart failure, cardiomyopathy, or other cardiovascular problems in individuals with these disorders.
Impact on Cardiomyocytes: VLCFA accumulation in cardiomyocytes (heart muscle cells) can disrupt normal cell function. For instance, these fatty acids can interfere with the normal lipid composition of cell membranes, affecting ion transport and electrical conduction in the heart. This can lead to arrhythmias (abnormal heart rhythms) and other forms of cardiac dysfunction.
Inflammation and Oxidative Stress: Excessive VLCFAs may also contribute to increased oxidative stress and inflammatory signaling, both of which are known to play a role in cardiovascular diseases. Chronic inflammation and oxidative damage can promote the development of atherosclerosis (plaque buildup in arteries), hypertension, and other conditions linked to cardiovascular damage.
Role in Metabolic Disorders: In some metabolic conditions like diabetes or metabolic syndrome, lipid metabolism, including the processing of VLCFAs, can be dysregulated. This can contribute indirectly to cardiovascular damage through mechanisms like insulin resistance, chronic inflammation, and changes in lipid profiles (e.g., elevated levels of triglycerides, LDL cholesterol, etc.).

However, it's important to note that VLCFAs are not typically implicated in cardiovascular disease in the general population. The major fatty acids associated with common forms of cardiovascular disease are usually saturated fats, trans fats, and certain types of cholesterol. VLCFAs are more specifically linked to rare metabolic and genetic disorders, but they can indeed contribute to cardiovascular damage when their metabolism is impaired.

Nutrition-Related Concerns in VLCFA Disorders and SMA

1. Malnutrition

Both conditions can lead to malnutrition due to feeding difficulties and poor nutrient absorption. Specialized nutritional support is often needed, such as high-calorie formulas or feeding tubes (G-tubes) to ensure adequate intake of calories and nutrients.

2. Energy Imbalance

In VLCFA-related disorders, the body's inability to properly metabolize long-chain fatty acids leads to an energy deficit. Similarly, in SMA, reduced muscle mass and motor function decrease caloric needs, but maintaining proper nutrition is still essential to preserve muscle function and general health.

3. Fatty Acid Metabolism

Patients with elevated VLCFAs often require dietary modifications to manage fat intake. For example, low-fat or VLCFA-restricted diets may be needed to avoid exacerbating the metabolic dysfunction. In SMA, the focus is more on ensuring adequate nutrition while managing difficulties with swallowing and digestion.

4. Vitamin and Mineral Deficiencies

Both conditions may increase the risk of deficiencies in key nutrients like vitamin D, calcium (for bone health), and other essential vitamins. Supplementation may be necessary to maintain proper muscle and nerve function.

So far research has not included the possibility of ME CFS connected to Spinal Muscular Atrophy (SMA) or Adrenoleukodystrophy (ALD)

https://swaresearch.blogspot.com/2024/01/is-me-cfs-spinal-muscular-atrophy.html

A lack of carnitine and issues with very long-chain fatty acids (VLCFAs) are associated with specific metabolic disorders that can disrupt how the body processes fats for energy.

Carnitine Deficiency

Carnitine is a nutrient that plays a crucial role in transporting long-chain fatty acids into the mitochondria, where they are broken down (oxidized) to produce energy. A deficiency in carnitine can lead to significant problems with fat metabolism. There are two primary types of carnitine deficiencies:

Primary Carnitine Deficiency: This is a genetic disorder where the body is unable to properly transport carnitine into cells. As a result, fats cannot be effectively transported into the mitochondria for energy production.
Secondary Carnitine Deficiency: This occurs due to another underlying condition, such as chronic kidney disease, liver disease, or the use of certain medications that interfere with carnitine metabolism.

Symptoms of Carnitine Deficiency:

Muscle weakness
Fatigue
Hypoglycemia (low blood sugar)
Enlarged liver (hepatomegaly)
Cardiomyopathy (disease of the heart muscle)

Very Long-Chain Fatty Acids (VLCFAs) and Their Role

Very long-chain fatty acids (VLCFAs) are a type of fatty acid that has a chain length of 22 or more carbon atoms. VLCFAs are typically metabolized in a specialized organelle called the peroxisome, where they are shortened and then further broken down in the mitochondria. Disorders that impair VLCFA metabolism are typically peroxisomal disorders, meaning they involve dysfunction of the peroxisomes.

One well-known disorder related to VLCFA metabolism is X-linked adrenoleukodystrophy (ALD). In ALD, the body has a problem breaking down VLCFAs due to a mutation in the ABCD1 gene, which affects the transporter protein responsible for moving VLCFAs into the peroxisomes for degradation.

Effects of VLCFA Accumulation:

VLCFAs can accumulate in tissues, particularly in the nervous system and adrenal glands.
This accumulation causes damage to the myelin sheath, which insulates nerve fibers, leading to neurological symptoms.
It can also affect the adrenal glands, causing adrenal insufficiency (Addison’s disease).

Symptoms of VLCFA Metabolism Disorders:

Progressive neurological problems (e.g., loss of motor function, cognitive decline)
Vision and hearing impairments
Seizures
Adrenal gland dysfunction (which can result in fatigue, weight loss, and low blood pressure)

Link Between Carnitine and VLCFAs

While carnitine is primarily involved in mitochondrial fatty acid oxidation, and VLCFAs are initially broken down in the peroxisomes, a dysfunction in either process can impair overall fat metabolism and energy production. A deficiency in carnitine will affect the oxidation of long-chain fatty acids in the mitochondria, while issues with VLCFAs will primarily affect the peroxisomal breakdown of these fatty acids. However, both types of issues can lead to an energy deficit and affect muscle, heart, and nervous system function.

Conclusion

Carnitine deficiency disrupts the transport of fatty acids into mitochondria, leading to energy production issues, particularly during fasting or physical exertion.
VLCFA metabolism disorders affect the breakdown of very long-chain fatty acids in the peroxisomes, leading to the accumulation of these fats in tissues, particularly in the brain and adrenal glands, causing neurological and endocrine issues.

Both issues require specific diagnostic approaches and treatments, such as carnitine supplementation for carnitine deficiency or specialized dietary modifications and therapies for peroxisomal disorders like ALD.

Conclusion

While Very Long-Chain Fatty Acids (VLCFAs) are not directly related to Spinal Muscular Atrophy (SMA), there are significant overlaps in symptoms, particularly in how metabolic dysfunction and muscle weakness present in both conditions. Muscle weakness, feeding difficulties, and nutritional challenges are common issues, and both conditions require careful management through collaboration between neurology, genetics, and nutrition specialists.

Early diagnosis and tailored treatments—whether through dietary modifications for VLCFA-related disorders or targeted therapies for SMA—are key to improving the quality of life for affected individuals.

Dietary treatment for X-linked adrenoleukodystrophy: Is “Lorenzo's oil” useful?

References and Further Reading:

X-linked Adrenoleukodystrophy (X-ALD) Overview
Peroxisomal Disorders and VLCFA Metabolism
Spinal Muscular Atrophy: Symptoms and Treatments
Role of Very Long-Chain Fatty Acids in Neurological Disorders
Peroxisomes Structure & Function
6. Celiac Disease and Dermatitis Herpetiformis: A Gluten-Sensitive Enteropathy
7. C26:0-Carnitine Is a New Biomarker for X-Linked Adrenoleukodystrophy in Mice and Man
One highly cited paper on VLCFA-related disorders and their effects on the body is:
- Moser HW, Raymond GV, et al. "Adrenoleukodystrophy: pathogenesis, diagnosis, and therapy." Journal of Inherited Metabolic Disease, 2001. DOI: 10.1023/A:1012439924283.
Books and Textbooks:
- "Fatty Acid Metabolism and Its Regulation" – This textbook covers lipid metabolism and includes sections on VLCFAs.
- "Peroxisomal Disorders and their Impact on Lipid Metabolism" – This resource provides detailed information on disorders affecting VLCFAs.
Medical Sites:
- NIH’s National Library of Medicine (PubMed): You can search for peer-reviewed articles using terms like "VLCFA cardiomyopathy" or "peroxisomal disorders cardiovascular impact." https://pubmed.ncbi.nlm.nih.gov/
- Genetics Home Reference on the NIH website provides reliable information about VLCFA-related genetic conditions, like adrenoleukodystrophy and their impacts, including on cardiovascular health: https://ghr.nlm.nih.gov/.
- Glycolysis is the metabolic pathway that converts glucose into pyruvate:
  https://www.google.com/search?client=firefox-b-d&q=glycolysis+pathway
Specialized Databases:
- OMIM (Online Mendelian Inheritance in Man): This database provides information about genetic conditions that affect VLCFA metabolism, including how they affect various organ systems such as the heart. https://omim.org/

By addressing both VLCFA metabolism and SMA-specific care, clinicians can better support individuals with these challenging conditions, improving both symptom management and nutritional health.