Interaction Between Phytanic Acid, P450 and Low Iron: Symptoms and Overview

By SWA

Phytanic acid is a branched-chain fatty acid primarily obtained from dietary sources such as dairy, beef, lamb, and some fish. Its metabolism is unique and requires peroxisomal α-oxidation, a specialized process that allows the body to break down this complex fatty acid. Phytanic acid metabolism is crucial because its accumulation can lead to significant health issues, particularly in individuals with metabolic disorders such as Refsum disease. On the other hand, iron plays a fundamental role in numerous biochemical processes, including oxygen transport, mitochondrial function, and various enzymatic activities.

While there isn't a direct or well-established relationship between iron deficiency and phytanic acid metabolism in healthy individuals, low iron levels may influence fatty acid metabolism overall. This article explores the potential interaction between phytanic acid and iron deficiency, particularly within the context of metabolic disorders like Refsum disease.

Symptoms Related to Phytanic Acid Accumulation

Phytanic acid accumulation is most commonly seen in Refsum disease, an inherited metabolic disorder. This disease occurs when mutations in the enzyme phytanoyl-CoA hydroxylase impair the breakdown of phytanic acid. The resultant buildup of phytanic acid leads to toxic effects on various systems, with symptoms that can be debilitating. These symptoms include:

  • Peripheral neuropathy: Tingling, numbness, weakness, and pain in the hands and feet due to nerve damage.
  • Retinitis pigmentosa: Progressive vision loss, particularly night blindness and tunnel vision.
  • Cerebellar ataxia: Impaired coordination and balance resulting from cerebellar dysfunction.
  • Anosmia: Loss of smell, often an early indicator of the disease.
  • Hearing loss: Progressive deafness due to nerve damage.
  • Ichthyosis: Scaly, dry skin.
  • Cardiac arrhythmias: Irregular heartbeats, which in severe cases can be life-threatening.

For more information on Refsum disease and its clinical manifestations, you can visit the NIH Rare Diseases Database.

Symptoms of Iron Deficiency

Iron deficiency is one of the most common nutrient deficiencies and can significantly impair metabolic function. Iron is integral to various enzymatic reactions, particularly those involving mitochondrial energy production and oxygen transport. Symptoms of iron deficiency often include:

  • Fatigue: Due to reduced oxygen transport from iron-deficiency anemia.
  • Weakness: Muscle weakness from impaired oxygen delivery to tissues.
  • Shortness of breath: Especially during physical activity.
  • Dizziness: Caused by decreased oxygenation to the brain.
  • Pallor: Pale skin due to low hemoglobin levels.
  • Cold intolerance: Feeling colder than usual due to reduced metabolic rate.
  • Restless legs syndrome (RLS): A condition associated with discomfort in the legs, often linked to iron deficiency.
  • Cognitive difficulties: Impaired concentration and memory issues.

Iron's Role in Fatty Acid Metabolism

Iron is an essential cofactor in many enzymatic processes involved in fatty acid metabolism. It plays a particularly crucial role in mitochondrial function, where it is needed for oxidative phosphorylation and the electron transport chain. Iron-containing enzymes, such as those in the cytochrome P450 family, are also critical for lipid metabolism, including the oxidation of fatty acids. Therefore, iron deficiency can lead to compromised mitochondrial function and reduced efficiency in fatty acid metabolism, including the breakdown of branched-chain fatty acids like phytanic acid.

Phytanic Acid Metabolism

Phytanic acid is metabolized primarily through α-oxidation in the peroxisomes, as its branched structure prevents degradation via the standard mitochondrial β-oxidation pathway. Any disruption in α-oxidation can lead to the accumulation of phytanic acid, which is toxic at high concentrations. This is particularly problematic in conditions like Refsum disease, where a genetic mutation impairs the enzyme necessary for α-oxidation.

Potential Interaction Between Phytanic Acid and Low Iron

Although there is no direct evidence linking iron deficiency with phytanic acid buildup in healthy individuals, some theoretical connections can be made. Low iron could impair mitochondrial function, leading to inefficient fatty acid metabolism, including the breakdown of phytanic acid. Mitochondrial dysfunction, due to reduced activity of iron-dependent enzymes, could aggravate the metabolic issues seen in conditions where phytanic acid already accumulates, such as Refsum disease.

Refsum Disease and Dietary Management

In Refsum disease, patients must follow a low-phytanic acid diet to avoid exacerbating the accumulation of this toxic fatty acid. The diet typically excludes phytanic-acid-rich foods like dairy products, beef, lamb, and certain fish. In addition to dietary restrictions, plasmapheresis (a blood filtering technique) can be used to lower phytanic acid levels in acute cases.

For more information on Refsum disease management, see Mills and Footitt’s GeneReviews entry on Refsum disease at the University of Washington’s GeneReviews.

What causes Refsum disease?

Refsum disease occurs because of a gene mutation (change) that you’re born with. You inherit these gene mutations from one or both of your biological parents.

There are over a dozen genes that can cause infantile Refsum. The most common are PEX1 (60%), PEX6 (15%), PEX12 (7.6%) and PEX26 (4.2%).

Adult Refsum also occurs because of an inherited gene mutation that’s present at birth. About 9 in 10 people with adult Refsum disease have a mutation in the PHYH gene. Most others with the condition have a PEX7 gene mutation. https://my.clevelandclinic.org/health/diseases/6091-refsum-disease

Indirect Effects of Iron Deficiency on Phytanic Acid Levels

In individuals with normal fatty acid metabolism, iron deficiency may not directly lead to phytanic acid accumulation. However, in individuals with compromised metabolism, such as those with Refsum disease, low iron levels may further exacerbate the inability to metabolize fatty acids effectively. Mitochondrial dysfunction due to iron deficiency could impair β-oxidation, potentially worsening metabolic symptoms related to phytanic acid accumulation.

Research into the broader effects of iron deficiency on mitochondrial function, particularly its impact on fatty acid metabolism.

Conclusion

While iron deficiency and phytanic acid metabolism are distinct biological processes, both are critical for maintaining overall metabolic health. Low iron levels could theoretically impair fatty acid metabolism, indirectly contributing to symptoms of disorders like Refsum disease, where phytanic acid accumulation is already a significant issue. Further research is needed to clarify the potential connection between iron deficiency and phytanic acid metabolism in the broader population.

By maintaining proper iron levels and adhering to appropriate dietary guidelines, individuals with metabolic disorders such as Refsum disease may mitigate some of the symptoms related to fatty acid accumulation.

References

Unfortunately, several links to the original papers are no longer available.

  1. Rouault, T. A., "Mammalian iron-sulfur proteins and related diseases," Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2016. 
  2. Jansen, G. A., & Wanders, R. J., "Phytanic acid metabolism in health and disease," Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2006.
  3. Walter, P. B., Knutson, M. D., Paler-Martinez, A., et al., "Iron deficiency and iron excess damage mitochondria and mitochondrial DNA in rats," Proceedings of the National Academy of Sciences, 2002.
  4. Mills, K., & Footitt, E., "Refsum Disease: Phytanic Acid Oxidase Deficiency," GeneReviews, University of Washington, Seattle, 1998.
© 2000-2025 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right.
Library of Congress Card Number: LCN 00-192742 ISBN: 0-9703195-0-9

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