The Primary Genetic Cause: Refsum Disease
The most common cause of high phytanic acid levels is Refsum disease, a rare inherited metabolic disorder. This condition prevents the body from properly breaking down phytanic acid, a type of fatty acid obtained from the diet, causing it to build up to toxic levels in the blood and tissues. It is an autosomal recessive condition, meaning an individual must inherit a mutated gene from both parents to develop the disorder.
Gene Mutations
The genetic basis of Refsum disease involves mutations in one of two key genes:
- PHYH Gene: This gene is responsible for producing the enzyme phytanoyl-CoA hydroxylase (PhyH). The PhyH enzyme catalyzes the initial step in the alpha-oxidation pathway, which is the process that breaks down phytanic acid in cellular compartments called peroxisomes. Mutations in the PHYH gene account for over 90% of classic Adult Refsum disease cases.
- PEX7 Gene: The PEX7 gene provides instructions for making the peroxin-7 protein, a receptor that transports specific enzymes, including PhyH, into the peroxisomes. Mutations in PEX7 prevent the PhyH enzyme from reaching its destination, rendering it non-functional and causing phytanic acid to accumulate. These mutations can also cause other peroxisomal disorders.
The Role of Peroxisomes
Peroxisomes are crucial organelles for cellular metabolism, and their dysfunction is central to the accumulation of phytanic acid. The alpha-oxidation of phytanic acid is an unusual process compared to the more common beta-oxidation used for other fatty acids. In a healthy individual, this process converts phytanic acid into pristanic acid, which can then be further metabolized. When the alpha-oxidation pathway is broken due to a genetic mutation, the acid accumulates.
Dietary Sources of Phytanic Acid
Phytanic acid is not produced by the human body but is consumed through certain foods. The acid originates from phytol, a component of chlorophyll, which is converted to phytanic acid by bacteria in the digestive systems of ruminant animals. It then accumulates in their fat tissue and, consequently, in food products derived from them.
Foods to be avoided by those with Refsum disease or related conditions include:
- Fat from ruminant animals such as beef, lamb, and goat
- Full-fat dairy products like whole milk, cheese, and butter
- Certain fatty fish and seafood, including cod, haddock, and tuna
Refsum Disease: Adult vs. Infantile
While both adult (classic) and infantile Refsum disease involve high phytanic acid, they are caused by different underlying genetic issues and have distinct clinical presentations.
| Feature | Adult Refsum Disease (ARD) | Infantile Refsum Disease (IRD) |
|---|---|---|
| Cause | Primarily PHYH or PEX7 gene mutations affecting the specific alpha-oxidation pathway. | Mutations in PEX genes, leading to broader peroxisomal biogenesis disorders (Zellweger spectrum disorders). |
| Onset | Typically late childhood, adolescence, or early adulthood, but can vary widely. | Appears in infancy, with symptoms starting in the first year of life. |
| Severity | Symptoms can progress slowly and are generally less severe than IRD. | More severe and disabling, often with a shortened lifespan. |
| Key Symptoms | Retinitis pigmentosa, anosmia, peripheral neuropathy, cerebellar ataxia, deafness, and ichthyosis. | Developmental delays, feeding difficulties, seizures, vision problems, and liver disease. |
| Pathology | Specific defect in phytanic acid alpha-oxidation. | Multiple metabolic abnormalities due to global peroxisome dysfunction. |
The Clinical Consequences of Accumulation
High phytanic acid is toxic to cells, particularly in the nervous system, eyes, and skin. The accumulation damages the myelin sheath, the fatty layer that protects nerve cells, and interferes with cellular function. This leads to the characteristic symptoms of Refsum disease:
- Neurological: Peripheral polyneuropathy (weakness and numbness), cerebellar ataxia (poor balance and coordination), and hearing loss.
- Ophthalmic: Retinitis pigmentosa (leading to night blindness and tunnel vision) and cataracts are common.
- Olfactory: A complete loss of the sense of smell, known as anosmia, is a hallmark symptom.
- Dermatological: Dry, rough, and scaly skin, also known as ichthyosis.
- Cardiac: High levels can cause dangerous heart arrhythmias, which can be life-threatening.
Management and Treatment Options
Managing high phytanic acid involves strict dietary changes to limit intake and, in severe cases, medical intervention to remove the acid from the blood.
- Dietary Restriction: The primary treatment is a lifelong diet low in phytanic acid. This requires avoiding products derived from ruminant animals and certain fish. A high carbohydrate intake is also encouraged to prevent the body from breaking down its own fat stores, which would release stored phytanic acid.
- Plasmapheresis: For dangerously high levels of phytanic acid or severe symptoms, this procedure can be used. It functions similarly to dialysis, filtering the blood to remove excess phytanic acid. It is often used for acute management, but some patients may require it chronically.
- Avoid Fasting: Rapid weight loss or fasting should be avoided as it mobilizes phytanic acid from adipose tissue, causing a spike in blood levels.
For more detailed information on Refsum disease and research efforts, you can visit the Global DARE Foundation.
Conclusion
In conclusion, high phytanic acid is almost always a result of an inherited metabolic disorder, most notably Refsum disease. This genetic defect impairs the body's ability to break down phytanic acid from dietary sources, particularly ruminant fats and dairy. The subsequent accumulation is toxic to the nervous system, eyes, and other organs, leading to progressive and severe symptoms. While there is no cure, careful dietary management and therapeutic interventions like plasmapheresis can effectively control phytanic acid levels and improve patient outcomes. Understanding the specific genetic and metabolic causes is the first step toward proper diagnosis and effective management of this complex condition.
