What to know about Refsum disease

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Refsum disease is a rare, genetic, and metabolic condition. It develops due to problems with special organelles, known as peroxisomes. When these organelles cannot function correctly, it causes an acid, known as phytanic acid, to build up in blood and tissues.

Refsum disease belongs to a group of conditions known as leukodystrophies. These conditions affect the CNS. Problems typically occur when a gene variation leads to damage to the white matter of the brain.

When problems occur with the white matter, they can slow or block communication between nerve cells. This can manifest as a variety of neurological problems, such as trouble with vision and movement.

Read more about leukodystrophies here.

The term Refsum disease may refer to one of two conditions — infantile Refsum disease (IRD) or adult Refsum disease (ARD).

ARD

ARD, also known as classic Refsum disease, occurs when the body is unable to produce an enzyme in the peroxisome, which breaks down phytanic acid. As a result, toxic levels of phytanic acid can accumulate in the brain, blood, and other tissues.

IRD

IRD is a Zellweger spectrum disorder. This term describes a group of rare genetic conditions. Health experts classify these disorders as variations of one disease, forming a spectrum of the disease.

IRD often occurs due to structural problems with peroxisomes. It also differs as it presents much earlier than ARD, can cause a number of different symptoms, and may be fatal in infancy or early childhood.

Refsum disease occurs due to problems with peroxisomes. These are special organelles present in cells. They contain different enzymes that help to break down molecules and produce hydrogen peroxide through a process known as alpha-oxidation.

Peroxisomes help break down fatty acids, such as phytanic acids. However, if peroxisomes are unable to function, these fatty acids can accumulate and cause damage to the white matter of the brain. These acids can also cause damage elsewhere in the body, such as the heart.

The majority of ARD cases occur due to genetic alterations in the PHYH gene. Specifically, alterations in this gene result in problems with the phytanoyl-CoA hydroxylase enzyme. This is the enzyme that the peroxisome uses to break down phytanic acid.

In other cases, ARD may develop due to variations in the PEX7 gene, which helps transport the enzyme into the peroxisomes.

IRD instead occurs due to alterations in the genes responsible for producing peroxisomes. Variations in other PEX genes can result in IRD or other Zellweger spectrum disorders. These genes include:

• PEX1
• PEX2
• PEX6
• PEX10
• PEX12
• PEX26

Symptoms of ARD typically manifest in late childhood or early adulthood. However, some people do not experience symptoms until their 40s or 50s. Symptoms can include:

• retinitis pigmentosa, or difficulty seeing in low light that can lead to vision loss
• hearing loss
• anosmia, or the loss of the sense of smell
• ataxia, or problems with balance and coordination
• dry and scaly skin
• arrhythmias, or an abnormal heartbeat
• shorter bones in the fingers and toes
• weakness or numbness of the hands and feet, known as peripheral neuropathy

As the name implies, symptoms of IRD often begin in infancy. Symptoms may include:

• retinitis pigmentosa
• hearing problems
• nystagmus, or rapid, jerky eye movements
• hypotonia, or floppy muscle tone
• ataxia
• enlargement of the liver
• growth problems
• intellectual difficulties
• abnormal facial features

A doctor may suspect either ARD or IRD if a person presents with certain symptoms, such as vision or hearing problems.

Initial diagnosis will typically involve a blood test. Individuals with Refsum disease will have high levels of phytanic acid in a blood sample. They will also typically have low levels of pristanic acid in their blood. This is the substance the peroxisomes should convert phytanic acid to.

To confirm the diagnosis, a medical professional can perform a molecular genetic test to identify gene variations. Alternatively, they can perform an enzyme analysis from a skin biopsy, which will determine if there are problems with the phytanoyl-CoA hydroxylase pathway.

Treatment and management of Refsum disease usually involves following dietary guidelines. This typically requires limiting foods rich in phytanic acids while maintaining sufficient carbohydrate intake. Eating enough carbs can help prevent phytanic acid from entering the blood from fat or liver stores.

A dietician can provide guidance and advice on how a person can manage a low-phytanic-acid diet. Dietary guidelines may recommend avoiding foods high in phytanic acids and phytyl fatty acid esters. These include:

• beef
• goat
• lamb
• dairy creams
• milk
• yogurt
• chocolate
• cod
• crab
• salmon
• cheese
• baked goods containing butter, milk, or other dairy products
• flaxseed oil
• fish oil

If phytanic acid levels are high, or symptoms are severe, the removal and reinfusion of blood, known as plasmapheresis or apheresis, may be necessary. Doctors typically base other treatment options on symptoms.

Refsum disease is a condition that can result in a fatty acid, known as phytanic acid, building up to toxic levels. There are two subclasses of Refsum disease — adult Refsum disease and infantile Refsum disease.

Research suggests that the conditions occur due to variations in different genes, which affect the function of peroxisomes. These are special organelles that usually break down phytanic acid. However, when peroxisomes do not function correctly, phytanic acid can accumulate.

This can damage the central nervous system, and other parts of the body, resulting in symptoms such as vision and hearing loss.

Treatment for Refsum disease will typically involve eating a low-phytanic-acid diet.