Refsum Disease

What is Refsum Disease?

Refsum disease was first explained by Sigvald Refsum in 1945, originally named heredoataxia hemeralopica polyneuritiformis. The name changed the following year to heredopathia atactica polyneuritiformis. Today, it’s known as “adult Refsum disease” or “classic Refsum disease.” This rare condition, as per the Online Catalog of Human Genes and Genetic Disorders (OMIM), is identified by MIM number #266500. It’s a condition people inherit from their parents and it involves issues with the function of peroxisomes in the cells.

Peroxisomes are tiny elements inside our cells that produce peroxide, a compound our bodies use in metabolism—the process of breaking down nutrients for energy. These small structures participate in various roles, including fat metabolism—breaking down and creating fat. The issues with fat metabolism are behind Refsum disease.

Refsum disease originates from an enzyme shortage. Specifically, there’s a shortage of the enzyme called phytanoyl-CoA hydroxylase. This leads to an inadequate breakdown of a fat called phytanic acid, resulting in its buildup. The essence of Refsum disease lies in the impact this buildup has on the nervous system.

Because different terms are often used to refer to Refsum disease, it’s worth clarifying that this condition is separate from infantile Refsum disease. The latter comes under the category of Zellweger spectrum disorders, which involve issues with the creation and assembly of peroxisomes. For more specifics on infantile Refsum disease, refer to our companion topic, “Zellweger Spectrum Disorder.”

What Causes Refsum Disease?

Refsum disease is a condition that’s inherited from both parents, meaning the affected person must receive a faulty gene from each parent. Scientists have linked this disease to issues with two specific genes. The most common issue, found in over 90% of Refsum disease cases, involves a gene called PHYH located on a small section of chromosome 10. This gene usually manages the production of an enzyme called phytanoyl-CoA hydroxylase (PAHX), but if the gene isn’t working correctly, the enzyme isn’t active. This leads to an unhealthy buildup of a substance called phytanic acid in the body.

For a small number of people with Refsum disease, the problem is with a different gene called peroxin 7 (PEX7) on chromosome 6. This gene should create a receptor called the peroxisome-targeting signal type 2 (or PTS2 for short), which is essential for moving certain proteins into the peroxisome, a part of the cell that helps with digestion and removing waste. If the PTS2 receptor isn’t working, it can also affect phytanoyl-CoA hydroxylase, again leading to a buildup of phytanic acid. It’s worth noting that problems with the PEX7 gene are most often linked with a different disease called rhizomelic chondrodysplasia punctata type 1.

Risk Factors and Frequency for Refsum Disease

Refsum disease is a really uncommon condition, which makes it difficult to accurately measure how often it occurs. In White populations within the United States, it’s estimated to affect fewer than 1 in every 1,000,000 people. Symptoms can start to appear at any age from 7 months to 50 years old, but they usually show up before the age of 20. However, it often takes about 12 years from the first symptoms for Refsum disease to be diagnosed.

Refsum disease is very rare, affecting fewer than 1 in 1,000,000 people in the United States’ White populations.
Symptoms can start appearing at any age from 7 months to 50 years old.
Most of the time, signs and symptoms show up before the age of 20.
It often takes around 12 years from the time symptoms first appear for the disease to be diagnosed.

Signs and Symptoms of Refsum Disease

Refsum disease is a condition that shows a range of symptoms which typically appear and progress slowly. Because of this, it’s important to track the sequence of symptoms to identify the disease from other potentially similar conditions. To diagnose the disease, medical professionals will usually document the clinical characteristics and then follow up with biochemical and genetic tests. The initial symptoms of Refsum disease usually appear during late childhood or adolescence, but in some cases, they may occur earlier or later.

The first symptoms to show up include:

Ophthalmologic: the patient experiences worsening night vision due to a condition called retinitis pigmentosa. This symptom is present in all cases of Refsum disease and is one of the earliest signs. As the disease progresses, the patient might experience reduced range of vision, miosis, and eventually cataracts.
Olfactory: the patient loses their sense of smell. This is one of the earliest symptoms and is consistent with Refsum disease.
Congenital skeletal malformations: about 30% of patients might have shortened metatarsals and metacarpals.

During the next 10 to 15 years, other signs and symptoms might develop:

Neurological: a condition called symmetric polyneuropathy, which affects both sensory and motor nerves, can develop. This causes weakness and numbness in the distal areas. Furthermore, deep tendon reflexes start to fade.
Sensorineural hearing loss in both ears is common, which is due to cochlear nerve involvement.
Cerebellar ataxia, a symptom relating to lack of muscle coordination, presents in the later stages of the disease.
Other organ systems: Ichthyosis, a skin condition, is sometimes present.

Additionally, patients might experience heart arrhythmias and develop a condition called cardiomyopathy. Some reports suggest that the release of a substance called phytanic acid from the liver after infection, or due to stress-induced release of catecholamines during a treatment called plasmapheresis, can cause these heart arrhythmias. In some cases, these arrhythmias have led to sudden death.

To describe the peripheral neuropathy associated with Refsum disease, the term Hereditary Motor and Sensory Neuropathy type 4 (HMSN4) has been used inconsistently. HMSN4 was initially synonymous with the neuropathy of Refsum disease. However, the classification for inherited neuropathies is evolving. Nowadays, HMSN4 is used more often interchangeably with Charcot-Marie-Tooth disease type 4 (CMT4), which includes all autosomal recessive motor and sensory neuropathies, including that of Refsum disease.

Testing for Refsum Disease

Refsum disease can be confirmed through a range of clinical tests:

A detailed eye examination can be conducted to check for retinitis pigmentosa, a condition that can cause problems with your vision. Findings might include irregular pigmentation in the eye, thinning of the retinal blood vessels, and changes to the appearance of the optic nerve. Initially, you might experience night blindness; this typically worsens over time, eventually affecting the sharpness of your vision. This is due to damage to specific cells in the eye responsible for vision. Visual field testing that checks the overall scope of your vision could indicate this. Specialized eye imaging or contrast vision testing could further solidify the diagnosis. Electroretinography, a test that analyses the electrical responses of various cells within the eyes, can help understand the initial pattern of damage and monitor the progression over time.

Issues with your sense of smell (anosmia) is also a symptom of Refsum disease. This could be checked using a smell identification test, like the one developed by the University of Pennsylvania. Nervous system tests assessing multiple sensory responses, strength, and reflexes can verify if you are experiencing neuropathy (nerve damage). This can be confirmed using electromyography (a test that measures the electrical activity of muscles) or nerve conductance studies (tests that measure the speed at which electrical impulses move through a nerve). Your coordination will also be checked. Note that Refsum disease does not affect cognition or mental abilities.

If you experience hearing loss, a detailed hearing examination will be required. This may include pure tone audiometry (a hearing test used to determine the presence and degree of hearing loss), single-frequency tympanometry (a test to measure the function of the middle ear), single-frequency acoustic reflexes (tests to measure the contraction of a small muscle in the ear), and brainstem auditory evoked potentials (tests to measure the hearing nerve’s responses).

Your hands and feet might show physical abnormalities. A combination of a physical and radiological (X-ray) examination can confirm this. Your heart will be monitored through heart tracing (electrocardiogram) and a heart ultrasound (echocardiogram) to check for irregular heart rhythms, heart muscle diseases, and heart failure. This is significant because sudden death due to heart abnormalities has been reported in cases of Refsum Disease.

To solidify the diagnosis, genetic profiling could also be conducted to look for abnormalities in certain genes, PHYH and PEX7. It could be beneficial to discuss your results with a genetic counselor or another clinical genetics professional.

From a biochemical standpoint, the hallmark of Refsum disease is a high level of a fatty acid called phytanic acid in your blood (>200 µmol/L). Generally, levels above 30 µmol/L are considered abnormal. Bear in mind that if your diet is low in phytanic acid, your blood levels may not be excessively high. A skin biopsy test can confirm a deficiency in the breakdown of this fatty acid in your body.

Treatment Options for Refsum Disease

Refsum disease, a rare genetic disorder that affects how your body processes certain types of fat, can often be managed by making specific changes to your diet and undergoing a medical procedure known as plasmapheresis.

Diet:

The main component of treating Refsum disease is changing what you eat to limit a type of fat called phytanic acid. You can find phytanic acid in foods like meat or fats from certain animals (such as lamb, beef, and specific fish), baked goods that contain animal fats, and dairy products like butter and cheese. The goal is to reduce your daily intake of phytanic acid to less than 10 mg.

However, it’s important not to lose weight too rapidly or go without food for a long time. These actions can cause the breakdown of fat stores (lipolysis) in your body, which can release phytanic acid stored in your liver and body fat.

If you stick to this diet carefully and control the levels of phytanic acid in your blood, you may see improvements in several symptoms of Refsum disease. These symptoms include neuropathy (nerve damage), ichthyosis (dry, scaly skin), and ataxia (difficulties with movement and balance). However, other symptoms like retinitis pigmentosa (an eye disease that causes blindness), loss of sense of smell (anosmia), and hearing loss might not improve.

Plasmapheresis:

This is a medical procedure that siphons off some of your blood, removes the phytanic acid from it, and then returns the modified blood back to your body. This can be particularly useful during severe episodes of Refsum disease, where there are very high levels of phytanic acid in your blood (for example, above 1500 µmol/L).

However, there’s no strong evidence that using plasmapheresis regularly provides any extra benefit when your blood levels of phytanic acid are already well controlled through diet.

Refsum disease is often first detected due to visual changes and retinitis pigmentosa, a condition that affects the retina. However, retinitis pigmentosa can be caused by several different conditions. These include certain genetic conditions, the effects of medication, and consequences of cancer, trauma or infection. Therefore, it’s important for people with this condition to see an eye doctor to discover the exact cause. Some conditions that should be considered include:

Usher syndrome: This is the most common cause of retinal degeneration and can cause both vision and hearing loss.
Bardet-Biedl syndrome: This also causes retinal degeneration and can come with additional symptoms such as cognitive impairment and obesity.
Alstrom syndrome: This condition is caused by a gene mutation and can also cause hearing loss and heart problems. However, unlike Refsum disease, vision loss is usually centrally located.
Kearns-Sayre syndrome: This affects most organs and causes vision and heart problems. It can also result in hearing loss and lack of coordination.
Alpha-methyl acyl-CoA racemase deficiency: This condition can lead to elevated levels of certain acids.
Zellweger spectrum disorder: This is caused by mutations in certain genes and can cause a variety of symptoms and disorders.
Rhizomelic chondrodysplasia punctata: This condition can cause severe cognitive impairments and congenital cataracts among other symptoms.

Each of these conditions share some similarities with Refsum disease, but also have their unique features and effects.

What to expect with Refsum Disease

The outlook for people with Refsum disease varies quite a bit. It can depend on several things, including how old the patient was when the disease started, how quickly the disease progresses, and how severe it is. One of the biggest factors that can affect a patient’s outlook is how well they can stick to the treatments, especially a diet that restricts a substance called phytanic acid.

Patients who develop heart problems due to Refsum disease can have a higher risk of early death due to irregular heart rhythms, which are also known as arrhythmias.

Possible Complications When Diagnosed with Refsum Disease

Refsum disease, if not treated, can have serious complications. This is because a fatty acid called “phytanic acid” begins to build up in the body. This buildup can lead to a number of different health problems such as:

Retinitis pigmentosa, a disease that affects the eyes
Anosmia, which is loss of smell
Iris atrophy, or degeneration of the colored part of the eye
Cataracts, or cloudy areas in the eye lens
Miosis, or unusual narrowing of the pupils
Sensorineural hearing loss, a type of hearing loss
Ataxia, a lack of muscle control during voluntary movements
Peripheral polyneuropathy, a disease that affects your nervous system
Cardiomyopathy, a disease of the heart muscle
Cardiac conduction abnormalities, or irregular heart rhythms
Skeletal malformations, especially shortened bones in hands and feet
Ichthyosis, a condition that causes dry, thickened skin

These problems can get worse over time, but some can be improved with treatment. Most patients will not experience all of these issues. Also, when phytanic acid levels get very high, there can be a quick and serious worsening of vision and physical health, a condition known as acute Refsum disease.

Preventing Refsum Disease

Genetic counseling is very important when dealing with Refsum disease. By educating patients and their families, they can make informed decisions about medical treatment and personal choices, like family planning.

For parents with a child who has Refsum disease:

– If the parents do not have the disease, they are still carriers, meaning they carry one gene mutation that causes Refsum disease (either in the PEX7 or PHYH gene). This doesn’t cause any symptoms and they won’t develop the disease.

For siblings of a patient with Refsum disease:

– If their parents don’t have the disease, each sibling has a 25% chance of having the disease, a 50% chance of being a carrier (i.e., having the gene mutation but no symptoms), and a 25% chance of not having the disease or carrying the gene mutation.

For the children of a person with Refsum disease:

– If their other parent doesn’t have the disease or carry the gene mutation, then the children will be “obligate carriers” – meaning they have the gene mutation but won’t develop the disease.

It’s recommended that patients with Refsum disease follow a certain diet to help manage their condition. They should avoid foods that contain a compound called phytanic acid. These foods include meats from animals like sheep, cows, and certain types of fish, baked goods made with animal fats, and dairy products like butter and cheese. Also, rapid weight loss or fasting can cause a sudden release of phytanic acid in the body, so it’s best to avoid these as well.

Frequently asked questions

The prognosis for Refsum Disease varies depending on several factors, including the age at which the disease started, the rate of progression, and the severity of the condition. Compliance with treatment, particularly a diet that restricts phytanic acid, can also impact the prognosis. Patients who develop heart problems as a result of Refsum Disease may have an increased risk of early death due to irregular heart rhythms.

Refsum disease is inherited from both parents, meaning the affected person must receive a faulty gene from each parent.

The signs and symptoms of Refsum Disease include: - Worsening night vision (retinitis pigmentosa), which is one of the earliest signs and is present in all cases of Refsum Disease. As the disease progresses, the patient may experience reduced range of vision, miosis, and eventually cataracts. - Loss of sense of smell (olfactory), which is one of the earliest symptoms and is consistent with Refsum Disease. - Congenital skeletal malformations, such as shortened metatarsals and metacarpals, which are present in about 30% of patients. - Symmetric polyneuropathy, which affects both sensory and motor nerves and causes weakness and numbness in the distal areas. Deep tendon reflexes start to fade. - Sensorineural hearing loss in both ears, which is due to cochlear nerve involvement. - Cerebellar ataxia, a symptom relating to lack of muscle coordination, which presents in the later stages of the disease. - Ichthyosis, a skin condition, which is sometimes present. - Heart arrhythmias and cardiomyopathy, which can be caused by the release of phytanic acid from the liver after infection or due to stress-induced release of catecholamines during plasmapheresis treatment. In some cases, these arrhythmias have led to sudden death. - Peripheral neuropathy, which is sometimes referred to as Hereditary Motor and Sensory Neuropathy type 4 (HMSN4) or Charcot-Marie-Tooth disease type 4 (CMT4).

To properly diagnose Refsum Disease, a doctor may order the following tests: 1. Eye examination: This can include visual field testing, specialized eye imaging, contrast vision testing, and electroretinography. 2. Smell identification test: This can assess any issues with the sense of smell. 3. Nervous system tests: These can include electromyography and nerve conductance studies to check for neuropathy. 4. Hearing examination: This can include pure tone audiometry, tympanometry, acoustic reflexes, and brainstem auditory evoked potentials. 5. Physical and radiological examination: This can help identify physical abnormalities in the hands and feet. 6. Heart monitoring: This can involve electrocardiogram and echocardiogram to check for heart abnormalities. 7. Genetic profiling: This can be done to look for abnormalities in certain genes. 8. Biochemical testing: This can measure the level of phytanic acid in the blood and confirm a deficiency in its breakdown. 9. Skin biopsy: This can further confirm a deficiency in the breakdown of phytanic acid. It is important to consult with a doctor to determine the specific tests needed for an individual case of Refsum Disease.

Usher syndrome, Bardet-Biedl syndrome, Alstrom syndrome, Kearns-Sayre syndrome, Alpha-methyl acyl-CoA racemase deficiency, Zellweger spectrum disorder, Rhizomelic chondrodysplasia punctata.

When treating Refsum Disease, there can be side effects such as neuropathy (nerve damage), ichthyosis (dry, scaly skin), and ataxia (difficulties with movement and balance). However, other symptoms like retinitis pigmentosa (an eye disease that causes blindness), loss of sense of smell (anosmia), and hearing loss might not improve. Additionally, there can be complications from Refsum Disease if left untreated, including retinitis pigmentosa, anosmia, iris atrophy, cataracts, miosis, sensorineural hearing loss, ataxia, peripheral polyneuropathy, cardiomyopathy, cardiac conduction abnormalities, skeletal malformations, and ichthyosis.

An ophthalmologist or an eye doctor should be seen for Refsum Disease.

Refsum disease is very rare, affecting fewer than 1 in 1,000,000 people in the United States' White populations.

Refsum Disease is treated through specific changes to the diet and the use of a medical procedure called plasmapheresis. The diet involves limiting the intake of phytanic acid, a type of fat found in certain foods. The goal is to reduce daily intake of phytanic acid to less than 10 mg. Plasmapheresis is a procedure that removes phytanic acid from the blood and returns the modified blood back to the body. However, plasmapheresis is typically used during severe episodes of Refsum Disease when blood levels of phytanic acid are very high.

Refsum Disease is a rare condition that involves issues with the function of peroxisomes in the cells. It is a condition that people inherit from their parents and is characterized by a shortage of the enzyme called phytanoyl-CoA hydroxylase, leading to an inadequate breakdown of a fat called phytanic acid. This buildup of phytanic acid has an impact on the nervous system.

Congenital Disorders Genetic Disorders Metabolic Disturbances Retinitis Pigmentosa Secondary Dyslipidemia