OVERVIEW

What is Refsum's disease?

Refsum's disease is a rare autosomal recessive genetic disorder, named after Refsum who first reported and systematically documented it in detail.

It also has many other names, such as Refsum syndrome, ataxia-polyneuritis syndrome, hereditary ataxia polyneuritis syndrome, Boussy-Levy syndrome, phytanic acid oxidase deficiency, etc.

It typically manifests around the age of 20, with symptoms including retinitis pigmentosa, cerebellar ataxia, polyneuropathy, hearing impairment, and cardiac conduction dysfunction. The patient's lifespan largely depends on how early the disease is detected.

Is Refsum's disease common? How many people have it?

It is very rare.

After Refsum's first report in 1945, Yang Renmin and others in China diagnosed the first case of Refsum's disease in 1981. Since then, only one or two cases have been reported every few years. Relatively speaking, the disease is more common in regions like the UK and Northern Europe.

What is the relationship between Refsum's disease and infantile Refsum's disease?

Some believe Refsum's disease and infantile Refsum's disease are two types of the same disorder, but most consider them distinct conditions due to differences in clinical manifestations and pathogenesis.

• Refsum's disease: Infants are usually normal at birth, with symptoms appearing in late childhood or adolescence. Fewer than one-third of patients develop symptoms before age 10, 50% between 10–30 years, and some cases have been reported as late as age 50.
  Initial symptoms are unstable and hard to detect. The disease typically progresses over time, with periods of mild or slow progression. Rapid weight loss, fever, or pregnancy may trigger acute or subacute onset, leading to sudden acceleration.

• Infantile Refsum's disease: Symptoms usually appear within the first year of life, characterized by developmental delays, vision and hearing impairment, hepatomegaly, severe hypotonia, and often death in infancy. Common causes of death include progressive apnea or respiratory infections. About 77% of children who survive the first year without progression may live to school age.

This article specifically refers to adult Refsum's disease, not the infantile form.

SYMPTOMS

What are the common symptoms and manifestations of Refsum disease?

• Retinitis pigmentosa: Gradual loss of night vision and peripheral vision. Patients find it increasingly difficult to see at night, experience a significant reduction in their field of vision, and suffer from severe visual decline. Retinal degeneration can be detected through ophthalmoscopy or specialized retinal function tests.
• Cerebellar ataxia: Patients often exhibit uncontrolled posture and gait while walking; impaired balance, causing involuntary swaying when standing; loss of depth perception, leading to collisions with walls or other objects; slurred speech and frequent tongue-tied episodes.
• Polyneuropathy: Typically manifests as muscle weakness, muscle atrophy, and sensory disturbances, starting from the distal lower limbs and gradually spreading upward to the trunk and upper limbs. Patients feel increasingly "weak," gradually lose sensation in their feet, and experience ascending numbness. Sometimes, they may feel tingling, numbness, or burning sensations on the skin. Eventually, disuse atrophy occurs due to the inability to walk or stand.
• Skin lesions: Localized ichthyosis-like lesions may develop, which can spread across the body in severe cases; hyperkeratosis occurs on the palms and soles.
• Cardiac damage: Affects cardiac electrical conduction and damages the myocardium, leading to symptoms such as tachycardia and arrhythmias (irregular heart rhythms). A significant proportion of patients may suffer sudden cardiac death.
• Others: May include sensorineural hearing loss, finger deformities, scoliosis, decreased sense of smell, etc.

How does Refsum disease progress?

Refsum disease has an insidious onset and progresses slowly. It is often discovered when patients seek medical attention for "night blindness." In later stages, progression accelerates, and patients suffer from multiple severe symptoms, leading to immense distress. Ultimately, death occurs due to the progression of one of these symptoms (typically heart failure or sudden cardiac death).

What severe consequences does Refsum disease cause?

Blindness, deafness, paralysis, and ultimately death.

CAUSES

What is the cause of Refsum disease?

Normally, the human body contains an enzyme called α-hydroxylase oxidase, which metabolizes and breaks down phytanic acid.

Patients with Refsum disease lack α-hydroxylase oxidase, leading to the inability to oxidize phytanic acid. This results in its accumulation in the blood and tissues, interfering with membrane function or increasing tissue sensitivity to damage, thereby causing tissue harm. This triggers the series of symptoms mentioned above.

Is Refsum disease hereditary? How is it inherited?

Yes, it is hereditary.

The inheritance pattern is autosomal recessive. Siblings of an affected individual have a 25% chance of also being affected, a 50% chance of being asymptomatic carriers, and a 25% chance of neither being affected nor carrying the disease-causing gene.

The incidence of Refsum disease increases significantly with consanguineous marriages.

DIAGNOSIS

How is Refsum disease diagnosed?

When diagnosing Refsum disease, doctors primarily rely on clinical symptoms and various tests, including:

• Biochemical tests: Typically, patients have plasma phytanic acid levels > 200 μmol/L (normal levels < 10 μmol/L), pristanic acid < 2 μmol/L (normal levels < 3 μmol/L), and an increased phytanic acid/pristanic acid ratio.
• Cerebrospinal fluid (CSF) tests: Protein levels are usually significantly elevated, with protein-cell dissociation observed. Glucose, cell counts, and chloride levels are often normal.
• Imaging studies: Plain X-rays may reveal bone changes. MRI scans can show symmetrical alterations in the corticospinal tract, cerebellar dentate nucleus, and corpus callosum.
• Nerve conduction studies: These demonstrate non-uniform slowing, indicative of demyelinating polyneuropathy.
• Nerve biopsy: Reveals hypertrophic changes in peripheral nerves, widespread demyelination and remyelination, forming an "onion-bulb" appearance.
• Electroretinography (ERG): May detect severe abnormalities.

Which diseases is Refsum disease easily confused with?

• Polyneuritis: Polyneuritis presents with motor and sensory disturbances in specific peripheral nerve distributions. Pain is a common symptom, often accompanied by neuropathic pain in areas of sensory loss and deep pain in affected limbs.
• Guillain-Barré syndrome: Also known as acute inflammatory demyelinating polyneuropathy, this condition can also cause muscle weakness. However, it typically worsens over days to weeks and then gradually resolves spontaneously. Treatment can shorten symptom duration.
• Neurosyphilis: When neurosyphilis affects the spinal cord, it can lead to muscle weakness and atrophy; ocular involvement may cause uveitis; auditory nerve involvement can result in hearing loss. It can be distinguished using Treponema pallidum serological tests.

TREATMENT

Which department should I visit for Refsum disease?

Neurology.

Can Refsum disease heal on its own?

No.

How should Refsum disease be treated?

There is currently no effective treatment for Refsum disease. The focus is on symptom management and prolonging the patient's life. Early diagnosis is crucial. Common treatment approaches include:

• Strict low-phytanic acid diet: Since dietary intake is the sole source of phytanic acid in the body, strictly limiting it can delay symptom onset and extend survival.
• Plasmapheresis: The only current treatment for Refsum disease, it reduces phytanic acid levels in the blood, minimizing tissue and cell damage.
• Gene therapy: Still under research but holds potential for curing Refsum disease.
• Others: Life support and symptomatic treatment for severe complications.

Can Refsum disease be cured?

There is currently no cure, but hope lies in advancements in gene therapy.

DIET & LIFESTYLE

What should patients with Refsum disease pay attention to in their diet?

Strictly limit the intake of phytanic acid while ensuring daily nutrition and calorie supply to prevent weight loss.

Avoid consuming green vegetables and reduce the intake of animal fat tissues, including beef, lamb, dairy products, and fish high in unsaturated fatty acids (such as tuna and cod). However, poultry like chicken and duck, lean pork, fruits, and non-green vegetables are allowed.

Dietary restrictions should be maintained for life after diagnosis.

What should patients with Refsum disease pay attention to in daily life?

In the later stages of the disease, symptoms such as blindness and paralysis may occur. Patients should always have dedicated caregivers to prevent accidents.

PREVENTION

Can Refsum disease be prevented? How to prevent Refsum disease?

Refsum disease is a genetic disorder. The so-called prevention mainly refers to preventing the birth of affected fetuses. Key measures include:

• Avoid consanguineous marriages.
• Individuals with the disease or family members who have the condition should seek genetic counseling at relevant institutions before reproduction to assess the risk of offspring inheriting the disease.