Refsum Disease – Causes, Pathophysiology and Complications


Refsum disease is a genetic disorder that affects the metabolism of the fatty acid phytanic acid. When phytanic acid accumulates, it causes a number of progressive problems, including retinitis pigmentosa, peripheral neuropathy, anosmia, deafness, cerebellar ataxia and elevated protein concentrations in the cerebrospinal fluid in the absence of an increased number of cells.

The age at which symptoms first present in RD can be variable although most cases present in adolescence. Because the patients are unable to metabolize phytanic acid derived from exogenous sources, highly raised plasma phytanic acid (PA) level in tissues and body fluids is the hallmark of RD.

Mutant forms of phytanoyl-CoA 2-hydroxylase (PHYH) which plays a key role of phytanic acid alpha-oxidation in peroxisomes have been shown to be responsible for some, but not all, cases of Refsum’s disease. Peroxisomal PHYH import occurs via PEX7 gene which is the peroxisomal matrix protein receptor. Though PEX7 has been identified another responsible gene, there still remain a small number of patients in whom no mutations in either of these two genes can be found.


Classic Refsum disease manifests in children aged 2-7 years; however, diagnosis usually is delayed until early adulthood. However, a patient was described with rare late-onset adult disease first evident at age 72 years. Infantile Refsum disease makes its appearance in early infancy.

Refsum Disease Pathophysiology

Refsum disease is associated with the accumulation of phytanic acid in plasma and tissues, which is an unusual branched-chain fatty acid (3,7,11,15-tetramethyl-hexadecanoic acid), derived from the chlorophyll and is present in the typical human diet (strictly exogenous source) consisting of dairy products, meats, and ruminant fats. Due to the mutations, patients are unable to degrade phytanic acid because of the impaired activity of phytanoyl-CoA hydroxylase. This peroxisomal enzyme catalyzes the first step of phytanic acid in alpha-oxidation.

Because of the presence of a 3-methyl group, phytanic acid cannot be degraded by beta-oxidation. Phytanic acid will have alpha-oxidation, which shortens phytanic acid by one carbon atom yielding pristanic acid and carbon dioxide. In this process, phytanic acid must first get activated to its coenzyme-A ester-phytanoyl-CoA, and later converted to 2-hydroxy-phytanoyl-CoA by PAHX.

PAHX activity was undetectable in the liver tissue of a Refsum disease patient. Hence, they concluded that Refsum disease is a true peroxisomal disorder type, unlike other variants.

Phytanic acid accumulates in adipose tissue, myelin sheaths, kidneys, and liver. It induces damage to the structural integrity of cells and tissues by interfering with covalent bonds, which leads to a wide array of symptoms.

Causes of Refsum Disease

In 90% of the cases, Refsum disease is due to a mutation in the PHYH gene (in chromosome 10). The gene code of PHYH for the  Phytanoyl-CoA enzyme is used to break down phytanic acid in the peroxisome. The typical presence of phytanic acid is dairy, beef, lamb and other feed originating from ruminant animals as well as certain sea foods. Due to the improper functioning of peroxisomes, phytanic acid accumulates in the cells.

In some cases, a mutation in the PEX7 gene (chromosome 6) is also seen. These gene mutations cause peroxisome abnormality.

Symptoms of Refsum Disease

The most common symptoms of Refsum disease include:

Retinitis pigmentosa: Retinitis pigmentosa is an expression of degenerative eye disease as the visual receptors are lost in the retina and the background structure of the eye is exposed. It manifests as a failure of night vision and later decreased peripheral vision, and eventually can lead to low vision or blindness.

Anosmia: Loss of the sense of smell and many aspects of the subtleties of taste

Peripheral polyneuropathy: Peripheral polyneuropathy is the term for dysfunction of the nerves outside of the spinal cord. Symptoms may include numbness, weakness, burning pain, and loss of reflexes occurring initially at the body extremes (feet or hands).

Deafness: Loss of hearing

Cerebellar ataxia: Ataxia is a nerve-derived form of unsteadiness. Cerebellar ataxia refers to the fact that the defect is in a specific part of the brain (the cerebellum) that coordinates muscle functions. As a result the brain fails to regulate the body posture, as well as the strength and direction of movements.

Skeletal dysplasia: Bone abnormalities including shortening or deformity of the tubular bones in the hands and feet and abnormal growth plates (epiphyseal dysplasia) at the knees, elbows and shoulders may be found.

Ichthyosis: A distinct type of scaliness of the skin different in appearance from eczema or psoriasis. These symptoms can range anywhere from fish-like scaliness of the palms and soles of the feet to being present on the trunk of the body.

Pupillary abnormalities: The pupil of the eye is often small in Refsum disease and does not respond well to light or drugs used to ‘open’ the eye by optometrists.

Cataract: A clouding of the lens in the eye causing deterioration in vision often associated with starburst haloes around bright objects.

Nystagmus: Rapid, involuntary, rhythmic eye movements

Cardiac Arrhythmia: Heart rhythm abnormalities are a rare but serious complication of very high phytanic acid levels and can be a cause of death in Refsum disease.

Weakness: significant slow-recovering weakness after illness is a feature of Refsum disease

The impact on an individual of these symptoms can increase based on their plasma phytanic acid level.  Higher levels will generally increase the severity of symptoms. Phytanic acid accumulates in the fat tissue of Refsum patients throughout their lives before their diagnosis.  This means that even with a strict diet low in phytanic acid an individual can still have higher levels of plasma phytanic acid throughout their lives due to release of phytanic acid from their fat cells into their blood.


  • Cardiac involvement (with conduction abnormalities and cardiomyopathy) has been associated with premature death.
  • Aminoaciduria is associated with reversible renal involvement as a result of extremely high phytanic acid levels.

Diagnosis and test

Lab results

  • CSF protein levels are usually elevated;
  • Plasma levels of phytanic acid measured by gas chromatography-mass spectroscopy are consistently elevated (normal range < 19 mmol/l). Phytanc acid levels > 800 mmol/l are not uncommon at presentation. Phytanic acid also accumulates to a lesser degree in the plasma of patients with peroxisomal deficiency disorders such as Zellweger disease, neonatal adrenoleukodystrophy and infantile Refsum’s disease. It has been reported at 941 mmol/l in rhizomelic chondrodysplasia punctate. Pristanic acid is also known to be elevated in peroxisomal deficiency disorders and peroxisomal branched chain oxidation defects, but should be low/normal in Refsum’s disease due to a lack of production from phytanate. However, it has been seen a patient where the pristanate to phytanate ratio was 0,005, far exceeding the Refsum’s range (< 0,007) and suggesting a biochemical variant of this disorder.

ENG: Nerve conduction studies are abnormal, with slowing of conduction velocities.

Electroretinogram: May be grossly abnormal.

Histopathology: Nerve biopsies from affected have shown onion bulb formation, and targetoid inclusion have been described in Schwann cells which have a similar appearance on electron microscopy to those seen in cultured fibroblast.

Treatment and medications

No curative therapy currently exists for Refsum disease.

The following treatments are indicated for adult Refsum disease:

  • Dietary restriction of phytanic acid intake
  • Avoidance of sudden weight loss
  • Lifelong treatment with hydrating creams. Appropriate medications consist of skin care products (eg, keratolytics, emollients). Research has shown that enzymes responsible for the omega-hydroxylation of phytanic acid could be useful in Refsum disease treatment. Elevation of CYP4 enzymes could have a favorable role in the elimination of phytanic acid in persons with Refsum disease. Targeting CYP4 enzymes may represent a future therapeutic option 15).
  • Regular care by a cardiologist for cardiac arrhythmias and cardiomyopathy in order to treat signs and symptoms properly with antiarrhythmic and cardiogenic supportive drugs
  • Plasmapheresis: The main indication for plasmapheresis in patients with Refsum disease is a severe or rapidly worsening clinical condition 16). A minor indication is failure of dietary management to reduce a high plasma phytanic acid level 17). Cascade filtration may be an alternative for plasmapheresis. It is as efficient as plasmapheresis and eliminates the need for albumin replacement 18).
  • Because the pupils do not dilate well if at all, other measures, such as use of iris hooks, may be necessary to allow sufficient pupillary enlargement during cataract surgery. In addition, an anterior chamber lens with iris fixation may be necessary because the brittleness of the zonular fibers holding the lens capsule may not allow positioning of an intraocular lens in the capsular bag after cataract removal, a complication observed in one patient.

By restricting dietary intake of phytanic acid or eliminating phytanic acid by plasmapheresis or lipid apheresis, plasma phytanic acid concentrations can be reduced by 50% to 70%, typically to about 100 to 300 µmol/L. This reduction in plasma phytanic acid concentration successfully resolves symptoms of ichthyosis, sensory neuropathy, and ataxia in approximately that order. However, it is uncertain whether treatment affects the progression of the retinitis pigmentosa, anosmia, and deafness 19). Although data are limited, it appears that despite strict dietary treatment the retinitis pigmentosa is very slowly progressive.

A high-calorie diet is necessary to avoid mobilization of stored lipids, including phytanic acid, into the plasma.

Postoperative care requires parenteral nutrition with solutions that do not contain phytanic acid – e.g., Intralipid® available in 10%, 20%, and 30% concentrations, which are all based on soybean oil and egg yolk phospholipid.

Prevention of Refsum Disease

There is no known way to prevent RD. However, parents with a family history of the disorder or who have had another child with RD are advised to consult a genetic counselor to assess their risk if they plan to have another child.

Minimizing intake of beef, lamb, certain seafood, and dairy products while maintaining carbohydrate intake, which helps prevent phytanic acid from entering the blood from fat or liver stores.

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