Refsum Disease

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Refsum disease is a rare autosomal recessive disease from the peroxisomal biogenesis spectrum of disorders. Peroxisomes are multiple membrane-bound intracellular organelles involved in catalyzing various functions in cellular metabolism and biosynthesis. The etiology for Refsum disease primarily depends on the presence of aberrant genes for specific enzymes. This activity describes the evaluation and management of Refsum disease. It highlights the role of the healthcare professionals in accurately evaluating and managing Refsum disease and providing surveillance to improving patient care and their overall well-being.


  • Review the etiology of Refsum disease.
  • Identify the evaluation of a patient with Refsum disease.
  • Outline various management options in Refsum disease.


Refsum disease is one of the four major peroxisomal biogenesis disorders. Peroxisomes are multiple membrane-bound intracellular organelles involved in catalyzing various functions of cellular metabolism and biosynthesis including beta-oxidation of very-long-chain-fatty-acids (VLCFA); alpha oxidation (strictly peroxisomal); catabolism of branched-chain fatty acids, amino acids, and ethanol; and biosynthesis of cholesterol, bile acids, and plasmalogens phospholipids found in the brain’s white matter.[1]

Due to such a central role of peroxisomes in the various cellular mechanisms, numerous peroxisomal disorders are known today. With ever-increasing advances, it is an expanding class of genetic disorders due to an impairment in either peroxisome biogenesis or one of the metabolic functions. The four most common peroxisomal biogenesis disorders are:

  1. Refsum disease (both infantile and classic)
  2. Zellweger syndrome
  3. Neonatal adrenoleukodystrophy
  4. Rhizomelic chondrodysplasia punctata

Refsum disease is classified into two subgroups, based on differences of the enzymes affected, metabolites accumulated, genetics, clinical presentations, and treatment. 

  • Classic/adult Refsum disease (CRD)
  • Infantile Refsum disease (IRD)

Classic/adult Refsum disease is also known as hereditary motor and sensory neuropathy IV or heredopathia atactica polyneuritiformis.


The etiology for Refsum disease primarily depends on the presence of aberrant genes for specific enzymes. Both are autosomal-recessive in inheritance.

Classic/adult Refsum disease

  1. Over 90% of CRD patients have a deficiency of phytanoyl-CoA hydroxylase (PAHX) encoded by PHYH, and fewer than 10% have a deficiency of type 2 peroxisomal targeting signal (PTS2) receptor encoded by peroxin (PEX)7.[1]
  2. Gene for PHYH is found on the short arm of chromosomes 10 (p11.2-pter), while for PEX7 is mapped to the short arm of chromosome 6p22-q24. 
  3. The mutations in the PHYH gene lead to an enzymatically inactive protein and dysregulating the downward pathways resulting in phytanic acid accumulation.
  4. It is noteworthy that the defective PTS2, suggests that the enzyme deficient in Refsum disease is targeted to peroxisomes from cytosol through PTS2.
  5. Mutations in PEX7 are usually seen with rhizomelic chondrodysplasia punctata but atypically can cause Refsum disease.[2]

Infantile Refsum disease

  1. Mutations in at least 12 different genetic loci have been implicated in IRD, including PEX1 (7q21.2), PEX2 (8q21.13), and PEX26 (22q11.21) that encodes for ATPases, which helps to import cytosolic proteins into peroxisomes.[3][4]


Refsum disease is a very rare disease. No exact estimates of Refsum disease prevalence are known. Most cases described in the literature are from the United Kingdom and Norway, where there is slightly more awareness as well.[1] No racial association is known. Refsum disease affects both sexes equally. CRD manifests later in life compared to IRD. CRD can be diagnosed as early as 2-7 years, but it usually gets delayed until early adulthood. IRD is evident in early infancy.[4]


Classic/adult Refsum disease

  1. CRD 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.[3] 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.
  2. 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.
  3. Jansen et al. reported that 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.[5]
  4. 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.[3]

Infantile Refsum disease

  1. IRD differs from CRD in the pathophysiology. CRD is mainly due to PAHX deficiency, and phytanic acid accumulation while IRD can have multiple enzyme deficiencies of PEX-class leading to the accumulation of many substrates at once, primarily VLCFA, di- and tri-hydroxycholestanoic acid, pipecolic acid, and phytanic acid with reduced plasmalogen levels in neural tissues and erythrocytes.[6]
  2. Phytanic acid levels can normalize with age.
  3. It is believed that elevated levels of phytanic acid and perhaps the other lipophilic intermediates intercalate into and disrupt retinal cell membranes leading to manifestations of this dystrophy.[6]
  4. Due to deficient beta-oxidation of VLCFA and alpha oxidation of phytanic acid and reduced plasmalogen synthesis, many similar symptoms as in CRD are observed. 

In both presentations, due to high phytanic acid levels that interfere with vitamin A esterification occurring in the retinal pigment epithelium, progressive visual failure occurs that helps to obtain an early diagnosis.[7]


Classic/adult Refsum Disease 

  1. Nerve biopsy on electron-microscopy reveals an onion bulb formation and targetoid inclusions in Schwann cells.[8]
  2. Microscopy of the liver shows a severely low amount or absence of peroxisomes. They are reduced in numbers with a proportional increase in size. These unusual liver peroxisomes lack catalase.
  3. Skin biopsy exhibits features of ichthyosis vulgaris, such as moderate hyperkeratosis and acanthosis with a thin granular layer. Many variably sized vacuoles can be seen in basal and suprabasal keratinocytes. On staining, cryostat-cut sections by lipid stain exhibit the presence of lipid aggregation in vacuoles.[8]

Infantile Refsum Disease

  1. Pathologically, notable findings include the complete absence of peroxisomes on liver biopsy and degeneration of all retinal layers evident on electroretinography.[9][10]

History and Physical

Symptoms are abundant, many of which overlap; therefore, it is particularly essential to assess the chronology of symptoms to distinguish between other peroxisomal biogenesis disorders and between CRD and IRD. The clinical findings, correlated along with a series of biochemical tests and genetic profiles, are the mainstay of accurate diagnosis.

Classic/adult Refsum Disease

  1. Usually presents in late childhood or adolescence, although onset maybe later.        
  2. Ocular: Typically, symptoms usually initiate with progressive deterioration of night vision due to retinitis pigmentosa. Electroretinography is used in children, which helps to obtain the diagnosis in the early stages.
    •  Reduced visual fields, miosis, and cataracts. Typically, patients experience night blindness years before the progressive changes of constricted visual fields and decreased central visual acuity.[9]
  3. Anosmia: Loss of the sense of smell. If a patient reports loss of taste, consider that as a pertinent symptom.[11]
  4. After 10–15 years, other associated symptoms entail including progressive sensorineural deafness, peripheral polyneuropathy (also known as hereditary sensory-motor neuropathy type IV) with raised cerebrospinal fluid (CSF), proteinuria and ataxia.[12]
  5. Neural: Characterized by mixed asymmetric polyneuropathy and involves motor and sensory nerves. As a result, the distal lower limbs have muscular atrophy and weakness, which progressively can become widespread, disabling not only the limbs but the trunk as well.
    • It may not be clinically evident initially, and symptoms often wax and wane.
    • Deep sensation, vibration, and proprioception in the legs are usually affected.
    • Hearing loss: Sensorineural hearing loss due to auditory nerve involvement affecting both ears is common. It can be assessed with a brainstem auditory evoked response test.[13][14]
    • Cerebellar ataxia: Presents as a late manifestation with an unsteady gait.
  6. Atypical:
    • Ichthyosis (scaly skin)
    • Kidney malfunction directly related to the plasma level of phytanic acid.[3]
    • Cardiac arrhythmias directly related to the plasma level of phytanic acid.[3] Premature deaths have been reported due to cardiac arrhythmias due to an acute release of a labile phytanic acid pool from the liver after an infection or as a result of stress-induced catecholamine release during plasmapheresis.[15]
    • Bilateral shortening of metacarpals or metatarsals is seen in around 30% of patients.
    • Psychiatric disturbances can occur in a small proportion of patients.

Infantile Refsum Disease

  1. It can present as early as the sixth month of infancy when the child displays symptoms of severe developmental delay.
  2. Visual impairment due to tapeto-retinal degeneration.[9][16]
  3. Neurologic manifestations
    • Hypotonia
    • Cerebellar ataxia and gait
    • Peripheral neuropathy
    • Severe mental retardation
    • Sensorineural deafness
    • Anosmia
    • Neurologic deterioration is slower than in Zellweger's syndrome or neonatal adrenoleukodystrophy. Patients can walk but might have ataxia. Many patients survive until adolescence.[7]
  4. Craniofacial dysmorphism[17]
  5. Some lesser observed findings are:
    • Hepatomegaly with cirrhosis
    • Sporadic bleeding events
    • Gastrointestinal manifestations including vomiting, diarrhea, and malabsorption[17]
  6. It is potentially fatal.
  7. Some patients might have a less severe phenotype, where they can survive until adulthood. This phenotype is commonly associated with the G843D mutation.[18]


Establishing the diagnosis depends on a three-pronged approach: clinical manifestations, biochemistry analysis of peroxisomal enzyme, phytanic acid concentration in plasma, and molecular genetic testing. Reaching an early diagnosis is essential for Refsum disease management, especially CRD, as it is the only peroxisomal disorder that has a good prognosis with dietary modifications coupled with plasmapheresis.

Classic/adult Refsum Disease

1. Clinical Examination:

  • Ocular examination: Complete ophthalmologist examination, including visual fields. Manifestations include arteriolar narrowing degeneration and reduced electroretinography, often not present until the third decade. Initially, there is peri-macular depigmentation. Pigmentary degeneration usually occurs later in life.[9]
  • Anosmia testing using the University of Pennsylvania smell identification test.[11] 
  • Neurological examination: In both CRD/IRD, no intellectual deficits are seen since there is no defect in plasmalogen synthesis, which is a major phospholipid component of the nervous system.[19]
  • Audiology: Pure tone audiometry or otoacoustic emission testing. A brainstem auditory evoked response test can be done if hearing difficulties are suspected but couldn't be identified on pure tone audiometry.[13]
  • Radiology: Along with a physical examination of hands, feet, and knees, a radiologic assessment for metacarpal/tarsal shortening. In contrast to other peroxisomal disorders, bone abnormalities are mild if at all present.[8][20]
  • Cardiology: Cardiac evaluation, including electrocardiogram and cardiac ultrasound examination to assess for arrhythmias and cardiomyopathy.

 2. Genetic Profiling: 

  • Consulting with a clinical geneticist or a genetic counselor.

 3. Biochemistry:  

  • The pathognomic finding of Refsum disease on plasma analysis is a highly raised phytanic acid level >200 µmol/L (normal <30 µmol/L), unlike other peroxisomal disorders where levels are usually lower.[21]
  • Albuminocytologic dissociation of CSF and much higher phytanic acid levels than in IRD.[19]
  • Enzyme phytanoyl-CoA hydroxylase is entirely undetectable in liver tissue, hence commonly referred to as true peroxisomal disorder.[1]

4. Histopathology: 

  • Biopsy of peripheral nerves shows hypertrophic changes with onion bulb formation, and on electron microscopy, paracrystalline inclusions are seen.[3]

Infantile Refsum Disease

1. Biochemistry:

  • The metabolic profile shows various derangements of peroxisomal metabolism, including elevated VLCFA (22 carbons in length), di- and tri-hydroxycholestanoic acid, pipecolic acid, and phytanic acid with reduced plasmalogens levels in tissues and erythrocytes. 
  • The pathognomic finding of Refsum disease on plasma analysis with a highly raised phytanic acid level is present.

2. Histopathology:

  • Notable findings include the complete absence of peroxisomes on liver biopsy and degeneration of all retinal layers.[9][10]

Treatment / Management

Classic/adult Refsum Disease

A. Diet:

  1. Dietary restriction to eliminate phytol-containing foods, such as meat or fats from ruminating animals (lamb, beef, and certain fish), baked goods containing animal fats, and dairy products such as butter and cheese.[22]
  2. The therapeutic goal is to reduce daily dietary intake of phytanic acid to less than 10 mg and avoiding rapid weight loss or fasting, conditions which stimulate lipolysis since such conditions cause the rapid mobilization of phytanic acid from hepatic lipid and body adipose stores leading to severe clinical relapse.[12][23]
  3. A high-calorie diet is essential to avoid the metabolism of stored lipids and phytate, and its dissemination into the plasma.
  4. Postoperative administration of parenteral nutrition with solutions deficient of phytanic acid such as soybean and egg yolk based formulas.[22]
  5. As pregnancy induces a catabolic state, levels of phytanic acid must be closely monitored. Pregnant patients will at the highest risk during the third trimester since there is enhanced catabolism leading to increased phytanic acid levels, which may worsen retinitis pigmentosa and reduce visual fields. Transplacental circulation of phytanic acid is seen in animal models; however, no teratogenic effects such as as-defective organogenesis is seen. A homogenous or heterogeneous child born to an affected mother is at risk, which can be reduced by a high calorie-phytate restricted diet.[24][25]
  6. Avoid ibuprofen, amiodarone, and other medications that might increase thyroxine levels. Amiodarone can induce hyperthyroidism producing a catabolic state and increasing phytanic acid levels. Ibuprofen can affect the metabolism of phytanic acid as both have it in common.
  7. Fish based oils are a better source of calories.[26]

B. Plasmapheresis: Therapeutic plasma exchange (TPE)

  1. Another effective way of reducing phytanic acid concentration is by plasmapheresis, which is used when rapid reduction is required and can be performed serially over weeks as well. TPE (also known as lipapheresis) efficiently filters-out phytanic acid associated with lipoproteins but does not efficiently eradicate phytanic acid in adipose and neural tissue. This approach halts the progression of the disease but does not entirely reverse neurologic abnormalities.[12][27][28] Ichthyosis, sensory neuropathy, and ataxia resolve in that order, and abnormal electrocardiogram may improve. Other atypical findings such as aminoaciduria, renal and GIT manifestations may also improve with TPE. However, treatment may not affect retinitis pigmentosa, hearing impairment, or anosmia. TPE can be used in conjunction with diet in both children and adults.[24]
  2. The decision to initiate TPE should be a clinical one. Usually, patients with rapidly worsening symptoms, especially the ones after a period of rapid lipolysis, should be considered for TPE.
  3. Plasma phytanic acid concentrations can be reduced by 50% to 70%, typically to about 100 µmol/L.[15]

Infantile Refsum Disease

A. Diet:

  1. Treatment consists of strict dietary restriction of phytanic acid sources and occasional TPE in critical circumstances.[29]
  2. Since phytanic acid is also seen in components of plasma triglycerides in the VLDL and LDL fractions hence, TPE helps just as much as in CRD.

B. Symptomatic treatment:

  1. Urea maintains hydration and helps in the removal of excess keratin seen in hyperkeratosis.
  2. Ammonium lactate: Due to lactic acid, an alpha-hydroxy acid, which has a keratolytic action, thus facilitating the release of comedones. It comes in 12% and 5% strengths.
  3. For skin manifestations, administer various keratolytic and emollients. Mineral oil provides relief of minor skin irritations and promotes the removal of excess keratin.

Differential Diagnosis

1. Zellweger syndrome: A peroxisomal biogenesis defect also characterizes caused by PEX gene mutations. Zellweger syndrome can be precisely differentiated from Refsum disease by its clinical presentation.[7]

2. Neonatal adrenoleukodystrophy: It is an autosomal recessive peroxisomal biogenesis disorder resulting from mutations in the PEX gene. Patients usually have a severe psychomotor delay and die several months after birth, usually before the 7th month. Patients who survive further are severely mentally disabled with sensorineural deafness and are blind due to retinopathy. Fibroblasts isolated from patients are impaired in their ability to oxidize phytanic acid and VLCFA and to synthesize plasmalogens.[20]

3. Rhizomelic chondrodysplasia: Due to abnormal variants of PEX7. Refsum disease can be differentiated from rhizomelic chondrodysplasia type 1 clinically, although, in few patients with a moderate variant, a Refsum disease-like phenotype has been described.[2][30]

4. Alpha-methyl acyl-CoA racemase deficiency: Can be distinguished by screening for peroxisome metabolites in the plasma, followed by fibroblast studies and genetic testing.

5. Retinitis pigmentosa: Progressive loss of vision and anosmia are typically one of the initial presenting symptoms in Refsum disease. Hence, it is advisable to measure plasma phytanic acid in anyone presenting with retinitis pigmentosa, particularly when coupled with other manifestations such as early-onset visual and sensorineural hearing loss, ataxia and ichthyosis which are suggestive of Refsum disease.

6. Alstrom syndrome: Has clinical features very similar to Refsum disease, such as dystrophy of rods and cons cells, progressive loss of hearing (sensorineural), obesity, dilated and hypertrophic cardiomyopathy, cirrhotic liver and even multiple organ collapse. All due to bi-allelic pathogenic variants in ALMS1 with autosomal recessive inheritance pattern. It can be differentiated from Refsum disease by biochemical and genetic profile.

7. Bardet-Bidel syndrome: Also marked by retinal cell dystrophy and retinitis pigmentosa, obesity, limbic deformities such as postaxial polydactyly, sensorineural type hearing loss, diabetes mellitus, mental issues, and hypogonadism. The retinitis pigmentosa in these patients is more severe than what we see in patients of Refsum disease. Pathogenic mutations are described in at least eighteen genes. 

8. Kearns-Sayre syndrome: Chararectrised by pigmentary retinopathy along with progressive ophthalmoplegia, which usually occurs before the second decade of life. Patients present at least one of the following anomalies: cardiac conduction block, CSF protein concentration >100 mg/dL, or cerebellar ataxia. Sensorineural hearing loss is also commonly seen. This syndrome is mainly sporadic and propagates due to mitochondrial DNA deletion caused by genetic aberrations exclusively from the maternal end.

9. Friedrich ataxia: Defined by gradually progressive ataxia with onset as early from 10 years of age, usually before 25 years. It shows symptoms like dysarthria, muscle weakness with spasticity in lower limbs with absent deep tendon reflexes, proprioception, and vibration sense. Patients also might have scoliosis, bladder dysfunction, and hearing loss. Caused by bi-allelic pathogenic variants in FXN.


Survival for IRD is generally 5-13 years and maybe until adulthood. Survival for CRD is until the 4th-5th decade. The prognosis is poor in untreated or non-compliant patients. The progressive degeneration of myelinated nerve fibers and the cardiac electro-conduction pathways lead to central and peripheral neuropathic symptoms, cardiac arrhythmias, impaired vision, and hearing loss. Arrhythmias are a frequent cause of death.

A relapse-free period and a good prognosis can be achieved with strict diet control augmented with TPE. Patients who are diagnosed early and are treated promptly have demonstrated that decreasing phytanic acid is always followed by an improvement of ichthyosis and, to some extent, the resolution of neurological manifestations such as cardiac arrhythmias, paraesthesia, loss of muscle tone and ataxia. Hearing and visual loss are not reversible, but the progression gets slowed. Even with complications, as long as patients are compliant with their treatment, comfortable life is expected.


1. Due to excessively high plasma levels of phytanic acid and with added high levels of VLCFA, di- & tri-hydroxycholestanoic acid, and pipecolic acid in IRD, if left untreated or if the patient is poorly complaint, phytanic acid accumulates in myelin sheaths, adipose tissue liver, and kidneys where damage may result in following complications: 

  • Cardiomyopathy
  • Arrhythmia
  • The progressive loss of vision
  • Cataracts
  • Lower limb neuropathy
  • Ataxia
  • Acidouria
  • Diabetic Mellitus
  • Hypertension
  • Muscular atrophy
  • Renal atrophy
  • Progressive hearing loss
  • Atheroma

2. The exact mechanism has not been clarified yet. However, it is thought that under a molecular distortion hypothesis, that phytanic acid and other metabolites penetrate and disrupt the structural integrity of the retinal cell membrane, cardiac Purkinje cells, ciliary ganglion cells, oligodendrocytes, Schwann cells, osteoblasts and insulin receptors leading to various symptoms and long term manifestations of Refsum disease.[6][31][32]

3. Structural similarities between phytanic acid and vitamin A and E have also been implicated for the ocular complications.[7][10]

4. A calcium driven apoptotic damage is implicated for cardiac and neuropathic disorders such as arrhythmias, peripheral neuropathies, hearing and vision loss, and ataxia.[10][30]

Deterrence and Patient Education

Genetic counseling plays a pivotal role in Refsum disease by educating patients and their family members through an in-depth discussion of the inheritance, to help them make informed medical and personal decisions, such as having children. 

 1. Parents

  • The parents of an affected individual are obligate heterozygotes (carriers of one PEX7 or PHYH pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.  

  2. Siblings

  • Each sibling of the patient has a 25% chance of being affected, a 50% likelihood of being an asymptomatic carrier (a heterozygote), and a 25% likelihood of being one of the unaffected non-carriers.
  • Once an at-risk sibling is known to be unaffected, there is a 2/3 risk of them being a carrier of a pathogenic PEX7 or PHYH.

 3. Offspring

  • The offspring of an individual with Refsum disease with a non-carrier partner, are obligate heterozygotes (carriers); therefore, they are not at risk for disease.

Dietary restriction is encouraged to eliminate phytol-containing foods, such as meat or fats, from ruminating animals (lamb, beef, and certain fish), baked goods containing animal fats, and dairy products such as butter and cheese.

The patient should avoid rapid weight loss or fasting because they cause a rapid mobilization of phytanic acid from hepatic lipid and body adipose stores.

Drugs like amiodarone and ibuprofen should not be used.

Enhancing Healthcare Team Outcomes

Refsum disease is a rare and complex disease. Managing this disease requires an interprofessional team of healthcare professionals that includes nurses, laboratory technologists, dietitians, and physicians in different specialties. While the internist is almost always involved in the care of patients, it is important to consult with an interprofessional team of specialists that include an ophthalmologist, neurologist, geneticist, nephrologist, dermatologist, cardiologist, and audiologist. Frequent plasma levels of phytanic acid should be measured. Routine ophthalmological and cardiological evaluations are done to identify visual and cardiac problems.

Collaboration shared decision making and communication are essential factors for best patient care outcomes. The interprofessional care given to the patient must have an integrated care approach compounded with an evidence-based strategy to evaluate and manage the patient with Refsum disease.

Article Details

Article Author

Rahul Kumar

Article Editor:

Orlando De Jesus


8/1/2022 8:02:38 PM



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