Refsum Disease

Clinical characteristics.

Refsum disease is characterized by anosmia and early-onset retinitis pigmentosa, which are both universal findings with variable combinations of neuropathy, deafness, ataxia, and ichthyosis. Onset of symptoms ranges from age seven months to older than age 50 years. Cardiac arrhythmia and heart failure caused by cardiomyopathy are potentially severe health problems that develop later in life.

Diagnosis/testing.

The diagnosis of Refsum disease is suspected on the basis of clinical findings and a plasma phytanic acid concentration greater than 200 µmol/L in most affected individuals. Confirmation of the diagnosis requires either (1) molecular genetic testing to identify biallelic pathogenic variants in either PHYH (encoding phytanoyl-CoA hydroxylase), which accounts for more than 90% of Refsum disease, or PEX7 (encoding the PTS2 receptor), which accounts for less than 10% of Refsum disease; or (2) enzyme analysis to identify deficiency of either phytanoyl-CoA hydroxylase enzyme activity or the peroxisome-targeting signal type 2 receptor.

Management.

Treatment of manifestations: Dietary restriction of phytanic acid intake helps resolve ichthyosis, sensory neuropathy, and ataxia. Supportive treatment includes hydrating creams for ichthyosis and drugs for cardiac arrhythmias and cardiomyopathy. Plasmapheresis or lipid apheresis is used for acute arrhythmias or extreme weakness. A high-calorie diet prevents mobilization of phytanic acid into the plasma.

Agents/circumstances to avoid: Fasting and/or sudden weight loss; ibuprofen.

Evaluation of relatives at risk: Testing of sibs of a proband ensures early treatment to reduce plasma phytanic acid concentration before symptoms occur.

Genetic counseling.

Refsum disease is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the PEX7 or PHYH pathogenic variants have been identified in an affected family member.

Suggestive Findings

Refsum disease, also referred to as "classic Refsum disease" (CRD) or "adult Refsum disease" (ARD), is suspected in individuals with late childhood-onset retinitis pigmentosa and variable combinations of the following clinical findings (listed in descending order of frequency):

• Anosmia
• Sensory motor neuropathy
• Hearing loss
• Ataxia
• Ichthyosis
• Short metacarpals and metatarsals present from birth (~35% of individuals)
• Cardiac arrhythmias and cardiomyopathy

It should be noted that: (1) the full constellation of signs and symptoms is rarely seen in an affected individual; (2) most features develop with age.

Establishing the Diagnosis

More than 90% of individuals with Refsum disease have deficiency of phytanoyl-CoA hydroxylase encoded by PHYH and fewer than 10% have a deficiency of the PTS2 receptor encoded by PEX7 [Waterham & Wanders, unpublished observations].

Establishing the diagnosis first requires analysis of phytanic acid concentration in plasma or serum and then either molecular genetic testing or enzyme analysis (if molecular genetic testing is not available or results are ambiguous).

Analysis of phytanic acid concentration in plasma or serum. Associated laboratory findings are summarized in Table 1. Note that alpha-methylacyl-CoA racemase (AMACR) deficiency, the major disorder in the differential diagnosis of Refsum disease, is included in Table 1 for comparison (see Differential Diagnosis). When present, normal plasma phytanic acid levels essentially rule out the two forms of Refsum disease.

Molecular genetic testing to detect biallelic pathogenic variants in PHYH or PEX7 is required to establish the diagnosis of Refsum disease (Table 2).

• One genetic testing strategy is serial single-gene molecular genetic testing in the order in which pathogenic variants most commonly occur (i.e., PHYH, then PEX7). Typically sequence analysis is performed first, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is identified.
• An alternative genetic testing strategy is use of a multigene panel that includes PHYH and/or PEX7 and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Studies of enzyme activity in fibroblasts distinguish between Refsum disease caused by PHYH or PEX7 pathogenic variants and AMACR deficiency.

• Deficiency of phytanoyl-CoA hydroxylase enzyme activity. Phytanoyl-CoA hydroxylase catalyzes the conversion of phytanoyl-CoA into 2-hydroxyphytanoyl-CoA, a key step in the breakdown of phytanic acid via alpha-oxidation in peroxisomes. To assess activity of this enzyme, phytanic acid alpha-oxidation is first measured in cultured fibroblasts. If alpha-oxidation is deficient, the activity of the enzyme phytanoyl-CoA hydroxylase is measured.
• Deficiency of the peroxisome-targeting signal type 2 (PTS2) receptor. The PTS2 receptor plays a key role in peroxisome biogenesis by catalyzing the transport across the peroxisomal membrane of proteins equipped with a peroxisome-targeting signal type 2 (like phytanoyl-CoA hydroxylase). Abnormalities in fibroblasts of such individuals include the presence of an abnormal molecular form of peroxisomal thiolase (44 kd) and a partial deficiency of alkyldihydroxyacetonephosphate synthase [van den Brink et al 2003a].

Clinical Description

Onset of symptoms in "classic Refsum disease" (CRD) or "adult Refsum disease" (ARD) ranges from age seven months to after age 50 years. However, because the onset is insidious, it is difficult for many individuals to know exactly when symptoms first started. A few individuals remain asymptomatic until adulthood [Skjeldal et al 1987]. Early-onset disease is not necessarily associated with a poor prognosis for life span.

Retinitis pigmentosa is in most cases an early clinical feature, as is anosmia. Other findings that may occur in the following ten to 15 years in decreasing order of frequency [Skjeldal et al 1987]:

• Neuropathy
• Deafness
• Ataxia
• Ichthyosis

Wierzbicki et al [2002] documented in 15 individuals the cumulative incidence of the following features over many decades:

• Retinitis pigmentosa (15/15)
• Anosmia (14/15)
• Neuropathy (11/15)
• Deafness (10/15)
• Ataxia (8/15)
• Ichthyosis (4/15)

In a few instances, psychiatric disturbances have also been observed.

The four cardinal features, originally described by Refsum [1946] (retinitis pigmentosa, a chronic polyneuropathy, ataxia, and raised CSF protein concentration) are rarely seen in a single individual.

Some investigators distinguish between acute ARD and chronic ARD. In acute ARD, polyneuropathy, weakness, ataxia, sudden visual deterioration, and often auditory deterioration are often accompanied by ichthyosis, possibly cardiac arrhythmias, and elevated liver transaminases and bilirubin. Triggers for acute presentations include weight loss, stress, trauma, and infections. In contrast, in chronic ARD, RP is present, but the other features of ARD are subtle.

Ophthalmologic findings. Retinitis pigmentosa (pigmentary retinal degeneration, tapeto-retinal degeneration) is present in all individuals with biochemical findings of Refsum disease and therefore appears to be an obligatory finding; in a series of 17 individuals, retinitis pigmentosa was present in all [Skjeldal et al 1987].

Virtually every individual ultimately diagnosed to have Refsum disease experiences visual symptoms first. If a detailed past medical history is obtained, many individuals confirm the onset of night blindness in childhood. The delay between first ophthalmologic evaluation and diagnosis ranged between one and 28 years (mean = 11 years) in one study of 23 individuals [Claridge et al 1992].

Typically, individuals with Refsum disease experience night blindness years before the progressive changes of constricted visual fields and decreased central visual acuity appear. Because night blindness can be difficult to ascertain, particularly in children, electroretinography, which shows either a reduction or a complete absence of rod and cone responses, can support the diagnosis in early stages (see Retinitis Pigmentosa Overview).

In general, individuals with retinitis pigmentosa due to Refsum disease keep some visual function until late in life albeit with severely concentrically constricted visual fields [Rüether et al 2010; Leroy, unpublished observations].

Anosmia. This is the absence of smell. Although the sense of smell and the sense of taste have their own specific receptors, they are intimately related. Both may be normal, reduced, or absent in individuals with Refsum disease. Studies by Wierzbicki et al [2002] have shown that anosmia is present in most, if not all, individuals with ARD/CRD. If smell is tested experimentally, all individuals with ARD/CRD have an abnormal smell test [Gibberd et al 2004].

Polyneuropathy. The polyneuropathy is a mixed motor and sensory neuropathy that is asymmetric, chronic, and progressive in untreated individuals. It may not be clinically apparent at the start of the illness. Initially, symptoms often wax and wane. Later, the distal lower limbs are affected with resulting muscular atrophy and weakness. Over the course of years, muscular weakness can become widespread and disabling, involving not only the limbs but the trunk.

Almost without exception, individuals with Refsum disease have peripheral sensory disturbances, most often impairment of deep sensation, particularly perception of vibration and position-motion in the distal legs.

Hearing loss. Bilaterally symmetric mild-to-profound sensorineural hearing loss affects the high frequencies or middle-to-high frequencies [Oysu et al 2001, Bamiou et al 2003]. Auditory nerve involvement (auditory neuropathy) may be evident on testing of auditory brain stem evoked responses (ABER) [Oysu et al 2001, Bamiou et al 2003]. Individuals with auditory nerve involvement may experience hearing difficulty even in the presence of a normal audiogram (see Hereditary Hearing Loss and Deafness Overview).

Ataxia. Although cerebellar dysfunction is considered to be a main clinical sign of Refsum disease, onset is nevertheless relatively late, particularly when compared with the onset of retinopathy and neuropathy. Unsteadiness of gait is the main symptom related to cerebellar dysfunction. Ataxia is thus characteristically more marked than the degree of muscular weakness and sensory loss would indicate (see Hereditary Ataxia Overview).

Skeletal abnormalities. Short metacarpals and metatarsals are present in about 30% of affected individuals [Plant et al 1990]. Short metatarsals most often cause a rather typical dorsal displacement of the fourth digit of the foot.

Ichthyosis. Mild generalized scaling may occur in childhood, but usually begins in adolescence. This finding is present in a minority of affected individuals.

Cardiac arrhythmias. Cardiac arrhythmia and heart failure resulting from cardiomyopathy are frequent causes of death in Refsum disease.

Other laboratory findings

• Elevated plasma concentration of pipecolic acid. A few individuals with elevated plasma concentrations of both phytanic acid and pipecolic acid have been described [Tranchant et al 1993, Baumgartner et al 2000]. Subsequently, sequencing of PIPOX (encoding human L-pipecolic acid oxidase) [Ijlst et al 2000] in these individuals did not reveal any pathogenic variants [Waterham & Wanders, unpublished results], supporting the view that the accumulation of pipecolic acid in these patients is a secondary event related to phytanoyl-CoA hydroxylase deficiency but with an unclear mechanism.
  Baumgartner et al [2000] described an individual with psychomotor retardation and abnormally short metatarsals and metacarpals, but no other signs of classic Refsum disease. Phytanoyl-CoA hydroxylase enzyme activity was deficient; a homozygous deletion of PHYH causing a frameshift was identified. L-pipecolic acid concentration was elevated in plasma. Microscopy of the liver showed the presence of peroxisomes, although they were reduced in number and increased in size. These abnormal liver peroxisomes lacked catalase. Moreover, in fibroblasts, a mosaic pattern of cells with and without peroxisomes was found, in contrast to the peroxisomes in fibroblasts from individuals with classic Refsum disease who cannot be distinguished from controls by catalase immunofluorescence. Most likely, this individual is affected by two distinct genetic disorders with pathogenic variants in different genes, of which one is PHYH and the other remains to be identified. The latter gene may well be one of the PEX genes.
  Tranchant et al [1993] described three members of a family diagnosed with Refsum disease. Two had a significant increase of pipecolic acid concentration in plasma and a fourth individual, a brother, died at age 17 years from a progressive neurologic disorder with unusual clinical and neuropathologic abnormalities. Homozygosity mapping localized the gene to chromosome 10p. Subsequently these sibs were confirmed to have phytanoyl-CoA hydroxylase deficiency in fibroblasts and pathogenic variants in PHYH [Waterham & Wanders, unpublished observations]. Most likely, the mild accumulation of pipecolic acid in these individuals is the secondary result of the accumulation of phytanic acid. This hypothesis is supported by data of Wierzbicki et al [2002] showing elevated plasma pipecolic acid levels in 20% of individuals with Refsum disease.
• CSF protein concentration in individuals with Refsum disease is considerably higher than normal. In one Arab family, CSF protein concentration was 101 mg/dL [Fertl et al 2001]. Normal CSF protein concentration in adults ranges from 15 to 50 mg/dL.

Genotype-Phenotype Correlations

More studies are needed to determine if Refsum disease caused by pathogenic variants in PHYH and Refsum disease caused by pathogenic variants in PEX7 are phenotypically different. The Refsum disease phenotype caused by pathogenic variants in PEX7 may be milder [Van den Brink et al 2003b], as exemplified by the patient described by Horn et al [2007].

Manifestations of Refsum disease may vary considerably among affected individuals in a family – i.e., among individuals with identical PHYH pathogenic variants. These phenotypic differences are comparable to those among affected individuals from different families. Consequently, no clear phenotype-genotype correlations have been identified as yet. Phenotypic variation may be related to the dietary intake of phytanic acid, which is thought to be the toxic compound.

Nomenclature

Adult Refsum disease was first described in 1946 by the Norwegian neurologist Sigwald Refsum as a distinct autosomal recessive neurologic entity, which he called "heredopathia atactica polyneuritiformis."

In the literature, Refsum disease is also referred to as "classic Refsum disease" (CRD) or "adult Refsum disease" (ARD) to distinguish it from so-called "infantile Refsum disease" (IRD), which belongs to the group of peroxisome biogenesis disorders, Zellweger syndrome spectrum. Distinction between "infantile Refsum disease" and "classic Refsum disease" is readily apparent on clinical grounds. IRD has a much earlier onset with cerebral and hepatic dysfunction, craniofacial dysmorphia, developmental delay, and death usually in infancy or early childhood. The only finding shared by IRD and CRD/ARD is the accumulation of phytanic acid in plasma and tissues. In CRD/ARD, phytanic acid metabolism is the only abnormality, whereas in IRD, a number of biochemical abnormalities result from the defect in peroxisome biogenesis. Thus, "infantile Refsum disease" is a poor designation, given the lack of resemblance to classic Refsum disease.

Prevalence

The prevalence of Refsum disease is probably very low. In the literature, no estimates of its prevalence have been reported. The fact that most individuals described in the literature have been identified in the United Kingdom and Norway, where awareness of Refsum disease is high, suggests that the true prevalence of Refsum disease may be much higher than currently reported. According to Wierzbicki (personal communication), the incidence is around one in 10⁶ in the United Kingdom.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Refsum disease, the following evaluations are recommended:

• Ophthalmology. Examination for retinitis pigmentosa/miosis, cataract, and visual fields [Claridge et al 1992]
• Anosmia testing using the procedure described by Gibberd et al [2004]
• Neurology. Ataxia, neuropathy, myography, and electrophysiologic assessment
• Audiology. Pure tone audiometry and possibly otoacoustic emission testing and auditory brain stem evoked response (ABER) testing if hearing difficulties are suspected but not identified on pure tone audiometry [Bamiou et al 2003]
• Radiology. Physical examination of hands, feet, and knees; radiologic assessment of hands and feet
• Cardiology. Cardiac evaluation including electrocardiography (ECG) and cardiac ultrasound examination
• Other. Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Prevention of Primary Manifestations

No curative therapy currently exists for Refsum disease.

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 [Gibberd & Wierzbicki 2000]. Although data are limited, it appears that despite strict dietary treatment the retinitis pigmentosa is very slowly progressive [BP Leroy, unpublished observations].

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 Secondary Complications

Treatment of hypertension may help in delaying cardiomyopathy, which inevitably leads to arrhythmias. It is probably better to avoid amiodarone as an anti-arrhythmic drug, because of the risk of hyperthyroidism, which results in catabolism and increased phytanic acid release from tissues if not recognized in time. This complication was observed in one individual [BP Leroy 2007, personal communication].

Once cardiomyopathy has become difficult to treat, cardiac transplantation can be lifesaving. One individual with PHYH-related Refsum disease and one with PEX7-related Refsum disease have successfully received a donor heart [BP Leroy 2007 & 2015, personal observations].

Surveillance

The following are appropriate:

• Measurement of plasma phytanic acid levels every three to six months and more frequently during illnesses or increased stress that may lead to a catabolic state
• Annual ophthalmologic examination to identify vision loss resulting from cataracts, which are treatable
• Annual cardiac examination to identify cardiomyopathy and concomitant arrhythmias

Agents/Circumstances to Avoid

Avoid the following:

• All food products containing phytanic acid, such as ruminant (cow, sheep, and goat) products and certain fish (cod) products. Some nuts should also be avoided [Brown et al 1993].
• Fasting, because stored lipids, including phytanic acid, are mobilized into the plasma
• Ibuprofen, because it is metabolized by AMACR and may interfere with the metabolism of phytanic acid
• Amiodarone because of the risk that hyperthyroidism would induce enhanced catabolism, with consequent increase of plasma phytanic acid

Evaluation of Relatives at Risk

It is appropriate to evaluate sibs of a proband before symptoms of Refsum disease occur in order to institute early treatment to reduce plasma phytanic acid concentration. Evaluations include:

• Molecular genetic testing if the pathogenic variants in the family are known;
• Measurement of phytanic acid concentration in plasma or serum if the pathogenic variants in the family are not known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Because of the tendency for pregnancy to induce catabolism, it is extremely important to manage plasma phytanic acid concentration during pregnancy in women with Refsum disease.

Fairly rapid reduction of visual fields has been observed during the third trimester of pregnancy [BP Leroy, unpublished observations], possibly due to increased plasma phytanic acid concentration resulting from increased catabolism.

Therapies Under Investigation

At present, the potential of enzyme replacement therapy (ERT) similar to that for lysosomal storage diseases (e.g., Hurler syndrome [see MPS I], Fabry disease, and Gaucher disease) is under investigation. This may eventually replace dietary restrictions and plasma- or lipapheresis.

In the long run, gene therapy may be the treatment of choice, but many issues need to be resolved before it can be applied.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.