Adult Refsum Disease

Clinical characteristics.

Adult Refsum disease (ARD is associated with elevated plasma phytanic acid levels, late childhood-onset (or later) retinitis pigmentosa, and variable combinations of anosmia, polyneuropathy, 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 ARD is established in a proband with suggestive clinical and biochemical findings by identification of biallelic pathogenic variants in either PHYH or PEX7 on molecular genetic testing.

Management.

Treatment of manifestations: Plasmapheresis or lipid apheresis to decrease phytanic acid levels is used only for acute arrhythmias or extreme weakness. Dietary restriction of phytanic acid intake helps resolve ichthyosis, sensory neuropathy, and ataxia. A high-calorie diet and avoidance of fasting prevent mobilization of phytanic acid stored in adipose tissue into the plasma. Hypercaloric parenteral infusions are required during periods of severe illness or postoperatively. Supportive treatment includes hydrating creams for ichthyosis and drugs for cardiac arrhythmias and cardiomyopathy.

Agents/circumstances to avoid: Food products containing phytanic acid, mostly from ruminants (cow, sheep, goat), some fish and walnuts; fasting and/or sudden weight loss; use of either ibuprofen or amiodarone.

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.

ARD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a PHYH or PEX7 pathogenic variant, each sib of an affected individual has at conception 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. Once the PHYH or PEX7 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, molecular genetic prenatal testing, and preimplantation genetic testing for ARD are possible.

Suggestive Findings

ARD should be suspected in individuals with the following clinical, laboratory, and family history findings.

Clinical findings. Late childhood-onset (or later) retinitis pigmentosa and variable combinations of the following findings (listed in descending order of frequency):

• Anosmia
• Polyneuropathy (sensory and motor)
• Hearing loss
• Ataxia
• Ichthyosis
• Short metacarpals and metatarsals present from birth
• Cardiac arrhythmias and cardiomyopathy

Note: (1) The full constellation of signs and symptoms is rarely seen in an affected individual. (2) Most features develop with age.

Laboratory findings. Elevated plasma phytanic acid level (>20x upper limit of normal) is highly suggestive of ARD. Other peroxisomal metabolites may be abnormal, with differences associated with the particular gene involved. See Table 1.

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of ARD is established in a proband with suggestive clinical and biochemical findings by identification of biallelic pathogenic variants in one of the genes listed in Table 2.

Note: Identification of biallelic variants of uncertain significance (or identification of one known pathogenic variant and one variant of uncertain significance) in one of the genes listed in Table 2 does not establish or rule out the diagnosis of this disorder.

If molecular genetic testing is unavailable or the results are not diagnostic, specialized biochemical testing can be used to establish the diagnosis.

Clinical Description

Clinical manifestations in adult Refsum disease (ARD) are retinitis pigmentosa, anosmia (loss of sense of smell), sensorineural hearing loss, polyneuropathy (sensory and motor), ataxia (balance issues), ichthyosis, skeletal abnormalities including shortened fingers and toes, and cardiac arrhythmias and cardiomyopathy.

To date, more than 200 individuals have been identified with biallelic pathogenic variants in PHYH or PEX7.

Onset of symptoms in ARD ranges from age seven months to after age 50 years. Most individuals report the onset of first symptoms between ages ten and 20. 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; Authors, unpublished observation]. Early-onset disease is not necessarily associated with a poor prognosis for life span.

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, retinitis pigmentosa is present, but the other features of ARD are relatively subtle.

Ophthalmologic findings. Retinitis pigmentosa (rod-cone dystrophy, pigmentary retinal degeneration, tapetoretinal degeneration) is present in all individuals with biochemical findings of ARD.

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

Typically, individuals with ARD 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 ARD keep some visual function until late in life, albeit with severely concentrically constricted visual fields [Rüether et al 2010; Leroy 2014; Leroy, unpublished observations].

Cataracts in ARD often develop at an earlier age than age-related cataracts, similar to what is seen in patients with other forms of rod-cone dystrophy. The cataracts in ARD are of the posterior subcapsular type, in addition to the classic corticonuclear type.

Cataract surgery (see Treatment of Manifestations) may be hampered by the poor pupillary dilatation typically seen in ARD and the brittle zonular fibers, which suspend the lens within the ciliary body. Poor pupillary dilatation may be due to atrophy of the iris dilator muscle.

Anosmia (i.e., absence of the sense of smell). While 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 ARD. Studies have shown that anosmia is present in most if not all individuals with ARD [Wierzbicki et al 2002, 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 ARD 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 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 [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 ARD, 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. Although less frequent, phalanges may also be short, leading to shortened finger nails.

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

Cardiomyopathy. Cardiac arrhythmia and heart failure resulting from cardiomyopathy are potentially severe health problems that develop later in life and are frequent causes of death in ARD.

Other laboratory findings

• Elevated plasma concentration of pipecolic acid. Wierzbicki et al [2002] found elevated plasma pipecolic acid levels in 20% of individuals with ARD.
• CSF protein concentration in individuals with ARD is considerably higher than normal. In one Arab family, CSF protein concentration was 101 mg/dL [Fertl et al 2001] (normal range in adults:15-50 mg/dL). Although this finding may be suggestive of ARD, spinal tap is not routinely performed in individuals with ARD for diagnosis or other indication.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Even in a family with identical pathogenic variants, the manifestations of ARD may vary considerably among affected individuals, comparable to those seen among affected individuals from different families. The observed phenotypic variation may be related to the dietary intake and subsequent accumulation of phytanic acid.

Nomenclature

ARD 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, ARD is also referred to as "classic Refsum disease" (CRD) or "Refsum disease." The terms ARD and CRD are preferred over the term “Refsum disease” because ARD and CRD distinguish the disorder from so-called "infantile Refsum disease" (IRD), which is a Zellweger spectrum disorder. Distinction between "infantile Refsum disease" and ARD 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 ARD is the accumulation of phytanic acid in plasma and tissues. In 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 ARD.

Prevalence

No estimates of the prevalence of ARD have been reported. The fact that most individuals described in the literature have been identified in the United Kingdom and Norway, where awareness of ARD is high, suggests that worldwide prevalence may be higher than expected. The estimated incidence is around one in 1,000,000 in the United Kingdom.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ARD, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Management by multidisciplinary specialists including ophthalmologist, neurologist, cardiologist, ENT specialist or audiologist, dietician, dermatologist, and clinical geneticist is recommended.

Surveillance

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 including almonds, coconut, peanuts, and walnuts were tested; except for walnuts, which contain phytanic acid and phytol, and thus should be avoided, all were negative for phytanic acid and phytol [Brown et al 1993].
• Fasting and/or sudden weight loss, because stored lipids, including phytanic acid, are mobilized into the plasma. Care should be taken during periods of illness or in the pre- and postoperative phase when undergoing surgical procedures, including prior discussions with the surgeon and anesthetist. If intravenous infusions are required, lipid emulsions in 10%, 20%, or 30% concentrations may be used.
• Ibuprofen, because it may interfere with the metabolism of phytanic acid
• Amiodarone because of the risk that it may cause hyperthyroidism, which 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 ARD 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 ARD.

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. However, Dubot et al [2019] reported no clinical events during pregnancies for an affected mother and her consanguineous, heterozygous husband, despite increasing phytanic acid levels during the last trimester of pregnancy.

Unaffected children born to mothers with ARD do not have ARD-related health concerns [Dubot et al 2019, Stepien et al 2016]. However, to prevent infant ingestion of high levels of phytanic acid, breastfeeding is not advised. More importantly, avoiding breastfeeding reduces the risk of a catabolic state in the affected mother after pregnancy.

Therapies Under Investigation

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. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Adult Refsum disease (ARD) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one PHYH or PEX7 pathogenic variant based on family history).
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a PHYH or PEX7 pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a PHYH or PEX7 pathogenic variant, each sib of an affected individual has at conception 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.
• Manifestations of ARD may vary considerably between sibs with identical pathogenic variants. These phenotypic differences are comparable to those among affected individuals from different families.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Unless an individual with ARD has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for a pathogenic variant in PHYH or a PEX7.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a PHYH or PEX7 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the PHYH or PEX7 pathogenic variants in the family.

Biochemical testing is not accurate for carrier testing, as the biochemical findings (i.e., plasma phytanic acid concentration) in obligate heterozygotes (carriers) are near normal [Wierzbicki et al 2003].

Related Genetic Counseling Issues

See Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative genetic alteration/s are unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the PHYH or PEX7 pathogenic variants have been identified in an affected family member, molecular genetic prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for ARD are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Pathogenic variants in PHYH and PEX7 are known to cause adult Refsum disease (ARD) by interfering with the alpha-oxidation (breakdown) of phytanic acid.

Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is derived from dietary sources only, mainly from dairy and ruminant fats. Phytanic acid is a 3-methyl branched-chain fatty acid, which cannot undergo straightforward beta-oxidation like other fatty acids since the presence of the methyl group at the 3 position blocks beta-oxidation. Nature has resolved this problem by creating an alpha-oxidation mechanism in which the terminal carboxyl group is released as CO₂. Accordingly, phytanic acid first undergoes alpha-oxidative chain shortening to produce pristanic acid (2,4,6,10-tetramethylpentadecanoic acid) and CO₂. All steps from phytanoyl-CoA to pristanic acid occur in peroxisomes [Wanders et al 2001, Wanders et al 2011] (Figure 1).

ARD is caused by deficits in the first step in this process by one of two causes:

• Deficient enzyme phytanoyl-CoA hydroxylase (encoded by PHYH), which is required for the hydroxylation of phytanoyl-CoA to 2-hydroxyphytanoyl-CoA
• Deficient PTS2 receptor (encoded by PEX7), which is required to target the PTS2 signal on phytanoyl-CoA hydroxylase to the peroxisome where the alpha-oxidation occurs.

As a consequence of the phytanoyl-CoA hydroxylase deficiency, phytanic acid cannot be degraded and will accumulate in body tissues to toxic levels.

Mechanism of disease causation. ARD occurs via a loss-of-function mechanism.

Revision History

• 30 September 2021 (ha) Comprehensive update posted live
• 11 June 2015 (me) Comprehensive update posted live
• 22 April 2010 (me) Comprehensive update posted live
• 20 March 2006 (me) Review posted live
• 30 March 2004 (rw) Original submission

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