Clinical Guidance

No clinically relevant 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.

Source: GeneReviews — "Adult Refsum Disease"

Diagnostic Criteria

Adult Refsum disease (ARD), also referred to as "classic Refsum disease," is a peroxisomal disorder. In the majority of individuals, it is caused by a deficiency of the peroxisomal enzyme phytanoyl-CoA hydroxylase due to biallelic pathogenic variants in PHYH. In ~10% of individuals, the disorder is milder and is associated with biallelic pathogenic variants in PEX7. No consensus clinical diagnostic criteria for ARD have been published. 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. Comparison of Peroxisomal Metabolites in Adult Refsum Disease by Gene Involved Adult Refsum Disease | Normal Associated Gene | PHYH | PEX7 | -- Plasma phytanic acid concentration1

Source: GeneReviews — "Adult Refsum Disease"

Differential Diagnosis

Table 4.

Genes of Interest in the Differential Diagnosis of Adult Refsum Disease

Gene(s) | Disorder | MOI | Clinical Features | Distinguishing Features / Comment

Disorders w/elevated phytanic acid

AMACR

| Alpha-methylacyl-CoA racemase (AMACR) deficiency1 (OMIM 614307) | AR | Typically adult-onset sensory motor neuropathy ± assoc pigmentary retinopathy.2 Other presentations are dominated by early-onset liver failure w/cholestasis, hepatomegaly, liver enzymes. | Distinguished from ARD by screening peroxisome metabolites in plasma

Source: GeneReviews — "Adult Refsum Disease"

Management Guidelines

No clinical practice guidelines for adult Refsum disease (ARD) have been published.

Evaluations Following Initial Diagnosis

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

Table 5.

Recommended Evaluations Following Initial Diagnosis in Individuals with Adult Refsum Disease

System/Concern | Evaluation | Comment

Retinitis

pigmentosa (RP) | Ophthalmologic eval incl extensive history taking on night blindness restricted visual fields; as well as:

• Visual field testing

• Electroretinography

• Autofluorescence imaging

• Spectral domain optical coherence tomography

| Although the degree to which the retina is affected by RP varies, there is no essential difference between what is seen in classic RP the retinal phenotype assoc w/ARD.

Anosmia

| University of Pennsylvania Smell Identification Test (described by ) or any other standardized test |

Polyneuropathy

| Complete neurologic eval incl electrophysiologic testing |

Ataxia

Deafness

| Pure tone audiometry possibly otoacoustic emission testing BAER testing if hearing difficulties are not identified on pure tone audiometry |

Skeletal

abnormalities | Clinical radiographic eval of hands feet for metacarpal metatarsal anomaly |

Cardiomyopathy

| Complete eval directed by cardiologist |

Genetic

Source: GeneReviews — "Adult Refsum Disease"

Clinical Guidance

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 .

• 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

Source: GeneReviews — "Adult Refsum Disease"

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.

Source: GeneReviews — "Adult Refsum Disease"

Surveillance Guidelines

Table 7.

Recommended Surveillance for Individuals with Adult Refsum Disease

System/Concern | Evaluation | Frequency

phytanic acid

levels | Plasma phytanic acid level | Every 3-6 mos; more frequently during illnesses or stress that may a catabolic state

Ophthalmologic

concerns | Ophthalmic exam to:

• Identify vision loss from cataracts

• Quantify extent of visual loss from RP (rod-cone dystrophy) w/visual fields electroretinography where when suitable

| Annually

Cardiomyopathy

| Cardiac eval to identify cardiomyopathy concomitant arrhythmias

RP = retinitis pigmentosa

Source: GeneReviews — "Adult Refsum Disease"