Refsum Disease

Etiology

Refsum disease is a genetic disorder that follows an autosomal-recessive inheritance pattern. Two genes have been implicated in this disease. Phytanoyl-CoA hydroxylase (PAHX), encoded by the PHYH gene located on chromosome 10p13, is defective in more than 90% of individuals with Refsum disease.[4][5][6] The causative mutations in this gene lead to an enzymatically inactive protein that prevents phytanic acid's metabolism, resulting in its systemic buildup.[7]

In a small minority of individuals with Refsum disease, the causative defect is in the peroxisome-targeting signal type 2 (PTS2) receptor, which is encoded by the peroxin 7 (PEX7) gene located on chromosome 6q21–q22.2.[8] The PTS2 receptor recognizes the PTS2 protein, which is present in a subset of peroxisomal proteins and is required for their import into the peroxisome. The disease most commonly associated with peroxin 7 gene mutations is rhizomelic chondrodysplasia punctata type 1, but the absence of PTS2 can also disrupt phytanoyl-CoA hydroxylase (PAHX) import; this also prevents the metabolism of phytanic acid and leads to systemic buildup.[7]

Epidemiology

Refsum disease's rarity poses challenges in generating precise, large-scale observations of its prevalence. Within White populations in the United States, it has been estimated at fewer than 1 in 1,000,000.[9] Age at onset of clinical manifestations has been described from 7 months to 50 years.[10] Typically, signs and symptoms manifest before age 20.[11] However, an estimated 12 years between initial clinical manifestations and Refsum disease diagnosis has been reported.[12]

Pathophysiology

Refsum disease occurs due to an isolated defect in the metabolism of the branched-chain fatty acid phytanic acid (3,7,11,15-tetramethylhexadecanoic acid), leading to its accumulation in tissues. Phytanic acid is strictly exogenous and is in ingestible form in dairy products, meats, and ruminant fats.[13] The molecule is a breakdown product of chlorophyll produced during its catabolism by ruminant bacteria.[14] Chlorophyll is bound to the phytanic acid precursor, phytol, by which it is anchored to the chloroplast membrane. In this form, phytol is undigestible,[15] so cleavage from chlorophyll and breakdown to phytanic acid is necessary for human digestion.[15][16] Because of the presence of a 3-methyl group, phytanic acid cannot be catabolized by beta-oxidation. Instead, it is transported to the peroxisome, where it undergoes alpha-oxidation, shortening the molecule by 1 carbon atom, yielding pristanic acid and formic acid.[2] The peroxisomal enzyme, phytanoyl-CoA hydroxylase, catalyzes the first step of alpha-oxidation; it is for this reason that mutations that decrease the level of functional enzyme in the peroxisome can prevent the catabolism of phytanic acid, leading to its systemic buildup, thereby causing Refsum disease.

The precise mechanism or mechanisms by which phytanic acid accumulation causes the signs and symptoms of Refsum disease has not been fully elucidated; nevertheless, the molecule's accumulation in many organ systems is well established. Signs and symptoms of Refsum disease can include:

• Retinitis pigmentosa
• Anosmia
• Iris atrophy
• Cataracts
• Miosis
• Sensorineural hearing loss
• Ataxia
• Peripheral polyneuropathy
• Cardiomyopathy
• Cardiac conduction abnormalities
• Skeletal malformations, especially shortened metacarpals, and metatarsals
• Skin manifestations (ichthyosis)[11][14][17]

History and Physical

Signs and symptoms of Refsum disease are abundant but appear and progress slowly; therefore, it is essential to assess the chronology of symptoms to distinguish it from other potentially similar disorders. Biochemical and genetic testing can follow documentation of clinical characteristics to confirm the diagnosis. The first clinical features of Refsum disease are usually present in late childhood or adolescence, although onset may be earlier or later.

 The first features to present are:

• Ophthalmologic: progressive deterioration of night vision due to retinitis pigmentosa is one of the first signs of the disease. Retinitis pigmentosa is present in all cases of Refsum disease. Constricted visual fields, miosis, and cataracts eventually follow.[11][17] 
• Olfactory: anosmia is one of the earliest presenting symptoms and, behind retinitis pigmentosa, one most consistently seen in Refsum disease.[9][14]
• Congenital skeletal malformations, especially shortening of the metatarsals and metacarpals, are seen in approximately 30% of patients.[13][18]

Over the subsequent 10 to 15 years, other associated signs and symptoms can develop:

• Neurological:
• Symmetric polyneuropathy that involves both motor and sensory nerves can develop. Distally predominant weakness and numbness occur. Deep tendon reflexes diminish in a length-dependent fashion.
• Sensorineural hearing loss due to cochlear nerve involvement affecting both ears is common.
• Cerebellar ataxia presents as a late manifestation.[13][19]
• Other organ systems:
• Ichthyosis is sometimes present.[13][20]
• Cardiac arrhythmias and cardiomyopathy can occur. There have been individual reports of cardiac arrhythmias induced by the release of phytanic acid from the liver after an infection or as a result of stress-induced catecholamine release during plasmapheresis. There have been reported instances of arrhythmias leading to sudden death.[13]

Hereditary motor and sensory neuropathy type 4 (HMSN4) has inconsistently been used to describe the peripheral polyneuropathy associated with Refsum disease. HMSN4 was initially synonymous with the neuropathy of Refsum disease. However, the classification for inherited neuropathies is evolving. Today, HMSN4 is more often used interchangeably with Charcot-Marie-Tooth disease type 4 (CMT4), which comprises all autosomal recessive motor and sensory neuropathies, including that of Refsum disease.[21]

Evaluation

The diagnosis of Refsum disease can be established through clinical examination and testing:

• Ophthalmology: An in-depth ophthalmological examination should be performed to assess for retinitis pigmentosa. Classic fundoscopic findings in retinitis pigmentosa include bone spicule pigmentation, retinal vessel attenuation, and waxy pallor of the optic nerve. The pattern of visual impairment typically seen in retinitis pigmentosa is nyctalopia (night blindness). Early in the course of the disease, the rod cells are damaged, followed by constriction of the visual fields as rod damage progresses and impaired visual acuity as the cones are affected later in the disease. Visual field testing may show constriction of the visual fields. Optical coherence imaging or other specialized imaging of the fundus and retina may reveal a pattern of damage consistent with retinitis pigmentosa. Contrast acuity testing may show nyctalopia. Electroretinography may help elucidate the pattern of damage initially and is also useful for monitoring the progression of the disease. Electroretinographic changes precede initial symptoms of night blindness.[22][23]
• Olfactory testing: Anosmia testing, such as the University of Pennsylvania's smell identification test, should be performed.[9][24]
• Neurology: A multimodal sensory examination, strength assessment, and reflex testing should be performed to assess for neuropathy. Electromyography and nerve conduction studies can be performed if physical examination is equivocal or to characterize the subtype of polyneuropathy.[25] Coordination should be assessed. Cognition is not affected in Refsum disease.[20]
• Audiology: A full audiometric evaluation should be performed on patients who report hearing loss. The evaluation should include pure tone audiometry and any single-frequency tympanometry, single-frequency acoustic reflexes, and brainstem auditory evoked potentials if necessary.[10][19]
• Musculoskeletal evaluation: A physical examination may reveal abnormalities of the metacarpals or metatarsals. A radiologic assessment of the hands and feet should be performed in addition to a physical exam.[10][26]
• Cardiology: An electrocardiogram and an echocardiogram should be performed to assess for arrhythmias, cardiomyopathy, and heart failure. Sudden death due to cardiac abnormalities has been reported in Refsum Disease.[14]

Genetic Profiling

• Confirmatory testing for abnormalities in the PHYH and PEX7 genes may be performed; this can be part of a larger genetic analysis panel. Consultation with a genetic counselor or other clinical genetics professional can be offered.[10]

Biochemistry

• The pathognomic finding of Refsum disease is an elevated phytanic acid level (>200 µmol/L) in the plasma. The reported normal range for phytanic acid varies, but >30 µmol/L is considered abnormal. A patient with Refsum disease might not have a very high phytanic acid level if dietary intake is low. Daily estimated phytanic acid intake in a standard Western diet is estimated to be 50 to 100 mg.[27] An enzymatic assay performed on a sample obtained by skin biopsy can confirm a deficiency of phytanic acid metabolism.[26]

Treatment / Management

Refsum disease can be managed predominantly by diet and plasmapheresis.

Diet

• The mainstay of treatment is dietary restriction of phytanic acid-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.[27]
• The therapeutic goal is to reduce dietary intake of phytanic acid to less than 10 mg daily.[28]
• Rapid weight loss and prolonged fasting should be avoided because these conditions cause lipolysis, which leads to phytanic acid release from the liver and adipose tissue.[20][28]
• Patients who adhere to dietary therapy and demonstrate control of plasma phytanic acid levels can see resolution of neuropathy, ichthyosis, and ataxia. Retinitis pigmentosa, anosmia, and sensorineural hearing loss may not improve.[18][20]

Plasmapheresis 

• Plasmapheresis and lipid apheresis can be used to remove phytanic acid from the blood.
• Apheresis techniques help treat acute presentations of Refsum disease, in which very high plasma phytanic acid levels (for example, >1500 µmol/L) are seen.
• There is no evidence that the use of apheresis as maintenance therapy provides additional benefit when plasma phytanic acid levels are well controlled with diet alone.[11][27]
(B3)

Differential Diagnosis

As the first clinical finding of Refsum disease is usually retinitis pigmentosa and associated visual changes, the initial differential diagnosis in a patient with Refsum disease will often consist of potential causes of retinitis pigmentosa. Many conditions can cause retinitis pigmentosa or a similar pattern of vision impairment. An incomplete list includes inherited retinal dystrophies, syndromic ciliopathies such as Usher and Bardet-Beidl syndromes, syndromic metabolic disorders in addition to Refsum disease, medication effects, and sequelae of cancer, trauma, or infection. Given the complexities inherent in determining the primary cause of retinitis pigmentosa, patients should undergo evaluation by an ophthalmologist.[22] Important entities to consider include:

• Usher syndrome, a ciliopathy, is the most common cause of syndromic retinal degeneration. Like Refsum disease, the first presenting symptom is night blindness due to retinitis pigmentosa. Patients with Usher syndrome also develop sensorineural hearing loss, the most common cause of combined vision and hearing loss.[29][30][31]
• Bardet-Biedl syndrome, also a ciliopathy,  is the second most common cause of syndromic retinal degeneration. Other features often seen in the syndrome are polydactyly, cognitive impairment, renal abnormalities, hypogonadism, and truncal obesity.[31][32]
• Alstrom syndrome is caused by mutations in ALMS1, a gene encoding a protein that is a component of the centrosome; this is a ciliopathy and shares several major clinical features, including retinal dystrophy, progressive sensorineural hearing loss, and cardiomyopathy, with Refsum disease. However, unlike in Refsum disease, the visual loss experienced will typically be central rather than peripheral.[33][34]
• Kearns-Sayre syndrome is a mitochondrial disorder that can affect most organ systems and is characterized by retinitis pigmentosum, progressive external ophthalmoplegia, cardiomyopathy, and cardiac conduction abnormalities. Night blindness may be an early symptom. Sensorineural hearing loss and cerebellar ataxia may also develop.[35][36]

 Peroxisomal Disorders

• Alpha-methyl acyl-CoA racemase deficiency: This enzyme is present in the peroxisome and the mitochondrion; it catalyzes reactions in both pristanic acid metabolism and the metabolism of bile acids. Deficiency of alpha-methyl acyl-CoA racemase, AMACR, is associated with increased levels of dihydroxycholestanoic acid and trihydroxycholestanoic acid, both bile acids. This deficiency is also associated with elevated levels of pristanic acid. Although phytanic acid can be elevated in AMACR deficiency, Refsum disease should not have elevations in fatty acid levels other than those of phytanic acid. In particular, patients with Refsum disease should have low pristanic acid levels.[37]
• Zellweger spectrum disorder: These are disorders of peroxisome biogenesis. All disorders within this spectrum are due to biallelic mutations in one of the 13 PEX genes in humans. These genes are necessary to transport peroxisomal proteins into the peroxisome membrane or matrix. Consequently, some of these disorders may reduce the quantity of functional peroxisomal phytanoyl-CoA hydroxylase enzyme. However, unlike in Refsum disease, multiple biochemical abnormalities will be present alongside elevations in systemic phytanic acid. Clinical characteristics and disease severity are heterogeneous. Depending on the subtype, symptom onset can occur from the neonatal through the adult period.[3][38]
• Rhizomelic chondrodysplasia punctata: This has multiple genetic subtypes that are clinically indistinguishable, but there is still a great deal of heterogeneity in the clinical characteristics and severity of this disease. Type 1 is caused by mutations in PEX7 and is a disorder of peroxisome biogenesis. Mutations in this gene are far more likely to cause rhizomelic chondrodysplasia punctata (RCDP) type 1 than Refsum disease. The peroxin expressed by PEX7 is responsible for the import of multiple enzymes into the peroxisome. The most common presentation of this disease is severe and usually fatal by age 12. RCDP's name derives from the clinical characteristics of stippled epiphyses (chondrodysplasia punctata) and growth impairment of the limbs at the shoulders and hips (rhizomelia). Patients also have severe cognitive impairments and congenital cataracts. There are milder presentations of the disease whose clinical characteristics can be similar to those of Refsum disease.[2][39][40] 

Prognosis

As with age of onset, rate of progression, and disease severity, the prognosis of Refsum disease is variable. For a given affected individual, prognosis depends on a patient's ability to adhere to therapies, most importantly, a diet restricting phytanic acid. Patients who develop cardiac abnormalities are at a greater risk of premature mortality from arrhythmias.

Complications

The complications of Refsum disease can be severe. If left untreated, phytanic acid will accumulate systemically, potentially leading to the following:

• Retinitis pigmentosa
• Anosmia
• Iris atrophy
• Cataracts
• Miosis
• Sensorineural hearing loss
• Ataxia
• Peripheral polyneuropathy
• Cardiomyopathy
• Cardiac conduction abnormalities
• Skeletal malformations, especially shortened metacarpals, and metatarsals
• Ichthyosis [11][14][17]

These are chronic and progressive, although some are potentially reversible. Most patients will develop only some but not all of the above-listed sequelae.[18] In addition to chronic morbidity, very high phytanic acid levels can lead to acute Refsum disease, which is characterized by rapid deterioration of vision and rapid worsening of sensorimotor neuropathy.[27]