Refsum Disease

Refsum disease is a rare genetic condition that affects how the body breaks down a specific type of fat called phytanic acid. Unlike most fats, our bodies cannot make phytanic acid; it comes entirely from the food we eat, particularly dairy products, beef, lamb, and certain types of fish. Because people with Refsum disease lack the enzyme needed to break down this fat, phytanic acid builds up to toxic levels in the blood and tissues, causing damage to the eyes, nerves, and other organs. The first sign of Refsum disease is usually night blindness, which often starts in childhood or the teenage years. Over time, this progresses to a loss of side (peripheral) vision and eventually affects central vision, a condition known as retinitis pigmentosa. Other common symptoms include a loss of the sense of smell, hearing loss, weakness and numbness in the hands and feet, unsteadiness when walking, and dry, scaly skin. In severe cases, the buildup of phytanic acid can cause serious heart problems. The most important thing for patients and families to know is that Refsum disease is treatable. The main treatment is a strict, lifelong diet that avoids foods high in phytanic acid. By carefully managing their diet, patients can stop the disease from getting worse and prevent severe nerve and heart damage. While the diet cannot reverse vision or hearing loss that has already occurred, early diagnosis and strict dietary control are essential for maintaining quality of life and preventing life-threatening complications.

Condition category: Syndromic IRD

Prevalence: Less than 1 in 1,000,000

Inheritance patterns: Autosomal Recessive

Age of onset: Late childhood to early adulthood (typically between 10 and 20 years of age), though onset can range from 7 months to over 50 years.

Clinical overview: Refsum disease, also known as classic or adult Refsum disease, is a rare autosomal recessive inborn error of lipid metabolism. It is classified as a peroxisomal disorder, specifically involving a defect in the alpha-oxidation of branched-chain fatty acids. The disease is characterized by the systemic accumulation of phytanic acid, an exogenous fatty acid derived from the diet. This accumulation leads to a classic tetrad of clinical features: retinitis pigmentosa, peripheral polyneuropathy, cerebellar ataxia, and elevated cerebrospinal fluid protein levels without pleocytosis. The clinical presentation of Refsum disease is variable and progressive. While it is often called "adult" Refsum disease to distinguish it from the genetically distinct infantile Refsum disease (a Zellweger spectrum disorder), symptoms typically begin in late childhood or adolescence. The earliest and most consistent manifestation is night blindness due to retinitis pigmentosa. Over time, patients may develop anosmia, sensorineural hearing loss, ichthyosis, skeletal abnormalities, and potentially fatal cardiac arrhythmias. Early diagnosis is crucial because Refsum disease is one of the few inherited retinal dystrophies and polyneuropathies that is treatable. Management focuses on strict dietary restriction of phytanic acid, which can halt the progression of neurological and cardiac symptoms, although existing sensory deficits like vision and hearing loss are typically irreversible. The condition is genetically heterogeneous, primarily caused by mutations in the PHYH gene, and less commonly in the PEX7 gene. The OMIM number for classic Refsum disease is 266500, and the Orphanet number is ORPHA773.

Patient and family guide: Refsum disease is a rare genetic condition that affects how the body breaks down a specific type of fat called phytanic acid. Unlike most fats, our bodies cannot make phytanic acid; it comes entirely from the food we eat, particularly dairy products, beef, lamb, and certain types of fish. Because people with Refsum disease lack the enzyme needed to break down this fat, phytanic acid builds up to toxic levels in the blood and tissues, causing damage to the eyes, nerves, and other organs. The first sign of Refsum disease is usually night blindness, which often starts in childhood or the teenage years. Over time, this progresses to a loss of side (peripheral) vision and eventually affects central vision, a condition known as retinitis pigmentosa. Other common symptoms include a loss of the sense of smell, hearing loss, weakness and numbness in the hands and feet, unsteadiness when walking, and dry, scaly skin. In severe cases, the buildup of phytanic acid can cause serious heart problems. The most important thing for patients and families to know is that Refsum disease is treatable. The main treatment is a strict, lifelong diet that avoids foods high in phytanic acid. By carefully managing their diet, patients can stop the disease from getting worse and prevent severe nerve and heart damage. While the diet cannot reverse vision or hearing loss that has already occurred, early diagnosis and strict dietary control are essential for maintaining quality of life and preventing life-threatening complications.

Symptoms and clinical features: The clinical presentation of Refsum disease is characterized by a slow, progressive onset of symptoms that typically evolve over decades. In the early stages, usually during late childhood or adolescence (ages 10 to 20), the most prominent and often sole symptom is nyctalopia (night blindness). This is due to the early involvement of rod photoreceptors in the retina. Another very early and nearly universal symptom is anosmia (loss of the sense of smell), which may go unnoticed or unreported by the patient for years. As the disease progresses into the intermediate stages, usually in early adulthood, the ophthalmologic symptoms worsen. Patients experience a progressive constriction of their visual fields (tunnel vision) and may develop cataracts, further impairing vision. Neurological symptoms begin to manifest, most notably a mixed motor and sensory peripheral polyneuropathy. This typically presents as symmetric, distal weakness and numbness in the lower extremities, leading to foot drop and absent deep tendon reflexes. Cerebellar ataxia also develops, causing an unsteady gait and balance issues that are often out of proportion to the degree of muscle weakness. Sensorineural hearing loss typically begins in this stage, affecting high frequencies first. In the advanced stages of untreated Refsum disease, the polyneuropathy can become severe and widespread, involving the trunk and upper limbs, leading to significant muscular atrophy and disability. Visual acuity severely declines, potentially leading to legal blindness. Hearing loss can progress to profound deafness. Dermatological manifestations, such as ichthyosis (dry, scaly skin), may become prominent. Most critically, advanced disease is associated with cardiac involvement, including cardiomyopathy and severe cardiac conduction abnormalities (arrhythmias), which can be life-threatening. Skeletal abnormalities, such as shortened metacarpals and metatarsals, may also be observed, though these are congenital rather than progressive.

Molecular pathology: Refsum disease is a disorder of lipid metabolism, specifically affecting the catabolism of branched-chain fatty acids. The primary biochemical defect is the inability to degrade phytanic acid (3,7,11,15-tetramethylhexadecanoic acid). Phytanic acid is entirely exogenous, derived from the diet, primarily from ruminant fats, meat, and dairy products, as well as some fish. It is a breakdown product of phytol, which is a component of chlorophyll. Because of the presence of a methyl group at the 3-position (beta-carbon), phytanic acid cannot undergo standard beta-oxidation. Normally, phytanic acid must first undergo alpha-oxidation in the peroxisome. This process shortens the fatty acid chain by one carbon atom, converting phytanic acid to pristanic acid, which can then be further degraded by beta-oxidation. The first step of this alpha-oxidation pathway is catalyzed by the peroxisomal enzyme phytanoyl-CoA hydroxylase (PhyH), which is encoded by the PHYH gene. In Refsum disease, mutations in PHYH lead to a deficiency of this enzyme. Alternatively, mutations in the PEX7 gene, which encodes the PTS2 receptor required for importing PhyH into the peroxisome, also result in deficient alpha-oxidation. The enzymatic block leads to a massive accumulation of phytanic acid in the blood and tissues. Phytanic acid incorporates into cell membranes, replacing essential fatty acids like linoleic and arachidonic acids, which alters membrane fluidity and function. The exact mechanisms of cellular toxicity are not fully understood, but the accumulation of phytanic acid is believed to cause calcium dysregulation, mitochondrial depolarization, and increased production of reactive oxygen species, leading to cellular damage and apoptosis, particularly in the retina, peripheral nerves, and cardiac tissue.

Genetics: Refsum disease is inherited in an autosomal recessive manner. This means an affected individual must inherit two pathogenic variants, one from each parent. The parents are typically asymptomatic carriers. The disease is genetically heterogeneous, caused by mutations in one of two known genes: PHYH (also known as PAHX) and PEX7. Mutations in the PHYH gene, located on chromosome 10p13, account for more than 90% of classic Refsum disease cases. The PHYH gene encodes the enzyme phytanoyl-CoA hydroxylase. Over 30 different mutations in PHYH have been identified, including missense, nonsense, and splice-site mutations, as well as small deletions and insertions. These mutations typically result in an enzymatically inactive protein, completely disrupting the first step of phytanic acid alpha-oxidation. A smaller subset of patients (less than 10%) have mutations in the PEX7 gene, located on chromosome 6q21-q22.2. The PEX7 gene encodes the peroxisome-targeting signal type 2 (PTS2) receptor, which is responsible for importing certain enzymes, including phytanoyl-CoA hydroxylase, into the peroxisome. Mutations in PEX7 can cause a spectrum of disorders; severe mutations typically cause rhizomelic chondrodysplasia punctata type 1 (RCDP1), while milder mutations that allow for some residual receptor function result in the adult Refsum disease phenotype. There is no clear genotype-phenotype correlation regarding the severity of the clinical presentation, as the accumulation of phytanic acid is heavily influenced by dietary intake.

Diagnostic evaluation: The diagnosis of Refsum disease is primarily established through biochemical testing demonstrating elevated plasma phytanic acid levels (typically >200 µmol/L, with normal being <30 µmol/L) alongside low or normal pristanic acid levels. This is followed by molecular genetic testing of the PHYH and PEX7 genes to confirm the diagnosis. If genetic testing is inconclusive, enzyme analysis in cultured skin fibroblasts can be performed to assess phytanoyl-CoA hydroxylase activity. Ophthalmologic evaluation is critical for diagnosis. Fundoscopy typically reveals classic signs of retinitis pigmentosa, including bone spicule pigmentation, retinal vessel attenuation, and waxy pallor of the optic disc. Optical coherence tomography (OCT) may show macular edema or retinal thinning. Electroretinography (ERG) is essential, often showing reduced or absent rod and cone responses early in the disease course, even before significant visual symptoms are reported by the patient. Neurological workup includes electromyography (EMG) and nerve conduction studies (NCS) to characterize the peripheral polyneuropathy, which is typically a mixed sensorimotor, demyelinating, and axonal neuropathy. Audiometry and auditory brainstem response (ABR) testing are used to evaluate sensorineural hearing loss and potential auditory neuropathy. Cerebrospinal fluid (CSF) analysis often shows albuminocytologic dissociation (elevated protein with normal cell count), though lumbar puncture is not routinely required for diagnosis. Differential diagnosis includes other causes of retinitis pigmentosa and polyneuropathy, such as Usher syndrome, Kearns-Sayre syndrome, abetalipoproteinemia, and other peroxisomal disorders like Zellweger spectrum disorders (including infantile Refsum disease, which is a distinct entity). Charcot-Marie-Tooth disease type 4 (CMT4) should also be considered, as the neuropathy in Refsum disease was historically classified as hereditary motor and sensory neuropathy type IV (HMSN IV).

Differential diagnosis: Differential diagnosis of Refsum disease includes: (1) Usher syndrome — RP with hearing loss but no elevated phytanic acid, no polyneuropathy. (2) Cockayne syndrome — pigmentary retinopathy with hearing loss, dwarfism, photosensitivity. (3) Kearns-Sayre syndrome — pigmentary retinopathy with ophthalmoplegia, cardiac conduction defects. (4) Charcot-Marie-Tooth disease — polyneuropathy without retinal dystrophy. (5) Hereditary sensory and autonomic neuropathy — peripheral neuropathy without RP. (6) Friedreich ataxia — ataxia, cardiomyopathy, possible optic atrophy but no elevated phytanic acid.

Natural history: The natural history of Refsum disease is characterized by a slow, insidious progression of symptoms, typically beginning in late childhood or adolescence. The first symptom is almost universally nyctalopia (night blindness) due to early rod photoreceptor degeneration. This is followed over years or decades by progressive constriction of the visual fields and eventual decline in central visual acuity. If left untreated, the disease progresses to include severe peripheral polyneuropathy, leading to distal muscle weakness, sensory loss, and ataxia. Sensorineural hearing loss and anosmia also develop and worsen over time. The accumulation of phytanic acid can lead to life-threatening cardiac arrhythmias and cardiomyopathy, which are significant prognostic factors and a primary cause of mortality in untreated individuals. The progression of the disease is highly dependent on dietary intake of phytanic acid. Periods of rapid weight loss, fasting, severe illness, or stress can trigger acute exacerbations of the disease, as phytanic acid stored in adipose tissue is rapidly mobilized into the bloodstream. With early diagnosis and strict adherence to a low-phytanic acid diet, the progression of neurological and cardiac symptoms can be halted or even partially reversed, though visual and auditory damage is generally irreversible.

Management and treatment research: ### Current Management and Standard of Care The main disease-specific treatment for adult Refsum disease is lifelong reduction of **phytanic acid**, a fatty acid that the body cannot break down normally in this condition. Lowering blood phytanic acid may help prevent or slow additional problems affecting the nerves, heart, skin, hearing, and vision. - A metabolic specialist and dietitian can help develop a low-phytanic-acid diet. Foods commonly restricted include ruminant meats and fats, such as beef and lamb, full-fat dairy products, and certain fish. - The diet may also limit foods containing **phytol**, a substance that can be converted to phytanic acid in the body. - Adequate calorie intake is important. Fasting, illness, rapid weight loss, or poor food intake can release stored phytanic acid from body fat and raise blood levels. Plans for weight loss and sick-day management should be discussed with the metabolic care team. - Blood phytanic acid levels are monitored regularly to assess dietary control and guide care. When phytanic acid levels are very high or symptoms are worsening rapidly, **plasmapheresis** may be used. This procedure removes and replaces blood plasma, helping lower phytanic acid more quickly. It may be considered during severe illness or in people with potentially dangerous heart rhythm problems. Supportive care is also important because some complications may not fully improve after phytanic acid levels are reduced. Care may include: - Regular eye care for retinitis pigmentosa, cataracts, and low-vision needs - Hearing evaluations, hearing aids, or cochlear implants when appropriate - Physical therapy, mobility aids, orthotics, and fall-prevention support for neuropathy, weakness, balance problems, or ataxia - Cardiac monitoring, including electrocardiograms and echocardiograms, to identify arrhythmias or cardiomyopathy - Dermatologic care for ichthyosis, which causes dry, scaly skin ### Approved Therapies There are no approved medicines, gene therapies, or cell therapies that correct the underlying metabolic defect in Refsum disease. Dietary phytanic acid restriction, regular monitoring, and plasmapheresis when needed remain the established approaches for reducing phytanic acid levels. ### Investigational Therapies There are currently no condition-specific investigational drug, gene therapy, cell therapy, or other disease-modifying treatment programs for Refsum disease in the current treatment pipeline. Research in inherited retinal diseases and peroxisomal disorders may improve understanding of Refsum disease and support future treatment development. However, no active investigational treatment can currently be identified as a Refsum disease therapy. ### Clinical Trial Participation The currently listed studies are registries, biobanks, or natural-history studies rather than Refsum disease treatment trials. These studies may collect medical information, imaging, or biological samples over time to improve understanding of rare diseases. - **NCT02435940** — Inherited Retinal Degenerative Disease Registry; recruiting - **NCT01668186** — Longitudinal Natural History Study of Patients With Peroxisome Biogenesis Disorders; recruiting - **NCT03047369** — The Myelin Disorders Biorepository Project; recruiting - **NCT01793168** — Rare Disease Patient Registry & Natural History Study; recruiting - **NCT02171104** — Allogeneic hematopoietic cell transplant for metabolic disorders and severe osteopetrosis; phase 2, active but not recruiting. This study is not a standard treatment study for Refsum disease. Eligibility depends on a person’s specific diagnosis, age, location, and study requirements. A metabolic specialist or inherited retinal disease specialist can help determine whether a registry or research study may be appropriate.

Outlook: The prognosis for individuals with Refsum disease depends heavily on the timing of diagnosis and adherence to dietary treatment. If left untreated, the disease is progressive and can lead to severe disability from blindness, deafness, and profound polyneuropathy. Furthermore, untreated individuals are at a high risk of sudden death due to cardiac arrhythmias or heart failure caused by phytanic acid accumulation in the heart muscle. With early diagnosis and strict adherence to a low-phytanic acid diet, the prognosis improves significantly. Dietary management can halt the progression of the peripheral neuropathy, ataxia, and ichthyosis, and may even lead to partial improvement in these symptoms. Cardiac risks are also substantially reduced. However, the sensory deficits, particularly the retinitis pigmentosa and sensorineural hearing loss, are generally irreversible, though their progression may be slowed. Quality of life can be maintained with proper management, but patients require lifelong monitoring and must avoid fasting or rapid weight loss, which can trigger acute and potentially dangerous releases of stored phytanic acid.

Epidemiology: Refsum disease is an exceptionally rare genetic disorder. The exact prevalence is unknown, but it is estimated to affect fewer than 1 in 1,000,000 individuals in the United States and European populations. It affects males and females equally. The condition has been reported worldwide with no specific ethnic or geographic predilection, though founder effects or consanguinity may increase prevalence in certain isolated populations. Due to the insidious onset of symptoms and the rarity of the condition, it is likely underdiagnosed, and there is often a significant delay—sometimes exceeding a decade—between the onset of symptoms and formal diagnosis.

Selected references: 1. Wanders RJA, Waterham HR, Leroy BP. Refsum Disease. 2006 Mar 20 [Updated 2015 Jun 11]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. PMID: 20301527 2. Jansen GA, Waterham HR, Wanders RJ. Molecular basis of Refsum disease: sequence variations in phytanoyl-CoA hydroxylase (PHYH) and the PTS2 receptor (PEX7). Hum Mutat. 2004;23(3):209-218. PMID: 14974078 3. Wanders RJ, Jansen GA, Skjeldal OH. Refsum disease, peroxisomes and phytanic acid oxidation: a review. J Neuropathol Exp Neurol. 2001;60(11):1021-1031. PMID: 11706932 4. Wills AJ, Manning NJ, Reilly MM. Refsum's disease. QJM. 2001;94(8):403-406. PMID: 11493716 5. van den Brink DM, Brites P, Haasjes J, et al. Identification of PEX7 as the second gene involved in Refsum disease. Am J Hum Genet. 2003;72(2):471-477. PMID: 12522768 6. Wierzbicki AS, Lloyd MD, Schofield CJ, Feher MD, Gibberd FB. Refsum's disease: a peroxisomal disorder affecting phytanic acid alpha-oxidation. J Neurochem. 2002;80(5):727-735. PMID: 11948235