Refsum Disease: Symptoms, Types, Causes and Treatment

Refsum disease is a rare, inherited metabolic disorder that has a profound impact on multiple organs and systems in the body. Characterized by the accumulation of phytanic acid—a type of fatty acid that the body cannot break down—this condition leads to a variety of neurological, visual, and other systemic symptoms. Understanding Refsum disease is crucial for early diagnosis, effective management, and improving the quality of life for affected individuals and their families. This article provides a comprehensive overview of the symptoms, types, causes, and treatment options for Refsum disease, with information synthesized from the latest research.

Symptoms of Refsum Disease

Refsum disease presents with a distinctive pattern of symptoms, often affecting the nervous system, eyes, skin, and heart. Many of these symptoms are progressive and can be debilitating if not recognized and managed early. Recognizing the key features can facilitate earlier diagnosis and intervention.

Symptom	Description	Onset/Progression	Source(s)
Retinitis pigmentosa	Progressive vision loss, starting with night blindness	Childhood/Adulthood	2 4 5 7 8 9
Ataxia	Loss of coordination and unsteady gait	Adolescence/Adulthood	1 2 7 8 9
Polyneuropathy	Numbness, weakness, reduced reflexes	Variable	1 2 7 8 9
Anosmia	Complete or partial loss of smell	Early, often permanent	2 3 8
Hearing loss	Sensorineural deafness	Variable	2 3 8
Ichthyosis	Dry, scaly skin	Variable	7 8
Cardiac arrhythmia	Irregular heart rhythms	Potentially life-threatening	7 8
Bone abnormalities	Skeletal and epiphyseal changes	50% of cases	7 8
Cataracts	Clouding of the eye lens	Variable	7
Elevated CSF protein	High protein in cerebrospinal fluid	Without increased cells	8 9

Table 1: Key Symptoms of Refsum Disease

Core Clinical Features

Refsum disease is best recognized by a tetrad of symptoms: retinitis pigmentosa, polyneuropathy, cerebellar ataxia, and elevated cerebrospinal fluid (CSF) protein without increased cell count 8 9. Retinitis pigmentosa, a progressive degeneration of the retina, often leads to night blindness in childhood, followed by peripheral vision loss and, eventually, blindness 4. Ataxia, or loss of muscle coordination, frequently results in an unsteady gait and difficulty with motor tasks 1 2. Polyneuropathy manifests as numbness, weakness, and reduced reflexes, stemming from damage to peripheral nerves 1 2 7 8 9.

Sensory and Neurological Symptoms

Other prominent symptoms include anosmia (loss of smell), which is often severe and persistent—even with treatment 3. Hearing loss, especially sensorineural deafness, is also frequently reported 2 3 8. Elevated protein in the CSF is a hallmark laboratory finding, distinguishable from other causes by the absence of increased cell count 8 9.

Additional Systemic Features

Refsum disease may also affect the skin (ichthyosis, or dry, scaly skin), the heart (cardiac arrhythmias), and the skeleton, with many patients showing bone abnormalities reminiscent of, but milder than, those caused by thalidomide 7 8. Cataracts have been documented in some patients, and fingernail abnormalities have occasionally been noted 7 16.

Symptom Progression and Variability

The onset and progression of symptoms vary significantly between individuals. Some features, such as retinitis pigmentosa and anosmia, can appear early, while ataxia and neuropathy may develop later in life. Not all patients exhibit every symptom, and the severity can range from mild to life-threatening, especially if cardiac arrhythmias develop 7 8.

Types of Refsum Disease

While often referred to as a single disorder, Refsum disease actually encompasses different genetic subtypes, each linked to specific molecular defects. Understanding these types is important for accurate diagnosis and potential future therapies.

Type	Genetic Cause	Clinical Features	Source(s)
Type 1 (Classic)	PHYH gene mutations (phytanoyl-CoA hydroxylase deficiency)	Typical Refsum symptoms	2 6 9 10
Type 2	PEX7 gene mutations (peroxin 7 defect)	Indistinguishable from Type 1	6
Atypical/Mild	Other peroxisomal disorders (e.g., rhizomelic chondrodysplasia punctata type 1a, α-methylacyl-CoA racemase deficiency)	Mild/Variable symptoms	2

Table 2: Types of Refsum Disease

Type 1: Classic Refsum Disease

The majority of cases are due to mutations in the PHYH gene, which encodes phytanoyl-CoA hydroxylase (PhyH), an enzyme critical for breaking down phytanic acid 2 9 10. Deficiency in this enzyme leads to the characteristic accumulation of phytanic acid in tissues and plasma.

Type 2: Peroxin 7 Deficiency

A smaller subset of patients have mutations in the PEX7 gene, which encodes peroxin 7, a protein essential for importing enzymes (like PhyH) into peroxisomes 6. Clinical features are indistinguishable from classic Refsum disease, so genetic testing is required for differentiation.

Atypical and Mild Variants

Some individuals present with milder symptoms or have low-plasma phytanic acid due to other peroxisomal disorders, such as rhizomelic chondrodysplasia punctata type 1a or α-methylacyl-CoA racemase deficiency 2. These cases broaden the spectrum of Refsum-like diseases and underscore the importance of comprehensive molecular analysis.

Clinical Implications

Although the types share overlapping features, identifying the genetic basis is important for family counseling, future gene-specific therapies, and understanding disease mechanisms 2 6.

Causes of Refsum Disease

The underlying cause of Refsum disease is a defect in the body's ability to metabolize phytanic acid, a branched-chain fatty acid found in certain foods. This defect is inherited and results from mutations in specific genes involved in peroxisomal function.

Cause	Mechanism	Inheritance/Genetics	Source(s)
PHYH gene mutations	Loss of phytanoyl-CoA hydroxylase (PhyH)	Autosomal recessive	2 9 10 11
PEX7 gene mutations	Defective peroxisomal enzyme import	Autosomal recessive	6 10
Peroxisomal dysfunction	Impaired α-oxidation of phytanic acid	Variable (peroxisomal disorders)	2 5
Phytanic acid accumulation	Toxic levels in blood and tissues	Consequence of above	1 2 5 7 8 9

Table 3: Causes of Refsum Disease

Genetic Defects

Refsum disease is inherited in an autosomal recessive manner, meaning both parents must be carriers of a defective gene for a child to be affected 2 9. The most common genetic defect is in the PHYH gene, which leads to deficient or absent activity of phytanoyl-CoA hydroxylase, the enzyme responsible for the first step in phytanic acid breakdown 2 9 10 11. Mutations in the PEX7 gene, which encodes a protein required for importing enzymes into peroxisomes, can also cause Refsum disease (Type 2) 6 10.

Defective Peroxisomal α-Oxidation

Phytanic acid cannot be broken down via the typical beta-oxidation pathway because of its branched structure. Instead, it requires alpha-oxidation in peroxisomes, an organelle specialized in lipid metabolism 2 5 9. In Refsum disease, the absence or malfunction of key peroxisomal enzymes halts this process, leading to phytanic acid buildup 2 5 9 10.

Phytanic Acid Toxicity

As phytanic acid accumulates in the blood and various tissues—including nerves, retina, skin, and heart—it exerts toxic effects, damaging these organs and producing the symptoms described earlier 1 2 5 7 8 9. The severity of symptoms correlates with the degree of accumulation and the duration of untreated disease.

Molecular and Biochemical Insights

Recent research has identified specific mutations in PHYH and PEX7 genes, including deletions and point mutations, that disrupt enzyme activity or its targeting to peroxisomes 10 11. Some mutations may leave the enzyme present but non-functional, while others may prevent it from reaching its site of action altogether 11.

Treatment of Refsum Disease

Although there is no cure, Refsum disease is one of the few inherited metabolic disorders where symptoms can be effectively managed and progression slowed through dietary and medical interventions. Early diagnosis and ongoing management are key to improving outcomes.

Treatment	Purpose/Effect	Notes/Considerations	Source(s)
Dietary restriction	Limit phytanic acid intake	Avoid dairy, ruminant fats, certain fish; lifelong adherence needed	12 14 16
Plasmapheresis/lipopheresis	Rapidly reduce phytanic acid levels	Used in severe or acute cases; plasma exchange or cascade filtration	12 13 15 16
High-calorie diet	Prevent mobilization of stored phytanic acid	Important during illness or weight loss	12 15 16
Supportive therapy	Manage complications (vision, hearing, heart, skin)	Individualized care	7 8 12

Table 4: Treatment Options for Refsum Disease

Dietary Management

The cornerstone of treatment is strict lifelong dietary restriction of phytanic acid. This means avoiding foods rich in phytanic acid, such as dairy products, beef, lamb, and certain fish 12 14 16. Effective dietary management, reinforced regularly by specialized dietitians, can reduce plasma phytanic acid by up to 89% and significantly limit disease progression 14. Patients must also avoid sudden weight loss, as this can mobilize phytanic acid stored in fat, leading to symptom worsening 12 15 16.

Plasmapheresis and Lipapheresis

In situations where phytanic acid levels are dangerously high or symptoms are rapidly progressing, therapeutic plasma exchange (plasmapheresis) or cascade filtration (lipapheresis) can rapidly remove phytanic acid from the bloodstream 12 13 15 16. Cascade filtration is often preferred due to reduced loss of immunoglobulins and no need for albumin replacement 13. These procedures are reserved for acute management and are not substitutes for long-term dietary control.

Supportive Care and Monitoring

There is no cure for the underlying enzyme defect, so treatment also focuses on managing complications:

• Vision: Low-vision aids and support for retinitis pigmentosa
• Hearing: Hearing aids for sensorineural deafness
• Heart: Monitoring and treatment for arrhythmias
• Skin: Emollients for ichthyosis
• Physical Therapy: To address ataxia and neuropathy

Regular monitoring of phytanic acid levels, neurological status, cardiac function, and nutritional state is vital 7 8 12.

Future Directions

Gene therapy or transplantation of enzyme-producing tissue remains experimental and is not currently available 13. Early diagnosis and compliance with management plans are essential for maintaining quality of life.

Conclusion

Refsum disease is a rare but potentially treatable inherited disorder. Early recognition of its symptoms and prompt intervention can significantly improve patient outcomes. The key points include:

• Symptoms: Characterized by vision loss (retinitis pigmentosa), ataxia, polyneuropathy, anosmia, hearing loss, skin, heart, and bone involvement
• Types: Most cases are due to PHYH gene mutations (Type 1); some are due to PEX7 mutations (Type 2); atypical cases exist
• Causes: Autosomal recessive inheritance of defective peroxisomal enzymes leading to phytanic acid accumulation
• Treatment: Involves lifelong dietary restriction of phytanic acid, acute removal by plasmapheresis/lipopheresis when necessary, and supportive management of complications

By following a carefully managed treatment plan, individuals with Refsum disease can experience significant symptom relief and improved quality of life.