Refsum Disease 

  • Author: Anna Zalewska, MD, PhD; Chief Editor: William D James, MD   more...
 
Updated: Aug 17, 2011
 

Background

Refsum disease (RD) is a neurocutaneous syndrome that is characterized biochemically by the accumulation of phytanic acid in plasma and tissues. Patients with Refsum disease are unable to degrade phytanic acid because of a deficient activity of phytanoyl-CoA hydroxylase (PhyH), a peroxisomal enzyme catalyzing the first step of phytanic acid alpha-oxidation.

Refsum first described this disease in 1946. Peripheral polyneuropathy, cerebellar ataxia, retinitis pigmentosa, and ichthyosis are the major clinical components. The symptoms evolve slowly and insidiously from childhood through adolescence and early adulthood.

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Pathophysiology

Refsum disease is a recessive disorder characterized by defective peroxisomal alpha-oxidation of phytanic acid.[1, 2, 3] Consequently, this unusual, exogenous C20-branched-chain (3,7,11,15-tetramethylhexadecanoic acid) fatty acid accumulates in blood and tissues. It is almost exclusively of exogenous origin and is delivered mainly from dietary plant chlorophyll and, to a lesser extent, from animal sources. Blood levels of phytanic acid are increased in patients with Refsum disease. These levels are 10-50 mg/dL, whereas normal values are less than or equal to 0.2 mg/dL, and account for 5-30% of serum lipids.

Phytanic acid replaces other fatty acids, including such essential ones as linoleic and arachidonic acids, in lipid moieties of various tissues.[4] This situation leads to an essential fatty acid deficiency, which is associated with the development of ichthyosis.[5] A Refsum disease gene, phytanoyl-CoA hydroxylase (PHYH), has been localized to band 10p13 between the markers D10S226 and D10S223.[6] Refsum disease is genetically heterogeneous, with up to 55% of cases not being linked to the PAHX gene locus at D10S547 to D10S223. Some patients have been found to carry a defect in perforin 7 (PEX7 defect).[7, 8]

Based on the above, it was proposed that adult Refsum disease could be divided into types 1 and 2, depending on which gene is defective.[9] Thus, Refsum disease, like other peroxisomal diseases, is a heterogeneous syndrome. Recently, a mouse model for Refsum disease (Phyh knockout mouse by targeted disruption of the PHYH gene). In humans, the PHYH gene is about 21 kb and consists of 9 exons and 8 introns. It encodes a protein of 38.6 kd.[10]

An infantile form of Refsum disease also exists and is an autosomal recessive disorder of peroxisomal biogenesis, leading to many biochemical abnormalities, including elevated plasma concentration of phytanic acid, pristanic acid, very long chain fatty acids, and C27 bile acids. The disease presents in the first year of life and manifests with developmental delay, visual and hearing disturbances, and dysmorphic features. Ichthyosis is an unusual symptom.[11, 12]

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Epidemiology

Frequency

International

Refsum disease is rare, with just 60 cases published worldwide.

Mortality/Morbidity

In patients who are untreated or diagnosed late, severe neurological impairment, wasting, and depression develop, subsequently leading to a high mortality rate. Attenuation of neurologic, ophthalmologic, and cardiac symptoms requires constant adherence to a suitable diet and plasmapheresis.

Race

No racial predominance is reported.

Sex

Only male cases were reported initially; however, now, neither sex predominates.

Age

Classic Refsum disease manifests in children aged 2-7 years; however, diagnosis usually is delayed until early adulthood. Infantile Refsum disease makes its appearance in early infancy.

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Contributor Information and Disclosures
Author

Anna Zalewska, MD, PhD  Professor of Dermatology and Venereology, Psychodermatology Department, Chair of Clinical Immunology and Microbiology, Medical University of Lodz, Poland

Disclosure: Nothing to disclose.

Coauthor(s)

Robert A Schwartz, MD, MPH  Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi

Disclosure: Nothing to disclose.

Specialty Editor Board

Jacek C Szepietowski, MD, PhD  Professor, Vice-Head, Department of Dermatology, Venereology and Allergology, Wroclaw Medical University; Director of the Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Poland

Disclosure: Stiefel GSK Company Salary Employment; Orfagen Consulting fee Consulting; Maruho Consulting fee Consulting; Astellas Consulting fee Consulting; Abbott Consulting fee Consulting; Leo Pharma Consulting fee Consulting

Michael J Wells, MD  Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine

Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association

Disclosure: Nothing to disclose.

Jeffrey P Callen, MD  Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of Louisville School of Medicine

Jeffrey P Callen, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and American College of Rheumatology

Disclosure: Amgen Honoraria Consulting; Abbott Honoraria Consulting; Electrical Optical Sciences Consulting fee Consulting; Celgene Honoraria Safety Monitoring Committee; GSK - Glaxo Smith Kline Consulting fee Consulting; TenXBioPharma Consulting fee Safety Monitoring Committee

Catherine M Quirk, MD  Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania

Catherine M Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD  Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System

William D James, MD is a member of the following medical societies: American Academy of Dermatology and Society for Investigative Dermatology

Disclosure: Elsevier Royalty Other

References

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