eMedicine Specialties > Dermatology > Pediatric Diseases

Refsum Disease

Author: Anna Zalewska, MD, PhD, Assistant Professor, Adjunct Professor, Department of Dermatology and Venereology, Medical University of Lodz, Poland
Coauthor(s): Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Contributor Information and Disclosures

Updated: Jul 10, 2009

Introduction

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.

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. This situation leads to an essential fatty acid deficiency, which is associated with the development of ichthyosis.4 A Refsum disease gene, phytanoyl-CoA hydroxylase, has been localized to band 10p13 between the markers D10S226 and D10S223.5 Refsum disease is genetically heterogeneous, with up to 55% of cases not being linked to the PAHX gene locus at D10S547 to D10S223. Some cases have been found to carry defect in perforin 7 (PEX7 defect).6,7 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.8  Thus, Refsum disease, like other peroxisomal diseases, is a heterogeneous syndrome.

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.9,10

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.

Clinical

History

  • Symptoms develop progressively and slowly with neurologic (eg, mild peripheral intermittent neuropathy, tinnitus, anosmia) and ophthalmic (eg, failing vision, night blindness as a result of progressive retinitis pigmentosa) manifestations.
  • Ichthyosis may accompany, but most often follows, the occurrence of the above symptoms.

Physical

Pertinent physical findings include neurologic, ophthalmic, cardiac, and skin defects.

  • Neurologic/ophthalmologic signs
    • Partial intermittent sensorimotor polyneuropathy
    • Cataract
    • Nystagmus
    • Retinitis pigmentosa
    • Anosmia
    • Concentric constriction of the visual fields
    • Sensorineural deafness
  • Signs resulting from cerebellar ataxia
    • Progressive weakness
    • Foot drop
    • Loss of balance
  • Cardiomyopathy with a serious conduction defect is a life-threatening sign.11,12
  • Hepatic/renal symptoms are clinically silent despite fatty degeneration.
  • An ichthyosiform desquamation occurs, resembling a mild acquired ichthyosis vulgaris with a fine, white scaling that is noticeable over the lower trunk but also affects the limbs. Ichthyotic symptoms may range from mild hyperkeratosis of the palms and soles to severe scaling of lamellar ichthyosis type observed on the trunk.
  • Skeletal defects (noticed in some patients) are not related directly to phytanic acid levels.
    • These defects occur in 35-75% of cases.
    • The knees, elbows, and short tubular bones of the hands and feet are affected; in particular, the terminal phalanx of the thumb also is affected.

Causes

Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase (PHYH) and the PTS2 receptor (PEX7) genes. This disorder is inherited in an autosomal recessive mode. A single peroxisomal enzyme defect that causes deficiency of alpha-oxidation leads to accumulation of phytanic acid in blood and tissues of patients with Refsum disease. The cytotoxic effect of phytanic acid seems to be due to a combined action of Ca2+ regulation, mitochondrial depolarization, and increased reactive oxygen species generation in brain cells.

More on Refsum Disease

Overview: Refsum Disease
Differential Diagnoses & Workup: Refsum Disease
Treatment & Medication: Refsum Disease
Follow-up: Refsum Disease
References
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References

  1. Jansen GA, Ferdinandusse S, Hogenhout EM, Verhoeven NM, Jakobs C, Wanders RJ. Phytanoyl-CoA hydroxylase deficiency. Enzymological and molecular basis of classical Refsum disease. Adv Exp Med Biol. 1999;466:371-6. [Medline].

  2. Jansen GA, Ofman R, Ferdinandusse S, et al. Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase gene. Nat Genet. Oct 1997;17(2):190-3. [Medline].

  3. Singh I, Pahan K, Singh AK, Barbosa E. Refsum disease: a defect in the alpha-oxidation of phytanic acid in peroxisomes. J Lipid Res. Oct 1993;34(10):1755-64. [Medline].

  4. Komen JC, Distelmaier F, Koopman WJ, Wanders RJ, Smeitink J, Willems PH. Phytanic acid impairs mitochondrial respiration through protonophoric action. Cell Mol Life Sci. Dec 2007;64(24):3271-81. [Medline].

  5. Foulon V, Asselberghs S, Geens W, Mannaerts GP, Casteels M, Van Veldhoven PP. Further studies on the substrate spectrum of phytanoyl-CoA hydroxylase: implications for Refsum disease?. J Lipid Res. Dec 2003;44(12):2349-55. [Medline].

  6. Horn MA, van den Brink DM, Wanders RJ, et al. Phenotype of adult Refsum disease due to a defect in peroxin 7. Neurology. Feb 27 2007;68(9):698-700. [Medline].

  7. 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. Mar 2004;23(3):209-18. [Medline].

  8. Fiskerstrand T, Knappskog P, Majewski J, Wanders RJ, Boman H, Bindoff LA. A novel Refsum-like disorder that maps to chromosome 20. Neurology. Jan 6 2009;72(1):20-7. [Medline].

  9. Bader PI, Dougherty S, Cangany N, Raymond G, Jackson CE. Infantile refsum disease in four Amish sibs. Am J Med Genet. Jan 17 2000;90(2):110-4. [Medline].

  10. Choksi V, Hoeffner E, Karaarslan E, Yalcinkaya C, Cakirer S. Infantile refsum disease: case report. AJNR Am J Neuroradiol. Nov-Dec 2003;24(10):2082-4. [Medline].

  11. Koh JT, Jeong BC, Kim JH, et al. Changes underlying arrhythmia in the transgenic heart overexpressing Refsum disease gene-associated protein. Biochem Biophys Res Commun. Jan 2 2004;313(1):156-62. [Medline].

  12. Leys D, Petit H, Bonte-Adnet C, et al. Refsum's disease revealed by cardiac disorders. Lancet. Mar 18 1989;1(8638):621. [Medline].

  13. Verny C, Prundean A, Nicolas G, et al. Refsum's disease may mimic familial Guillain Barre syndrome. Neuromuscul Disord. Nov 2006;16(11):805-8. [Medline].

  14. Cakirer S, Savas MR. Infantile Refsum disease: serial evaluation with MRI. Pediatr Radiol. Feb 2005;35(2):212-5. [Medline].

  15. Gibberd FB, Feher MD, Sidey MC, Wierzbicki AS. Smell testing: an additional tool for identification of adult Refsum's disease. J Neurol Neurosurg Psychiatry. Sep 2004;75(9):1334-6. [Medline].

  16. Duranti G, Boenzi S, Rizzo C, et al. Urine acylcarnitine analysis by ESI-MS/MS: a new tool for the diagnosis of peroxisomal biogenesis disorders. Clin Chim Acta. Dec 2008;398(1-2):86-9. [Medline].

  17. Harari D, Gibberd FB, Dick JP, Sidey MC. Plasma exchange in the treatment of Refsum's disease (heredopathia atactica polyneuritiformis). J Neurol Neurosurg Psychiatry. Jul 1991;54(7):614-7. [Medline].

  18. Gutsche HU, Siegmund JB, Hoppmann I. Lipapheresis: an immunoglobulin-sparing treatment for Refsum's disease. Acta Neurol Scand. Sep 1996;94(3):190-3. [Medline].

  19. Xu F, Ng VY, Kroetz DL, de Montellano PR. CYP4 isoform specificity in the omega-hydroxylation of phytanic acid, a potential route to elimination of the causative agent of Refsum's disease. J Pharmacol Exp Ther. Aug 2006;318(2):835-9. [Medline].

  20. Raine CH, Kurukulasuriya MF, Bajaj Y, Strachan DR. Cochlear implantation in Refsum's disease. Cochlear Implants Int. Jun 2008;9(2):97-102. [Medline].

  21. Davies MG, Marks R, Dykes PJ, Reynolds D. Epidermal abnormalities in Refsum's disease. Br J Dermatol. Oct 1977;97(4):401-6. [Medline].

  22. Dykes PJ, Marks R, Davies MG, Reynolds DJ. Epidermal metabolism in heredopathia atactica polyneuritiformis (Refsum's disease). J Invest Dermatol. Mar 1978;70(3):126-9. [Medline].

  23. Griffiths WAD, Judge MR. Refsum's disease. In: Champion RH, Burton JL, Burns, eds. Rook/Wilkinson/Ebling Textbook of Dermatology. Oxford: Blackwell Science; 1998:1516-17.

  24. Jansen GA, Hogenhout EM, Ferdinandusse S, et al. Human phytanoyl-CoA hydroxylase: resolution of the gene structure and the molecular basis of Refsum's disease. Hum Mol Genet. May 1 2000;9(8):1195-200. [Medline].

  25. Kahlert S, Schonfeld P, Reiser G. The Refsum disease marker phytanic acid, a branched chain fatty acid, affects Ca2+ homeostasis and mitochondria, and reduces cell viability in rat hippocampal astrocytes. Neurobiol Dis. Feb 2005;18(1):110-8. [Medline].

  26. van den Brink DM, van Miert JN, Dacremont G, Rontani JF, Wanders RJ. Characterization of the final step in the conversion of phytol into phytanic acid. J Biol Chem. Jul 22 2005;280(29):26838-44. [Medline].

  27. Weinstein R. Phytanic acid storage disease (Refsum's disease): clinical characteristics, pathophysiology and the role of therapeutic apheresis in its management. J Clin Apher. 1999;14(4):181-4. [Medline].

  28. Wierzbicki AS, Mitchell J, Lambert-Hammill M, et al. Identification of genetic heterogeneity in Refsum's disease. Eur J Hum Genet. Aug 2000;8(8):649-51. [Medline].

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Further Reading

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Keywords

Refsum disease, heredopathia atactica polyneuritiformis, RD, neurocutaneous syndromes, peripheral polyneuropathy, cerebellar ataxia, retinitis pigmentosa, ichthyosis

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Contributor Information and Disclosures

Author

Anna Zalewska, MD, PhD, Assistant Professor, Adjunct Professor, Department of Dermatology and Venereology, 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, UMDNJ-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.

Medical Editor

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 Salary Employment; Orfagen Consulting fee Consulting; Maruho Consulting fee Consulting; Astellas Consulting fee Consulting

Pharmacy Editor

Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center
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.

Managing Editor

Jeffrey P Callen, MD, Professor of Medicine, 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 Honoraria Consulting; Centocor Honoraria Consulting; Genetech Honoraria Consulting; Celgene Honoraria Consulting

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
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