eMedicine Specialties > Dermatology > Pediatric Diseases

Refsum Disease: Differential Diagnoses & Workup

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

Differential Diagnoses

Ichthyosis Fetalis
Ichthyosis Vulgaris, Hereditary and Acquired
Ichthyosis, Lamellar
Ichthyosis, X-Linked
Sjogren-Larsson Syndrome

Other Problems to Be Considered

Chronic and intermittent polyneuritis (eg, alpha-lipoprotein deficiency)
Relapsing infectious polyneuritis
Mitochondrial myopathies
Acute intermittent porphyria
Recurrent exposure to toxins (eg, alcohol, lead)
Various hereditary motor neuropathies
Acquired hyperkeratoses and ichthyosiform dermatoses (when evaluating skin scaling in patients with Refsum disease)
Familial Guillain-Barré syndrome13

Workup

Laboratory Studies

  • In Refsum disease (RD), the phytanic acid level in the blood is increased. The normal range is equal to or less than 0.2 mg/dL; however, phytanic acid levels are 10-50 mg/dL or even higher in patients with Refsum disease.
  • Cerebrospinal fluid (CSF) shows an albuminocytologic dissociation with a protein level of 100-600 mg/dL.
  • Low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels are decreased.
  • Routine laboratory investigations of blood and urine do not reveal any consistent diagnostic abnormalities.

Imaging Studies

  • Skeletal radiography is required to estimate bone changes.
  • MRI findings could reveal symmetrical signal changes involving the corticospinal tracts, cerebellar dentate nuclei, and corpus callosum.14
  • Proton nuclear magnetic resonance (1 H-NMR) spectroscopy of blood plasma or serum lipid extracts can be used to correctly identify and quantify lipids, including unusual lipids in the blood of patients with inborn errors of lipid metabolism, which could be applicable in clinical diagnosis and follow up. 

Other Tests

  • Phytanic oxidase activity estimation in skin fibroblast cultures is important.
  • Electrocardiogram (ECG) is helpful to rule out cardiac conduction defect.
  • UPSIT (University of Pennsylvania Smell Identification Test) reveals anosmia or grossly impaired smell function.15
  • Urine acylcarnitine analysis by nuclear magnetic resonance electrospray ionization-MS/MS seems to be a new tool for the diagnosis of peroxisomal biogenesis disorders.16

Histologic Findings

Skin biopsy shows features of ichthyosis vulgaris, such as moderate hyperkeratosis and acanthosis with thin granular layer. Variably sized vacuoles are visible in basal and suprabasal keratinocytes. The lipid stains performed on cryostat cut sections revealed presence of lipid accumulation in vacuoles. Nerve biopsy examination shows nerve demyelination with marked Schwann cell proliferation and onion bulb formation.

Ultrastructural skin examination reveals many intracellular non–membrane-bound vacuoles in the basal layer and less numerous in keratinocytes of suprabasal epidermis. Transmission electron microscopy does not reveal changes of keratohyalin observed in dominant ichthyosis vulgaris.

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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