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Refsum disease

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Refsum disease
Other namesAdult Refsum disease, heredopathia atactica polyneuritiformis, phytanic acid oxidase deficiency, and phytanic acid storage disease[1][2][3][4]
Phytanic acid
SpecialtyNeurology Edit this on Wikidata

Refsum disease is an autosomal recessive[5] neurological disease that results in the over-accumulation of phytanic acid in cells and tissues. It is one of several disorders named after Norwegian neurologist Sigvald Bernhard Refsum (1907–1991).[6][7] Refsum disease typically begins to show symptoms during adolescence, although symptoms may first appear anywhere between infancy and old age. Refsum disease is definitively diagnosed by lab tests showing above average serum levels of phytanic acid, or through genetic testing.[8]

Signs and symptoms

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Individuals with Refsum disease present with neurologic damage, cerebellar degeneration, and peripheral neuropathy. Most cases are symmetric (affecting the left and right sides of the body equally) and feature both motor and sensory nerve deficits with similar time of onset and rate of disease progression.[8] Onset is most commonly in childhood or adolescence with a progressive course, although periods of stagnation or remission do occur. Rarely, symptoms may not appear until adulthood.[8] Common symptoms include dry, scaly skin; difficulty hearing; variable (but typically significant) muscle weakness; anosmia, which is the loss of sense of smell; and eye problems, including retinitis pigmentosa, cataracts, and night blindness.[9][8] Cerebellar ataxia is also common but usually presents later in life than other symptoms.[8] In 80 percent of patients diagnosed with Refsum disease, sensorineural hearing loss has been reported. This is hearing loss as the result of damage to the inner ear or the nerve connecting ear to the brain.[10]

Approximately 30% of patients with Refsum disease are known to have congenital malformations of bones. The metatarsal and metacarpal bones are the most commonly affected, often being shorter than normal. In theory, this might be the earliest observable symptom of Refsum disease, but such abnormalities are often nonspecific or too minor to be noticed.[8]

Rarely, patients with Refsum disease may develop a cardiac arrhythmia. There is evidence that the risk of cardiac problems may increase following an infection or catecholamine-related illness, but this is not firmly established.[8]

Cause

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Refsum disease is a peroxisomal disorder caused by the impaired alpha-oxidation of branched chain fatty acids resulting in buildup of phytanic acid and its derivatives in the plasma and tissues. This may be due to deficiencies of phytanoyl-CoA hydroxylase or peroxin-7 activity, encoded by the genes PHYH[11] and PEX7,[12] respectively. In at least 90% of cases, Refsum disease is caused by PHYH mutations.[1][8][13]

PEX7 gene mutations can interrupt the peroxisomal transport of proteins as this gene codes for the peroxin-7 protein receptor. These mutations in the PEX7 gene generally lead to rhizomelic chondrodysplasia punctata type 1, which impairs development of many parts of the body.[14] Refsum disease is inherited in an autosomal recessive pattern, meaning that it requires both copies of the mutation to inherit the disease.[8]

Diagnosis

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Histopathologic examination of the skin from a suspected patient commonly shows hyperkeratosis, hyper-granulosis and acanthosis. The presence of cells in the basal and suprabasal layers of the epidermis containing variably sized vacuoles with accumulated lipids is pathognomonic for the disease.[15]

Classification

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Adult Refsum disease may be divided into the adult Refsum disease 1 and adult Refsum disease 2 subtypes. The former stems from mutations in the phytanoyl-CoA hydroxylase (PAHX aka PHYH) gene, on the PHYH locus on chromosome 10p13.[1] It was initially believed this was the sole mutation; however 55% of cases are now attributed to mutations in other genes.[16]

Refsum disease 2 stems from mutations in the peroxin 7 (PEX7) gene.[1][13] The PEX7 gene is located in the region of chromosome 6q22-24, and mutations were found in patients presenting with accumulation of phytanic acid with no PHYH mutation.[14]

Adult Refsum disease should not be confused with infantile Refsum disease, a peroxisome biogenesis disorder resulting from deficiencies in the catabolism of very long chain fatty acids and branched chain fatty acids (such as phytanic acid) and plasmalogen biosynthesis.[1][13]

Treatment

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Since phytanic acid is not endogenously produced in the human body, individuals with Refsum disease are commonly placed on a phytanic-acid–restricted diet and avoid the consumption of fats from ruminant animals and certain fish, such as tuna, cod, and haddock.[9][17] Grass feeding animals and their milk are also avoided.[16] Recent research has shown that CYP4 isoform enzymes could help reduce the over-accumulation of phytanic acid in vivo.[18] Plasmapheresis is another medical intervention used to treat patients. This involves the filtering of blood to ensure there is no accumulation of phytanic acid.[16]

Biological sources of phytanic acid

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In ruminant animals, the gut fermentation of consumed plant materials liberates phytol, a constituent of chlorophyll, which is then converted to phytanic acid and stored in fats.[19] Although humans cannot derive significant amounts of phytanic acid from the consumption of chlorophyll present in plant materials, it has been proposed that the great apes (chimpanzees, gorillas and orangutans) as well as other captive non-human primates can derive significant amounts of phytanic acid from the hindgut fermentation of plant materials.[20][21]

See also

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References

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  1. ^ a b c d e Online Mendelian Inheritance in Man (OMIM): Refsum Disease, Classic - 266500
  2. ^ Freedberg; et al. (2003). Fitzpatrick's Dermatology in General Medicine (6th ed.). McGraw-Hill. p. 499. ISBN 978-0-07-138076-8.
  3. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology (10th ed.). Saunders. p. 564. ISBN 978-0-7216-2921-6.
  4. ^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 978-1-4160-2999-1.
  5. ^ Jayaram, H.; Downes, S. M. (March 2008). "Midlife diagnosis of Refsum Disease in siblings with Retinitis Pigmentosa – the footprint is the clue: a case report". Journal of Medical Case Reports (Free full text). 2: 80. doi:10.1186/1752-1947-2-80. PMC 2275283. PMID 18336720.
  6. ^ Refsum S (1945). "Heredoataxia hemeralopica polyneuritiformis - et tidligere ikke beskrevet familiært syndrom? En foreløbig meddelelse". Nordisk Medicin (in Norwegian). 28: 2682–6.
  7. ^ Refsum S (1946). "Heredopathia atactica polyneuritiformis. A familial syndrome not hitherto described. A contribution to the clinical study of hereditary diseases of the nervous system". Acta Psych. Neur. (Suppl.38): 1–303.
  8. ^ a b c d e f g h i Kumar, Rahul; Hodis, Brendan; De Jesus, Orlando (2025), "Refsum Disease", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 32809453, retrieved 2025-04-02
  9. ^ a b National Institutes of Health. "Synonym(s): Phytanic Acid Storage Disease, Heredopathia Atactica Polyneuritiformis <Internet>". Archived from the original on 9 July 2007. Retrieved 8 July 2007.
  10. ^ Nogueira, C.; Meehan, T. & O’Donoghue, G. (2014). "Refsum's Disease and Cochlear Implantation". Annals of Otology, Rhinology, and Laryngology. 123 (6): 425–7. doi:10.1177/0003489414526846. PMID 24690989. S2CID 39345035.
  11. ^ "PHYH gene". Medline Plus. Bethesda, Maryland: National Library of Medicine. 1 January 2010. Retrieved 3 April 2023.
  12. ^ "PEX7 gene". Medline Plus. Bethesda, Maryland: National Library of Medicine. 1 July 2010. Retrieved 3 April 2023.
  13. ^ a b c Online Mendelian Inheritance in Man (OMIM): Peroxisome Biogenesis Disorder 3B; PBD3B - 266510
  14. ^ a b Lambert-Hamill, M.; Mitchell, J.; Wierzbicki, A. S.; Haasjes, J.; Brites, P.; Waterham, H. R.; et al. (2003). "Identification of PEX7 as the Second gene involved in Refsum disease". The American Journal of Human Genetics. 72 (2): 471–7. doi:10.1086/346093. PMC 379239. PMID 12522768.
  15. ^ Davies, M. G.; Marks, R.; Dykes, P.J.; Reynolds, D. (1977). "Epidermal abnormali-ties in Refsum's disease". Br J Dermatol. 97 (4): 401–406. doi:10.1111/j.1365-2133.1977.tb14248.x. PMID 73380. S2CID 12698297.
  16. ^ a b c Metoyer, K. "Adult Refsum Disease. In C. Noggle". The Encyclopedia of Neuropsychological Disorders.
  17. ^ Baldwin, R. J.; et al. (2010). "The effectiveness of long-term dietary therapy in the treatment of adult Refsum disease" (PDF). J Neurol Neurosurg Psychiatry. 81 (9): 954–7. doi:10.1136/jnnp.2008.161059. PMID 20547622. S2CID 207002195.
  18. ^ Xu F, Ng VY, Kroetz DL, de Montellano PR (2006). "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. 318 (2): 835–9. doi:10.1124/jpet.106.104976. PMID 16707724. S2CID 23068060.
  19. ^ Verhoeven, N. M.; Wanders, R. J.; Poll-The, B. T.; Saudubray, J. M.; Jakobs, C. (1998). "The metabolism of phytanic acid and pristanic acid in man: a review". Journal of Inherited Metabolic Disease. 21 (7): 697–728. doi:10.1023/A:1005476631419. PMID 9819701. S2CID 10325980.
  20. ^ Watkins, P. A.; Moser, A. B.; Toomer, C. B.; Steinberg, S. J.; Moser, H. W.; Karaman, M. W.; Ramaswamy, K.; Siegmund, K. D.; Lee, D. R.; Ely, J. J.; Ryder, O. A.; Hacia, J. G. (2010). "Identification of differences in human and great ape phytanic acid metabolism that could influence gene expression profiles and physiological functions". BMC Physiology. 10: 19. doi:10.1186/1472-6793-10-19. PMC 2964658. PMID 20932325.
  21. ^ Moser, AB; Hey, J; Dranchak, PK; Karaman, MW; Zhao, J; Cox, LA; Ryder, OA; Hacia, JG (4 February 2013). "Diverse captive non-human primates with phytanic acid-deficient diets rich in plant products have substantial phytanic acid levels in their red blood cells". Lipids in Health and Disease. 12: 10. doi:10.1186/1476-511X-12-10. PMC 3571895. PMID 23379307.
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  • Waterham HR, Wanders RJ, Leroy BP (2021). Adam MP, Ardinger HH, Pagon RA (eds.). "Adult Refsum Disease". GeneReviews® [Internet]. University of Washington. PMID 20301527. NBK1353.


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