Refsum Disease: An Overview

  • Post author:Haseeb N. Akhtar, Ayesha Salejee, Hassan A. Mirza
  • DOIDOI:10.48089/jfo7688261
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Haseeb N. Akhtar,*1, Ayesha Salejee,*1 Hassan A. Mirza1 

*These authors contributed equally.

1University College London, London, UK

Introduction

Refsum disease, originally termed Heredopathia Atactica Polyneuritiformis, is a metabolic disorder characterised by the accumulation of phytanic acid in blood and tissues (1,2). Originally described in 1946, its four hallmark findings were: retinitis pigmentosa (RP), peripheral neuropathy, cerebellar ataxia and elevated protein content in the cerebrospinal fluid (1). Most cases result from variants in the PHYH gene, encoding phytanoyl-CoA hydroxylase, the enzyme responsible for the first step in phytanic acid alpha-oxidation; some cases are also attributed to variants in the PEX7 gene which is involved in transporting this enzyme into peroxisomes (3-5).

Although Refsum disease remains a significant cause of syndromic retinal degeneration, early diagnosis and prompt intervention can minimise both ocular and systemic complications. This is because, unlike other causes of inherited retinal disease, Refsum disease has potential dietary and therapeutic interventions (2).

Epidemiology

Refsum disease is rare and inherited in an autosomal recessive manner (6). Estimates of prevalence are not firmly established, likely due to underdiagnosis or misclassification as non-syndromic RP. Although typically diagnosed in the second or third decade of life, there is considerable variability in age of onset (2). Furthermore, cases have been reported worldwide across a diverse range of ethnicities (2). Because of its rarity, Refsum disease is most often identified either through genetic testing or in highly specialised centres. The index of suspicion should be raised when patients present with a pigmentary retinopathy and associated neurological symptoms.

Pathophysiology

Phytanic acid, a branched-chain fatty acid, enters the body from dietary sources such as dairy products and certain fish (3,6). In healthy individuals, the alpha-oxidation of phytanic acid is a key metabolic step in ensuring there is no pathologic build-up of phytanic acid (3).

In Refsum disease, the aforementioned genetic mutations can lead to phytanic acid accumulation in multiple tissues, e.g. eye, peripheral nerves, brain and the skin leading to a multitude of systemic signs (3,6). The retina, with its high metabolic demands, is vulnerable to even moderately elevated levels of phytanic acid, which can cause progressive degeneration of the photoreceptors (2).

Clinical Features

Clinical presentation is heterogeneous and ranges from mild ocular involvement to severe multisystem disease. Most patients experience:

  • Retinitis pigmentosa (RP): this typically manifests as nyctalopia (night blindness) and peripheral visual field constriction (2). Fundus examination may show bone spicule–like pigmentation and vessel attenuation resembling classic RP.
  • Peripheral neuropathy: patients often report distal numbness, reduced proprioception, and a high-stepping gait due to motor and sensory nerve involvement (2).
  • Cerebellar signs: unsteadiness and ataxia, which reflect cerebellar involvement, may occur in more advanced cases (1,7).
  • Anosmia: a reduced or absent sense of smell is common and may be overlooked by both patients and clinicians (2).
  • Other systemic manifestations: these include cardiac arrhythmias, hearing loss, and cutaneous changes such as dry, thickened skin dubbed ichthyosis (2).

It is worth bearing in mind that whilst ‘’classic’’ Refsum disease may present with a more severe phenotype, attenuated forms do exist. These may be due to residual enzyme activity or hypomorphic variants in the PHYH gene (8).

Diagnosis

Clinicians should suspect Refsum disease in patients with an otherwise unexplained pigmentary retinopathy alongside sensorimotor neuropathy, and anosmia, particularly if there is even mild elevation of phytanic acid (6,9). Below is a helpful list of investigations to consider:

  • Biochemical testing: elevated plasma phytanic acid is the hallmark of the disease. However, levels can vary significantly and may even be normal in some patients with milder alleles, underscoring the importance of targeted testing if clinical suspicion is high (2).
  • Genetic testing: biallelic variants in PHYH account for approximately 80-90% of cases, although some also involve PEX7 (8). Genetic testing helps to provide definitive confirmation, inform family counselling and guide screening for at-risk relatives.
  • Ocular examination: ophthalmological assessment (fundoscopy, optical coherence tomography and fundus autofluorescence imaging) classically demonstrates a rod-cone dystrophy pattern (2); electroretinography can help to ascertain the integrity and function of the photoreceptors (8).
  • Systemic examination: full neurological examination, cardiac monitoring (due to arrhythmia risk) and potential tissue biopsy for phytanic acid storage can be supportive, especially in unequivocal cases (10). A multidisciplinary approach is key in managing both the ocular and systemic manifestations of Refsum disease.

Management

Although there is no definitive cure, effective management strategies focus on controlling phytanic acid accumulation, preventing end-organ damage and optimising vision. Dietary restriction of phytanic acid rich foods (dairy, ruminant fats) is a cornerstone of current therapy (11). Studies have shown that a low phytanic acid diet can stabilise or partially improve clinical findings, including vision and neuropathy (11). In cases with severe symptoms or markedly high levels of phytanic acid, removing phytanic acid from the plasma via plasmapheresis can provide more rapid clinical benefit (2,11). Systemic complications, e.g. life-threatening arrhythmias, neuropathy should be managed with the help of other members of the multidisciplinary team.

It is worth also noting that supportive measures, such as referral to the low vision clinic can help in providing further symptomatic management in Refsum disease (12).

Conclusion

Refsum disease is a rare cause of syndromic RP. Early suspicion, based on combined retinal findings and neurological symptoms enables prompt biochemical and genetic confirmation, facilitating interventions that may prevent irreversible ocular and systemic damage. The potential for disease modulation in Refsum disease means that clinicians should refer for metabolic evaluation in any patient with suspected syndromic RP. Recognising the principal features of Refsum disease remains central to preserving quality of life in this rare but significant phytanic acid storage disorder.

References

  1.  Refsum S. Heredopathia Atactica Polyneuritiformis: A Familial Syndrome not Hitherto Described; A Contribution to the Clinical Study of the Hereditary Diseases of the Nervous System. With 28 Figures. Vol. 38. Oslo: JG Tanum; 1946.
  2.  Claridge KG, Gibberd FB, Sidey MC. Refsum disease: the presentation and ophthalmic aspects of Refsum disease in a series of 23 patients. Eye. 1992; 6(4): 371–375
  3.  Jansen GA, Oftnan R, Ferdinandusse S, et al. Refsum disease is caused by mutations in the phytanoyl–CoA hydroxylase gene. Nat Genet. 1997; 17(2): 190–193.
  4.  Van Den Brink DM, Brites P, Haasjes J, et al. Identification of PEX7 as the second gene involved in Refsum disease. Am J Hum Genet. 2003; 72(2): 471–477.
  5.  Wierzbicki AS. Peroxisomal disorders affecting phytanic acid α-oxidation: a review. Biochem Soc Trans. 2007; 35(5): 881–886.
  6.  Klenk E, Kahlke W. Über das Vorkommen der 3.7. 11.15-Tetramethyl-hexadecansäure (Phytansäure) in den Cholesterinestern und anderen Lipoidfraktionen der Organe bei einem Krankheitsfall unbekannter Genese (Verdacht auf Heredopathia atactica polyneuritiformis [Refsum-Syndrom]). 1963
  7.  Refsum S, Stokke O, Eldjarn L, Fardeau M. Heredopathia atactica polyneuritiformis (Refsum disease). Peripher Neuropathy. 1984; 2: 1680–1703.
  8.  Daich Varela M, Schiff E, Malka S, et al. PHYH c.678+5G>T leads to in-frame exon skipping and is associated with attenuated refsum disease. Invest Ophthalmol Vis Sci. 2024;65(2):38.
  9.  Jansen GA, Wanders RJA, Watkins PA, Mihalik SJ. Phytanoyl–coenzyme a hydroxylase deficiency—the enzyme defect in Refsum’s disease. N Engl J Med. 1997; 337(2): 133–134.
  10.  Kumar R, De Jesus O. Refsum Disease. [Updated 2023 Aug 23]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024, Available from: https://www.ncbi.nlm.nih.gov/books/NBK560618/
  11.  Baldwin EJ, Gibberd FB, Harley C, Sidey MC, Feher MD, Wierzbicki AS. The effectiveness of long-term dietary therapy in the treatment of adult Refsum disease. J Neurol Neurosurg Psychiatry. 2010; 81(9): 954LP–957LP.
  12.  Waterham HR, Wanders RJA, Leroy BP. Adult Refsum Disease. Seattle: University of Washington; 1993, https://europepmc.org/abstract/MED/20301527.

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