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SURVEY OF OPHTHALMOLOGY VOLUME 55 ! NUMBER 6 ! NOVEMBER–DECEMBER 2010 MAJOR REVIEW Adult Refsum Disease: A Form of Tapetoretinal Dystrophy Accessible to Therapy Klaus Rüether, MD,1 Eleanor Baldwin, BSc, RD,2 Minne Casteels, MD, PhD,3 Michael D. Feher, MD, FRCP,2 Morten Horn, MD,4 Susan Kuranoff, MA,5 Bart P. Leroy, MD, PhD,6 Ronald J. Wanders, PhD,7 and Anthony S. Wierzbicki, DM, Dphil, FRCPath2 1 Charité-Eye Hospital, Campus Virchow-Klinikum, Berlin, Germany; 2Refsums Clinic Chelsea and Westminster Hospital Foundation Trust, London, UK; 3Department of Molecular Cell Biology, Katholieke Universiteit Leuven, Belgium; 4 Department of Neurology, Ulleval University Hospital, Oslo, Norway; 5Refsum Disease Support Network, Basel, Switzerland; 6Department of Ophthalmology and Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium; and 7Genetic Metabolic Diseases Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Abstract. Adult Refsum disease is characterized by an elevated plasma phytanic acid level and high concentrations of phytanic acid in a variety of tissues. Besides tapetoretinal degeneration, additional symptoms are anosmia, skeletal malformations, chronic polyneuropathy, cerebellar ataxia, sensorineural hearing loss, ichthyosis, and cardiac abnormalities. A diet low in phytanic acid ameliorates polyneuropathy and ataxia and slows or even stops the other manifestations. In order to be able to apply dietary therapy, as many patients as possible (even better if all of them are) have to be identified at an early stage. The ophthalmologist plays a crucial role in achieving this goal because of the early manifestation of the tapetoretinal degeneration. (Surv Ophthalmol 55:531--538, 2010. ! 2010 Elsevier Inc. All rights reserved.) Key words. adult Refsum ichthyosis ! phytanic acid degeneration ! disease ! anosmia ! ataxia ! blood plasma polyneuropathy ! sensorineural hearing loss I. Introduction ! filtration ! tapetoretinal hearing loss, a chronic sensorimotor polyneuropathy, ataxia, ichthysosis and, in severe cases, cardiomyopathy34 (Table 1). The disorder was first described in 1946 by Norwegian neurologist Sigvald Refsum (1907-1991).28 British neurologist Brian Gibberd (1931-2006) further characterized the manifestations of the disease and established the routine treatment with a diet low in phytanic acid. This was possible after Klenk and Kahlke in 1963 discovered elevated Adult Refsum disease (ARD, OMIM # 266500), often referred to as Refsum disease, has long been conceived as a complex disorder with involvement of multiple systems, including the retina. The modern view is that adult Refsum disease is first and foremost a retinopathy in which additional symptoms may develop if not treated appropriately. The full clinical picture includes retinitis pigmentosa (RP), hand--feet deformities, anosmia, sensorineural 531 ! 2010 by Elsevier Inc. All rights reserved. 0039-6257/$ - see front matter doi:10.1016/j.survophthal.2010.03.007 532 Surv Ophthalmol 55 (6) November--December 2010 TABLE 1 Ophthalmic and Non-ocular Symptoms in Adult Refsum Disease Ophthalmologic Symptoms Retinitis pigmentosa Miosis Attenutated pupillary light response Attenuated effect of mydriatica Iris atrophy Cataract Other Symptoms Peripheral polyneuropathy Ataxia Anosmia Shortened metacarpals und metatarsals Sensorineural hearing loss Ichthyosis Cardiac arrythmias levels of phytanic acid3,7,11,15 (tetramethylhexadecanoic acid) in blood and other tissues of patients with adult Refsum disease.16 An isolated elevation of phytanic acid is the pathognomonic biochemical abnormality. An increase of plasma phytanic acid levels, along with other biochemical abnormalities, may be seen in disorders that completely lack peroxisomes or exhibit severe loss of their function. These cause a more serious clinical picture than adult Refsum disease (Table 2).36 II. Clinical Features Adult Refsum disease is rare; its exact prevalence is not known. It usually becomes manifest before the age of 20. However, the disease has been diagnosed up to age 50. The diagnosis can be supported by the presence of shortened metacarpal and 4th metatarsal bones early in life,27 found in about 30% of patients (Fig. 1). Most of the patients also suffer from anosmia athough many do not realize it, and this manifestation needs to be elicited with detailed TABLE 2 Additional Disorders Associated with an Elevated Blood Plasma Level of Phytanic Acid 1. Zellweger spectrum disorders, including - Zellweger syndrome - Neonatal adrenoleukodystrophy - Infantile Refsum disease 2. Autosomal recessive rhizomelic chondrodysplasia punctata type 1 (PEX7 deficiency) These diseases constitute disorders in which the biogenesis of peroxisomal enzymes is deficient (1) or essential peroxisomal enzymes are lacking (2). The term ‘‘infantile Refsum Disease’’ is an unfortunate one, since the cause of the disease (defect in peroxisome biogenesis) is entirely different from the adult form of Refsum disease and, like other diseases mentioned here, follows a much more serious course. RÜETHER ET AL questioning and examination.10 Untreated adult Refsum disease carries a poor prognosis.28 Blindness and the complete loss of hearing prior to age 40 cause severe impairment to the patient’s quality of life, and cardiac arrhythmias can be fatal. An early sign of the disease is retinal degeneration, found in all patients at the time of diagnosis. This cannot be distinguished from the isolated form of retinitis pigmentosa (Figs. 2--4). Patients complain of night blindness during childhood or adolescence. Later on, visual field constriction and attenuation of visual acuity emerge. Fundoscopy reveals attenuated retinal vessels and pigment epithelium degeneration; however, adult Refsum disease often lacks the typical spicular intraretinal pigmentation characteristic of RP.21 Claridge et al found that there is an average gap of 11 years between the first visit of a Refsum patient to an ophthalmologist and the diagnosis of ‘‘adult Refsum disease’’ (range 1--28 years).5 III. Biochemistry In the majority of cases the isolated increase in the plasma level of exclusively phytanic acid is caused by the deficient activity of phytanoylCoA-hydroxylase (PHYH ), a peroxisomal protein that catalyzes the first step in the a-oxidation of phytanic acid (Fig. 5).3,12,13 In a few cases levels of phytanic acid are only slightly raised, but in all patients levels of pristanic acid are grossly reduced so a phytanic:pristanic acid ratio may be a more sensitive diagnostic indicator. Phytanic acid is transported in blood plasma, bound to very low density lipoprotein and low density lipoprotein (LDL).33 Plasma lipid level changes account for some of the daily variation in phytanic acid levels. In most patients adult Refsum disease is caused by mutations in the gene coding for phytanoyl-CoA hydroxylase, called PAHX (or PHYH ). Direct metabolization of this branched long chain fatty acid via b-oxidation is impossible because of the methyl group at the third carbon atom. In 1997, the gene for phytanoyl-CoA-hydroxylase was localized on chromosome 10,9,25 but because not all patients demonstrate this gene defect, the disorder has to be considered a genetically heterogeneous disease. In 2003, mutations in a second gene, PEX7 on chromosome 6, was identified as an alternative cause of adult Refsum disease.11,30 PEX7 encodes the Peroxin-7 receptor protein in the peroxisomaltargeting system-2 (PTS-2) pathway. This protein promotes the uptake of several proteins into peroxisomes, thus playing an essential role in the transport of phytanoyl-CoA hydroxylase. The consequence is once again a disruption of the a-oxidation 533 ADULT REFSUM DISEASE Fig. 1. Shortening of proximal phalanxes, metacarpals, and the 4th metatarsal in a Refsum patient. of phytanic acid. PEX7 was already known previously because it is also responsible for another, more severe peroxisomal disease, the autosomal recessive rhizomelic chondrodysplasia punctata type 1. An alternative variable capacity metabolic pathway exists for phytanic acid through u-oxidation to produce urinary 3-methyl-adapic acid as a final excretion product.33 Fig. 2. IV. Pathogenesis Phytanic acid cannot be synthesized in the human body; it is solely derived from exogenous dietary sources as a byproduct of the degradation of chlorophyll. While chlorophyll in vegetables is a potential source of phytanic acid, it cannot be digested by humans.6 In contrast, ruminant animals, with the help of their gastric flora, are able to absorb Fundus of a 16-year-old patient with Refsum disease. A: Central view. B: Peripheral view. 534 Surv Ophthalmol 55 (6) November--December 2010 RÜETHER ET AL Fig. 3. Visual field (Goldmann perimeter III4) of a 16-year-old patient with Refsum disease (same patient as in Fig. 2). Visual acuity is 1.0, bilateral. the chlorophyll-bound phytol and metabolize it to phytanic acid. The main sources of phytanic acid are milk products and meat of ruminant animals, such as beef, lamb, and veal, as well as predatory fish (e.g., cod, tuna).The daily intake with a normal diet is 50--100 mg. The accumulation of phytanic acid in fatcontaining tissues, including nerves, brain, and adipose tissue, is considered to be the main culprit of the symptom complex of adult Refsum disease. Although it is supposed that symptoms arise from the accumulation of phytanic acid in nerve tissues, the total percentage of body phytanic acid in nerves is low. In contrast, although representing only 1--5% of total fatty acids, body fat is the most important storage compartment of phytanic acid because of the large amount of body fat. To date, the pathogenesis of adult Refsum disease has not yet been elucidated in its entirety. High levels of phytanic acid could probably cause changes of the cell membrane with subsequent functional disturbances.37 Another hypothesis is that an increased phytanic acid level could be detrimental to the prenylation of proteins, because there are isoprenoids with a structure similar to phytanic acid.31 There are indications that the accumulation of phytanic acid during gene expression can contribute to the development of adult Refsum disease by influencing nuclear receptors.15 Finally, it has been shown that phytanic acid causes damage to Fig. 4. Electroretinogram (ERG) of a 16-year-old patient with Refsum disease (same patient as in Fig. 2) The left side shows the scotopic ERG with increasing stimulus intensity. On the right side the oscillatory potentials and the photopic recordings are displayed. In all recordings no responses are detectable. 535 ADULT REFSUM DISEASE O A C OH phytanic acid acyl-CoA synthetase ATP, CoA, Mg2+ O C CoA S phytanoyl-CoA phytanoyl-CoA hydroxylase Fe2+, Na-ascorbate, 2-ketoglutarate, ATP, Mg2+, O2 O C CoA S 2-hydroxyphytanoyl-CoA OH HACL1, 2-hydroxyphytanoyl-CoA-lyase TTP, Mg2+ H O C pristanal S O CoA formyl-CoA NAD+ aldehyde dehydrogenase C +H H HCOOH C pristanic acid O CO2 activation – beta-oxidation OMEGA-OXIDATION OF PHYTANIC ACID AS AN ALTERNATIVE THERAPY FOR REFSUM DISEASE B COOH NADPH, O2 CH3 15 NADP, H2O Cytochrome P450 11 7 3 COOH CH2OH 15 11 7 alpha-oxidation 3 Alcohol dehydrogenase Deficient in Refsum disease COOH CHO 15 11 7 3 Aldehyde dehydrogenase COOH COOH 15 11 7 3 Beta-oxidation from the omega-end 3-Methyl adipic acid Fig. 5. A: a-oxidation pathway of 3-methyl-branched fatty acids. B: u-oxidation as alternative metabolic pathway for phytanic acid. 536 Surv Ophthalmol 55 (6) November--December 2010 mitochondria, either by oxidative stress comparable to rotenone29 and/or through its protonophoric action at the mitochondrial membrane.19 The functions of phytanol-CoA-hydroxylase other than the a-oxidation of phytanic acid,14 such as its participation in protein--protein interactions,4 may play a role in the pathogenesis of adult Refsum disease. V. Therapeutic Aspects Adult Refsum disease is among those rare forms of retinal dystrophies for which a treatment is available. The aim of a therapeutic intervention in adult Refsum disease is to lower the body’s content of phytanic acid. The primary question relates to how this goal can be achieved, and for ophthalmologists in particular, what can be gained by doing so. A. DIET A special diet for Refsum patients was first reported in 1966,7 but has subsequently been substantially amended to reduce the number of highly restricted foods. A number of publications detail the specifics,22--24 and the latest version of the diet is available from www.refsumdisease.org. The diet centers on the avoidance of milk products, meat, and fats of ruminant animals, as well as fish. Fat-free dairy products and soy products, such as soy cheeses and fish substitutes, can reduce the perception of dietary restriction. Pork and poultry are acceptable, as are all vegetables. Because food products vary in their content of phytanic acid, both seasonally and regionally, consultation with a professional dietician is mandatory. Repeated skilled dietetic support seems important to help with dietary compliance.1 The aim of these diets is to limit the intake of phytanic acid to less than 10 mg a day, the amount that can be degraded via uoxidation. In a healthy person, the half-time for eliminating the entire body store of phytanic acid is 1 to 2 years. In patients with adult Refsum disease, this period is extended considerably, even though a rudimentary path of metabolism occurs by way of u-oxidation.17,18,35 The effects of the diet on reducing the blood plasma level of phytanic acid has been well documented.2 Despite early publications showing a paradoxical increase in the level of phytanic acid at the beginning of the diet,20 phytanic levels drop quickly. This requires that adequate nutrition is maintained, as reducing caloric intake and acute starvation mobilizes tissue reserves.34 The highest concentration of phytanic acid is found in liver—up to 50% of total fatty acids—and this pool can be RÜETHER ET AL quickly mobilized in response to stress or starvation.31 This also explains why even minimal weight loss can lead to a considerable increase of blood levels of phytanic acid. Thus, it is very important not to reduce caloric intake, especially when beginning a Refsum diet. This also means that other causes of a reduced caloric intake, such as surgery, infections, or other concomitant diseases, may have be counterproductive to efforts aimed at lowering the blood level of phytanic acid and may in some cases aggravate clinical signs. Refsum patients and their treating physicians should be aware of this, and treatment should always be accompanied by a diet that avoids a negative caloric balance. B. BLOOD PLASMA FILTRATION PROCEDURES Very high blood plasma levels of phytanic acid—exceeding 100 mg/dL (3,200 mmol/L)—may be toxic, resulting in life threatening conditions.22 In this situation, it is advisable to apply blood plasma filtration procedures such as plasmapheresis; although, nowadays, more selective procedures are implemented (e.g., LDL-apheresis). Particularly at the beginning of a diet, apheresis can be helpful in reducing blood plasma levels. Nevertheless, an appropriate diet is the major priority, and apheresis alone cannot be considered an alternative to dietary management. If diet results in acceptable blood plasma levels (!10 mg/dL [320 mmol/L])), there is no evidence that additional plasmapheresis has any further positive effect on the course of the disease. Because of the small number of patients, it is difficult to carry out a systematic study to fulfil the required evidence-based criteria, and it is particularly important to document the course of disease in those patients treated with plasmapheresis or similar procedures. C. COURSE OF DISEASE DURING DIET The dietary effects are undisputed. Nearly all Refsum patients registered in Norway prior to the introduction of a disease-specific diet progressed to near blindness. Half died before reaching age 30. By lowering the blood plasma level of phytanic acid, the peripheral neuropathy can be halted and often reversed. Unsteadiness in gait and muscle strength may improve, and sensory deficits may decrease. But although manifestations of adult Refsum disease such as retinal dystrophy, hearing loss, and anosmia appear not to be reversible, their progress can be slowed.31 Starting the diet early increases the probability of maintaining vision until late in life and is a prerequisite for a normal lifespan. Making a diagnosis as early as possible is essential and is an important role for the ophthalmologist.5,9 537 ADULT REFSUM DISEASE D. FUTURE THERAPEUTIC OPTIONS Alternative therapies are being pursued. As has happened in other enzyme-deficiency disorders, enzyme therapy, based on supplementation of the missing enzyme phytanoyl-CoA-hydroxylase, may become a reality. Also, induction of the remaining residual activity of the phytanoyl-CoA hydroxylase by adding an alternative substrate (co-substrate rescue therapy26) may be achievable. Another approach could be the utilization of an alternative metabolic pathway for phytanic acid, by means of u-oxidation, which can be achieved through hydroxylation of phytanic acid.17 The latter is even more promising, as established drugs may increase phytanic acid hydroxylation via the cytochrome P450 4A1 system.32 Any new form of therapy will have to equal or improve upon the effects of diet and the encumbrances diet puts upon the patient. In the near future the existing mouse model for adult Refsum disease will likely play a major role in the development of new therapeutic strategies.8 VI. Conclusion When first diagnosing a tapetoretinal dystrophy, the ophthalmologist should consider adult Refsum disease as part of the differential diagnosis and specifically ask for associated manifestations such as skeletal deformities (examining hands and feet can be useful), an impaired sense of smell, neurological changes, loss of hearing, skin changes, and, in severe polysymptomatic cases, cardiac rhythm disorders. Known RP-patients should be asked whether such symptoms have emerged. In cases of RP, where no X-linked or dominant inheritance pattern is evident and where the above-mentioned symptoms cannot be ruled out entirely, the blood level of phytanic acid should be determined—and preferably also a phytanic:pristanic acid ratio. Gas chromatography/mass spectrometry is a standard test available in many laboratories specializing in the diagnosis of inborn errors of metabolism. Reference labs performing this test can be found through the Directory of Rare Analyses (American Association of Clinical Chemistry; www.aacc.org), the Association of Clinical Biochemistry (UK; www.acb.org.uk), or through the Society for Study of Inborn Errors of Metabolism (www.ssiem.org). Although the efficacy of dietary management varies among individual patients, a diet low in phytanic acid is the therapy of choice for adult Refsum disease. Individualized treatment and close follow-up by a dietician is crucial to success. Supportive apheresis may be used when necessary for symptomatic management in acute flare-ups. Medical care of Refsum patients requires interdisciplinary cooperation, whereby ophthalmologists need to collaborate closely with neurologists, pediatricians, internists, metabolic specialists, and dieticians. Patients should be informed of patient organisations. Information about groups in different countries can be obtained from Retina International (www.retina-international.org). VII. Method of Literature Search This paper is based on the conclusions of the 1st International Refsum Disease Symposium held at the Charité - Hospital, Humboldt University, Berlin, Germany April 1--2, 2005. At that symposium a group of clinicians and basic science researchers interested in adult Refsum disease, as well as patients and relatives, shared available knowledge. Our own experiences, as well as published case reports about missed diagnoses, prompted us to summarize the essential information on adult Refsum disease in an ophthalmologic journal. The aim is to bring adult Refsum aisease to mind and minimize the rate of false or missed diagnoses. The available knowledge about the clinical features, biochemistry, pathogenesis, and therapeutic aspects has been reviewed in the literature using PubMed. As all authors are working on this subject, our own experiences have also been incorporated. References 1. Baldwin E, Harley C, Gibberd FB, et al. Adult Refsums disease—diet modification results in sustained reduction in phytanic acid and absence of acute complications. J Inherit Metab Dis. 2006;29(Suppl 1):39 2. Baldwin E, Gibberd FB, Harley C. et al.The effectiveness of long-term dietary therapy in the treatment of adult Refsum disease. J Neurol Neurosurg Psychiat. 2010;81(9):954--7 3. Casteels M, Croes K, Van Veldhoven PP, et al. Peroxisomal localization of alpha-oxidation in human liver. J Inherit Metab Dis. 1997;20:665--73 4. Chambraud B, Radanyi C, Camonis JH, et al. Immunophilins, Refsum disease, and lupus nephritis: the peroxisomal enzyme phytanoyl-CoA alpha-hydroxylase is a new FKBPassociated protein. Proc Natl Acad Sci USA. 1999;96:2104--9 5. Claridge KG, Gibberd FB, Sidey MC. Refsum disease: the presentation and ophthalmic aspects of Refsum disease in a series of 23 patients. Eye. 1992;6:371--5 6. Coppack SW, Evans R, Gibberd FB, et al. Can patients with Refsum’s disease safely eat green vegetables? Br Med J (Clin Res Ed). 1988;296:828 7. Eldjarn L, Try K, Stokke O, et al. Dietary effects on serumphytanic-acid levels and on clinical manifestations in heredopathia atactica polyneuritiformis. Lancet. 1966;1:691 8. Ferdinandusse S, Zomer AW, Komen JC, et al. Ataxia with loss of Purkinje cells in a mouse model for Refsum disease. Proc Natl Acad Sci USA. 2008;105:17712--7 9. Finsterer J, Regelsberger G, Voigtländer T. Refsum disease due to the splice-site mutation c.135--2AOG before exon 3 of the PHYH gene, diagnosed eight years after detection of retinitis pigmentosa. J Neurol Sci. 2008;266:182--6 10. Gibberd FB, Feher MD, Sidey MC, et al. Smell testing: an additional tool for identification of adult Refsum’s disease. 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Über das Vorkommen der 3,7, 11, 15—Tetramethylhexadecansäure (Phytansäure) in den Cholesterinestern und anderen Lipidfraktionen der Organe bei einem Krankheitsfall unbekannter Genese (Verdacht auf Heredopathia atactica polyneuritiformis, Refsum Syndrom) [About phytanic acid in the cholesterol esters and other lipid fractions of the organs in a suspect of Refsum disease]. Hoppe Seylers Z Physiol Chem. 1963;333:133 17. Komen JC, Duran M, Wanders RJ. Omega-hydroxylation of phytanic acid in rat liver microsomes: implications for Refsum disease. J Lipid Res. 2004;45:1341--6 18. Komen JC, Duran M, Wanders RJ. Characterization of phytanic acid omega-hydroxylation in human liver microsomes. Mol Genet Metab. 2005;85:190--5 19. Komen JC, Distelmaier F, Koopman WJ, et al. Phytanic acid impairs mitochondrial respiration through protonophoric action. Cell Mol Life Sci. 2007;64:3271--81 20. Lenz H, Sluga E, Bernheimer H, et al. [Course of Refsum’s disease under diabetic treatment. 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Clin Sci (Lond). 2001;101:697--705 The authors reported no proprietary or commercial interest in any production mentioned or concept discussed in this article. The authors wish to thank Frank Brunsmann, Rainald von Gizycki, Alfred Hildebrandt (leaders of the project ‘‘Rare retinal degenerations’’, supported by the German Ministry of Health [BMG]) for organizing the 1st International Refsum Disease symposium held at the Charité - Hospital, Humboldt University, Berlin, Germany April 1--2, 2005, and for reviewing the manuscript. Reprint address: Prof. Dr. Med. Klaus Rüther, Charité Augenklinik Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany. e-mail: [email protected]. Outline I. II. III. IV. V. Introduction Clinical features Biochemistry Pathogenesis Therapeutic aspects A. Diet B. Blood plasma filtration procedures C. Course of disease during diet D. Future therapeutic options VI. Conclusion VII. Method of literature search