Download Adult Refsum Disease: A Form of Tapetoretinal Dystrophy

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
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All rights reserved.
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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.
J Neurol Neurosurg Psychiatry. 2004;75:1334--6
538
Surv Ophthalmol 55 (6) November--December 2010
11. Horn MA, van den Brink DM, Wanders RJ, et al. Phenotype
of adult Refsum disease due to a defect in peroxin 7.
Neurology. 2007;68:698--700
12. Jansen GA, Ofman R, Ferdinandusse S, et al. Refsum disease
is caused by mutations in the phytanoyl-CoA hydroxylase
gene. Nat Genet. 1997;17:190--3
13. Jansen GA, Wanders RJ, Watkins PA, et al. Phytanoylcoenzyme A hydroxylase deficiency: the enzyme defect in
Refsum’s disease. N Engl J Med. 1997;337:133--4
14. 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. 2004;23:209--18
15. Kitareewan S, Burka LT, Tomer KB, et al. Phytol metabolites
are circulating dietary factors that activate the nuclear
receptor RXR. Mol Biol Cell. 1996;7:1153--66
16. Klenk E, Kahlke W. 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. Clinical, biochemical and
neuropathological data (author’s transl)]. Nervenarzt. 1979;
50:52--60
21. Leroy BP, Hogg CR, Rath PR, et al. Clinical features and
retinal function in patients with adult Refsum syndrome.
Adv Exp Med Biol. 2003;544:57--8
22. Lundberg A, Lilja LG, Lundberg PO, et al. Heredopathia
atactica polyneuritiformis (Refsum’s disease). Experiences
of dietary treatment and plasmapheresis. Eur Neurol. 1972;
8:309--24
23. Masters-Thomas A, Bailes J, Billimoria JD, et al. Heredopathia atactica polyneuritiformis (Refsum’s disease): 1.
Clinical features and dietary management. J Hum Nutr.
1980;34:245--50
24. Masters-Thomas A, Bailes J, Billimoria JD, et al. Heredopathia atactica polyneuritiformis (Refsum’s disease): 2.
Estimation of phytanic acid in foods. J Hum Nutr. 1980;34:
251--4
RÜETHER ET AL
25. Mihalik SJ, Morrell JC, Kim D, et al. Identification of PAHX,
a Refsum disease gene. Nat Genet. 1997;17:185--9
26. Mukherji M, Chien W, Kershaw NJ, et al. Structure--function
analysis of phytanoyl-CoA 2-hydroxylase mutations causing
Refsum’s disease. Hum Mol Genet. 2001;10:1971--82
27. Plant GR, Hansell DM, Gibberd FB, et al. Skeletal
abnormalities in Refsum’s disease (heredopathia atactica
polyneuritiformis). Br J Radiol. 1990;63. 537--4.
28. Refsum S. Heredopathia atactica polyneuritiformis. Acta
Psychiatr Scand (Suppl). 1946;38:1
29. Schönfeld P, Reiser G. Rotenone-like action of the
branched-chain phytanic acid induces oxidative stress in
mitochondria. J Biol Chem. 2006;281:7136--42
30. 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;72:471--7
31. Wanders RJA, Jakobs C, Skjeldal OH, et al. Refsum disease,
in Scriver CR, Beaudet AL, Sly WS (eds) The Metabolic and
Molecular Bases of Inherited Disease. New York, McGraw
Hill, 2001, pp 3303--21
32. Wanders RJ, Komen JC. Peroxisomes, Refsum’s disease and
the alpha- and omega-oxidation of phytanic acid. Biochem
Soc Trans. 2007;35:865--9
33. Wierzbicki AS, Sankaralingam A, Lumb PJ, et al. Transport
of phytanic acid on lipoproteins in Refsum disease. J Inherit
Metab Dis. 1999;22:29--36
34. Wierzbicki AS, Lloyd MD, Schofield CJ, et al. Refsum’s
disease: a peroxisomal disorder affecting phytanic acid
a--oxidation. J Neurochem. 2002;80:727--35
35. Wierzbicki AS, Mayne PD, Lloyd MD, et al. Metabolism of
phytanic acid and 3-methyl-adipic acid excretion in patients
with adult Refsum disease. J Lipid Res. 2003;44:1481--8
36. Wierzbicki AS. Peroxisomal disorders affecting phytanic acid
alpha-oxidation: a review. Biochem Soc Trans. 2007;35:881--6
37. Young SP, Johnson AW, Muller DP. Effects of phytanic acid
on the vitamin E status, lipid composition and physical
properties of retinal cell membranes: implications for adult
Refsum disease. 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