Q J Med 2001; 94: 403-406
© 2001 Association of Physicians
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Refsum's disease
1 From the Neurology Department, University Hospital Nottingham, Nottingham, 2 Department of Chemical Pathology and Neonatal Screening, The Children's Hospital, Sheffield, and 3 Department of Clinical Neurology, The National Hospital for Neurology and Neurosurgery, London, UK
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Introduction |
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Refsum's disease (hereditary motor and sensory neuropathy type IV) is a rare autosomal recessive condition first characterized by Sigvald Refsum in 1945. He initially chose the name heredoataxia hemeralopica polyneuritiformis,1 subsequently amending this to heredopathia atactica polyneuritiformis.2 Thankfully, the eponymous version now predominates in the literature, and these earlier terms have been largely abandoned.
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Biochemistry |
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Refsum's disease is caused by defective alpha oxidation of phytanic acid (3,7,11,15 tetramethylhexadecanoic acid), a branched-chain fatty acid present in a wide range of foodstuffs including dairy products, some meats and fish.3 The defective enzyme is phytanoyl-coenzyme A hydroxylase, which normally catalyses the second step in the breakdown of phytanic to pristanic acid using the CoA derivative as a substrate (the first step in alpha oxidation is the conversion of phytanic acid to phytanoyl CoA by Phytanoyl CoA ligase).4 This results in accumulation of phytanic acid, with elevated levels in blood and other tissues including fat and neurons (Figure 1
). Phytanic acid can also be catabolized from the non-carboxyl end by omega oxidation, but the capacity of this pathway is severely limited to 
10 mg of phytanic acid per day.5 The average diet contains 50 mg/day, and this factor, in combination with limited excretory mechanisms (via the kidneys and skin), leads to phytanic acid accumulation. The mechanism of phytanic acid toxicity is unclear, but it may be incorporated into tissue lipids and result in impaired myelin function. An alternative hypothesis is that excess levels affect the metabolism of fat-soluble vitamins. Levy has suggested that high phytanic acid levels interfere with vitamin A esterification in the retinal pigment epithelium leading to the production of a toxic substance and progressive visual failure.6 The physiological role of phytanic acid is unknown.
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Clinical features |
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The onset of symptoms is typically in late childhood or adolescence, but may be as late as the fifth decade. The disease usually follows a progressive course, but acute and sub-acute presentations have been described. The cardinal neurological manifestations of the disease include a demyelinating neuropathy, pes cavus, cerebellar ataxia, sensorineural deafness, anosmia and cranial nerve involvement.7 There may be marked nerve hypertrophy. Nyctalopia and visual failure secondary to retinitis pigmentosa often precede the neurological symptoms. Most patients have gross constriction of the visual fields by the time they present.8 Cataracts and photophobia caused by impaired pupillary light responses are also described. Miosis may occur because of high lipid levels in the iris or as a consequence of a generalized dysautonomia. Cardiac involvement (conduction abnormalities and a cardiomyopathy) has resulted in premature death. Aminoaciduria secondary to reversible renal involvement is usually associated with extremely high phytanic acid levels. The skin is also affected, with rough scaly thickening over the extremities.9 Epiphyseal dysplasia results in syndactyly and a characteristic shortening of the fourth toe, which is diagnostically useful (Figure 2
).
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Diagnosis |
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Nerve conduction studies are abnormal, with slowing of conduction velocities. CSF protein levels are usually elevated. The electroretinogram may be grossly abnormal. Nerve biopsies from affected patients have shown ‘onion bulb’ formation, and targetoid inclusions have been described in Schwann cells which have a similar appearance on electron microscopy to those seen in cultured fibroblasts. Plasma levels of phytanic acid measured by gas chromatography-mass spectroscopy are consistently elevated (normal range <19 mmol/l). Phytanic acid levels >800 mmol/l are not uncommon at presentation. Phytanic acid also accumulates to a lesser degree (<118 mmol/l) in the plasma of patients with peroxisomal deficiency disorders such as Zellweger disease, neonatal adrenoleukodystrophy, infantile Refsum's disease and has been reported at 941 mmol/l in rhizomelic chondrodysplasia punctata.10 Pristanic acid is also known to be elevated in peroxisomal deficiency disorders and peroxisomal branched chain oxidation defects, but should be low/normal in Refsum's disease due to lack of production from phytanate. However, we have seen a patient with a Refsum's phenotype where the pristanate to phytanate ratio was 0.005, far exceeding the Refsum's range (<0.0007) and suggesting a biochemical variant of this disorder. In this patient, the characteristic skeletal abnormalities were absent and there was a latency of many years before the development of deafness (either clinically or audiologically).11 Ferdinandusse and co-workers have described a patient with a neuropathy, retinitis pigmentosa and raised pristanate levels secondary to a deficiency of alpha-methylacyl-CoA racemase.12 We are in the process of assaying enzymic activity in our patient. Tranchant and co-workers have also described a family with a Refsum's phenotype who demonstrated accumulation of pipecolic (up to 13.2 mmol/l) as well as phytanic acid.13 Our patient also had raised pipecolic acid levels (13.3 mmol/l, normal range <2.6 mmol/l), although when we measured other Refsum's patients (with normal pristanic acid levels) the range was 3.2–13.2 mmol/l (n=5). This mild elevation may be due to lack of sufficient fasting, a common cause of spuriously elevated pipecolate levels.14 Phytanic acid levels can be moderately elevated in heterozygotes, but clinical concomitants have not been described.15
Friedreich's ataxia, mitochondrial cytopathies, other hereditary motor and sensory neuropathies, abetalipoproteinaemia and vitamin E deficiency can usually be differentiated on clinical grounds or by appropriate investigations.
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Genetics |
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Classical Refsum's disease is one of a group of disorders of the peroxisome, an organelle that is found in most tissues (Table 1
). Peroxisomal disorders are subdivided into two major categories.16 The first category involves disorders of peroxisomal biogenesis or assembly, and collectively these disorders are called peroxisomal biogenesis disorders (PBD). They include infantile Refsum's disease, neonatal adrenoleukodystrophy (ALD), Zellweger syndrome and rhizomelic chondrodysplasia. PBD disorders have been divided into 12 complementation groups of which the genes are known for 11.17 Phytanic acid levels can be raised in PBD disorders, as discussed above. The second category of peroxisomal disorders, which include classical Refsum's disease and X-linked adrenoleukodystrophy, differ in that they have a defect involving a single peroxisomal enzyme, and the peroxisomal structure is intact. The single enzyme deficient in classical Refsum's disease is phytanoyl-CoA hydroxylase. The gene (PAHX) for this enzyme is on chromosome 10, and both point mutations and deletions have been described in PAHX associated with Refsum's disease.18,19 Some patients with the Refsum's disease phenotype and raised phytanic acid levels have also been shown to have elevated pipecolic acid levels, as described above. This condition maps to the same locus on chromosome 10p as PAHX and probably represents an allele-specific variant.20 Further evidence for this comes from a recent report of an 18-year old patient with psychomotor retardation and abnormally short metatarsals and metacarpals and elevated pipecolic acid levels.21 This patient was shown to have a homozygous deletion in the phytanoyl-CoA hydroxylase gene PAHX.
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Infantile Refsum's disease is one of the PBD disorders. Clinically, these patients have mental retardation, pigmentary retinopathy, sensorineural deafness, dysmorphic features, hepatomegaly and may have a peripheral neuropathy. Infantile Refsum's disease, neonatal ALD and Zellweger syndrome are considered to be a disease continuum. Infantile Refsum's disease is the least severe of the three diseases, with neonatal ALD being of intermediate severity and Zellweger syndrome the most severe.
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Treatment |
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Phytanic acid is almost exclusively of exogenous origin, and dietary restriction reduces plasma and tissue levels.5 Fish, beef, lamb and dairy products should be avoided.22 The average daily intake of phytanic acid is 50–100 mg/day, and ideally this should be reduced to 10–20 mg/day. Phytanic acid is also present in vegetables, but is tightly bound (as phytol) to chlorophyll. Ruminants have the capacity to convert phytol to phytanic acid, and the meat of these animals is thus a significant source of phytanic acid. Diets which are very low in phytanic acid (<10 mg/day) are extremely unpalatable, and patient compliance is poor. As a consequence, dietary regimens have become more liberal, and poultry, pork, fruit and vegetables are now freely allowed.23 The diet should contain enough calories to prevent weight loss and subsequent mobilization of phytanic acid from fat.24 In spite of strict adherence to a diet, there may be a time lag before serum levels of phytanic acid start to fall, probably secondary to release from adipose stores. The neurological, cardiac and dermatological sequelae can be reversed by reduction of phytanic acid levels, but the visual and hearing impairments are less responsive to treatment. Rapid weight loss, fever and pregnancy have been associated with acute and sub-acute presentations that mimic Gullain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy. Lowering the plasma phytanic acid level by plasma exchange usually produces a rapid clinical improvement.25 Plasma exchange should also be considered where dietary control is inadequate. Dialysis is ineffective, as plasma phytanic acid is bound to lipoproteins. Dietary treatment should be lifelong.
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Conclusion |
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Although rare, Refsum's disease is partially treatable, and early recognition may prevent visual and auditory deterioration. The diagnosis should be considered in any patient with retinitis pigmentosa and an appropriate family history. The genetic and biochemical mechanisms underlying this fascinating illness continue to be unravelled, and the promise of more targeted treatments in the near future is a realistic possibility.
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Notes |
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Address correspondence to Dr A.J. Wills, Neurology Department, University Hospital Nottingham, Nottingham. e-mail: ade{at}wills99.swinternet.co.uk
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References |
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20.
Nadal N, Rolland MO, Tranchant C, et al. Localization of Refsum disease with increased pipecolic acidaemia to chromosome 10p by homozygosity mapping and carrier testing in a single nuclear family. Hum Mol Genet 1995; 4:1963–6.
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25. Lou JS, Snyder R, Griggs RC. Refsum's disease: long term treatment preserves sensory nerve action potentials and motor function. J Neurol Neurosurg Psychiat 1997; 62:671–2.
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