#266500
ICD+
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| REFSUM DISEASE, ADULT | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| REFSUM DISEASE, CLASSIC PHYTANIC ACID OXIDASE DEFICIENCY HEREDOPATHIA ATACTICA POLYNEURITIFORMIS HEREDITARY MOTOR AND SENSORY NEUROPATHY IV; HSMN4 HMSN IV | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Other entities represented in this entry: | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| REFSUM DISEASE, ADULT, 1, INCLUDED | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| REFSUM DISEASE, ADULT, 2, INCLUDED | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because of evidence that adult Refsum disease can be caused by mutation in the gene encoding phytanoyl-CoA hydroxylase (PHYH, or PAHX; 602026) on chromosome 10 or the gene encoding peroxin-7 (PEX7; 601757) on chromosome 6q. The former is referred to as adult Refsum disease-1 and the latter as adult Refsum disease-2. Infantile Refsum disease (266510) is a distinct disorder with a different phenotype and genetic basis. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Refsum disease is an autosomal recessive inborn error of lipid metabolism classically characterized by a tetrad of clinical abnormalities: retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia, and elevated protein levels in the cerebrospinal fluid (CSF) without an increase in the number of cells. However, not all patients show all these features. All patients have accumulation of an unusual branched-chain fatty acid, phytanic acid, in blood and tissues. Other variable features include cardiac dysfunction, nerve deafness, ichthyosis, and multiple epiphyseal dysplasia (review by Skjeldal et al., 1987). Increased levels of phytanic acid can also be found in peroxisomal disorders, including Zellweger syndrome (214100), infantile Refsum syndrome (266510), and rhizomelic chondrodysplasia punctata (RCDP1; 215100), the latter of which is also caused by mutation in the PEX7 gene (601757) (Skjeldal et al., 1987). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Refsum (1946) first described this disorder and noted the hereditary aspect. Skjeldal et al. (1987) reported the clinical features of 17 patients with Refsum disease. Although onset of symptoms was reportedly insidious, they generally were reported to occur late in the first decade through the third decade of life. All patients had retinitis pigmentosa with night blindness and constriction of the visual fields, and many patients had cataracts. All had some sign of polyneuropathy, most commonly impaired reflexes, and most patients also had sensory disturbances and limb paresis or atrophy. Only 5 patients had clear cerebellar ataxia. Other common features included anosmia and progressive hearing loss. Skin changes, cardiac abnormalities, and skeletal manifestations were less common. Serum phytanic acid was increased in those who had not been treated by diet, and phytanic acid oxidase activity in fibroblasts was very low. Leys et al. (1989) described 2 brothers who presented in their twenties with severe heart failure as the predominant clinical manifestation of Refsum disease. Both of them had retinitis pigmentosa with lack of ERG response, miosis, anosmia, and bilateral shortening of the fourth metatarsals, but no cataracts or deafness. One of them had mild bilateral ptosis. Van den Brink et al. (2003) reported 2 probands with Refsum disease. The first proband originated from a family comprising 8 sibs and was 1 of 3 affected. He became ataxic at age 12 years and on examination at age 19 years had retinitis pigmentosa, with limited ocular fields, absence of night blindness, and normal ERG. Other features included anosmia, short fifth metacarpal and palmar ichthyosis, pes cavus, musculature weakness, and nerve hypertrophy, which was confirmed by sural nerve biopsy. His sister presented at age 20 years with postpartum ataxia and numbness in her fingers and toes. She had profound retinitis pigmentosa, abnormal ERG, anosmia, sensory and motor dysfunction with nerve hypertrophy, and mild pes cavus. The third affected sib, a brother, had mild retinitis pigmentosa and anosmia, but no other signs on screening at age 24 years. The second proband originated from a family comprising 8 sibs with 2 living affected members. Although born with bilateral cataracts, she presented to a neurology clinic at age 20 years with polyneuritis and onset of ataxia at age 19 years. She had bilateral short fifth metacarpals and metatarsals, and mild retinitis pigmentosa. Her brother presented at age 34 years with mild ataxia and mild retinitis pigmentosa but no night blindness, obvious anosmia, or deafness. Neither patient had any episodes of ichthyosis or signs of deafness. One other male sib died of supposed poliomyelitis with symptoms of weakness and ataxia at age 12 years. Horn et al. (2007) reported follow-up of a man with Refsum disease originally diagnosed by Dr. Refsum in 1948 and reported again by Eldjarn et al. (1966). He presented at age 7 years with all of the classic clinical features, including progressive retinopathy with loss of night vision and concentric narrowing of the visual fields. Pupils were small and irregular in shape and showed impaired response to light stimulation. He had neurogenic hearing loss and anosmia. A chronic sensorimotor neuropathy manifest as lower limb atrophy, lack of distal reflexes, and impaired distal sensation. Subcutaneous nerves were thickened and palpable. There was a history of ichthyosis, and he had hammertoe deformity. Long-term dietary restriction of phytanic acid intake stabilized his progressive loss of vision and hearing. However, at age 40, he developed progressive cardiac disease with arrhythmias and heart failure necessitating cardiac transplant at age 58. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Biochemical Features | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Klenk and Kahlke (1963) discovered that patients with hereditary ataxia and polyneuritis of the Refsum type have accumulation of the phytanic acid, an unusual branched-chain fatty acid (3,7,11,15-tetramethyl-hexadecanoic acid), in tissues and body fluids. Further studies showed that the defect in Refsum disease involves lack of proper degradation of phytanic acid, which is exclusively derived from exogenous sources. Exogenous phytol is readily converted to phytanic acid. Steinberg et al. (1967) found that cultured fibroblasts from patients with Refsum disease showed very low oxidation of C14-labeled phytanic acid, but normal oxidation of pristanic acid, which is known to be the first product of phytanic acid degradation. The authors concluded that the defect resides in the enzyme that catalyzes the alpha-oxidative process by which phytanic acid is shortened by one carbon atom. Studies of cultured fibroblasts from patients with Refsum disease also led Herndon et al. (1969) to the conclusion that the enzyme involved in alpha-hydroxylation of phytanate is deficient, whereas enzymes involved in later steps are normal. Steinberg (1982) suggested that the enzyme deficient in this disorder may be a mixed-function oxygenase. Jansen et al. (1997) noted that phytanic acid normally undergoes alpha-oxidation in which the chain is shortened by 1 carbon atom, yielding pristanic acid and carbon dioxide. Pristanic acid can be degraded by beta-oxidation to yield 3 molecules of acetyl-coenzyme A (CoA), 3 of propionyl-CoA, and 1 of isobutyryl-CoA. Patients with Refsum disease have deficient alpha-oxidation of (14)C-phytanic acid to pristanic acid, whereas the subsequent beta-oxidation of pristanic acid is normal. Jansen et al. (1997) reported that phytanoyl-CoA hydroxylase activity was undetectable in liver tissue from a patient with Refsum disease. On the basis of these findings, they stated that Refsum disease can be classified as a true peroxisomal disorder. Mihalik et al. (1997) observed that decreased phytanic-acid oxidation is also observed in human cells lacking PEX7 (601757), the receptor for the type 2 peroxisomal targeting signal (PTS2), suggesting that the enzyme defective in Refsum disease is targeted to peroxisomes by a PTS2. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Management | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Eldjarn et al. (1966) showed that with a diet free of chlorophyll and of foods which might contain phytol, phytanic acid or their precursors, phytanic acid could be reduced in the blood and clinical improvement effected. Plasmapheresis performed once or twice a month effectively removes phytanic acid from the body and permits liberalization of dietary restriction while preventing progression of the clinical features (Gibberd et al., 1979; Moser et al., 1980). Robertson et al. (1988) treated 2 patients with low phytanic acid diet and reported a decrease in plasma phytanic acid levels, a marked decrease in plasma pipecolic acid, and a relatively slow decrease in the C26-C22 fatty acid ratios, which remained markedly abnormal even after 2 years. Clinical data suggested stabilization or perhaps slight improvement. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mapping | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Nadal et al. (1995) localized the Refsum disease gene to chromosome 10p by homozygosity mapping and carrier testing in a single nuclear family. The PHYH gene maps to this region (Mihalik et al., 1997). Genetic Heterogeneity In a linkage study of 8 genetically informative families including 17 living patients with Refsum disease, Wierzbicki et al. (2000) excluded linkage to the region of chromosome 10 containing the PAHX gene in 3 families with 9 affected individuals. The findings indicated genetic heterogeneity. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mutations in the PHYH Gene Mihalik et al. (1997) found that both Refsum disease patients examined were homozygous for inactivating mutations in the PHYH gene (602026.0001 and 602026.0002). Independently, Jansen et al. (1997) identified mutations in the PHYH gene in 5 patients with Refsum disease, including a 1-bp deletion, a 111-bp deletion, and a point mutation (602026.0002-602026.0004). Some of the patients had been reported by Skjeldal et al. (1987). In 22 patients with Refsum disease, Jansen et al. (2000) identified mutations in the PHYH gene, including 14 different missense mutations, a 3-bp insertion, and a 1-bp deletion, which were all confirmed at the genome level (see, e.g., 602026.0005-602026.0009). A 111-bp deletion (602026.0002) identified in the PHYH cDNA of several patients with Refsum disease was due to either 1 of 2 different mutations in the same splice acceptor site, which result in skipping of exon 3. Six mutations were expressed in S. cerevisiae, and all led to an enzymatically inactive PhyH protein. Mutations in the PEX7 Gene In a 58-year-old patient with a phenotype indistinguishable from that of Refsum disease, Braverman et al. (2002) found compound heterozygosity for mutations in the PEX7 gene (601757.0007-601757.0008), the site of mutations causing rhizomelic chondrodysplasia punctata type 1 (215100). Horn et al. (2007) provided follow-up of this patient. In 3 affected sibs with Refsum disease, van den Brink et al. (2003) found compound heterozygosity for 2 mutations in the PEX7 gene: Y40X (601757.0009) and a 7-bp duplication (601757.0010). Another unrelated patient was compound heterozygous for Y40X and a missense mutation (T14P; 601757.0011). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Nomenclature | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| The designation 'infantile Refsum disease' (266510), or infantile phytanic acid storage disease, was used for a congenital disorder with some clinical features resembling Refsum disease and with phytanic acid accumulation. However, since it subsequently proved to be a peroxisome biogenesis disorder, Jansen et al. (2004) suggested that the designation is unfortunate and should be discarded. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| History | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Nyberg-Hansen (1992) provided an obituary of Sigvald Refsum, 1907-1991. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See Also: | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ashenhurst et al. (1958); Billimoria et al. (1982); Clark and Critchley (1951); Djupesland et al. (1983); Herndon et al. (1969); Kahlke and Wagener (1966); Mize et al. (1969); Poulos et al. (1984); Refsum (1981); Refsum (1952); Refsum et al. (1949); Richterich et al. (1965); Steinberg et al. (1967); Steinberg et al. (1970); Steinberg et al. (1967); Watkins et al. (1994) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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