Alternative titles; symbols
SNOMEDCT: 25362006; ICD10CM: G60.1; ICD9CM: 356.3; ORPHA: 773; DO: 10582;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 10p13 | Refsum disease | 266500 | Autosomal recessive | 3 | PHYH | 602026 |
A number sign (#) is used with this entry because of evidence that classic Refsum disease is caused by homozygous or compound hterozygous mutation in the gene encoding phytanoyl-CoA hydroxylase (PHYH, or PAHX; 602026) on chromosome 10p13.
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 biogenesis disorders; see Zellweger syndrome (see 214100) (Skjeldal et al., 1987).
Infantile Refsum disease (see PBD1B, 601539) is a distinct disorder with a different phenotype and genetic basis.
A phenotype clinically indistinguishable from that of classic Refsum disease (PBD9B; 614879), but with a different biochemical profile, can be caused by mutation in the gene encoding peroxin-7 (PEX7; 601757) on chromosome 6q.
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.
The transmission pattern of classic Refsum disease in the family of patients 1 and 2 reported by Jansen et al. (1997) was consistent with autosomal recessive inheritance.
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.
Tranchant et al. (1993) described 4 patients with adult Refsum disease having, in addition to the usual biochemical features, accumulation of L-pipecolic acid, another metabolite (derived from L-lysine) catabolized in peroxisomes. The youngest brother died at age 17 from a rapidly progressing neurologic deterioration, suggesting that the patients may suffer from a peroxisomal disorder intermediate between infantile Refsum disease and adult Refsum disease. Nadal et al. (1995) referred to this disorder as Refsum disease with increased pipecolic acidemia.
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.
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).
Nadal et al. (1995) performed genomewide linkage analysis in the family described by Tranchant et al. (1993) with increased pipecolic acidemia and demonstrated linkage with significant lod score values by the combination of 3 independent sources of information: multiple affected sibs, first-degree consanguinity, and biochemical discrimination between healthy heterozygous carriers and noncarriers. The study illustrated the power of a dense map of microsatellite markers combined with classic linkage analysis and homozygosity mapping. They obtained a lod score of 3.6 between the phenotype and the interval defined by D10S249 and D10S466 on 10p in this single consanguineous family. Since this disorder maps to the same site at the tip of the short arm of chromosome 10 where the gene for phytanoyl-CoA hydroxylase (PHYH) also maps, and since the PHYH gene is the site of mutations in classic Refsum disease, mutations in that gene should be sought in these cases.
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.
The designation 'infantile Refsum disease' (see 601539), 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.
Nyberg-Hansen (1992) provided an obituary of Sigvald Refsum, 1907-1991.
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