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PubMed1967

Refsum's disease: nature of the enzyme defect.

Two siblings with Refsum's disease, an inherited disorder of lipid metabolism, oxidized intravenously injected uniformly labeled phytanic acid-C(14) at rates less than 5 percent of those found in normal subjects. The defect in oxidation of phytanic acid persisted in cultures of fibroblasts from the patients' skin. The rate of oxidation of the phytanic acid-C(14) was less than 1 percent of that found in cultures of fibroblasts from normal skin. However, pristanic acid, previously shown to be the first product of phytanic acid degradation, was oxidized at a normal rate in the patients' cultures. These results indicate that the enzymatic defect in Refsum's disease is in the first step of the pathway for degradation of phytanic acid, that is, in the unusual alpha-oxidative process that leads to a shortening of phytanic acid by one carbon atom.

Carbon Dioxide↗
PubMed1985

Changes in sterol and phospholipid fatty acid composition in Refsum's disease fibroblasts grown in the presence of phytol.

Fibroblasts derived from an individual with Refsum's disease (GM 3896) and a normal control (GM 1717) were grown in the presence of 0, 0.1, 0.2, and 0.3 mM phytol. Cultures were analyzed for total sterol content, and the fatty acid composition of the extractable phospholipids. The fatty acid composition of the phospholipids are similar for control and Refsum's disease fibroblasts when grown on media lacking phytol. However, the addition of phytol to the growth medium produces differences in fatty acid composition between the phospholipids extracted from control and Refsum's disease cells. With regard to sterol composition, data are presented which suggest that an altered sterol is induced in Refsum's disease fibroblasts by the presence of phytol in the growth medium. The possible relationship of these findings to the mechanism of Refsum's disease is discussed.

Cell Line↗
PubMed1986

Partial deficiency of dihydroxyacetone phosphate acyltransferase activity in both classical and infantile Refsum's diseases.

We measured the activity of dihydroxyacetone phosphate acyltransferase (DHAP-AT) in fibroblasts of controls and patients with classical Refsum's disease (RD), infantile Refsum's disease (IRD) and Zellweger's syndrome (ZS). We confirmed that DHAP-AT activity is severely reduced in ZS fibroblasts and amniocytes. We also demonstrated a partial deficiency of DHAP-AT activity in RD and IRD fibroblast cultures. These diseases are probably distinct but related entities in which peroxisomal biogenesis is affected to varying degrees.

Acyltransferases↗
PubMed1986

Infantile Refsum's disease: biochemical findings suggesting multiple peroxisomal dysfunction.

Infantile Refsum's disease was diagnosed in three male patients, presenting with facial dysmorphia, retinitis pigmentosa, neurosensory hearing loss, hepatomegaly, osteopenia and delayed growth and psychomotor development. An elevated plasma phytanic acid concentration and a deficient phytanic acid oxidase activity in fibroblasts were found with an accumulation of very long chain fatty acids in plasma and fibroblasts. There were elevated pipecolic acid levels in plasma, urine and CSF, and abnormal bile acid metabolites in plasma. Deficient activity of acylCoA: dihydroxyacetone phosphate acyl transferase was found in thrombocytes and fibroblasts of these patients as well as an impaired de novo plasmalogen biosynthesis in fibroblasts. These biochemical abnormalities, previously described in the Zellweger syndrome, suggest multiple peroxisomal dysfunction in our patients.

Acyltransferases↗
PubMed1985

Peroxisomes in fibroblasts from skin of Refsum's disease patients.

Skin fibroblasts were cultured from young adult patients with Refsum's disease, an inherited metabolic disorder characterized by a deficiency in oxidation of phytanic acid and by increased serum and tissue concentrations of this fatty acid. These cultures were compared to cultures of normal fibroblasts in terms of the number and distribution of peroxisomes demonstrable cytochemically in preparations incubated for catalase activity. Refsum's fibroblasts were found to contain 1-10 peroxisome profiles per 100 micron 2 of cytoplasm; the controls contained 1-2 profiles per 100 micron 2. The peroxisomes in normal fibroblasts were found in all regions of the cytoplasm. In the Refsum's material they were relatively scarce in the perinuclear region, where many of the cells showed numerous large inclusions containing lipid-like material and myelin figures. Our findings indicate that in the adult form of Refsum's disease, which is the more thoroughly studied variety, peroxisomes in fibroblasts are not diminished in number. This contrasts with a recent report concerning a case of what is thought to be an infantile form of the disorder, in which no peroxisomes were detected in a liver biopsy. If phytanic acid accumulations in the adult form are a consequence of peroxisomal defects, the defects presumably are at the level of specific enzymatic deficiencies and do not involve a generalized absence of peroxisomes.

Adult↗
PubMed1980

Heredopathia atactica polyneuritiformis (Refsum's disease): 1. Clinical features and dietary management.

In a patient with Refsum's disease successful dietary control of the disease has been shown to depend on adequate energy and protein intake from phytanic acid-free sources and restriction of dietary phytanic acid to a maximum of 10 mg per day, with the provision of a generous amount of the essential fatty acid, linoleic acid. The present work gives data on the phytanic-acid content of various foodstuffs and suggests dietary manipulation of the patient. Although the role that chlorophyll-bound phytol plays in Refsum's disease is uncertain, it is advisable that this is eliminated until its role is more clearly identified.

Adipose Tissue↗
PubMed1985

Cerebro-hepato-renal (Zellweger) syndrome, adrenoleukodystrophy, and Refsum's disease: plasma changes and skin fibroblast phytanic acid oxidase.

Cerebro-hepato-renal (Zellweger) syndrome, adrenoleukodystrophy, and Refsum's disease patients can be divided into at least five distinct groups, according to the nature of their plasma changes and their fibroblast phytanic acid oxidase activities. The biochemical changes in the plasma vary from an increase in a single metabolite or group of structurally related metabolites, such as in X-linked adrenoleukodystrophy (ALD) and classical Refsum's disease, to an increase in a number of structurally distinct metabolites, as in neonatal ALD/Zellweger syndrome, and infantile Refsum's disease. All patients, with the exception of those with the X-linked form of adrenoleukodystrophy are deficient in phytanic acid oxidase activity. The great similarity observed in neonatal adrenoleukodystrophy/Zellweger syndrome and infantile Refsum's disease suggests that the basic biochemical lesion in each may be similar or at least closely related.

Adrenoleukodystrophy↗
PubMed1985

Refsum's disease: management by diet and plasmapheresis.

A case of Refsum's disease treated by serial plasma exchanges together with a moderate low phytanate diet is reported. Serial plasma exchanges determined a rapid significant clinical improvement (neuropathy and cerebellar ataxia) that allowed immediate return to full-time employment. The initial improvement could be maintained by intermittent serial plasmapheresis despite partial failure of the initially introduced low phytanate diet bringing 20 mg phytanic acid daily. A new dietary regimen bringing 10 mg phytanic acid was later introduced that was well tolerated. No liquid formula was used. The clinical improvement was clearly correlated to a fall in serum phytanic acid from 45.3 to 16.2 mg/100 ml.

Adult↗
PubMed1969

Refsum's disease: characterization of the enzyme defect in cell culture.

Refsum's disease (heredopathia atactica polyneuritiformis, HAP) is an inherited neurological disorder associated with storage of the branched-chain fatty acid, phytanic acid (3,7,11,15-tetramethylhexadecanoic acid). Cultured fibroblasts derived from skin biopsies of HAP patients did not contain elevated levels of phytanate, yet showed rates of phytanate-C-(14)C oxidation less than 3% of those seen in cells from control subjects. Cells of control subjects converted phytanate to alpha-hydroxyphytanate, to pristanate (the [n-1] homologue of phytanate) and to 4,8,12-trimethyltridecanoate, compounds previously identified as intermediates on the major pathway for phytanate metabolism in animals, providing the first direct evidence that this same oxidative pathway is operative in human cells. None of these breakdown products could be found after incubation of phytanate with HAP cells. Labeled alpha-hydroxyphytanate and labeled pristanate were oxidized at normal rates by HAP cells. Oxidation of the latter proceeded at normal rates both when added to the medium at very low tracer levels and at levels 100 times greater. Phytanate was incorporated into and released from lipid esters at normal rates by HAP cells. Elevated levels of free phytanate in the medium were no more toxic to HAP cells than to control cells over the 48- to 72-hr exposures involved in these studies, as evidenced by morphologic criteria and by ability to oxidize labeled palmitate. These findings are consistent with the hypothesis that the cells from HAP patients are deficient in a single enzyme involved in the alpha-hydroxylation of phytanate, while the enzymes involved in later steps are present at normal or near-normal levels.

Carbon Dioxide↗
PubMedDate not supplied

[2 new cases of Refsum's disease. Course during diet].

The authors report two cases of Refsum's disease treated with a low phytanic acid and low phytol diet for more than 5 years. The clinical, neurological improvement was undoubted in both cases but it was very gradual, appearing after 10 1/2 and 6 months treatment respectively. During these 5 years, no neurological aggravation occurred in the first patient ; but her sister presented in september 1972, 18 months after she started the diet, a mild attack from which she recovered. On the other hand, the sight and hearing disorders remained unchanged in spite of the considerable fall in phytanemia. In spite of the demanding and unagreeable character of the diet, almost constant moderate diarrhoea, the diet was worth following.

Adult↗
PubMed1984

Infantile Refsum's disease (phytanic acid storage disease): a variant of Zellweger's syndrome?

The activity of phytanic acid oxidase is low in infantile and adult Refsum's disease, and in the cerebro-hepato-renal (Zellweger's) syndrome. The plasma of patients with the infantile but not the adult form of Refsum's disease contains increased amounts of pipecolic acid and of at least two abnormal bile acids, one of which has been identified as 3 alpha, 7 alpha, 12 alpha trihydroxy-5 beta-cholestan-26-oic acid. These changes are similar to those reported in the Zellweger syndrome and indicate that there may be similarities in the metabolic defects in Zellweger's syndrome and the infantile form of Refsum's disease.

Abnormalities, Multiple↗
PubMed1967

Studies on the metabolic error in Refsum's disease.

Studies utilizing mevalonic acid-2-(14)C and D(2)O as precursors failed to provide evidence for an appreciable rate of endogenous biosynthesis of phytanic acid in a patient with Refsum's disease. Orally administered tracer doses of phytol-U-(14)C were well absorbed both by seven normal control subjects (61 to 94%) and by two patients with Refsum's disease (74 and 80%). The fraction of the absorbed dose converted to (14)CO(2) in 12 hours was 3.5 and 5.8% in Refsum's disease patients and averaged 20.9% in seven control subjects. Labeled phytanic acid was demonstrated in the plasma of both control subjects and patients given phytol-U-(14)C, establishing phytol in the diet as a potential precursor of phytanic acid. This labeled phytanic acid had disappeared almost completely from the plasma of the seven control subjects by 24 to 48 hours, whereas it persisted at high concentrations in the plasma of the two patients for many days. We conclude that the phytanic acid accumulating in Refsum's disease is primarily of exogenous origin and that patients with Refsum's disease have a relative block in the degradation of phytanic acid and possibly other similar branched-chain compounds. This may relate to a deficiency in mechanisms for release of phytanic acid from stored ester forms or, more probably, to reactions essential to oxidative degradation of the carbon skeleton.

Adult↗
PubMed1985

Identification of 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestan-26-oic acid, an intermediate in cholic acid synthesis, in the plasma of patients with infantile Refsum's disease.

The plasma bile acid profiles of three children with the inherited metabolic disorder, infantile Refsum's disease, were found to contain 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestan-26-oic acid. This intermediate in the synthesis of cholic acid was identified by combined gas-liquid chromatography-mass spectrometry and accounted for approximately 25% of the total bile acids which were present at elevated concentrations in plasma. Infantile Refsum's disease appears to share several biochemical features with the cerebro-hepato-renal syndrome (Zellweger's disease), including abnormal bile acid metabolism.

Bile Acids and Salts↗
PubMed1989

A child with Refsum's disease: successful treatment with diet and plasma exchange.

A child with Refsum's disease presented with cardiac failure, marked muscle wasting, weakness and inco-ordination. Management with multiple plasma exchanges and dietary restriction of phytanic acid intake has reversed the disabling features of the disease, although levels still remain higher than target values. Low phytanic acid intake is being achieved by restriction of total fat to 10 to 12 g/day, while allowing free amounts of fruit and green vegetables.

Child↗