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At least 19 recordsLinked to original sources
PubMed1992

[Peroxisomal neurologic diseases and Refsum disease: very long chain fatty acids and phytanic acid as diagnostic markers].

Peroxisomal disorders are genetic metabolic diseases with generalized, multiple, or single functional disturbances of the peroxisome. According to the extent of the functional disturbances 3 groups of diseases can be differentiated: disorders with generalized loss of peroxisomal functions (Zellweger syndrome, ZS; neonatal adrenoleukodystrophy, NALD; infantile Refsum's disease), disorders with multiple enzymatic defects (e.g. rhizomelic chondrodysplasia punctata), and disorders with a single enzymatic defect in the peroxisome, the most important being adrenoleukodystrophy/adrenomyeloneuropathy (ALD/AMN). Adult Refsum's disease, a genetic neurological disorder with phytanic acid accumulation, is due to a mitochondrial enzyme deficiency, but is often considered together with peroxisomal diseases because of phytanic acid (PHYT) accumulation in most peroxisomal diseases. The main clinical and pathological criteria of the major disorders and the biochemical parameters of their differentiation are presented. Elevated levels of very long chain fatty acids (VLCFA) and/or PHYT are the primary diagnostic markers for all peroxisomal disorders and adult Refsum's disease, respectively. Our investigations disclosed 30 ALD/AMN hemizygotes, 16 ALD/AMN heterozygotes, 8 cases of ZS/NALD and 7 patients with adult Refsum's disease. In addition, 15 cases of peroxisomal disorders were confirmed by biochemical investigations in autopsy material. With regard to peroxisomal disorders, therapeutic concepts exist only for ALD/AMN: corticosteroid substitution for adrenal insufficiency, dietary treatment, and bone marrow transplantation (BMT). Adult Refsum's disease can be treated successfully by dietary therapy. In case of dietary treatment and BMT, assay of VLCFA and/or PHYT is important for the biochemical evaluation of these therapies.

Adolescent↗
PubMed1977

[Heredopathia atactica polyneuritiformis. Hexadecanoic acid storage disease (Refsum's disease). Definition, treatment and pathogenesis. A short review].

Heredopathia atactica polyneuritiformis is a clinical-genetic-biochemical entity. It is therefore not a syndrome, but a nosological entity, a morbus sui generis and it is caused by a single autosomal gene. The importance of phytanic acid accumulation in this disease was first demonstrated by Klenk and Kahlke. To the author's knowledge no case with all the typical symptoms and signs of heredopathia atactica polyneuritiformis and without any atypical clinical features, has yet been reported without a concomitant disturbance of phytanic acid metabolism. The dietary treatment--(a low phytol, low phytanic acid diet)--was first proposed by Eldjarn, when the preliminary experimental results indicated that the phytanic acid was of exogenous origin. Whatever the biochemical mechanism is between accumulation of phytanic acid and clinical manifestations in heredopathia atactica polyneuritiformis, it appears that the observations made on patients following successful dietary treatment are convincing and leave little doubt that most, if not all, the manifestations in this disease are caused in some way by the accumulation of phytanic acid.

Blood-Brain Barrier↗
PubMed1992

Refsum disease: the presentation and ophthalmic aspects of Refsum disease in a series of 23 patients.

Refsum disease (heredopathia atactica polyneuritiformis) was first described in 1946 and is a rare recessively inherited metabolic disease affecting phytanic acid metabolism. It causes retinitis pigmentosa, cataracts, a chronic polyneuropathy, cerebellar ataxia and cardiac arrhythmias amongst other clinical signs. By limiting dietary intake, plasma phytanic acid levels fall with an improvement in the neurological signs. The onset of retinitis pigmentosa usually precedes biochemical diagnosis by several years by which time the retinal damage is severe. A series of 23 patients have been reviewed. There was an average delay of 11 years (range 1-28 years) between the patient presenting to the ophthalmologist and being diagnosed as having Refsum disease. Although serial examinations have failed to show a definite change in the course of visual deterioration with treatment, early diagnosis is important to prevent the development of neurological disease.

Adult↗
PubMed1992

Plasma lipoproteins and monocyte-macrophages in a peroxisome-deficient system: study of a patient with infantile refsum disease.

Hypocholesterolaemia in infantile Refsum disease (IRD) may link peroxisomes and lipoprotein metabolism. In our patient, plasma cholesterol levels were reduced to 26% and 29% of control in LDL and HDL fractions, respectively. Plasma apolipoproteins B-100 and A-I levels were 52% and 66% of controls, respectively. In the kindred, plasma cholesterol concentration was 61-73% of controls. The HDL-cholesterol/apo A-I ratios were: patient 0.12; kindred 0.17; controls 0.28. Analysis of the IRD patient's lipoprotein revealed compositional abnormalities in all fractions. The patient's LDL demonstrated a substantial reduction in its lipid-to-protein ratio. Alterations in plasma lipoproteins affect their interaction with macrophages. Upon incubation of the patient's LDL with J-774 macrophages, its cellular uptake, measured as cholesterol esterification rate, was only 66% of a control rate. The abnormal LDL of the IRD patient showed also only 25% of control susceptibility to in vitro oxidation. Studies of cellular cholesterol metabolism in the patient's monocyte-derived macrophages (MDM) showed 57% increased cholesterol esterification rate in comparison to normal MDM. The possible link between lipoprotein abnormalities and monocyte-macrophage cholesterol metabolism is discussed.

Animals↗
PubMed1986

Infantile Refsum disease: deficiency of catalase-containing particles (peroxisomes), alkyldihydroxyacetone phosphate synthase and peroxisomal beta-oxidation enzyme proteins.

In recent years a number of biochemical abnormalities have been described in patients with the infantile form of Refsum disease, including the accumulation of very long chain fatty acids, trihydroxycoprostanoic acid and pipecolic acid. In this paper we show that catalase-containing particles (peroxisomes), alkyl dihydroxyacetone phosphate synthase and acyl-CoA oxidase protein are deficient in patients with infantile Refsum disease. These findings suggest that in the infantile form of Refsum disease, as in the cerebro-hepato-renal (Zellweger) syndrome the multiplicity of biochemical abnormalities is due to a deficiency of peroxisomes and hence to a generalized loss of peroxisomal functions. As a consequence the infantile form of Refsum disease can be diagnosed biochemically by methods already available for the prenatal and postnatal diagnosis of the cerebro-hepato-renal (Zellweger) syndrome.

Acatalasia↗
PubMed1987

Infantile Refsum disease: an inherited peroxisomal disorder. Comparison with Zellweger syndrome and neonatal adrenoleukodystrophy.

Three patients affected by infantile Refsum disease are described with mental retardation, minor facial dysmorphia, chorioretinopathy, sensorineural hearing deficit, hepatomegaly, failure to thrive and hypocholesterolaemia. Initially, only an accumulation of phytanic acid was thought to be present. More recent findings showed a biochemical profile very similar to that found in classical Zellweger syndrome or neonatal adrenoleukodystrophy. Morphologically typical peroxisomes were absent in the liver. All three disorders are associated with multiple peroxisomal dysfunction. Because of these similarities pertinent clinical data of our three patients are compared with those of reported patients diagnosed as having infantile Refsum disease, neonatal adrenoleukodystrophy or Zellweger syndrome who survived for several years. Attention is drawn to the difference in severity of clinical features, ranging from infantile Refsum's disease to neonatal adrenoleukodystrophy and, finally, to Zellweger syndrome.

Adrenoleukodystrophy↗
PubMed1992

Effect of phytanic acid on cultured retinal pigment epithelium: an in vitro model for Refsum's disease.

Refsum's disease (heredopathia atactica polyneuritiformis) is an autosomal recessive retinitis pigmentosa syndrome caused by the excessive deposition of phytanic acid in ocular tissues. It is thought that phytanic acid causes retinal degeneration either by interfering with vitamin A metabolism in the retinal pigment epithelium or by altering photoreceptor cell membrane structure. Efforts to elucidate the molecular mechanism of phytanic acid's retinal toxicity have been hampered by the rarity of human pathological specimens and by the inability to reproduce the disease in living animal models. In this study, an in vitro model for Refsum's disease was established by exposing cultured human and bovine retinal pigment epithelial cells to phytanic acid bound to bovine serum albumin at concentrations comparable to levels found in affected humans. Ultrastructural studies show that these cells exhibit morphological changes consistent with those observed in pathological specimens from patients with Refsum's disease. Biochemical assays of retinoid metabolism by cell membranes from control cells and from cells exposed to 200 microM phytanic acid demonstrate that the ability to esterify retinol and to isomerize all-trans retinoids to 11-cis retinoids remains intact despite the deposition of large amounts of phytanic acid. The work described here is strong evidence against the hypothesis that phytanic acid inhibits vitamin A metabolism in the retinal pigment epithelium, and it demonstrates the potential use of cultured retinal pigment epithelial cells in modeling this and other degenerative diseases of the retina.

Animals↗
PubMed1989

A case of Refsum disease with atypical clinical picture in family members.

A typical case of Refsum disease with high phytanic acid plasma levels is described. Two siblings showed some features but not the entire clinical spectrum of the disease. The unusual condition of the patient's father, a presumed heterozygotic carrier with characteristic bone abnormalities and a delayed onset retinopathy, is discussed.

Adult↗
PubMed1992

Infantile refsum disease: gastrointestinal presentation of a peroxisomal disorder.

This article describes two siblings with infantile Refsum disease (IRD) whose initial presentation was that of malabsorption and mimicked a-beta- or homozygous hypo-beta-lipoproteinemia. Failure to recognize IRD in the first-born child precluded proper genetic counseling and prenatal diagnosis in subsequent pregnancies and also caused considerable delay in diagnosing IRD in the second child. The clinical heterogeneity of peroxisomal disorders constitutes a diagnostic challenge, which demands a high degree of awareness from the part of the clinician. This is particularly the case with IRD, where protracted diarrhea with low serum cholesterol levels appears to be a frequently occurring initial feature during the 1st months of life.

Abetalipoproteinemia↗
PubMed1991

Long-term plasma exchange in a case of Refsum's disease.

Refsum's disease (Heredopathia atactica polyneuritiformis) is caused by accumulation of phytanic acid in all body tissues due to an inherited failure of alpha-oxidation of branched chain fatty acids. Plasmapheresis has been reported to be beneficial by removal of phytanic acid from the blood. We describe a patient with Refsum's disease in whom long-term plasmapheresis did not improve clinical, biochemical or electrophysiological parameters.

Adult↗
PubMed1986

Hepatic peroxisomes are deficient in infantile refsum disease: a cytochemical study of 4 cases.

We examined liver biopsies from 4 patients with the infantile form of Refsum disease. No peroxisomes were visualized by light microscopy after cytochemical staining for catalase, a marker enzyme for this organelle. Absence of peroxisomes was confirmed by electron microscopy in 3 patients; in the 4th patient we observed organelles of peculiar size and structure and with minimal catalase activity. Light microscopy also showed birefringent macrophages containing P.A.S.-positive material; they were abundant in the 3 older children, and rare in the youngest (8 months). Peroxisomes and birefringent macrophages were absent in 2 patients with the cerebrohepatorenal syndrome of Zellweger. The simultaneous presence of these unique light microscopical characteristics may be of diagnostic value.

Birefringence↗
PubMedDate not supplied

[Refsum's disease].

Refsum's disease although rare is of great interest for it may benefit at least partially from treatment. Its clinical diagnosis depends on the association of pigmented retinitis, polyneuritis and cerebellar syndrome. It is confirmed beyond doubt by the increased C.S.F. protein and phytanemia. A full family history is necessary for it is possible to detect heterozygous carriers of the defect by enzyme studies on fibroblast cultures.

Adolescent↗
PubMed1979

Skeletal changes in Refsum's disease.

Refsum's disease is a rare inherited disease of lipid metabolism. The cardinal diagnostic features include polyneuritis, cerebellar ataxia, an atypical pigmentosa and a high CSF protein. The disorders is accompanied by the accumulation in the tissues, especially the liver and kidneys, of the lipid 'phytanic acid'. The disease is due to the absence of the enzyme phytanic acid alpha-hydroxylase which catalyses the conversion of phytanic acid to alpha-hydroxy phytanic acid the initial step in its further metabolism. In his original monograph Refsum (1945) documented a number of skeletal abnormalities and the full spectrum of changes that occur has become clear though the accumulating subsequent reports. This paper documents the osseous changes in three members with the disease in a single family. These include epiphyseal dysplasia, especially pronounced in the knees, and shortening and deformity of many of the tubular bones in the hands and feet.

Adult↗
PubMed1986

Biosynthesis and maturation of peroxisomal beta-oxidation enzymes in fibroblasts in relation to the Zellweger syndrome and infantile Refsum disease.

The biosynthesis of the peroxisomal enzymes acyl-CoA oxidase, 3-oxoacyl-CoA thiolase (acetyl-CoA acyl-transferase, EC 2.3.1.16), and catalase (EC 1.11.1.6) was studied in cultured skin fibroblasts from a control subject and from patients with Zellweger syndrome and the infantile form of Refsum disease, inherited disorders in which peroxisomes are deficient and certain peroxisomal functions are impaired. The results of continuous labeling and pulse-chase experiments indicate that in control fibroblasts, as in rat liver, acyl-CoA oxidase is synthesized as a 72-kDa percursor that is converted to two polypeptides of 52 and 20 kDa and 3-oxoacyl-CoA thiolase is synthesized as a 44-kDa precursor that is converted to the 41-kDa mature protein. In fibroblasts from the patients the precursors of the two enzymes are formed but their maturation is impaired, and they are rapidly degraded. In contrast, the biosynthesis of catalase is not impaired. We conclude that functional peroxisomes are required for the maturation and stability of acyl-CoA oxidase and 3-oxoacyl-CoA thiolase but not for catalase.

Abnormalities, Multiple↗
PubMed1992

Autopsy findings in two siblings with infantile Refsum disease.

Recognition of adrenal atrophy during a review of autopsy findings in two sisters who died at 8 months and 3 1/2 years prompted estimation of very long chain fatty acids, phytanic acid and pristanic acid on wet liver fixed in formalin for 12 years. These were shown to be markedly increased and defects in multiple peroxisomal functions and decrease in particulate catalase were shown in cultured fibroblasts, confirming an abnormality of peroxisomal biogenesis. The patients had presented with failure to thrive, recurrent diarrhoea and vomiting, poor mental development, retinal pigmentation, blindness and in the older patient deafness, with only mild dysmorphic features. Autopsy in the older patient showed adrenal atrophy, cirrhosis, and foamy histiocytes in multiple organs. The brain showed no demyelination, little cytoarchitectural abnormality, occasional perivascular histiocytes in the grey matter and meninges and prominent Purkinje cells in the molecular layer of the cerebellum. In the younger patient the changes were very subtle in spite of the marked clinical similarity. Despite the young age at death the clinicopathological features are most suggestive of infantile Refsum disease. In many situations anatomical pathology can be very useful in the recognition and study of peroxisomal disorders.

Adrenal Glands↗