The deficient oxidation and accumulation of very-long-chain fatty acids in the Zellweger cerebro-hepatorenal syndrome (CHRS) and X chromosome-linked adrenoleukodystrophy (ALD), coupled with the observation that peroxisomes are lacking in CHRS, prompted us to investigate the subcellular localization of the catabolism of lignoceric acid (C24:0). Peroxisomal and mitochondrial-rich fractions were separated from rat liver crude mitochondria by sucrose density gradient centrifugation. Enzyme activity for the oxidation of l1-4C]palmitic acid to water-soluble acetate was 2-to 3-fold higher in the mitochondrial than in the peroxisomal-rich fraction whereas [1-I4C~lignoceric acid was oxidized at a 2-to 3-fold higher rate in the peroxisomal than in the mitochondrial fraction. Moreover, unlike palmitic acid oxidation, lignoceric acid oxidation was not inhibited by potassium cyanide in either rat liver fractions or human skin cultured fibroblasts, showing that lignoceric acid is mainly and possibly exclusively oxidized in peroxisomes. We also conducted studies to clarify the striking phenotypic differences between CHRS and the childhood form of ALD. In contrast to CHRS, we found normal hepatocellular peroxisomes in the liver biopsy of a childhood ALD patient. In addition, in the presence of potassium cyanide, the oxidation of palmitic acid in cultured skin fibroblasts was inhibited by 62% in control and X chromosome-linked ALD patients compared with 88% in CHRS and neonatal ALD. This differential effect may be related to differences in peroxisomal morphology in those disorders.Peroxisomes are now known to have a variety of physiological functions in addition to their previously recognized role in the formation and reduction of hydrogen peroxide. More than 40 enzymes have now been localized to this organelle (1). These include those playing a major role in the ,B oxidation of fatty acids, particularly long-chain-length fatty acids (2, 3). It has been estimated that 30% of palmitate (2) and 50-67% of erucic acid (C22:1) (3) oxidation takes place in the peroxisomes. Among other peroxisomal enzymes are those involved in certain steps in the biosynthesis of glycerolipids and glycerol/ether lipids (4) and of bile acids (5), D-amino acid oxidases, the enzymes of the glyoxylate cycle, and those concerned with ethanoxanthine and urate (6) metabolism. Recently, 3-hydroxy-3-methylglutaryl-Co A reductase has also been localized in the peroxisome (7). The recognition that peroxisomes have a wide range of physiological functions, coupled with the demonstration that they are absent or diminished in certain disease states, has led to the concept of a newly recognized category of diseases, namely, disorders of the peroxisome (8, 9 The present studies of lignoceric acid (n-tetracosanoic acid, C24:0) metabolism were prompted by our observation that striking elevation of plasma and tissue levels of verylong-chain (>22) fatty acids-particularly hexacosanoic acid-are present in all patients with CHRS (19). These acids are normal constitue...
Hepatocyte transplantation is an investigational alternative to orthotopic liver transplantation to treat liver based inborn errors of metabolism. We report successful hepatocyte transplantation in a 4-year-old girl with infantile Refsum disease. Hepatocytes were isolated from the left liver segment of two male donors using a classic two-step perfusion method. Fresh cells were transplanted first and then cryopreserved cells, for a total of 2 billion cells. Total bile acids and abnormal dihydroxycoprostanoïc acid markedly decreased in the patient's serum, indicating resolution of cholestasis and re-population of liver cells. Pipecholic acid decreased by 40% and c26:c22 fatty acid ratio by 36% after 18 months. Donor chromosomes sequences were detected on biopsy posttransplant, indicating engraftment. Hepatocyte transplantation is a safe and promising technique in the treatment of rare inborn errors of metabolism. Future improvements of cell viability and prevention of apoptosis may increase engraftment and subsequent re-population.
SummaryWe compared the formation of I4CO2 from [I-I4C]fatty acids in homogenates of cultured skin fibroblasts and white blood cells from 25 patients with adrenoleukodystrophy (ALD) and from 24 controls. The ALD group included 16 boys with childhood ALD, five men with adrenomyeloneuropathy (AMN), and two boys and two girls with neonatal ALD. The substrates were unbranched saturated fatty acids ranging in chain length from 16-26 carbons. From C24:0, the radioactive C 0 2 production by homogenates of ALD fibroblasts and white blood cells was 17% and 37% of control, respectively, and from C26:O it was 17% of control in ALD fibroblasts. The C 0 2 evolution from palmitate (C16:O) in the ALD was identical to the control group; for C18:0, the value for ALD cells was 76% of control, and fatty acids with chain lengths between C18:O and C24:O gave intermediate results.Results for childhood ALD patients were similar to those for the AMN patients. More limited studies with cultured amniocytes of fetuses with childhood ALD gave results similar to those obtained with cultured skin fibroblasts, and results with neonatal ALD patients appeared to be the same as for childhood ALD and AMN. Studies of three women who were carriers for childhood ALD gave values intermediate between ALD and control. The total C26:O levels in ALD cultured skin fibroblasts and white blood cells were 4-6 times that of control; the total C24:O levels were increased 10-30%, whereas the C22:O levels were unchanged.The results suggest that ALD patients have a defect in the oxidation of very long chain fatty acids (C24:O and longer) but not for the degradation of fatty acids with a chain length of 18 carbons or less. Such a defect could account for the accumulation of the very long chain fatty acids in a variety of tissues and lipid moieties. The accumulation of these fatty acids, coupled with the metabolic data presented here, suggests that normal catabolism of very long chain fatty acids involves a metabolic pathway which is distinct from that for other fatty acids, and that this pathway is genetically deficient in patients with ALD.Abbreviations ALD, adrenoleukodystrophy AMN, adrenomyeloneuropathy C22:0, docosanoic acid (behenic acid) C24:0, tetracosanoic acid (lignoceric acid) C26:0, hexacosanoic acid (cerotic acid) C27:0, heptacosanoic acid GLC, gas liquid chromatography WBC, white blood cell ALD is a genetically-determined, progressive disorder which affects mainly the adrenal cortex and the white matter of the nervous system (32). It is associated with the accumulation of saturated very long chain fatty acids (mainly C26:0, C25:0, and C24:O) in the cholesterol esters and gangliosides in these tissues (1 1, 17, 30). Accumulation of these same fatty acids has also been reported in sphingomyelin and other lipid moieties of plasma (23) and red blood cells (38) and in cultured skin fibroblasts (22), cultured muscle cells (I), and cultured amniocytes (24).Several types of ALD have been described. The most common type is the childhood form (32) that usually p...
Adrenoleukodystrophy (ALD) is a genetically determined disorder associated with progressive central demyelination and adrenal cortical insufficiency. All affected persons show increased levels of saturated unbranched very-long-chain fatty acids, particularly hexacosanoate (C26:0), because of impaired capacity to degrade these acids. This degradation normally takes place in a subcellular organelle called the peroxisome, and ALD, together with Zellweger's cerebrohepatorenal syndrome, is now considered to belong to the newly formed category of peroxisomal disorders. Biochemical assays permit prenatal diagnosis, as well as identification of most heterozygotes. We have identified 303 patients with ALD in 217 kindreds. These patients show a wide phenotypic variation. Sixty percent of patients had childhood ALD and 17% adrenomyeloneuropathy, both of which are X-linked, with the gene mapped to Xq28. Neonatal ALD, a distinct entity with autosomal recessive inheritance and points of resemblance to Zellweger's syndrome, accounted for 7% of the cases. Although excess C26:0 in the brain of patients with ALD is partially of dietary origin, dietary C26:0 restriction did not produce clear benefit. Bone marrow transplant lowered the plasma C26:0 level but failed to arrest neurological progression.
The characteristic clinical differences between homozygous P426L and compound heterozygous I179S patients establish a distinct genotype-phenotype correlation in late-onset metachromatic leukodystrophy.
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