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Relapse crisis situations resulting in successful coping (i.e., abstinence) and unsuccessful coping (i.e., relapse) were examined in 90 male and 35 female alcohol clients over the first 12 weeks following treatment discharge. More similarities than differences were observed between the genders in the relapse crisis situations encountered, the number and type of coping strategies used, and the drinking outcome results. A similar proportion of males and females successfully abstained in the first 12 weeks posttreatment; a combination of cognitive and behavioral coping was most frequently used by both genders, and negative emotional states constituted the most commonly reported relapse crisis situation. Survival of a relapse crisis was strongly associated with the number of coping strategies used by both men and women. There was a nonsignificant trend for females to relapse more frequently in negative affect situations (i.e., negative emotions, conflict with others) and males in the presence of other drinkers. Further studies employing larger sample sizes are needed to examine gender differences in the process of relapse.

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This study investigates the influence of coping on the outcome of a relapse crisis for a sample of 125 treated alcoholics during the first 12 weeks following treatment completion. Both number and type of coping responses were examined. Results indicated that survival of a relapse crisis was most strongly related to the number of coping strategies used. Termination of a drinking episode was also related to number of coping responses. In addition, the type of coping strategy influenced survival, with the exclusive use of active coping strategies significantly associated with abstinence outcome compared with the exclusive use of avoidant strategies. Combining active and avoidant strategies appeared to be most effective for terminating a drinking episode. Results are discussed in the context of the cognitive-behavioral model of relapse, the general literature on coping behavior and the findings of other relapse studies.

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This article classifies and describes the various entities that comprise the generalized peroxisomal disorder. The variability in both phenotype and genotype is stressed. A heretofore undescribed generalized peroxisomal disorder is reported.

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We describe new pathologic findings in two sibs with Farber lipogranulomatosis. The first child, a 3-month-old boy, presented with only hepatosplenomegaly and had a fulminant clinical course suggestive of malignant histiocytosis. The second child, a 5 1/2-month-old girl, had the typical clinical presentation of Farber disease, with hoarseness and painful swollen joints. At autopsy, storage material was demonstrated in the second child at laryngeal and periarticular subcutaneous sites. Visceral involvement was prominent in both sibs, although not typical of the disease, and included a newly described nephropathy with elevated urine ceramide levels. Liver and spleen contained massive histiocytic infiltrates in association with elevated ceramide levels. Lymph nodes also contained histiocytic infiltrates but without the sinusoidal involvement typical of proliferative histiocytic disorders. These two cases demonstrate new pathologic anomalies in Farber disease, indicating that biochemical analyses of biopsy specimens may be necessary to establish the diagnosis of Farber disease when atypical clinical and morphologic anomalies are present.

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A mild variant of Zellweger (cerebro-hepato-renal) syndrome was diagnosed in male and female siblings aged 7 and 2 years. They had mild facial dysmorphia, moderate psychomotor retardation, tapetoretinal degeneration, sensorineural deafness and hepatomegaly. Ultrastructural examination of a liver biopsy in the younger patient revealed the absence of recognizable peroxisomes. In both patients plasma levels of pipecolic acid, phytanic acid, trihydroxycoprostanoic acid and dihydroxycoprostanoic acid were elevated. The very long chain fatty acid C26:0 and the C26:0/C22:0 fatty acid ratio were elevated in plasma, but less than in classical Zellweger syndrome. In cultured fibroblasts, deficient acyl-CoA:dihydroxyacetone phosphate acyltransferase and increased concentrations of C26:0 as well as C26:1 very long chain fatty acids were found within the ranges previously established for patients with classical Zellweger syndrome. Particle-bound catalase was absent in fibroblasts. Despite the relatively mild clinical expression the biochemical abnormalities found in these patients are the result of a general peroxisomal dysfunction similar to the changes in classical Zellweger syndrome.

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Prenatal diagnosis of the cerebro-hepato-renal (Zellweger) syndrome has been performed in 10 pregnancies at risk by measuring both the activity of acyl CoA: dihydroxyacetone-phosphate acyltransferase (DHAP-AT) and the de novo plasmalogen biosynthesis, either in cultured amniotic fluid cells or in fibroblasts cultured from a chorionic villus biopsy. In 7 of the pregnancies both tests indicated no abnormality. All 7 continued to term and normal infants were delivered. However, in amniotic fluid cells from 2 fetuses affected by Zellweger syndrome unequivocal differences from control values were found. The activity of DHAP-AT was clearly deficient and the de novo plasmalogen biosynthesis was impaired. In one pregnancy at risk prenatal diagnosis was performed during the first trimester by measuring both the DHAP-AT activity and the de novo plasmalogen biosynthesis in fibroblasts cultured from a chorionic villi biopsy. From the deficient DHAP-AT activity and the impaired de novo plasmalogen biosynthesis it was concluded that the fetus was affected. This was confirmed biochemically after induced abortion. It can be concluded that measurement of the DHAP-AT activity and the de novo plasmalogen biosynthesis provides convenient methods for the early prenatal detection of Zellweger syndrome.

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The prenatal diagnosis of the cerebro-hepato-renal syndrome of Zellweger (CHRS) was made by assaying the levels of very long chain fatty acids (VLCFAs) in amniotic fluid cell cultures, obtained by amniocentesis at 16 1/2 weeks of pregnancy. The family-at-risk, because they had previously borne a child with CHRS, accepted these results as indications of an affected fetus, and chose to terminate the pregnancy at 20 1/2 weeks of gestation. The diagnosis was confirmed by the phenotype of the aborted fetus and the presence of markedly elevated levels of VLCFAs in fetal liver homogenates. The prenatal diagnosis of CHRS, which can now readily be determined from amniotic fluid cell cultures, is an important step in genetic counselling of families-at-risk for this disease.

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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.

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An allogeneic bone marrow transplant (BMT) from a normal HLA identical sibling donor was performed in a 13-year-old boy with rapidly progressive adrenoleukodystrophy (ALD). Engraftment and complete hematologic recovery occurred within 4 weeks, but neurologic deterioration continued. The patient died of an adenovirus infection 141 days after BMT. ALD is characterized by abnormally high plasma levels of very long chain fatty acids (VLCFA) as a result of impaired capacity to degrade them. Ten days after BMT, the white blood cell VLCFA levels and enzyme activity became normal; after 3 months, there was progressive reduction of plasma VLCFA to levels only slightly above normal.

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Adrenoleukodystrophy is an inherited, progressive disorder of the CNS white matter and adrenal glands, associated with the pathognomonic accumulation of saturated very long-chain fatty acids, particularly C26:0. It has been previously demonstrated that the fatty acids that accumulate in adrenoleukodystrophy are, at least in part, of dietary origin. This observation, coupled with success of dietary phytanic acid restriction in a related disorder, Refsum's disease, encouraged us to develop a diet that would restrict dietary C26:0 intake. We report here the very long-chain fatty acids content of 135 common foods and development of a diet that restricts C26:0 intake to 3 mg, compared to 12 to 40 mg in the standard American diet. To limit C26:0 intakes it was found necessary to restrict fatty foods and the outer coverings of vegetables and fruits. In contrast to the success of phytanic acid restriction in limiting disease progress in Refsum's patients, administration of the very long-chain fatty acid-restricted diet to seven adrenoleukodystrophy patients for 3- to 24-month periods was found to be ineffective in lowering their plasma very long-chain fatty acids or in improving clinical status. Recently endogenous synthesis of C26:0 has been demonstrated and this may account for the failure of dietary therapy in adrenoleukodystrophy. It is possible that dietary restriction may augment other therapies in the future.

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The deficient oxidation and accumulation of very-long-chain fatty acids in the Zellweger cerebro-hepato-renal 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 [1-14C]palmitic acid to water-soluble acetate was 2- to 3-fold higher in the mitochondrial than in the peroxisomal-rich fraction whereas [1-14C]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.

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The cerebrohepatorenal (Zellweger) syndrome is a fatal autosomal recessive disorder manifested in the neonatal period by profound hypotonia, psychomotor retardation, dysmorphic features, and an enlarged liver. In this study we demonstrate fivefold or greater increases of very-long-chain fatty acid levels, particularly hexacosanoic acid (C26:0) and hexacosenoic acid (C26:1), in plasma and cultured skin fibroblasts from 20 patients. Similar findings in cultured amniocytes from 3 of 14 women in whom the fetus was at risk of the Zellweger syndrome permitted prenatal diagnosis. Oxidation of very-long-chain fatty acids, which normally takes place in the peroxisome, was impaired in homogenates of cultured skin fibroblasts and amniocytes. This observation extends the evidence that the Zellweger syndrome belongs to the newly formulated category of peroxisomal disorders. The pattern of excess very-long-chain fatty acids differs from that demonstrated previously in patients with childhood adrenoleukodystrophy. The study of very-long-chain fatty acids provides a convenient method for the early diagnosis and prenatal detection of the Zellweger syndrome.

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We compared the formation of 14CO2 from [I-14C]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 CO2 production by homogenates of ALD fibroblasts and white blood cells was 17% and 37% of control, respectively, and from C26:0 it was 17% of control in ALD fibroblasts. The CO2 evolution from palmitate (C16:0) 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 C18:0 and C24:0 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 C26:0 levels in ALD cultured skin fibroblasts and white blood cells were 4-6 times that of control; the total C24:0 levels were increased 10-30%, whereas the C22:0 levels were unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

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The concentrations of very long chain fatty acids in plasma and cultured skin fibroblasts were studied in 96 women who were obligate heterozygotes for X-linked adrenoleukodystrophy, in 34 women who were mothers of single probands with ALD, and in 32 normal women of comparable age. Discriminant analysis was used to develop a classification function for the plasma values. With this function, plasma values in 88% of the women who were obligate heterozygotes for ALD and 77% of the mothers of single probands were identified as abnormal. With subsequent inclusion of the fibroblast assay data, abnormal plasma values were found in 93% of the obligate heterozygotes.

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Two pregnancies at risk for Farber's disease were monitored with amiocentesis at 15 and 16 weeks' gestation. In the first pregnancy tested, cultured amniotic-cell ceramidase activity was 7.8% of the control mean and an affected fetus was predicted. The pregnancy was terminated at 22 weeks' gestation and the diagnosis was confirmed by the demonstration of considerably elevated renal and hepatic ceramide concentrations and severe reduction of ceramidase activity in fetal brain and cultured fibroblasts. In the second pregnancy tested, cultured amniotic-cell ceramidase activity was within the control range, and the prediction of an unaffected fetus was confirmed in the newborn.

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Two series of metabolic studies were prompted by the previous finding that the brain and adrenal tissues of patients with adrenoleukodystrophy, an X-linked genetic disorder, contain unusually long-chain (C22--C32) fatty acids in cholesterol esters and gangliosides. Postmortem brain tissues from three patients were assayed for activities of the three distinct cholesterol ester hydrolases, using [4-14C]cholesterol oleate, lignocerate and cerotate as the substrates. No deficiency of the crude mitochrondrial (pH 4.2), the microsomal (pH 6.0), or the myelin-localized cholesterol ester hydrolases was detected, although the activities of the myelin-localized cholesterol ester hydrolase against cholesteryl lignocerate and cerotate were too low for reliable assays. The activities of the microsomal and myelin-localized hydrolases were actually higher in adrenoleukodystrophy than in controls. Uptake and exclusion by cultured fibroblasts of [1-14C]stearic, [1-14C]lignoceric and [1-14C)cerotic acids were also examined. All fatty acids were avidly taken up by the fibroblasts. Stearic acid was excluded from the cells much more rapidly than lignoceric or cerotic acid. No difference was observed in the uptake and exclusion of fatty acids between the controls and adrenoleukodystrophy, except that cells from some cases of adrenoleukodystrophy consistently took up the very long chain fatty acids at greater rates than the control cells. Neither did the distribution of the label among individual lipids reveal differences between the controls and adrenoleukodystrophy, although there were interesting and dramatic differences in the metabolism of lignoceric acid and cerotic acid. Cerotic acid appeared largely inert with 90--95% remaining intact over eight days, while lignoceric acid was mostly incorporated into complex lipids. This series of studies did not uncover the fundamental genetic defect underlying adrenoleukodystrophy.

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