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Biomedical subjects

F R Brown

Publications and source records attributed to F R Brown.

At least 37 records · Page 2Linked to original sources
PubMed1989

Reye syndrome: rate of oxidation of fatty acids in leukocytes and serum levels of lipid peroxides.

We examined the oxidation of different chain length fatty acids in the leukocytes and the quantity of lipid peroxides in the plasma of two Reye syndrome patients. We have found that the oxidation of [1-14C] octanoic acid in homogenates of leukocytes from one of the Reye syndrome patients was only 38 percent of the control, whereas oxidation of [1-14C] palmitic and [1-14C] lignoceric acid was slightly increased. The level of lipid peroxides in the serum of both of the Reye Syndrome patients was 4.42 and 3.04 times higher than the control level. These results suggest that impaired oxidation of medium chain fatty acids (octanoic acid) and higher levels of lipid peroxides may contribute to the pathogenesis of cellular toxicity in Reye Syndrome. Reye Syndrome (RS) was first described by Reye et. al. in 1963 and is now recognized as an important cause of morbidity and mortality in infants and children. The clinical course in RS consists of an antecedent viral illness with subsequent encephalopathy and hepatic dysfunction. Laboratory findings in RS include hypoglycemia, hyperammonemia, free fatty acidemia, elevated organic acids and amino aciduria. The ultrastructural findings in RS patients include changes in mitochondria, smooth endoplasmic reticulum morphology, and an increase in the number of peroxisomes. The elevation of serum free fatty acids in RS and their decrease in patients who improve clinically suggests a disturbance in fatty acid metabolism. To understand the role of free fatty acids in the pathogenesis of RS, we examined the levels of lipid peroxides in plasma and catabolism of fatty acids of different chain lengths in leukocytes from RS patients.

Child↗
PubMed1988

Peroxisomal disorders. Biochemical and clinical diagnostic considerations.

The peroxisomal disorders are a group of inherited metabolic diseases with serious clinical sequelae. The number of recognized peroxisomal disorders has increased substantially since 1973, when an absence of peroxisomes was observed in patients with the cerebro-hepato-renal (Zellweger's) syndrome. More subtle peroxisomal dysfunction is now recognized, including that deriving from single peroxisomal enzymes. Peroxisomal disorders are relatively rare. However, these disorders assume importance because of our growing ability to relate clinical sequelae to specific enzymatic and biochemical deficits, because some of these disorders can now be identified prenatally and their recurrence can be prevented, and because therapies are rapidly evolving. We reviewed these disorders in light of increasing understanding of the biochemistry of the peroxisome.

Humans↗
PubMed1988

Effect of salicylic acid on mitochondrial-peroxisomal fatty acid catabolism.

To understand the possible role of salicylic acid in the pathogenesis of Reye's syndrome, we examined its effect on the oxidative metabolism of fatty acids in the rat liver mitochondrial-peroxisomal fraction. Fatty acids of different chain lengths are oxidized in different organelles. Octanoic acid is oxidized in mitochondria, lignoceric acid in peroxisomes, and palmitic acid in both mitochondria and peroxisomes. Salicylic acid (up to 1 mM concentration) had no effect on the oxidation of [1-14C]lignoceric acid. However, at the same concentration it inhibited the oxidation of [1-14C]palmitic acid by 26% and [1-14C] octanoic acid by 42%. The apparent Ki for the oxidation of [1-14C] octanoic acid, [1-14C]palmitic acid and [1-14C]lignoceric acid were 0.27, 6.0, and 14.8 mM, respectively. This selective inhibition of mitochondrial oxidation of medium-chain (octanoic acid) and long-chain (palmitic acid) fatty acids by salicylic acid may potentiate the accumulation of fatty acids in plasma in Reye's syndrome patients.

Animals↗
PubMed1986

Adrenal and testicular function in 14 patients with adrenoleukodystrophy or adrenomyeloneuropathy.

Testicular and adrenal function were evaluated in 12 patients with adrenoleukodystrophy and 2 patients with adrenomyeloneuropathy. Although only 5 subjects had clinical symptoms suggesting adrenal insufficiency, an additional 5 showed laboratory evidence of reduced adrenal reserve. 9 of the 14 patients developed neurological deficits prior to the onset of clinical or biological adrenal insufficiency. In the remaining 5 patients, adrenal insufficiency antedated the appearance of neurological symptoms; 2 of these 5 patients had only laboratory evidence of hypoadrenocorticism, and 3 had both clinical and laboratory abnormalities. None of the prepubertal patients had detectable signs of testicular insufficiency, while 3 of the 7 pubertal/adult patients had elevated serum LH or FSH levels. This mild testicular deficiency was seen only in association with clinical adrenal insufficiency and significant neurological impairment.

17-Hydroxycorticosteroids↗
PubMed1985

Effect of proteolipid protein on central nervous system myelin membrane fluidity.

The effect which intrinsic (proteolipid) protein has on fluidity of central nervous system myelin membrane was measured through differences in temperature-dependent anisotropy of the lipid-soluble fluorescence probe, 1,6-diphenyl-1,3,5-hexatriene (DPH), in multilamellar vesicles (MLV) prepared from total myelin lipids in the presence and absence of proteolipid protein. Very little difference was observed in the anisotropies of DPH incorporated into intact myelin membrane vesicles compared with MLV reconstituted from total myelin lipid plus proteolipid protein but excluding myelin basic protein. In contrast, a significant decrease (P less than 0.01) in anisotropy was observed when MLV prepared from total myelin lipids depleted of proteolipid protein were compared with vesicles containing proteolipid protein. Given the different distributions of myelin basic protein and proteolipid protein suggested by freeze-fracture, neutron and X-ray diffraction studies, and the fact that the hydrophobic DPH probe is known to distribute in the non-polar regions of lipid bilayers, we interpret the marked decrease in anisotropy when proteolipid protein is excluded from MLV to suggest that at least part of the proteolipid is distributed in the hydrocarbon region of the MLV. These findings are consistent with the earlier physical studies and recent postulations that extensive hydrophobic segments exist in proteolipid protein and that these hydrophobic segments are buried in the myelin lipid bilayer and alternate with hydrophilic extra-membrane segments.

Brain↗
PubMed1985

Familial spastic paraparesis: an adrenoleukodystrophy phenotype?

Adrenoleukodystrophy (ALD) must be considered in the diagnosis of men with progressive nervous system disease. We found the biochemical defect characteristic of ALD in two brothers with spastic paraparesis of late adult onset. Family study then revealed other affected men and asymptomatic heterozygotes in a pattern that conformed to an X-linked pattern of inheritance.

Adrenoleukodystrophy↗
PubMed1984

The cerebrohepatorenal (Zellweger) syndrome. Increased levels and impaired degradation of very-long-chain fatty acids and their use in prenatal diagnosis.

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.

Abnormalities, Multiple↗
PubMed1984

The design of a diet restricted in saturated very long-chain fatty acids: therapeutic application in adrenoleukodystrophy.

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.

Adrenoleukodystrophy↗
PubMed1984

Bone marrow transplant in adrenoleukodystrophy.

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.

Adolescent↗
PubMed1983

Striated adrenocortical cells in cerebro-hepato-renal (Zellweger) syndrome.

Adrenal glands from eight patients with the cerebro-hepato-renal syndrome, a disease in which there are no morphologically demonstrable peroxisomes, were studied histologically; one of the eight was also examined ultrastructurally. Seven of the eight demonstrated striated adrenocortical cells in the inner portion of the adrenal cortex. Ultrastructural examination confirmed that the striated cells contained the lammellae and lamellar-lipid profiles of very long chain fatty acids-cholesterol esters that are characteristic of adreno-leukodystrophy. This morphologic observation further emphasizes the common pathogenetic features of the cerebro-hepato-renal (Zellweger) syndrome and adreno-leukodystrophy.

Adrenal Cortex↗
PubMed1983

Ocular histopathologic studies of neonatal and childhood adrenoleukodystrophy.

Histopathologic studies of the eyes of one patient (a boy who died at 14 years of age) with childhood adrenoleukodystrophy and two patients (girls who died at 24 and 31 months of age) with neonatal adrenoleukodystrophy showed the accumulation of the characteristic bileaflet inclusions in optic nerve macrophages, retinal neurons, and macrophages and loss of ganglion cell and nerve fiber layer. Additionally, in the two cases of neonatal adrenoleukodystrophy, changes resembling early retinitis pigmentosa were found, with accumulation of characteristic inclusions in the retinal pigment epithelium and pigment-laden macrophages. One of the patients with neonatal adrenoleukodystrophy also had an anterior subcapsular cataract and cystoid macular edema.

Adrenoleukodystrophy↗
PubMed1983

Ocular histopathologic and biochemical studies of the cerebrohepatorenal syndrome (Zellweger's syndrome) and its relationship to neonatal adrenoleukodystrophy.

The eyes of three infants with cerebrohepatorenal disease (Zellweger's syndrome) who died demonstrated ganglion cell loss, gliosis of the nerve fiber layer and optic nerve, optic atrophy, and changes resembling those of retinitis pigmentosa in the retina and pigment epithelium. Ultrastructural examination showed bileaflet inclusions identical to those seen in neonatal adrenoleukodystrophy in the pigment epithelium and in pigmented macrophages, but these were absent in the cornea. Biochemical analysis of tissues demonstrated an excessive amount of very-long-chain fatty acids in the ocular tissues, an abnormality also found in adrenoleukodystrophy. These histopathologic and biochemical results demonstrated that the cerebrohepatorenal syndrome and neonatal adrenoleukodystrophy are similar in regard to ocular abnormalities and the presence of saturated very-long-chain fatty acids.

Adrenoleukodystrophy↗
PubMed1983

Myelin membrane from adrenoleukodystrophy brain white matter--biochemical properties.

Adrenoleukodystrophy (ALD) is an X-linked progressive neurological disorder characterized by the accumulation of saturated very-long-chain fatty acids (C24 to C30) in lipids, especially cholesterol esters of the brain white matter and adrenal cortex. In the present study we have investigated the localization of accumulated cholesterol esters in brain white matter. During isolation of purified myelin membrane from regions of active demyelination, significant enrichment in cholesterol ester was found in two fractions, mainly in a low-density floating fraction and to a lesser degree in the purified myelin preparation. The fatty acid composition of cholesterol esters from both the ALD floating and myelin fractions was enriched approximately 10-fold in saturated very-long-chain fatty acids (greater than or equal to C24) compared with control preparations.

Adrenoleukodystrophy↗
PubMed1982

Administration of iduronate sulfatase by plasma exchange to patients with the Hunter syndrome: a clinical study.

The Hunter syndrome (MPS II) is the only mucopolysaccharidosis in which there is appreciable activity of the deficient enzyme in normal plasma. We performed enzyme-replacement treatment by plasma exchange in five Hunter syndrome children. Carefully monitoring the cardiovascular status, we administered monthly single plasma volume exchanges for a 3 to 8 mo period. The results indicate a substantial gain of enzyme activity, persisting with a t50% = 19 +/- 5 hr. The maximal level and persistence of increased enzyme activity did not change after repeated exchanges, suggesting that immune responses were not elicited. Despite this, no demonstrable clinical benefit was apparent when the study group was compared with an age-matched control group of Hunter syndrome patients.

Adolescent↗
PubMed1982

Cutis laxa.

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Collagen↗