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Biomedical subjects

W B Rizzo

Publications and source records attributed to W B Rizzo.

At least 55 records · Page 3Linked to original sources
PubMed1992

Dietary fatty acids temporarily alter liver very long-chain fatty acid composition in mice.

To determine the influence of dietary fatty acids on tissue very long-chain fatty acid (VLFA) composition, mice were fed four diets containing 15 g fat/100 g diet derived largely from either safflower oil, peanut oil, olive oil or glycerol trioleate oil. The diets varied widely in the composition of VLFA and other fatty acids. Digestibility of total dietary VLFA ranged from 84.6% in mice fed the glycerol trioleate diet to 96.7% in those fed the safflower oil diet. After 3 mo, the saturated VLFA composition of liver total lipids and sphingomyelin was lower in animals fed the glycerol trioleate oil diet than in mice fed most other diets. Although the saturated VLFA content of the peanut oil diet was more than 15-fold greater than that of the other diets, animals fed the peanut oil diet showed little or no selective increase in liver saturated VLFA. The VLFA composition of brain was comparable in all dietary groups. After 8 mo of feeding, the liver saturated VLFA composition tended to increase and differences between groups disappeared. Liver peroxisomal beta-oxidation of lignocerate (24:0) was similar among all dietary groups. These results demonstrate that dietary fatty acids shorter than VLFA temporarily influence the saturated VLFA composition of liver.

Animals↗
PubMed1992

Peroxisomal abnormality in fibroblasts from involved skin of CHILD syndrome. Case study and review of peroxisomal disorders in relation to skin disease.

BACKGROUND AND DESIGN: Peroxisomal deficiency has been described in a number of syndromes characterized by chondrodysplasia punctata, including the Conradi-Hünermann (C-H) syndrome. Because of overlapping clinical features of X-chromosome inheritance, ichthyosis, and limb-reduction defects in C-H and CHILD (congenital hemidysplasia with ichthyosiform erythroderma and limb defects) syndromes, we examined peroxisomal content using diaminobenzidine cytochemistry and peroxisomal functions in fibroblasts from involved vs uninvolved skin of CHILD syndrome. RESULTS: Fibroblasts from involved skin of a patient with CHILD syndrome accumulated cytoplasmic lipid, visualized with the fluorescent probe, nile-red. Ultrastructurally, fibroblasts of involved skin of CHILD syndrome accumulated lamellated membrane and vacuolar structures. By diaminobenzidine ultracytochemistry, fewer peroxisomes were present. Moreover, the activities of two peroxisomal enzymes, catalase and dihydroxyacetone phosphate acyltransferase, were decreased (approximately 30% of normal). However, peroxisomal oxidation of very-long-chain and branched-chain fatty acids was preserved. Moreover, plasma very-long-chain fatty acids, plasma phytanic acid, and erythrocyte plasmalogen content were normal. CONCLUSIONS: The CHILD, C-H, and rhizomelic chondrodysplasia punctata syndromes are all characterized by ichthyosis, chondrodysplasia punctata, and limb defects, as well as peroxisomal deficiency. Thus, these syndromes may be related pathogenically. Because peroxisomes are involved in prostaglandin metabolism, peroxisomal deficiency may directly contribute to the previously reported alterations in prostaglandin metabolism in fibroblasts of involved skin of fibroblasts.

Acyltransferases↗
PubMed1991

Attitudes toward presymptomatic testing and prenatal diagnosis for adrenoleukodystrophy among affected families.

One hundred and thirty-six individuals with a family history of X-linked adrenoleukodystrophy (ALD) or adrenomyeloneuropathy (AMN) were given a questionnaire surveying their sociodemographic characteristics, knowledge of X-linked inheritance, and attitudes toward prenatal, presymptomatic, and carrier testing. Of the respondents, 68% indicated that they would use prenatal testing. Of these, 57.1% would terminate a pregnancy of a male fetus hemizygous for the ALD gene and 13.5% would reportedly choose to terminate a heterozygote female fetus. Presymptomatic testing would be used by 88.7% of respondents to test at-risk sons and carrier testing would reportedly be used by 95.4% of respondents to test their at-risk daughters. Respondents correctly answered an average of 61% of the questions testing understanding of X-linked inheritance. This indicates a strong interest in prenatal, presymptomatic, and carrier testing and a need for genetic counselors to provide information about these available tests and X-linked inheritance.

Adrenoleukodystrophy↗
PubMed1991

Dyggve-Melchior-Clausen syndrome with increased pipecolic acid in plasma and urine.

A child with the Dyggve-Melchior-Clausen syndrome associated with elevated pipecolic acid levels in plasma and urine is described. Other studies of peroxisomal function, including phytanic acid, very long-chain fatty acids, and plasmalogen synthesis, were normal. This disorder may represent an incompletely characterized defect in peroxisomal metabolism.

Bone Diseases, Developmental↗
PubMed1991

Clinical variation in X-linked adrenoleukodystrophy: fatty acid and lipid metabolism in cultured fibroblasts.

To determine whether the clinical phenotype of ALD correlates with the extent of metabolic abnormality, we investigated VLFA metabolism in cultured fibroblasts from patients with the clinically severe childhood from of ALD and the milder AMN variant. No differences were seen in the content of neutral lipids or phospholipids, in incorporation of [1-14C]lignocerate into cellular lipids, or in the fatty acid composition of fibroblasts from patients with childhood ALD or AMN. [1-14C]Lignocerate oxidation was deficient to a similar extent (35-40% of normal) in both intact fibroblasts and cell homogenates from patients with childhood ALD and AMN. With the use of fibroblast homogenates, oxidation of lignocerate was partially inhibited by various long-chain fatty acids, and residual activity in ALD homogenates was more susceptible to inhibition by palmitate than normal. In the presence of competing palmitate, residual lignocerate oxidative activity in fibroblast homogenates was reduced to 20 +/- 4% of normal in childhood ALD and 24 +/- 2% of normal in AMN. These results indicate that residual VLFA oxidative activity, fatty acid composition, VLFA metabolism, and lipid content of cultured fibroblasts do not correlate with the clinical expression of the ALD gene.

Adrenoleukodystrophy↗
PubMed1991

Sjögren-Larsson syndrome: case reports.

Sjögren-Larsson syndrome (SLS) is a rare, autosomal recessive disorder with worldwide distribution. It consists of ichthyosis, spastic diplegia, and mental retardation. An enzymatic defect in fatty alcohol oxidation recently was identified and is thought to be responsible for the disorder. We report two siblings with SLS. In addition to the typical features of the syndrome, the sister had marked hyperkeratosis of the palms and soles, which is rarely seen to this degree. The brother had joint hyperextensibility, which has not been reported previously. Both individuals had documented deficient activity of fatty alcohol:NAD+ oxidoreductase.

Adult↗
PubMed1991

Sjögren-Larsson syndrome. Deficient activity of the fatty aldehyde dehydrogenase component of fatty alcohol:NAD+ oxidoreductase in cultured fibroblasts.

Sjögren-Larsson syndrome (SLS) is an inherited disorder associated with impaired fatty alcohol oxidation due to deficient activity of fatty alcohol:NAD+ oxidoreductase (FAO). FAO is a complex enzyme which consists of two separate proteins that sequentially catalyze the oxidation of fatty alcohol to fatty aldehyde and fatty acid. To determine which enzymatic component of FAO was deficient in SLS, we assayed fatty aldehyde dehydrogenase (FALDH) and fatty alcohol dehydrogenase in cultured fibroblasts from seven unrelated SLS patients. All SLS cells were selectively deficient in the FALDH component of FAO, and had normal activity of fatty alcohol dehydrogenase. The extent of FALDH deficiency in SLS cells depended on the aliphatic aldehyde used as substrate, ranging from 62% of mean normal activity using propionaldehyde as substrate to 8% of mean normal activity with octadecanal. FALDH activity in obligate SLS heterozygotes was partially decreased to 49 +/- 7% of mean normal activity using octadecanal as substrate. Differential centrifugation studies in fibroblasts indicated that this FALDH enzyme was largely particulate; soluble FALDH activity was normal in SLS cells. Intact SLS fibroblasts oxidized octadecanol to fatty acid at less than 10% of the normal rate, but oxidized free octadecanal normally, suggesting that the FALDH affected in SLS is chiefly involved in the oxidation of fatty alcohol to fatty acid. These results show that the primary enzymatic defect in SLS is the FALDH component of the FAO complex, which leads to deficient oxidation of fatty aldehyde derived from fatty alcohol.

Alcohol Oxidoreductases↗
PubMed1990

Ichthyosis, mental retardation, and asymptomatic spasticity. A new neurocutaneous syndrome with normal fatty alcohol:NAD+ oxidoreductase activity.

A number of inherited disorders of cornification have been related to abnormal lipid metabolism. In the recessively inherited Sjögren-Larsson syndrome, defined by the triad of ichthyosis, mental retardation, and spasticity, fatty alcohol:NAD+ oxidoreductase deficiency has recently been reported. These patients accumulate fatty alcohol in the plasma and cultured fibroblasts. A 19-year-old woman with ichthyosis, mental retardation, and mild spasticity is described in whom fatty alcohol metabolism was normal, as determined by plasma octadecanol level and fibroblast fatty alcohol:NAD+ oxidoreductase activity. Ultrastructural studies on skin from the patient revealed morphologically abnormal epidermal lamellar bodies, not unlike those seen in neutral lipid storage disease with ichthyosis. We postulate that this patient has a novel neurocutaneous syndrome that may be secondary to abnormal lipid metabolism.

Adolescent↗
PubMed1990

Isolation and characterization of a Chinese hamster ovary cell line deficient in fatty alcohol:NAD+ oxidoreductase activity.

We have isolated a mutant Chinese hamster ovary cell line that is defective in long-chain fatty alcohol oxidation. The ability of the mutant cells to convert labeled hexadecanol to the corresponding fatty acid in vivo was reduced to 5% of the parent strain. Whole-cell homogenates from the mutant strain, FAA.1, were deficient in long-chain fatty alcohol:NAD+ oxidoreductase (FAO; EC 1.1.1.192) activity, which catalyzes the oxidation of hexadecanol to hexadecanoic acid, although the intermediate fatty aldehyde was formed normally. A direct measurement of fatty aldehyde dehydrogenase showed that the FAA.1 strain was defective in this component of FAO activity. FAA.1 is a two-stage mutant that was selected from a previously described parent strain, ZR-82, which is defective in ether lipid biosynthesis and peroxisome assembly. Because of combined defects in ether lipid biosynthesis and fatty alcohol oxidation, the ability of the FAA.1 cells to incorporate hexadecanol into complex lipids was greatly impaired, resulting in a 60-fold increase in cellular fatty alcohol levels. As the FAO deficiency in FAA.1 cells appears to be identical to the defect associated with the human genetic disorder Sjögren-Larsson syndrome, the FAA.1 cell line may be useful in studying this disease.

Alcohol Oxidoreductases↗
PubMed1990

Fatty acid alterations and carboxylase deficiencies in the skin of biotin-deficient rats.

Full-thickness biopsies of haired and alopecic skin of biotin-deficient rats had less subcutaneous fat and showed lipophilic follicular plugging, vascular engorgement, epidermal hyperplasia, and abnormal keratinization. Mean activities of the three mitochondrial biotin-dependent carboxylases in the skin of biotin-deficient animals were reduced to 3-18% of control whereas the cytosolic enzyme, acetyl-CoA carboxylase, was reduced only to 38-61%. The total fatty acid content of haired and alopecic skin of deficient rats was 30% of those in the corresponding skin sites of control animals. Skin from deficient rats contained less of several long-chain fatty acids (16:0, 16:1, 18:0, 18:1, and 18:2) and more very-long-chain fatty acid, particularly 24:1 and 26:1. These alterations in fatty acids in biotin-deficient rats suggest that the skin findings in biotin and biotinidase deficiencies in humans may be due to similar fatty acid changes.

Animals↗
PubMed1990

MR imaging appearance of childhood adrenoleukodystrophy with auditory, visual, and motor pathway involvement.

Childhood adrenoleukodystrophy is an X chromosome-linked disorder characterized by progressive demyelination of cerebral white matter and adrenal insufficiency. Magnetic resonance (MR) imaging was performed in 15 patients with symptomatic disease and three with presymptomatic disease. MR imaging findings were abnormal only in symptomatic patients. Major sites of disease were the occipital, parietal, and temporal lobes, with all patients showing involvement of occipital lobes, optic radiations, and splenium of the corpus callosum. Follow-up images obtained in four patients demonstrated a posterior-to-anterior progression of disease. Correlation of results from MR imaging with those from evoked potential studies indicated that MR imaging was the method of choice for detecting demyelination of visual, auditory, and motor systems in adrenoleukodystrophy.

Adrenoleukodystrophy↗
PubMed1989

Sjögren-Larsson syndrome: inherited defect in the fatty alcohol cycle.

We investigated fatty alcohol metabolism in eight patients with Sjögren-Larsson syndrome, and in nine obligate heterozygotes. Fatty alcohol: nicotinamide-adenine dinucleotide oxidoreductase (FAO) activity was deficient in cultured skin fibroblasts (mean 18% of normal, n = 8) and peripheral blood leukocytes (mean 22% of normal, n = 3) from patients with Sjögren-Larsson syndrome. The palmitoyl coenzyme A-inhibitable component of FAO activity was decreased to 10% and 15% of normal in fibroblasts and leukocytes, respectively, of patients with Sjögren-Larsson syndrome. Most affected patients accumulated long-chain fatty alcohol in plasma, with a greater relative accumulation of octadecanol (mean threefold greater than normal) than hexadecanol (mean twofold greater than normal). Erythrocyte lipid alkyl ether linkages derived from hexadecanol were slightly increased in three of four patients. Fibroblasts and leukocytes from heterozygotes with Sjögren-Larsson syndrome showed mean FAO activities that were intermediate between those seen in homozygotes and in normal control subjects. The heterozygotes had normal fatty alcohol concentrations in plasma. These studies demonstrate FAO deficiency in patients with Sjögren-Larsson syndrome, and suggest that accumulation of fatty alcohol or its metabolic products may be important in the pathogenesis of this disorder.

Adolescent↗
PubMed1989

Dietary erucic acid therapy for X-linked adrenoleukodystrophy.

We investigated the biochemical and clinical efficacy of dietary erucic acid (C22:1) therapy for X-linked adrenoleukodystrophy (ALD). In a double-blind crossover study of patients who were on chronic oleic acid (C18:1) therapy, addition of erucic acid to the diet led to a further reduction in plasma hexacosanoic acid (C26:0) concentration. We treated 12 newly diagnosed ALD patients with a diet enriched with erucic acid and oleic acid for 2 to 19 months. Mean plasma C26:0 concentration decreased to normal by 4 weeks, and the C26:0 composition of plasma sphingomyelin and phosphatidylcholine became normal by 4 months on therapy. Fatty acid analysis of postmortem tissues from 1 boy treated for 10 months suggested that dietary erucic acid entered the heart, liver, adrenal gland, and brain. Eight patients remained on treatment long enough (mean, 12 +/- 3 months) to evaluate their clinical response; 6 of these patients with moderate to advanced disease deteriorated neurologically or showed progression of white matter disease on brain magnetic resonance imaging whereas 2 mildly affected patients remained clinically stable after 10 and 19 months. No adverse effects of the diet occurred. We conclude that dietary erucic acid therapy is effective in lowering plasma C26:0 to normal in ALD patients, and may prevent further demyelination in some mildly affected boys.

Adrenoleukodystrophy↗
PubMed1988

Oral carnitine therapy in children with cystinosis and renal Fanconi syndrome.

11 children with either cystinosis or Lowe's syndrome had a reduced content of plasma and muscle carnitine due to renal Fanconi syndrome. After treatment with oral L-carnitine, 100 mg/kg per d divided every 6 h, plasma carnitine concentrations became normal in all subjects within 2 d. Initial plasma free fatty acid concentrations, inversely related to free carnitine concentrations, were reduced after 7-20 mo of carnitine therapy. Muscle lipid accumulation, which varied directly with duration of carnitine deficiency (r = 0.73), improved significantly in three of seven rebiopsied patients after carnitine therapy. One Lowe's syndrome patient achieved a normal muscle carnitine level after therapy. Muscle carnitine levels remained low in all cystinosis patients, even though cystinotic muscle cells in culture took up L-[3H]carnitine normally. The half-life of plasma carnitine for cystinotic children given a single oral dose approximated 6.3 h; 14% of ingested L-carnitine was excreted within 24 h. Studies in a uremic patient with cystinosis showed that her plasma carnitine was in equilibrium with some larger compartment and may have been maintained by release of carnitine from the muscle during dialysis. Because oral L-carnitine corrects plasma carnitine deficiency, lowers plasma free fatty acid concentrations, and reverses muscle lipid accumulation in some patients, its use as therapy in renal Fanconi syndrome should be considered. However, its efficacy in restoring muscle carnitine to normal, and the optimal dosage regimen, have yet to be determined.

Administration, Oral↗
PubMed1988

Sjögren-Larsson syndrome. Impaired fatty alcohol oxidation in cultured fibroblasts due to deficient fatty alcohol:nicotinamide adenine dinucleotide oxidoreductase activity.

Lipid metabolism was studied in cultured skin fibroblasts from patients with the inherited disorder, Sjögren-Larsson syndrome (SLS). Intact SLS fibroblasts incubated in the presence of [1-14C]palmitate accumulated more radioactive hexadecanol than did normal cells, whereas incorporation of radioactivity into other cellular lipids was unaltered. The hexadecanol content of SLS fibroblasts was abnormally elevated. Hexadecanol accumulation was not due to increased fatty alcohol synthesis nor its deficient utilization for glycerol ether synthesis. The half-life of intracellular hexadecanol loaded into SLS fibroblasts was increased (70 min) compared with normal (15 min), and intact SLS fibroblasts showed impaired oxidation of [14C]-hexadecanol to fatty acid. Fatty alcohol:NAD+ oxidoreductase, the enzyme catalyzing this reaction, was deficient in SLS fibroblasts. Mean total activity in SLS fibroblasts (n = 5) was 13% of that in normal fibroblasts, and palmitoyl CoA-inhibitable activity was 1% of normal. Fibroblasts from two obligate SLS heterozygotes had enzyme activities intermediate between that in normal fibroblasts and individuals with SLS. These results suggest that the primary defect in SLS is deficiency of fatty alcohol:NAD+ oxidoreductase. SLS represents the first inherited disorder in man associated with an isolated abnormality in fatty alcohol metabolism.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1987

Fatty alcohol metabolism in cultured human fibroblasts. Evidence for a fatty alcohol cycle.

Intact cultured human fibroblasts reduced [1-14C]palmitate to radioactive hexadecanol in a concentration-dependent manner. In the presence of 30 microM radioactive palmitate, cellular levels of labeled hexadecanol increased over time and reached a steady state corresponding to at least 0.1% of cell-associated radioactive palmitate. These levels of [14C]hexadecanol were increased up to 10-fold when exogenous nonradioactive hexadecanol was present, suggesting that radioactive hexadecanol was actively metabolized. Cells incubated in fatty acid-free medium with [1-14C]hexadecanol rapidly oxidized it to palmitic acid; less than 2% of the hexadecanol taken up by the cells was incorporated into the ether linkage of phosphatidylethanolamine, and no incorporation into wax esters was detected. Double-label experiments involving incubation of intact fibroblast with [3H]palmitate and [14C]hexadecanol demonstrated simultaneous synthesis of hexadecanol from palmitate and oxidation of hexadecanol to palmitate. Addition of exogenous palmitate to the medium of intact cells inhibited the oxidation of hexadecanol to fatty acid in a concentration-dependent fashion. This was associated with an increase in the fibroblast content of hexadecanol and loss of hexadecanol into the medium. Activity of fatty alcohol:NAD+ oxidoreductase, which catalyzes the oxidation of hexadecanol to palmitic acid, was inhibited by palmitoyl-CoA and NADH, but not by palmitic acid. These results are consistent with the presence of a "fatty alcohol cycle" in which hexadecanol is synthesized from palmitate via acyl-CoA and simultaneously oxidized back to free fatty acid. Fatty acyl-CoA, which is the primary substrate for fatty alcohol synthesis, may also regulate the intracellular level of fatty alcohol by inhibiting its oxidation.

Acyl Coenzyme A↗
PubMed1987

Cysteamine therapy for children with nephropathic cystinosis.

We treated 93 children with nephropathic cystinosis with oral cysteamine (mean dose, 51.3 mg per kilogram of body weight per day) for up to 73 months. This agent is known to be effective in depleting cells of cystine. In our study, the mean cystine depletion from leukocytes was 82 percent. A historical control group of 55 children received either ascorbic acid (27 children) or placebo (28). At age six, 2 of 17 controls had a serum creatinine level less than 1.0 mg per deciliter, as compared with 17 of 27 patients treated with cysteamine for at least one year (odds ratio, 12.8; 95 percent confidence interval, 2.1 to 33.9). At the end of the study, creatinine clearance was higher in the cysteamine group than in the control group (38.5 vs. 29.7 ml per minute per 1.73 m2; 95 percent confidence limits on the difference, 1.8 and 15.8), even though the cysteamine group was on average 1.4 years older than the control group. Cysteamine also improved growth; those in the cysteamine group between two and three years of age grew at 93 percent of the normal velocity, as compared with 54 percent in the control group. Fourteen percent of the patients could not tolerate the taste and smell of cysteamine. Concurrent controls treated in a blinded fashion with a placebo were not included in this study. With this limitation in mind, we conclude that oral cysteamine, by depleting cells of cystine, helps maintain renal glomerular function, improves growth, and constitutes the current treatment of choice for nephropathic cystinosis.

Administration, Oral↗