Adrenoleukodystrophy: biochemical procedures in diagnosis, prevention and treatment.
ABSTRACT The childhood form of adrenoleukodystrophy is an X-linked recessive disorder which is characterized biochemically by elevated concentrations of saturated very long chain fatty acids in tissues and plasma and impaired very long chain fatty acid oxidation in fibroblasts and leukocytes from adrenoleukodystrophy patients. The most consistently observed increase is that in hexacosanoic acid (C26:0); thus, measurement of plasma C26:0 concentration by gas-liquid chromatography provides a rapid, sensitive method of diagnosis. Prenatal diagnosis of adrenoleukodystrophy can be made by measurement of C26:0 concentrations in amniocytes and chorionic villus cells. Heterozygote (carrier) detection has also been accomplished by biochemical measurement of C26:0 in plasma and skin fibroblasts. In a study of over 200 obligate heterozygotes, greater than 90% showed abnormal concentrations of C26:0. Hybridization studies using the cloned DNA fragment St14 detects polymorphisms in the distal end of the long arm of the X chromosome (Xq27-28) and six informative kindreds have shown co-segregation of adrenoleukodystrophy and the St14 marker through 65 meioses. Thus, such studies can supplement very long chain fatty acid concentrations in heterozygote detection. Therapeutic interventions for adrenoleukodystrophy, such as dietary restriction of very long chain fatty acids, administration of clofibrate or carnitine, immunosuppression and adrenal hormone replacement, have not been successful. Recently, a modification of the very long chain fatty acid-restricted diet has been employed in which this diet is supplemented with synthetic glycerol trioleate. The rationale for this diet is that decreased very long chain fatty acid synthesis by fibroblasts from patients with adrenoleukodystrophy was observed when oleic acid was added to the culture medium.(ABSTRACT TRUNCATED AT 250 WORDS)
- SourceAvailable from: Richard J Auchus[Show abstract] [Hide abstract]
ABSTRACT: Steroidogenesis entails processes by which cholesterol is converted to biologically active steroid hormones. Whereas most endocrine texts discuss adrenal, ovarian, testicular, placental, and other steroidogenic processes in a gland-specific fashion, steroidogenesis is better understood as a single process that is repeated in each gland with cell-type-specific variations on a single theme. Thus, understanding steroidogenesis is rooted in an understanding of the biochemistry of the various steroidogenic enzymes and cofactors and the genes that encode them. The first and rate-limiting step in steroidogenesis is the conversion of cholesterol to pregnenolone by a single enzyme, P450scc (CYP11A1), but this enzymatically complex step is subject to multiple regulatory mechanisms, yielding finely tuned quantitative regulation. Qualitative regulation determining the type of steroid to be produced is mediated by many enzymes and cofactors. Steroidogenic enzymes fall into two groups: cytochrome P450 enzymes and hydroxysteroid dehydrogenases. A cytochrome P450 may be either type 1 (in mitochondria) or type 2 (in endoplasmic reticulum), and a hydroxysteroid dehydrogenase may belong to either the aldo-keto reductase or short-chain dehydrogenase/reductase families. The activities of these enzymes are modulated by posttranslational modifications and by cofactors, especially electron-donating redox partners. The elucidation of the precise roles of these various enzymes and cofactors has been greatly facilitated by identifying the genetic bases of rare disorders of steroidogenesis. Some enzymes not principally involved in steroidogenesis may also catalyze extraglandular steroidogenesis, modulating the phenotype expected to result from some mutations. Understanding steroidogenesis is of fundamental importance to understanding disorders of sexual differentiation, reproduction, fertility, hypertension, obesity, and physiological homeostasis.Endocrine reviews 11/2010; 32(1):81-151. · 19.76 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The object of the present work has been to assess some aspects of the control of the metabolism of polyunsaturated fatty acids. In these studies we have used isolated cells; hepatocytes and cardiac myocytes from rat, and lymphocytes and fibroblasts from humans. Attention has focused on the importance of dietary and hormonal factors which can exert an effect shortly after activation of fatty acid, and thus may determine whether the fatty acid will be desaturated, chain-elongated, directly esteri-fied or oxidized. Both the short-term and long-term regulation excerted by dietary fat have been studied in both rat and human. Profound sex-differences exist in fatty acid esterification, oxidation and fatty acid composition in lipoproteins. It is suggested that these differences, at least in part are due to a different content of intracellular fatty acid binding proteins in female and male liver. The peroxisomal retroconversion of C(22)-unsaturated fatty acids to their C(20)-homologues is probably involved in the regulation of fatty acid composition in membrane phospholipids, being a sort of "overflow valve". In several somewhat different diseases the patients have no peroxisomes or their peroxisomes are defective. In these peroxisomal diseases the beta-oxidation of very long-chain fatty acids is deficient. In this present work we show that fibroblast from patients with the peroxisomal diseases, Zellweger disease, X-linked adrenoleukodystrophy and neonatal adrenoleukodystrophy differ in their ability to shorten C(22)-fatty acids.Scandinavian journal of clinical and laboratory investigation 01/1988; 48(S191):33-46. · 1.38 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: We report the case of a young man with a history of attention deficit/hyperactivity disorder and mild cognitive impairment who presented with chronic fatigue, anorexia and progressive darkening of the skin. On laboratory testing, severely depressed concentrations of morning cortisol, along with highly elevated values of adrenocorticotropic hormone (ACTH) revealed primary adrenal insufficiency as the primary cause of the patient's symptomatology. Imaging of the brain showed altered signal intensities in the parieto-occipital regions of the brain. The demonstration of increased very long chain fatty acids (VLCFA) established the diagnosis of adolescent X-linked adrenoleukodystrophy (X-ALD). Presenting at an advanced yet slowly progressive stage the patient was not a suitable candidate for haematopoietic stem cell transplantation (HSCT), and treatment focused on hormone replacement therapy, family counselling and supportive care. On follow-up visits within the following year, fatigue had diminished and there was no evidence of progressive neurological deficits. However, exacerbation of the psychiatric symptomatology resulted in admittance to a psychiatric ward.Case Reports 01/2010; 2010.