triolein and 4-phenylbutyric-acid

Topics: Adrenoleukodystrophy; Age of Onset; ATP Binding Cassette Transporter, Subfamily D, Member 1; ATP-Binding Cassette Transporters; Biomarkers; Bone Marrow Transplantation; Chromosomes, Human, X; Dementia; Diagnosis, Differential; Drug Combinations; Erucic Acids; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lovastatin; Magnetic Resonance Imaging; Male; Mutation; Phenylbutyrates; Triolein

X-linked adrenoleukodysrophy is the most frequent genetic disorder affecting central and peripheral nervous system myelin. One of the biochemical abnormalities is the accumulation of very long chain fatty acids (VLCFA) in tissues and body fluids subsequent to defective catabolism in the peroxysomes. The principal characteristic of the disease is an association between a neurological disorder and an endocrine disorder: primary adrenal insufficiency and testicular failure. Clinical manifestations are variable. There are two main forms, one affecting boys between the age of 5 and 10 years with severe rapidly fatal cerebral involvement, and the other affecting young adults between the age of 20 and 30 years with degeneration of the anterior and posterior long spinal cord tracts, similar to the disorders observed in multiple sclerosis. About 20% of the heterozygous women may develop a syndrome which resembles adrenomyeloneuropathy, rarely adrenal insufficiency. Adrenal insufficiency is present in 85% of the childhood cerebral forms and in about 70% of the adult forms. It may occur before, after or at the same time as the neurological disease but is not correlated with the severity of the neurological disorder. Careful screening is required to avoid missing subclinical forms. Adrenoleukodystrophy should be envisaged in young boys with primary adrenal insufficiency, accounting for about 30% of the cases of primary adrenal insufficiency in children under 3 years of age and about 13% of those in adults. Experience with dietary therapy (low-VLCFA diet and supplementation with unsaturated fatty acids such as glyceryl trioleate (GTO) and glyceryl trierucate (GTE), commonly called Lorenzo's oil) has not demonstrated any clinical improvement in the cerebral forms. Bone marrow transplantation is recommended for children who show early evidence of cerebral involvement. Gene therapy is a promising perspective. Lovastatin and 4-phenlbutyrate have recently been shown to normalize plasma VLCFA levels. Their therapeutic efficacy must be assessed in a randomized trial.

Topics: Adrenal Insufficiency; Adrenoleukodystrophy; Adult; Anticholesteremic Agents; Bone Marrow Transplantation; Child; Child, Preschool; Drug Combinations; Erucic Acids; Female; Genetic Therapy; Humans; Lovastatin; Male; Mass Screening; Phenylbutyrates; Testicular Diseases; Treatment Outcome; Triolein

Clinically, peroxisome biogenesis disorders (PBDs) are a group of lethal diseases with a continuum of severity of clinical symptoms ranging from the most severe form, Zellweger syndrome, to the milder forms, infantile Refsum disease and rhizomelic chondrodysplasia punctata. PBDs are characterised by a number of biochemical abnormalities including impaired degradation of peroxide, very long chain fatty acids, pipecolic acid, phytanic acid and xenobiotics and impaired synthesis of plasmalogens, bile acids, cholesterol and docosahexaenoic acid. Treatment of PBD patients as a group is problematic since a number of patients, especially those with Zellweger syndrome, have significant neocortical alterations in the brain at birth so that full recovery would be impossible even with postnatal therapy. To date, treatment of PBD patients has generally involved only supportive care and symptomatic therapy. However, the fact that some of the milder PBD patients live into the second decade has prompted research into possible treatments for these patients. A number of experimental therapies have been evaluated to determine whether or not correction of biochemical abnormalities through dietary supplementation and/or modification is of clinical benefit to PBD patients. Another approach has been pharmacological induction of peroxisomes in PBD patients to improve overall peroxisomal biochemical function. Well known rodent peroxisomal proliferators were found not to induce human peroxisomes. Recently, our laboratory demonstrated that sodium 4-phenylbutyrate induces peroxisome proliferation and improves biochemical function (very long chain fatty acid beta-oxidation rates and very long chain fatty acid and plasmalogens levels) in fibroblast cell lines from patients with milder PBD phenotypes. Dietary supplementation and/or modification and pharmacological induction of peroxisomes as treatment strategies for PBD patients will be the subject of this review.

Topics: Antineoplastic Agents; Dietary Supplements; Drug Combinations; Erucic Acids; Humans; Peroxisomal Disorders; Phenylbutyrates; Triolein; Zellweger Syndrome

Topics: Adrenoleukodystrophy; ATP Binding Cassette Transporter, Subfamily D; ATP Binding Cassette Transporter, Subfamily D, Member 1; ATP-Binding Cassette Transporters; Drug Combinations; Erucic Acids; Gene Expression Regulation; Humans; Microbodies; Phenylbutyrates; Protein Conformation; Proteins; Triolein; X Chromosome