Peroxisomal Defects in Neonatal-Onset and X-Linked Adrenoleukodystrophies

Abstract

Accumulation of very long chain fatty acids in X-linked and neonatal forms of adrenoleukodystrophy (ALD) appears to be a consequence of deficient peroxisomal oxidation of very long chain fatty acids. Peroxisomes were readily identified in liver biopsies taken from a patient having the X-linked disorder. However, in liver biopsies from a patient having neonatal-onset ALD, hepatocellular peroxisomes were greatly reduced in size and number, and sedimentable catalase was markedly diminished. The presence of increased concentrations of serum pipecolic acid and the bile acid intermediate, trihydroxycoprostanic acid, in the neonatal ALD patient are associated with a generalized diminution of peroxisomal activities that was not observed in the patient with X-linked ALD.

The 22-kD Peroxisomal Integral Membrane Protein in Zellweger Syndrome—Presence, Abundance, and Association with a Peroxisomal Thiolase Precursor Protein

“…ma1 proteins into peroxisomes are often proposed as possible primary defects ( [16][17][18]. However, the results of our study and others (18, 21-23, 26, 39) show that in Zellweger syndrome the Fig.…”

“…The integral membrane proteins, especially the 22-kD PMP, are speculated to have important roles in maintaining the integrity of the peroxisomal membrane and in transporting peroxisomal matrix components (10, 1 1, 15). The primary defect in Zellweger syndrome is unknown but may be related to defective synthesis or impaired import of peroxisomal proteins (12,(16)(17)(18)(19). Previous studies have shown that in patients with Zellweger syndrome the 22-kD PMP is absent (20), present in normal amounts (1 8, 2 l), or varies from absent to markedly reduced (22,23).…”

Effects of long-chain, saturated fatty acids on membrane microviscosity and adrenocorticotropin responsiveness of human adrenocortical cells in vitro.

“…The x-linked type may present in childhood, or as the adrenomyeloneuropathy variant with a more chronic onset, usually affecting young adults (6). Although the exact pathophysiologic mechanisms are not fully understood, the enzymatic defect in both genotypes appears to be in the peroxisomal ,B-oxidation system leading to abnormal metabolism of LCFA (7,8). The role that the accumulated LCFA play in the pathogenesis of the disease, particularly the adrenal insufficiency, is unknown.…”

Biochemical and Morphologic Aspects of Peroxisomes in the Human Rectal Mucosa: Diagnosis of Zellweger Syndrome Simplified by Rectal Biopsy

“…We consider this of potential value for diagnosis of other peroxisomal deficiency disorders with multiple dysfunction such as infantile Refsum disease (30, 3 1) and neonatal adrenoleukodystrophy (32,33). Biochemical studies of peroxisomal P-oxidation and ether phospholipid in biopsied rectal mucosa will lead to an accurate diagnosis of other peroxisomal disease such as rhizomelic chondrodysplasia punctata (McKusick 2 15 10) with a deficiency of DHAP-AT (34), pseudo-ZS with a.single deficiency of peroxisomal 3-ketoacyl-CoA thiolase (35), pseudoneonatal adrenoleukodystrophy with acyl-CoA oxidase deficiency (36), and Zellweger-like syndrome with deficient proteins of peroxisoma1 P-oxidation enzymes and detectable peroxisomes (37).…”