Disease relevance of Peroxisomal Disorders

• Adrenoleukodystrophy, a sex-linked peroxisomal disorder that results in the impaired oxidation of long-chain saturated fatty acids and causes neurologic impairment, is a rare cause of Addison's disease in children [1].
• Our observation that Pas7p also interacts with the human peroxisomal thiolase suggests that in the human peroxisomal disorders characterized by an import defect for PTS2 proteins (classical rhizomelic chondrodysplasia punctata), a functional homologue of Pas7p may be impaired [2].
• X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder with impaired beta-oxidation of very long chain fatty acids (VLCFAs) and reduced function of peroxisomal very long chain fatty acyl-CoA synthetase (VLCS) that leads to severe and progressive neurological disability [3].
• We present here genome wide linkage analysis of an atypical Refsum disease family where L-pipecolic acid level in blood was also increased, suggesting that the patients suffer from a new peroxisomal disorder intermediate between ARD and Infantile Refsum Disease (IRD, a peroxisomal deficiency disease) [4].
• Peroxisome biogenesis disorders, including Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease, are lethal hereditary diseases caused by abnormalities in peroxisomal assembly [5].

High impact information on Peroxisomal Disorders

• These studies have revealed important new insights regarding the mechanism of protein translocation across the peroxisomal membrane, the conservation of PEX genes through evolution, the role of peroxins in fatal human peroxisomal disorders, and the biogenesis of the organelle [6].
• This observation extends the evidence that the Zellweger syndrome belongs to the newly formulated category of peroxisomal disorders [7].
• The conservation of the PTS1 receptor in several yeasts has led to the cloning and characterization of the gene encoding its human homolog, PTS1R, which is mutated in a group of patients afflicted with fatal peroxisomal disorders [8].
• The peroxisomal oxidation of the long chain fatty acid palmitate (C16:0) and the very long chain fatty acids lignocerate (C24:0) and cerotate (C26:0) was studied in freshly prepared homogenates of cultured skin fibroblasts from control individuals and patients with peroxisomal disorders [9].
• These findings demonstrate that mice with a PEX2 gene deletion have a peroxisomal disorder and provide an important model to study the role of peroxisomal function in the pathogenesis of this human disease [10].

Chemical compound and disease context of Peroxisomal Disorders

• The first steps of ether lipid biosynthesis are exclusively localized to peroxisomes and hence some peroxisomal disorders are characterized by a severe deficiency of plasmalogens, the main ether lipids in humans [11].
• Phytanic acid (PA) accumulates in patients with adult Refsum disease (ARD) and with peroxisomal disorders [12].
• Severe deficiency of docosahexaenoic acid in peroxisomal disorders: a defect of delta 4 desaturation [13]?
• Patients with generalized peroxisomal disorders have extremely low levels of DHA in the brain and other tissues [14].
• Therapeutic effects of docosahexaenoic acid ethyl ester in patients with generalized peroxisomal disorders [15].

Biological context of Peroxisomal Disorders

• CG8 is one of the more common of these and is associated with varying phenotypes, ranging from the most severe, Zellweger syndrome (ZS), to the milder neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD) [16].
• Using this procedure, normal de novo plasmalogen biosynthesis was found in X-linked adrenoleukodystrophy, adrenomyeloneuropathy, X-linked chondrodysplasia punctata, adult Refsum disease, as well as in heterozygotes for Zellweger syndrome and infantile Refsum disease [17].
• In addition, we could determine its position in relation to known microsatellite framework markers; this will allow to test its role in Zellweger syndrome and/ or related peroxisomal disorders [18].
• Also, improvements are seen in signal transduction processes associated with behavioral deficits, learning activity, peroxisomal disorders, and psychotic changes in schizophrenia, depression, hyperactivity, stroke, and Alzheimer disease [19].
• We report the molecular findings in 14 patients (12 families) with X-linked adrenoleukodystrophy (X-ALD, MIM# 300100), a well-defined peroxisomal disorder attributed to mutations in the ABCD1 gene on chromosome Xq28 [20].

Anatomical context of Peroxisomal Disorders

• Generalized peroxisome-deficient disorders including cerebro-hepato-renal Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease are autosomal recessive diseases, where catalase-containing particles (peroxisomes) are morphologically absent [21].
• Adrenoleukodystrophy (ALD) is a peroxisomal disorder that commonly manifests as demyelination of the central nervous system (CNS) [22].
• Since these alterations are reflected elsewhere, they can be detected in vivo in patients with generalized peroxisomal disorders by measuring the PUFA content of plasma and erythrocytes, which show very low concentrations of DHA [23].
• Resistance to erucic acid as a selectable marker for peroxisomal activity: isolation of revertants of an infantile Refsum disease cell line [24].
• X-linked adrenoleukodystrophy (ALD), a leukodystrophy characterized by abnormal accumulation of saturated very long chain fatty acids in brain white matter and adrenal cortex, is the most common inherited peroxisomal disorder [25].

Gene context of Peroxisomal Disorders

• These results demonstrate that PEX1 is the causative gene for CG-I peroxisomal disorders [26].
• The TRIM37 gene encodes a peroxisomal RING-B-box-coiled-coil protein: classification of mulibrey nanism as a new peroxisomal disorder [27].
• Mutations in PEX7 normally cause rhizomelic chondrodysplasia punctata type 1, a severe peroxisomal disorder [28].
• Adrenoleukodystrophy (ALD), the most frequent peroxisomal disorder, is a severe neurodegenerative disease associated with an impairment of very long chain fatty acids beta-oxidation [29].
• A major subgroup of the PBDs includes Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD) [30].

Analytical, diagnostic and therapeutic context of Peroxisomal Disorders

• The virtual lack of peroxisomes in a liver biopsy specimen lends further support to the contention that at least some patients with Leber congenital amaurosis may have one of the recently defined "peroxisomal disorders." The biochemical findings indicate the possibility of prenatal diagnosis [31].
• Gas chromatography/mass spectrometry analysis of very long chain fatty acids, docosahexaenoic acid, phytanic acid and plasmalogen for the screening of peroxisomal disorders [32].
• Electron microscopy and cytochemical staining for catalase were used to identify peroxisomes in two boys with infantile Refsum's disease (IRD), a girl with autopsy confirmed neonatal adrenoleukodystrophy (NALD), and two boys with pseudo-Zellweger syndrome (PZS) [33].

References