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Neonatal adrenoleukodystrophy/disorders of peroxisomal biogenesis
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Chemical analysis of the lipid of the brain revealed an increase in cholesterol esters and a diminution in constituents of myelin [1]. Hexacosanoic (C26:0) acid accounted for 25 percent of the total fatty acid [24, 41]. Examination of the VLCFA of the plasma and cultured fibroblasts also reveals accumulation of VLCFA. Levels are similar to those found in X-linked ALD [4]. The mean C26:C22 ratio in fibroblasts in two patients [3] was 0.5, while that in ALD was 0.7. The value for controls was 0.03. The accumulation tends to be less than that seen in Zellweger syndrome. In another patient, the ratio was 1.8 [9]. The levels of C26:0 in postmortem liver and adrenal were higher than those reported in ALD [3]. Accumulation of VLCFA has also been observed in retina [23]. Oxidation of lignoceric acid (C24:0) in cultured fibroblasts is impaired [3], and the level of activity is similar to that of cells derived from patients with ALD. Defective plasmalogen synthesis tends to be less than that of Zellweger syndrome. A systematic approach to the biochemical diagnosis of peroxisomal disorders has been set out [42]. Biochemical tests are supplemented with functional studies in cultured fibroblasts, and by molecular analysis. It is clear that peroxisomal fission disorders may be elucidated in patients with normal levels of peroxisomal metabolites. Complementation studies may be used to determine which of many PEX genes is abnormal.
Inborn errors of metabolism
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
No attempt is made here to describe or even list the large number of inborn errors, mostly very rare, that have been documented. The Metabolic and Molecular Bases of Inherited Disease, now in electronic form (see Appendix 1), is a definitive source of information. Some disorders have been covered in the present volume in the specific system chapters. Peroxisomal disorders are mentioned in Chapter 6. For the great majority of disorders where the inheritance is autosomal recessive, this means that a high genetic risk (one in four) is usually confined to sibs of the affected individual. Unless consanguinity exists, or the gene is especially common in a particular population, the risks to the offspring of healthy sibs or more distant relatives are low or extremely low, and carrier detection or prenatal diagnosis is not likely to be required in such situations. Indeed, it may be unwise to embark on tests whose margin of error may be greater than the individual's prior risk of having an affected child (see Chapter 7), unless there are particular reasons in the individual situation. The risk of error used to arise from difficulties in interpreting enzyme assay results, where there could be a clear overlap between healthy ‘carriers’ and those affected; now, the scope for error or confusion enters when the unrelated partner of a patient's healthy sibling has gene testing (‘to provide reassurance’, or to ‘make sure they don't also carry the same condition’) and a variant is identified whose clinical significance is uncertain.
Mitochondrial and peroxisomal disorders
Published in Steve Hannigan, Inherited Metabolic Diseases: A Guide to 100 Conditions, 2018
Peroxisomes are small membrane-bound intracellular organelles containing enzymes that serve many important functions in the body, including β-oxidation of very-long-chain fatty acids (VLCFA), β-oxidation of phytanic acids and β-oxidation of di- and trihydroxycholestanoic acids to chenodeoxycholic acid and cholic acid, which are bile acid precursors. Peroxisomal disorders are classiied into two main groups: multiple enzyme deficiencies resulting from disorders of peroxisomal biogenesissingle peroxisomal enzyme deficiencies.
Putative adjunct therapies to target mitochondrial dysfunction and oxidative stress in phenylketonuria, lysosomal storage disorders and peroxisomal disorders
Published in Expert Opinion on Orphan Drugs, 2020
Nadia Turton, Tricia Rutherford, Dick Thijssen, Iain P Hargreaves
Peroxisomes are membrane-bound organelles which contain around 50 different enzymes to fulfil their critical roles in a range of metabolic processes including catabolism of polyamines, prostaglandins, purines and eicosanoids, ether phospholipid biosynthesis, fatty acid oxidation, peroxide and ROS metabolism, glyoxylate clearing, and possibly the biosynthesis of isoprenoids [64]. Peroxisomal disorders are heterogeneous metabolic diseases that result from either mutations in genes that encode peroxisomal enzymes (Refsum disease and adrenoleucodystrophy: ALD) [65,66] or occur as the result of defects in peroxisome biogenesis (Zellweger syndrome spectrum disorders and Rhizomelic chondrodysplasia punctate: RCDP) [67]. Peroxisome biogenesis disorders encompass two phenotypic groups: 1. Zellweger syndrome, neonatal ALD, and infantile Refsum disease, which all belong to the Zellweger syndrome spectrum of diseases, and 2. RCDP1 [67].
An overview of nanosomes delivery mechanisms: trafficking, orders, barriers and cellular effects
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Gamaleldin I. Harisa, Mohamed M. Badran, Fars K. Alanazi, Sabry M. Attia
In such cases, nanosomes can be delivered to the mitochondria, nucleus, endoplasmic reticulum (ER), Golgi complex or other organelles. Labelling nanocargoes with a signal sequence such as nuclear localization sequences, mitochondrial localization sequences or other organelle specified signal enhances drug targeting to the organelle [13–16]. These approaches can aid the fabrication of smart nanocarriers to the targeted cytosol, mitochondria, nucleus or other organelles [12–16]. The signal peptide and mTOR can be used in the fabrication of drug nanocargoes to target the ER–Golgi network. Understanding of the ubiquitin–proteasome system (UPS) protein degradation is challenging researchers to discover promising therapeutic proteasomal targets. Bortezomib is a prototype of proteosome inhibitors. Peroxisomal drug delivery has a therapeutic value for the treatment of peroxisomal disorders [12–16]. Engineered catalase containing was fabricated and efficiently delivered into catalase-defected fibroblasts [12–16].
Histologic and ultrastructural features in early and advanced phases of Zellweger spectrum disorder (infantile Refsum disease)
Published in Ultrastructural Pathology, 2018
Mikako Warren, Gary Mierau, Eric P. Wartchow, Hiroyuki Shimada, Shoji Yano
Peroxisomal disorders (PD) are a genetically heterogeneous group of inherited metabolic disorders that affect multiple organs. PD are divided into two major categories: peroxisomal biogenesis disorders (PBD) and single peroxisomal enzyme deficiencies (SPED). SPED are caused by the deficiency of a single peroxisomal enzyme, and peroxisomes in patients with SPED are morphologically intact. PBD are further divided into Zellweger spectrum disorders (ZSD) and rhizomelic chondrodysplasia punctuate (RCDP) type 1.3 ZSD are characterized by impaired peroxisomal functions and lack of peroxisomes confirmed by EM. ZSD are caused by mutations in the 14 known PEX genes [PEX1, PEX2, PXMP3 [PEX2], PEX3, PEX5, PEX6, PEX10, PEX11ts PEX12, PEX13, PEX14, PEX16, PEX19, and PEX26] encoding peroxins. Peroxins are essential proteins required for normal peroxisome assembly.4–7 Mutations in PEX1 account for 58.9% of ZSD followed by PEX6 (15.9%), PEX12 (7.1%), PEX10 (4.2%), and PEX26 (4.2%).