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Ronald J.a. Wanders - One of the best experts on this subject based on the ideXlab platform.

  • Peroxisomal Disorders: Improved laboratory diagnosis, new defects and the complicated route to treatment.
    Molecular and cellular probes, 2018
    Co-Authors: Ronald J.a. Wanders
    Abstract:

    Peroxisomes catalyze a number of essential metabolic functions of which fatty acid alpha- and beta-oxidation, ether phospholipid biosynthesis, glyoxylate detoxification and bile acid synthesis are the most important. The key role of peroxisomes in humans is exemplified by the existence of a group of Peroxisomal Disorders, caused by mutations in > 30 different genes which code for proteins with a role in either peroxisome biogenesis or one of the metabolic pathways in peroxisomes. Technological advances in laboratory methods at the metabolite-, enzyme-, and molecular level have not only allowed the identification of new Peroxisomal Disorders but also new phenotypes associated with already identified genetic defects thus extending the clinical spectrum. Unfortunately, progress in the field of pathogenesis and treatment has lagged behind although there are certainly new and hopeful developments with respect to X-linked adrenoleukodystrophy and hyperoxaluria type 1.

  • Plasma lipidomics as a diagnostic tool for Peroxisomal Disorders
    Journal of inherited metabolic disease, 2017
    Co-Authors: Katharina Herzog, Hans R Waterham, Sacha Ferdinandusse, Ronald J.a. Wanders, Mia L. Pras-raves, Martin A. T. Vervaart, Angela C. M. Luyf, Antoine H. C. Van Kampen, Frédéric M. Vaz
    Abstract:

    Peroxisomes are ubiquitous cell organelles that play an important role in lipid metabolism. Accordingly, Peroxisomal Disorders, including the peroxisome biogenesis Disorders and Peroxisomal single-enzyme deficiencies, are associated with aberrant lipid metabolism. Lipidomics is an emerging tool for diagnosis, disease-monitoring, identifying lipid biomarkers, and studying the underlying pathophysiology in Disorders of lipid metabolism. In this study, we demonstrate the potential of lipidomics for the diagnosis of Peroxisomal Disorders using plasma samples from patients with different types of Peroxisomal Disorders. We show that the changes in the plasma profiles of phospholipids, di- and triglycerides, and cholesterol esters correspond with the characteristic metabolite abnormalities that are currently used in the metabolic screening for Peroxisomal Disorders. The lipidomics approach, however, gives a much more detailed overview of the metabolic changes that occur in the lipidome. Furthermore, we identified novel unique lipid species for specific Peroxisomal diseases that are candidate biomarkers. The results presented in this paper show the power of lipidomics approaches to enable the specific diagnosis of different Peroxisomal Disorders.

  • Identification and diagnostic value of phytanoyl- and pristanoyl-carnitine in plasma from patients with Peroxisomal Disorders.
    Molecular Genetics and Metabolism, 2017
    Co-Authors: Katharina Herzog, Ronald J.a. Wanders, Hans R Waterham, Henk Van Lenthe, Frédéric M. Vaz, Ronald J.a. Wanders, Sacha Ferdinandusse
    Abstract:

    Phytanic acid is a branched-chain fatty acid, the level of which is elevated in patients with a variety of Peroxisomal Disorders, including Refsum disease, and Rhizomelic chondrodysplasia punctata type 1 and 5. Elevated levels of both phytanic and pristanic acid are found in patients with Zellweger Spectrum Disorders, and pristanic acid is elevated in patients with α-methylacyl-CoA racemase deficiency. For the diagnosis of Peroxisomal Disorders, a variety of metabolites can be measured in blood samples from suspected patients, including very long-chain fatty acids, phytanic and pristanic acid. Based on the fact that very long-chain fatty acylcarnitines are elevated in tissues and plasma from patients with certain Peroxisomal Disorders, we investigated whether phytanoyl- and pristanoyl-carnitine are also present in plasma from patients with different Peroxisomal Disorders. Our study shows that phytanoyl- and pristanoyl-carnitine are indeed present in plasma samples from patients with different types of Peroxisomal Disorders, but only when the total plasma levels of their corresponding fatty acids, phytanic acid and pristanic acid, are markedly elevated. We conclude that the measurement of phytanoyl- and pristanoyl-carnitine is not sensitive and specific enough to use these acylcarnitines as conclusive diagnostic markers for Peroxisomal Disorders.

  • Clinical and Laboratory Diagnosis of Peroxisomal Disorders.
    Methods in molecular biology (Clifton N.J.), 2017
    Co-Authors: Ronald J.a. Wanders, Hans R Waterham, Femke C. C. Klouwer, Sacha Ferdinandusse, Bwee Tien Poll-the
    Abstract:

    The Peroxisomal Disorders (PDs) are a heterogeneous group of genetic diseases in man caused by an impairment in peroxisome biogenesis or one of the metabolic functions of peroxisomes. Thanks to the revolutionary technical developments in gene sequencing methods and their increased use in patient diagnosis, the field of genetic diseases in general and Peroxisomal Disorders in particular has dramatically changed in the last few years. Indeed, several novel Peroxisomal Disorders have been identified recently and in addition it has been realized that the phenotypic spectrum of patients affected by a PD keeps widening, which makes clinical recognition of Peroxisomal patients increasingly difficult. Here, we describe these new developments and provide guidelines for the clinical and laboratory diagnosis of Peroxisomal patients.

  • Clinical and Biochemical Pitfalls in the Diagnosis of Peroxisomal Disorders.
    Neuropediatrics, 2016
    Co-Authors: Femke C. C. Klouwer, Hans R Waterham, Ronald J A Wanders, Marc Engelen, Irene C. Huffnagel, Sacha Ferdinandusse, Ronald J.a. Wanders, Bwee Tien Poll-the
    Abstract:

    Peroxisomal Disorders are a heterogeneous group of genetic metabolic Disorders, caused by a defect in peroxisome biogenesis or a deficiency of a single Peroxisomal enzyme. The Peroxisomal Disorders include the Zellweger spectrum Disorders, the rhizomelic chondrodysplasia punctata spectrum Disorders, X-linked adrenoleukodystrophy, and multiple single enzyme deficiencies. There are several core phenotypes caused by Peroxisomal dysfunction that clinicians can recognize. The diagnosis is suggested by biochemical testing in blood and urine and confirmed by functional assays in cultured skin fibroblasts, followed by mutation analysis. This review describes the phenotype of the main Peroxisomal Disorders and possible pitfalls in (laboratory) diagnosis to aid clinicians in the recognition of this group of diseases.

Jutta Gärtner - One of the best experts on this subject based on the ideXlab platform.

  • clinical diagnosis biochemical findings and mri spectrum of Peroxisomal Disorders
    Biochimica et Biophysica Acta, 2012
    Co-Authors: B T Pollthe, Jutta Gärtner
    Abstract:

    Abstract Peroxisomal Disorders are an important group of neurometabolic diseases. The clinical presentation is varied in terms of age of onset, severity, and different neurological symptoms. The clinical course spans from death in infancy, rapid functional decline, slow decline on long-term followup, to apparent stable course. Leukoencephalopathy and developmental anomalies are characteristic findings on cerebral MR imaging. From a diagnostic point of view the Disorders can be clinically subdivided into four broad categories: (1) the Zellweger spectrum Disorders and the Peroxisomal s-oxidation Disorders, (2) the rhizomelic chondrodysplasia punctata spectrum Disorders, (3) the X-linked adrenoleukodystrophy/adrenomyeloneuropathy complex and (4) the remaining Disorders. This article discusses the role of MRI findings in the clinical approach of Peroxisomal Disorders with neurological disease. This article is part of a Special Issue entitled: Metabolic Functions and Biogenesis of peroxisomes in Health and Disease.

  • Clinical diagnosis, biochemical findings and MRI spectrum of Peroxisomal Disorders
    Biochimica et biophysica acta, 2012
    Co-Authors: Bwee Tien Poll-the, Jutta Gärtner
    Abstract:

    Peroxisomal Disorders are an important group of neurometabolic diseases. The clinical presentation is varied in terms of age of onset, severity, and different neurological symptoms. The clinical course spans from death in infancy, rapid functional decline, slow decline on long-term followup, to apparent stable course. Leukoencephalopathy and developmental anomalies are characteristic findings on cerebral MR imaging. From a diagnostic point of view the Disorders can be clinically subdivided into four broad categories: (1) the Zellweger spectrum Disorders and the Peroxisomal ß-oxidation Disorders, (2) the rhizomelic chondrodysplasia punctata spectrum Disorders, (3) the X-linked adrenoleukodystrophy/adrenomyeloneuropathy complex and (4) the remaining Disorders. This article discusses the role of MRI findings in the clinical approach of Peroxisomal Disorders with neurological disease.

  • Organelle interplay in Peroxisomal Disorders
    Trends in Molecular Medicine, 2009
    Co-Authors: Sven Thoms, Sabine Grønborg, Jutta Gärtner
    Abstract:

    Peroxisomes are no longer regarded as autonomous organelles because evidence for their interplay with other cellular organelles is emerging. Peroxisomes interact with mitochondria in several metabolic pathways, including β-oxidation of fatty acids and the metabolism of reactive oxygen species. Both organelles are in close contact with the endoplasmic reticulum (ER) and share several proteins, including organelle fission factors. Today, the study of peroxisome biogenesis Disorders mainly focuses on metabolic defects such as accumulation of very long chain fatty acids or plasmalogen deficiency. In addition to metabolic dysregulation, mitochondria and ER abnormalities have also been observed. Whether these contribute to disease pathology is not yet known, but recent findings suggest that this possibility should be considered. Here, we discuss the potential involvement of organelle interplay in Peroxisomal Disorders.

  • Organelle interplay in Peroxisomal Disorders
    Trends in molecular medicine, 2009
    Co-Authors: Sven Thoms, Sabine Grønborg, Jutta Gärtner
    Abstract:

    Peroxisomes are no longer regarded as autonomous organelles because evidence for their interplay with other cellular organelles is emerging. Peroxisomes interact with mitochondria in several metabolic pathways, including beta-oxidation of fatty acids and the metabolism of reactive oxygen species. Both organelles are in close contact with the endoplasmic reticulum (ER) and share several proteins, including organelle fission factors. Today, the study of peroxisome biogenesis Disorders mainly focuses on metabolic defects such as accumulation of very long chain fatty acids or plasmalogen deficiency. In addition to metabolic dysregulation, mitochondria and ER abnormalities have also been observed. Whether these contribute to disease pathology is not yet known, but recent findings suggest that this possibility should be considered. Here, we discuss the potential involvement of organelle interplay in Peroxisomal Disorders.

  • Organelle disease: Peroxisomal Disorders
    European Journal of Pediatrics, 2000
    Co-Authors: Jutta Gärtner
    Abstract:

    Peroxisomes are virtually ubiquitous organelles involved in numerous catabolic and anabolic pathways. Interest in peroxisomes stems from an expanding group of genetic diseases in which there is either deficiency of a specific Peroxisomal function (single protein defects) or failure to assemble the organelle resulting in defects of multiple peroxisome functions (peroxisome biogenesis Disorders). The paradigm for the former is X-linked adrenoleukodystrophy caused by mutations in the adrenoleukodystrophy gene and, for the latter, Zellweger syndrome caused by mutations in peroxin genes. Conclusion The identification and functional characterisation of the Peroxisomal disease genes is proceeding at rapid pace helped immeasurably by work in various yeast model systems. The ultimate goal is to elucidate how the encoded proteins produce normal appearing and functioning peroxisomes. The achievement of this goal will lead to a better understanding of Peroxisomal Disorders, their pathogenesis and treatment.

Tadao Orii - One of the best experts on this subject based on the ideXlab platform.

  • Urinary organic acids in Peroxisomal Disorders: a simple screening method.
    Journal of chromatography. B Biomedical sciences and applications, 2001
    Co-Authors: Seiji Yamaguchi, Nobuyuki Shimozawa, Yasuyuki Suzuki, Naomi Kondo, Misako Iga, Masahiko Kimura, Toshiyuki Fukao, Yusaku Tazawa, Tadao Orii
    Abstract:

    Using GC-MS, we studied urinary organic acids in 20 Japanese patients with Peroxisomal Disorders, including Zellweger syndrome (ZS), neonatal adrenoleukodystrophy, and single deficiency of Peroxisomal beta-oxidation enzymes. Non-ketotic dicarboxylic aciduria with elevated sebacate/adipate molar ratio was observed in 19 of the 20 patients. Elevation of 2-hydroxysebacate and epoxydicarboxylic acids were seen in 13 and 18, respectively. Tyrosyluria was remarkable in all patients. In two ZS patients, we tracked the time course from birth to infancy, and all the above stated findings were detected, except for one sample. Urinary organic acid analysis is indeed useful for screening subjects with Peroxisomal Disorders.

  • urinary organic acids in Peroxisomal Disorders a simple screening method
    Journal of Chromatography B: Biomedical Sciences and Applications, 2001
    Co-Authors: Seiji Yamaguchi, Nobuyuki Shimozawa, Yasuyuki Suzuki, Naomi Kondo, Misako Iga, Masahiko Kimura, Toshiyuki Fukao, Yusaku Tazawa, Tadao Orii
    Abstract:

    Abstract Using GC–MS, we studied urinary organic acids in 20 Japanese patients with Peroxisomal Disorders, including Zellweger syndrome (ZS), neonatal adrenoleukodystrophy, and single deficiency of Peroxisomal β-oxidation enzymes. Non-ketotic dicarboxylic aciduria with elevated sebacate/adipate molar ratio was observed in 19 of the 20 patients. Elevation of 2-hydroxysebacate and epoxydicarboxylic acids were seen in 13 and 18, respectively. Tyrosyluria was remarkable in all patients. In two ZS patients, we tracked the time course from birth to infancy, and all the above stated findings were detected, except for one sample. Urinary organic acid analysis is indeed useful for screening subjects with Peroxisomal Disorders.

  • Peroxisomal Disorders: Clinical Aspectsa
    Annals of the New York Academy of Sciences, 1996
    Co-Authors: Yasuyuki Suzuki, Nobuyuki Shimozawa, Naomi Kondo, Yukitoshi Takahashi, Atsushi Imamura, Tadao Orii
    Abstract:

    Peroxisomal Disorders are divided into two groups from a clinical point of view. Diseases in the first group, peroxisome-deficient Disorders (PDD), Zellweger-like syndrome, and isolated deficiencies of Peroxisomal beta-oxidation enzymes, are characterized by common clinical features including psychomotor retardation, hypotonia, hepatic dysfunction and visual disturbance. The second group includes diseases with a unique manifestation, such as X-linked adrenoleukodystrophy, hyperoxaluria type I and rhizomelic chondrodysplasia punctata. We investigated clinical aspects and the genetic basis of PDD, and the significance of peroxisomes in the development of human brain. Neuroradiological and neurophysiological studies revealed that thick cortex, colpocephaly and multifocal spikes were characteristic findings of PDD patients in the early infantile period. Cytogenetic studies elucidated the presence of eleven complementation groups among PDD, indicating the presence of eleven pathogenic genes for PDD. Molecular studies elucidated two of these genes, PAF-1 and PXR-1. Immunohistochemical studies clarified that the catalase-positive neurons appeared in the basal ganglia, thalamus, and cerebellum at 28 weeks of gestation, and in the cortex at 35 weeks. Immunopositive glial cells appeared from the deep to superficial white matter with increasing gestational age. These results suggest the important role of peroxisomes in neuronal maturation and myelinogenesis.

  • Incidence of Peroxisomal Disorders in Japan.
    The Japanese journal of human genetics, 1996
    Co-Authors: Yasuyuki Suzuki, Nobuyuki Shimozawa, Shigehiro Yajima, Kyoko Inoue, Tadao Orii, Naomi Kondo
    Abstract:

    Japanese patients with Peroxisomal Disorders in the pediatric field were screened. Very long chain fatty acid analysis in the serum sphingomyelin was introduced since 1987 and was useful for the first screening of Peroxisomal Disorders. Seventy-five patients were diagnosed since 1980: 15 patients with Zellweger syndrome, 2 with neonatal adrenoleukodystrophy (ALD), 1 with rhizomelic chondrodysplasia punctata, 1 with Zellweger-like syndrome. 2 with acyl-CoA oxidase deficiency, 2 with bifunctional enzyme deficiency and 52 with X-linked ALD. The incidence of peroxisome-deficient Disorders was estimated to be approximately 1 in 800,000 births which is far less than that in the USA. However, the incidence in Okinawa Islands was 1 in 30,000. Japanese Zellweger patients belonged to 5 complementation groups (A, B, C, E, F) and the patients in Okinawa Islands belonged to groups A and C. The results of this screening were useful for genetic counseling, prenatal diagnosis, carrier detection and early medical care of patients with Peroxisomal Disorders.

  • Immunohistochemistry for a bifunctional protein in patients with Peroxisomal Disorders
    Pediatric neurology, 1995
    Co-Authors: Atsushi Imamura, Yasuyuki Suzuki, Tadao Orii, Naomi Kondo, Atsushi Kamei, Sachio Takashima
    Abstract:

    Immunohistochemical studies using antisera against bifunctional protein, a beta-oxidation enzyme, were performed on liver, kidney, and brain tissue specimens from patients with Peroxisomal Disorders and from controls to investigate the distribution and development of peroxisomes. Bifunctional protein-positive granules were not found in patients with Zellweger syndrome or neonatal adrenoleukodystrophy, whereas positive immunoreactivity was observed from 8 and 6 weeks gestation in the liver and kidney, respectively, and in the brain, from 23-25 weeks in the brainstem neurons and from 12-14 weeks in the white matter glia, in controls. Bifunctional protein immunoreactivity then increased with gestation in the brain. These results suggest that bifunctional protein immunohistochemistry is useful for the detection of peroxisomes, which are closely related to neuronal maturation and gliogenesis in premyelination in human brain development.

Hans R Waterham - One of the best experts on this subject based on the ideXlab platform.

  • Plasma lipidomics as a diagnostic tool for Peroxisomal Disorders
    Journal of inherited metabolic disease, 2017
    Co-Authors: Katharina Herzog, Hans R Waterham, Sacha Ferdinandusse, Ronald J.a. Wanders, Mia L. Pras-raves, Martin A. T. Vervaart, Angela C. M. Luyf, Antoine H. C. Van Kampen, Frédéric M. Vaz
    Abstract:

    Peroxisomes are ubiquitous cell organelles that play an important role in lipid metabolism. Accordingly, Peroxisomal Disorders, including the peroxisome biogenesis Disorders and Peroxisomal single-enzyme deficiencies, are associated with aberrant lipid metabolism. Lipidomics is an emerging tool for diagnosis, disease-monitoring, identifying lipid biomarkers, and studying the underlying pathophysiology in Disorders of lipid metabolism. In this study, we demonstrate the potential of lipidomics for the diagnosis of Peroxisomal Disorders using plasma samples from patients with different types of Peroxisomal Disorders. We show that the changes in the plasma profiles of phospholipids, di- and triglycerides, and cholesterol esters correspond with the characteristic metabolite abnormalities that are currently used in the metabolic screening for Peroxisomal Disorders. The lipidomics approach, however, gives a much more detailed overview of the metabolic changes that occur in the lipidome. Furthermore, we identified novel unique lipid species for specific Peroxisomal diseases that are candidate biomarkers. The results presented in this paper show the power of lipidomics approaches to enable the specific diagnosis of different Peroxisomal Disorders.

  • Identification and diagnostic value of phytanoyl- and pristanoyl-carnitine in plasma from patients with Peroxisomal Disorders.
    Molecular Genetics and Metabolism, 2017
    Co-Authors: Katharina Herzog, Ronald J.a. Wanders, Hans R Waterham, Henk Van Lenthe, Frédéric M. Vaz, Ronald J.a. Wanders, Sacha Ferdinandusse
    Abstract:

    Phytanic acid is a branched-chain fatty acid, the level of which is elevated in patients with a variety of Peroxisomal Disorders, including Refsum disease, and Rhizomelic chondrodysplasia punctata type 1 and 5. Elevated levels of both phytanic and pristanic acid are found in patients with Zellweger Spectrum Disorders, and pristanic acid is elevated in patients with α-methylacyl-CoA racemase deficiency. For the diagnosis of Peroxisomal Disorders, a variety of metabolites can be measured in blood samples from suspected patients, including very long-chain fatty acids, phytanic and pristanic acid. Based on the fact that very long-chain fatty acylcarnitines are elevated in tissues and plasma from patients with certain Peroxisomal Disorders, we investigated whether phytanoyl- and pristanoyl-carnitine are also present in plasma from patients with different Peroxisomal Disorders. Our study shows that phytanoyl- and pristanoyl-carnitine are indeed present in plasma samples from patients with different types of Peroxisomal Disorders, but only when the total plasma levels of their corresponding fatty acids, phytanic acid and pristanic acid, are markedly elevated. We conclude that the measurement of phytanoyl- and pristanoyl-carnitine is not sensitive and specific enough to use these acylcarnitines as conclusive diagnostic markers for Peroxisomal Disorders.

  • Clinical and Laboratory Diagnosis of Peroxisomal Disorders.
    Methods in molecular biology (Clifton N.J.), 2017
    Co-Authors: Ronald J.a. Wanders, Hans R Waterham, Femke C. C. Klouwer, Sacha Ferdinandusse, Bwee Tien Poll-the
    Abstract:

    The Peroxisomal Disorders (PDs) are a heterogeneous group of genetic diseases in man caused by an impairment in peroxisome biogenesis or one of the metabolic functions of peroxisomes. Thanks to the revolutionary technical developments in gene sequencing methods and their increased use in patient diagnosis, the field of genetic diseases in general and Peroxisomal Disorders in particular has dramatically changed in the last few years. Indeed, several novel Peroxisomal Disorders have been identified recently and in addition it has been realized that the phenotypic spectrum of patients affected by a PD keeps widening, which makes clinical recognition of Peroxisomal patients increasingly difficult. Here, we describe these new developments and provide guidelines for the clinical and laboratory diagnosis of Peroxisomal patients.

  • Clinical and Biochemical Pitfalls in the Diagnosis of Peroxisomal Disorders.
    Neuropediatrics, 2016
    Co-Authors: Femke C. C. Klouwer, Hans R Waterham, Ronald J A Wanders, Marc Engelen, Irene C. Huffnagel, Sacha Ferdinandusse, Ronald J.a. Wanders, Bwee Tien Poll-the
    Abstract:

    Peroxisomal Disorders are a heterogeneous group of genetic metabolic Disorders, caused by a defect in peroxisome biogenesis or a deficiency of a single Peroxisomal enzyme. The Peroxisomal Disorders include the Zellweger spectrum Disorders, the rhizomelic chondrodysplasia punctata spectrum Disorders, X-linked adrenoleukodystrophy, and multiple single enzyme deficiencies. There are several core phenotypes caused by Peroxisomal dysfunction that clinicians can recognize. The diagnosis is suggested by biochemical testing in blood and urine and confirmed by functional assays in cultured skin fibroblasts, followed by mutation analysis. This review describes the phenotype of the main Peroxisomal Disorders and possible pitfalls in (laboratory) diagnosis to aid clinicians in the recognition of this group of diseases.

  • The important role of biochemical and functional studies in the diagnostics of Peroxisomal Disorders
    Journal of inherited metabolic disease, 2016
    Co-Authors: Sacha Ferdinandusse, Hans R Waterham, Frédéric M. Vaz, Merel S. Ebberink, Ronald J.a. Wanders
    Abstract:

    Peroxisomes are dynamic organelles that play an essential role in a variety of metabolic pathways. Peroxisomal dysfunction can lead to various biochemical abnormalities and result in abnormal metabolite levels, such as increased very long-chain fatty acid or reduced plasmalogen levels. The metabolite abnormalities in Peroxisomal Disorders are used in the diagnostics of these Disorders. In this paper we discuss in detail the different diagnostic tests available for Peroxisomal Disorders and focus specifically on the important role of biochemical and functional studies in cultured skin fibroblasts in reaching the right diagnosis. Several examples are shown to underline the power of such studies.

James M. Powers - One of the best experts on this subject based on the ideXlab platform.

  • myelin lesions associated with lysosomal and Peroxisomal Disorders
    Expert Review of Neurotherapeutics, 2010
    Co-Authors: Phyllis L Faust, Edward M Kaye, James M. Powers
    Abstract:

    Abnormalities of myelin are common in lysosomal and Peroxisomal Disorders. Most display a primary loss of myelin in which the myelin sheath and/or oligodendrocytes are selectively targeted by diverse pathogenetic processes. The most severe and, hence, clinically relevant are heritable diseases predominantly of infants and children, the leukodystrophies: metachromatic, globoid cell (Krabbe disease) and adreno-leukodystrophy. Our still limited understanding of these diseases has derived from multiple sources: originally, neurological-neuropathologic-neurochemical correlative studies of the natural disease in humans or other mammals, which has been enhanced by more sophisticated and contemporary techniques of cell and molecular biology. Transgenic mouse models seem to be the most promising methodology, allowing the examination of the cellular role of lysosomes and peroxisomes for formation and maintenance of both myelin and axons, and providing initial platforms to evaluate therapies. Treatment options are woefully inadequate and in their nascent stages, but still inspire some hope for the future.

  • Peroxisomal Disorders: genotype, phenotype, major neuropathologic lesions, and pathogenesis.
    Brain pathology (Zurich Switzerland), 2006
    Co-Authors: James M. Powers, Hugo W. Moser
    Abstract:

    Neurological dysfunction is a prominent feature of most Peroxisomal Disorders. Enormous progress in defining their gene defects has been achieved. The genes and gene products, peroxins (PEX), in five of the complementation groups have been defined. These studies confirm that Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD) are a disease continuum. The gene defect in adreno-leukodystrophy (ALD) / adrenomyeloneuropathy (AMN) involves an integral Peroxisomal membrane protein. Neuropathologic lesions are of three major classes: (i) abnormalities in neuronal migration or differentiation, (ii) defects in the formation or maintenance of central white matter, and (iii) postdevelopmental neuronal degenerations. The central white matter lesions are those of: (i) inflammatory demyelination, (ii) non-inflammatory dysmyelination, and (iii) non-specific reductions in myelin volume or staining with or without reactive astrocytosis. The neuronal degenerations are of two major types: (i) the axonopathy of AMN involving ascending and descending tracts of the spinal cord, and (ii) cerebellar atrophy in rhizomelic chondrodysplasia punctata and probably IRD. We postulate that the abnormal fatty acids in Peroxisomal Disorders, particularly very long chain fatty acids and phytanic acid, are incorporated into cell membranes and perturb their microenvironments resulting in dysfunction, atrophy and death of vulnerable cells. The advent of mouse models for ZS and ALD is anticipated to provide even greater pathogenetic insights into the Peroxisomal Disorders.

  • the pathology of Peroxisomal Disorders with pathogenetic considerations
    Journal of Neuropathology and Experimental Neurology, 1995
    Co-Authors: James M. Powers
    Abstract:

    Peroxisomal Disorders are rare systemic maladies in which specific major organ systems are typically involved: most importantly the central nervous system (CNS), but also the peripheral nervous system, eyes, liver, adrenal, kidney and skeleton. Zellweger syndrome (ZS) is the most severe of the generalized types and exhibits major neocortical migration defects, less severe and non-inflammatory white matter lesions, and dysmorphic features. In adrenoleukodystrophy (ALD) the major lesion again is in the CNS, but consists of extensive dysmyelination/inflammatory demyelination without neuronal migration defects or dysmorphism. In adrenomyeloneuropathy long tract degeneration of spinal cord, peripheral neuropathy, and variable CNS dysmyelinative to inflammatory demyelinative lesions are the dominant nervous system lesions. Saturated very long chain fatty acids, either free in the cytoplasm of affected endocrine cells or as components of membrane lipids (e.g. gangliosides, glycerophospholipids, and proteolipid protein) in axons or myelin, may be central to the pathogenesis of these neuronal migration defects, dysmyelination/inflammatory demyelination and spinal tract degeneration. Cytokines, particularly tumor necrosis factor-alpha, and delayed cellular hypersensitivity appear to be major secondary pathogenic factors in ALD.