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PDF hosted at the Radboud Repository of the Radboud University Nijmegen The following full text is a publisher's version. For additional information about this publication click this link. http://hdl.handle.net/2066/113165 Please be advised that this information was generated on 2017-12-06 and may be subject to change. J £/Т'J THE CEREBRO-HEPATO-RENAL SYNDROME OF ZELLWEGER .•¿\3 - ı Vfi • ••;t'\ ,r *:*І-^,^Г'^Й>«(.. 1 #***•—т*^. '*•• LUTGARDE СР. GOVAERTS Electron micrograph of part of a human hepatocyte, showing a number of single-membrane-bound peroxisomes and mitochondrial profiles. Magnification: 50.000 χ THE CEREBRO-HEPATO-RENAL SYNDROME OF ZELLWEGER Promotor : Prof. Dr. L.A.H. Monnens Co-referent: Dr. Ir. J.M.F. Trijbels THE CEREBRO-HEPATO-RENAL SYNDROME OF ZELLWEGER PROEFSCHRIFT TER VERKRIJGING VAN DE GRAAD VAN DOCTOR IN DE GENEESKUNDE AAN DE KATHOLIEKE UNIVERSITEIT TE NIJMEGEN OP GEZAG VAN DE RECTOR MAGNIFICUS PROF. DR. J.H.G.I. GIESBERS VOLGENS BESLUIT VAN HET COLLEGE VAN DEKANEN IN HET OPENBAAR TE VERDEDIGEN OP DONDERDAG 29 NOVEMBER 1984 DES NAMIDDAGS TE 2.00 UUR PRECIES DOOR LUTGARDE CELESTINE PETRA GOVAERTS GEBOREN TE HASSELT (BELGIË) 1984 DRUK: STICHTING STUDENTENPERS NIJMEGEN CIP-GEGEVENS KONINKLIJKE BIBLIOTHEEK, DEN HAAG Govaerts, Lutgarde Celestine Petra The cerebro-hepato-renal syndrome of Zellweger Lutgarde Celestine Petra Govaerts. - (S.l. : s.n.) (Nijmegen: Stichting Studentenpers). - 111. Proefschrift Nijmegen. - Met lit. opg. - Met samenvatting in het Nederlands. ISBN 90-9000739-3 SISO 605.99 UDC 616-098:575.1 Trefw.: peroxisomen; pipecolinezuur. The investigations described in this thesis were performed in the De­ partment of Paediatrics (head: Prof.Dr.G. Stoelinga) and in the Labora­ tory for Paediatrics and Surgery (head: Dr.P. van Munster) of the Sint Radboudhospital of the Catholic University of Nijmegen, The Netherlands. Financial support was given by the Faculty of Medicine of the K.U.N, and a graduate scholarship of the Rotary Foundation, Evanston, U.S.A. was obtained. Printing-expenses were partly subsidized by the Jan Dekkerstlchting and Dr.Ludgardine Bouwmanstichting. CONTENTS ABBREVIATIONS 14 GENERAL INTRODUCTION 15 CHAPTER I: 17 PEROXISOMES IN MAMMALS AND IN MAN INTRODUCTION 18 MORPHOLOGY 18 BIOGENESIS OF PEROXISOMES 19 CYTOCHEMISTRY 22 ENZYMATIC COMPOSITION AND METABOLIC PATHWAYS 22 Catalase L-α ^hydroxy acid oxidase and D-amino acid oxidase Glyoxylate metabolism and aminotransferases Urate oxidase Fatty acid g-oxidation Glycerolipid biosynthesis Bile acid synthesis DEVELOPMENTAL CHANGES 31 PEROXISOMES AND HUMAN METABOLIC DISEASES 32 Acatalasemia Cerebrotendinous xanthomatosis Adrenoleukodystrophy The cerebro-hepato-renal syndrome REFERENCES 34 7 CHAPTER II: 38 THE CEREBRO-HEPATO-RENAL SYNDROME OF ZELLWEGER INTRODUCTION 40 HISTORICAL SURVEY 40 NOMENCLATURE AND CLASSIFICATION 41 THE CLINICAL MANIFESTATIONS OF ZELLWEGER SYNDROME 42 Clinical signs Age at death and cause of death Heredity ROENTGENOLOGIC AND ELECTROPHYSIOLOGIC STUDIES 49 Roentgenologic studies Electrophysiologic studies HISTOPATHOLOGIC STUDIES 51 Central nervous system Liver Kidneys Skeletal muscle - peripheral nerve Hemato-lymphatic system Adrenal glands Pancreas The eyes Other organs BIOCHEMICAL STUDIES 63 Introduction Iron overload Pipecolic acid metabolism Liver dysfunction - Abnormal bile acid pattern Immune deficiency Organic aciduria Very long chain fatty acid pattern Deficiency of plasmalogens in tissues Mitochondrial defects in the CHR-S; relation to the deficiency of peroxisomes 8 RELATED DISORDERS 77 Introduction Hyperpipecolic acidemia Trihydroxycoprostanic acidemia CHAPTER III: 97 CEREBRO-HEPATO-RENAL SYNDROME OF ZELLWEGER: CLINICAL SYMPTOMS AND RELEVANT LABORATORY FINDINGS IN 16 PATIENTS ABSTRACT 98 INTRODUCTION 99 PATIENTS AND METHODS 99 RESULTS 100 History of the families Gestation and delivery Clinical features Laboratory data Special neurologic examinations DISCUSSION 106 REFERENCES 108 CHAPTER IV: Ш A NEUROPHYSIOLOGICAL STUDY OF CHILDREN WITH THE CEREBRO-HEPATO-RENAL SYNDROME OF ZELLWEGER ABSTRACT 112 INTRODUCTION 1|3 SUBJECTS AND METHODS 115 Subjects Methods 9 RESULTS 116 EEC's BAEP's - SSEP's Echo-encephalography - CT scan DISCUSSION 124 SUMMARY 125 REFERENCES 126 CHAPTER V: 129 DISTURBED ADRENOCORTICAL FUNCTION IN CEREBRO-HEPATO-RENAL SYNDROME OF ZELLWEGER ABSTRACT 130 INTRODUCTION 131 PATIENTS AND METHODS 132 Patients Methods RESULTS 132 DISCUSSION 134 REFERENCES 136 CHAPTER VI: 139 DISTURBED VERY LONG CHAIN FATTY ACID PATTERN IN FIBROBLASTS OF ZELLWEGER PATIENTS SUMMARY 140 INTRODUCTION 141 10 PATIENTS AND METHODS 142 Patients Methods RESULTS 143 DISCUSSSION 146 REFERENCES 148 CHAPTER VII: 153 PIPECOLIC ACID LEVELS IN SERUM AND URINE FROM NEONATES, AND NORMAL INFANTS; COMPARISON WITH VALUES REPORTED IN ZELLWEGER SYNDROME SUMMARY 154 INTRODUCTION 155 PATIENTS AND METHODS 156 Patients Methods RESULTS 157 DISCUSSION 164 REFERENCES 166 CHAPTER VIII: 169 GENERAL CONSIDERATIONS MORPHOLOGIC EVIDENCE FOR THE ROLE OF PEROXISOMES IN CNS 170 AND THE EYES 11 PATHOGENESIS OF BIOCHEMICAL DISORDERS AND ITS CLINICAL SIGNIFICANCE 17 1 Catabollsm of pipecollc acid Pathogenesis of liver dysfunction Deficiency of plasmologens Increased saturated VLCFA levels BASIC DEFECT IN CHR-S 174 RELATION BETWEEN CHR-S AND THE NEONATAL FORM OF ALD 175 Clinical features Biochemical data Pathologic studies Conclusion ANTENATAL DIAGNOSIS OF CHR-S 178 REFERENCES 179 SUMMARY 185 SAMENVATTING 187 SAMENVATTING VOOR DE LEEK 189 ACKNOWLEDGEMENTS 193 CURRICULUM VITAE 195 12 ABBREVIATIONS ACTH adrenocorticotrophic hormone ALD adrenoleukodystrophy AMN adrenomyeloneuropathy BAEP brainstem auditory evoked potentials CHR-S cerebro-hepato-renal syndrome CNS central nervous system CoA coenzyme A CSF cerebrospinal fluid CTX cerebrotendlnous xanthomatosis DAB d iaminobenz id ine DHAP dihydroxy-acetone-phosphate DHCA dihydroxy coprostanic acid EEG electro-encephalography EMG electro-myo-graphy ER endoplasmic reticulum ERG electro-retino-graphy FAD flavin adenine dinucleotide GABA γ-aminobutyric acid ΗΡΑ hyperpipecolic acidemia НРа hyperpipecolic aciduria ΡΑ pipecolic acid PAS periodic acid-Schiff SSEP somatosensory evoked potentials тз 3, 5, 3' - triiodothyronine T4 thyroxin THCA trihydroxy coprostanic acid VEP visual evoked potentials TSH thyroid stimulating hormone VLCFA very long chain fatty acids 14 GENERAL INTRODUCTION This study contains clinical, electrophysiologic, morphologic and bio­ chemical investigations in children with the cerebro-hepato-renal syn­ drome (CHR-S) of Zellweger. In the first chapter the present knowledge about peroxisomes is presented. This is required to understand the in­ vestigations reported in Chapter IV, V and VI. Chapter II reviews the literature on the Zellweger syndrome. Special attention is also given to data referring to clinically and/or biochemically related disorders. Chapter III and IV give a survey of clinical symptoms, relevant labora­ tory findings and neurophysiological data from our patients. As the neo­ natal form of adrenoleukodystrophy (ALD) has a clinical and biochemical resemblance to CHR-S, the adrenocortical function -disturbed in ALD- was tested in CHR-S (Chapter V). The very long chain fatty acids measured in cultured skin fibroblasts of CHR-S patients demonstrated a constant increased concentration of С., η (Chapter VI). This finding offers the possibility of antenatal diagnosis (Chapter VI and VIII). Pipecolic acid (PA) level in serum and urine, the first reported bioche­ mical abnormality in CHR-S, remains a valuable tool for the confirmation of the clinical diagnosis of CHR-S, when gestational age and age after birth are taken into consideration (Chapter VII). 15 CHAPTER I PEROXISOMES IN MAMMALS AND IN MAN INTRODUCTION Microbodies were first described in the proximal tubular epithelium of mouse kidney by Rhodin in 1954 and by Rouiller and Bernhard in hepatic parenchymal cells in 1956. They are now considered as ubiquitous subcel­ lular organelles in eukaryotic cells. The term microbody is only a mor­ phological description and includes also a percentage of quite unrelated structures such as the hydrogenosome in Trichomonas and the glycosome in protozoan blood parasites. De Duve and Baudhuin, 1966, who developed procedures for isolating microbodies, introduced the name peroxisomes, for cellular organelles characterized by their content of catalase and several oxidative enzymes. The function of peroxisomes involves the production and degradation of hydrogen peroxide. The peroxisomes are a subgroup of the microbodies. They should be distinguished from glyoxyso- mes present e.g. in Tetrahymena, the latter containing in addition at least malate synthetase and isocitrate lyase allowing the functioning of the glyoxylate cycle (De Duve, 1983) . We will limit this short review to the peroxisomes of mammals. MORPHOLOGY Peroxisomes are particles ranging in diameter from 0.1 to 1.5 μπι (avera­ ge about 0.5 um)· The limiting membrane is a single membrane consisting of a triple layered structure. The membrane is thinner than that of ly- sosomes and plasma membrane. The peroxisomal membrane is highly permea­ ble to small molecules such as sucrose and hydrogen peroxide. Freeze- fracture replicas of hepatic peroxisomes reveal numerous particles (7-8 nm) often in clusters, on the protoplasmic face of the limiting membra­ ne, whereas the extracellular face is almost devoid of such particles (Reddy et al, 1974). The matrix has a granular appearance. An electron- dense core (nucleoid), in which a series of
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  • Descriptions of Phenotypes

    Descriptions of Phenotypes

    Descriptions of phenotypes September 27, 2006 Contents 1 Mapping of disease names onto ICD-9 codes 7 2 Disease list and descriptions: A 15 2.1 Amino acid (AA) metabolism (aromatic) (Albinism, Alkaptonuria, Tyrosinemia, Waardenburg syndrome) . 15 2.1.1 Albinism . 15 2.1.2 Alkaptonuria . 15 2.1.3 Tyrosinemia . 15 2.1.4 Waardenburg syndrome . 15 2.2 Amino acid (AA) metabolism (branched) (maple syrup urine disease) . 16 2.2.1 Maple syrup urine disease . 16 2.3 Amino acid (AA) metabolism (Lowe) (Beta-alaninemia, Hydroxyprolinemia, Hyperproline- mia, Sarcosinemia) . 16 2.3.1 Beta-alaninemia . 16 2.3.2 Hydroxyprolinemia . 16 2.3.3 Hyperprolinemia . 16 2.3.4 Sarcosinemia . 17 2.4 Amino acid (AA) metabolism (sulfur-bearing) (Homocystinuria) . 17 2.4.1 Homocystinuria . 17 2.5 Amino acid (AA) metabolism (straight-chain) (Hyperglycinemia, Hyperlysinemia, Pipecolic acidemia, Saccharopinuria) . 17 2.5.1 Hyperglycinemia . 17 2.5.2 Hyperlysinemia . 17 2.5.3 Pipecolic acidemia . 17 2.5.4 Saccharopinuria . 18 2.6 Amino acid (AA) transport (Cystinosis, Cystinuria, Hartnup disease) . 18 2.6.1 Cystinosis . 18 2.6.2 Cystinuria . 18 2.6.3 Hartnup disease . 18 2.7 Acanthosis nigricans . 18 2.8 Acidosis . 19 2.9 (Organic) Aciduria . 19 2.10 Actinomycosis . 19 2.11 Acute leukemia . 20 2.12 Acute promyelocytic leukemia . 20 2.13 Ainhum . 20 2.14 Albright (-McCune)-Sternberg syndrome . 21 2.15 Alcoholism . 21 2.16 Allergic rhinitis . 21 2.17 Alkalosis . 21 2.18 Alopecia (baldness) . 22 1 2 2.19 Alopecia areata . 22 2.20 Alzheimer’s disease .