Table Of ContentLipids and Lipidoses
Edited by C. Schettler
Contributors
R. M. Burton . D. C. Cornwell . W .F uhrmann . W. Kahlke
L. W. Kinsell . D. Kritchevsky . R.]. Rossiter . G. Schettler
C. Schlierf . B. Shapiro . W. Stoffel . H. Wagener
With 146 Figures
Springer-Verlag Berlin· Heidelberg· New York 1967
The clinical chapters were translated into English by
Gunter Schlierf
ISBN-13: 978-3-642-87369-0 e-ISBN-13: 978-3-642-87367-6
DOl: 10.1007/978-3-642-87367-6
.All rights. especially that of translation Into foreign languages, reserved.
It Is also forbidden to reproduce this book, either whole or In part by photomechanical means
(photostat, microfilm and/or microcard) or by other procedure without written permission
from Springer-Verlag. © by Springer-Verlag Berlin, Heidelberg 1967. Library of Congress
Catalog Card Number 65-26055
Softcover reprint of the hardcover 1s t edition 1967
The use of general descriptive names, trade names, trade marks, etc. In this publication, even
if the former are not especially identified, Is not to be taken as a sign that such names, as
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by anyone
Title-No. 1307
Preface
Advances which have been made in the field of lipid chemistry and bio
chemistry during the last ten years mainly are the results of progress in metho
dology. The introduction of isotopic and chromatographic techniques has not
only enriched our knowledge of normal lipid metabolism but has also greatly
enhanced the understanding of the various lipidoses. This is well illustrated by
a comparison of the contents of the present monograph with those of my 1955
review in Handbuch der Inneren Medizin (Springer).
In addition to better information about the classic lipid thesaurismoses Nie
mann-Pick disease, Gaucher's disease and Tay-Sachs disease, the number of
hereditary lipid storage diseases has increased considerably through the recogni
tion of new syndromes such as metachromatic leukodystrophy, Fabry's disease,
Refsum's disease (heredopathia atactica polyneuritiformis), a-p-lipoproteinemia,
and Tangier disease. Conversely, disorders such as Hand-Scholler-Christian
disease which has been considered a lipidosis up to 1958 (THANNHAUSER) must
now be differentiated from the hereditary disturbances of lipid metabolism.
Essential hyperlipemia which at one time seemed to be a well defined entity
has now been recognized to consist of a number of subgroups, whose pathogeneses
appear to be quite different, and whose classification is by no means definite.
Similar problems exist for "essential hypercholesterolemia".
Since the knowledge of today is the key for the solutions of tomorrow, we
are fortunate that the chapters on lipidoses are supplemented by a comprehensive
account of lipid chemistry and biochemistry which has been coordinated by
W. STOFFEL.
In accordance with our interpretation of the term lipidoses as hereditary
disorders of lipid metabolism, a review of secondary hyperlipidemias has not
been attempted here. Since they are considered as associated phenomena of
disorders such as diabetic ketoacidosis, nephrosis or pancreatitis, their exclusion
seems to be justifiable.
The book would not have been possible without the help of many coworkers.
I would like to acknowledge gratefully the assistance of P. D. S. WOOD in the
translation, the excellent secretarial work of Miss A. VAN OOSTEN, A. REINARTZ
and M. KUCIAK, and the efforts of the Springer publishing company. Numerous
colleagues have contributed valuable suggestions and criticisms. We shall ap
preciate any comments from the readers of this first English edition.
Heidelberg 1967 G.SCHETTLER
Contributors
R. M. BURTON, Ph. D., Associate Professor, Department of Pharmacology and Beaumont·May
Institute of Neurology, Washington University Medical School, Saint Louis, Missouri,
63110, U.S.A.
D. G. CORNWELL, Ph. D., Professor and Chairman, Department of Physiological Chemistry,
College of Medicine, The Ohio State University, Columbus, Ohio, 43210, U.S.A.
W. FUHRMANN, Dr. med., Dozent, Institut fiir Anthropologie und Humangenetik der Uni·
versitat Heidelberg, 6900 Heidelberg, Germany.
W. KABLKE, Dr. med., Medizinische Klinik (Ludolf Krehl.Klinik) der Universitat Heidelberg,
6900 Heidelberg, Germany.
L. W. KINSELL, M. D., D. Sc., Director, The Institute for Metabolic Research, Highland
General Hospital, Oakland, California, 94606, U.S.A.
D. KRITOHEVSKY, Ph. D., Member of The Wistar Institute of Anatomy and Biology, Professor
of Biochemistry, Division of Animal Biology, School of Veterinary Medicine, University
of Pennsylvania, Philadelphia, Pennsylvania, 19104, U.S.A.
R. J. ROSSITER, Ph. D., Professor of Biochemistry, Department of Biochemistry, University
of Wes tem Ontario, London, Ontario, Canada.
G. SCHETTLER, Dr. med., Professor fur Innere Medizin, Direktor der Medizinischen Klinik
(LudolfKrehl.Klinik) der Universitat Heidelberg, 6900 Heidelberg, Germany.
G. SCHLIERF, Dr. med., Medizinische Klinik (LudolfKrehl-Klinik) der Universitat Heidelberg,
6900 Heidelberg, Germany.
B. SHAPmo, Ph. D., Professor, The Hebrew University, Hadassah Medical School, Depart.
ment of Biochemistry, Jemsalem, Israel.
W. STOFFEL, Dr. med., Dr. chem., Dozent, Physiologisch-chemisches Institut der Universitat
Koln, 5000 Koln, Germany.
H. WAGENER, Dr. med., Dozent, Medizinische Klinik (Ludolf Krehl-Klinik) der Universitat
Heidelberg, 6900 Heidelberg, Germany.
Contents
Part I. Lipids
Biochemistry, Physiology, Methodology
The Chemistry of Mammalian Lipids. By W. STOFFEL (With 11 Figures)
Introduction. . . 1
A. Simple Lipids. . . . . 2
I. Glycerides . . . . 2
1. Monoglycerides . 3
2. D-ex, P-Diglycerides 3
3. Triglycerides 4
II. Cholesterol and Cholesterol Esters 4
III. Bile Acids 7
B. Complex Lipids . . . . . . 7
I. Glycerophospholipids. . 7
1. Phosphatidic Acids . . . 8
2. Phosphatidyl Cholines (Lecithins) .. 9
3. Phosphatidyl Ethanolamines (Cephalins) 10
4. Phosphatidyl Serines . . . 11
5. Lyso-glycerophospholipids. . . . . . . 11
6. Cardiolipin . . . . . . . . . . . . . 12
7. Phosphatidyl Glycerol . . . . . . . . 13
8. Phosphatidyl Inositols . . . . . . . . 13
9. Choline and Ethanolamine Plasmalogens 14
10. Glyceryl Ether Phospholipids 15
II. Sphingolipids . . . . 16
1. Sphingomyelin. . 16
2. Glycosphingolipids 17
a) Cerebrosides 17
b) Sulfatides . . . 19
c) Ceramide-polyhexosides 19
d) Gangliosides ..... 20
III. Fatty Acids and Fatty Aldehydes 23
IV. Prostaglandins . 24
References 25
C. Fatty Acid Oxydation 31
I. p-Oxydation of Saturated Fatty Acids 31
II. p-Oxydation of Unsaturated Fatty Acids . 32
III. <x-Oxydation . . . . . . . . . . . 32
D. Biosynthesis of Fatty Acids . . . . . . . . 33
I. Biosynthesis of Saturated Fatty Acids . . 33
II. Biosynthesis of Mono- and Polyunsaturated Fatty Acids 35
a) Monoenoic Acids . . . . . . . . . . . . 35
b) Polyunsaturated Fatty Acids ...... . 35
c) Control Mechanisms of Fatty Acid Synthesis 36
Referenoes . . . . . . . . . . . . . . . . . . . 37
VI Contents
Biochemistry of Triglycerides. By B. SHAPmo (With 4 Figures)
Introduction 40
I. Absorption from the Intestine 40
1. Lipolysis in the Lumen . . 40
a) Pancreatic Lipase . . . 41
b) The Extent of Hydrolysis 41
c) Emulsification . . . . . 42
2. Uptake and Metabolism in the Intestinal Cells . 43
a) Uptake ............... . 43
b) Resynthesis of Triglycerides in Mucosal Cells 44
c) Phospholipids. . . . . . . . . . . . 44
d) Fate of Short Chain J!'atty Acids . . . 44
II. Metabolism of Lymph and Blood Chylomicra 45
1. Rate and Site of Removal ........ .. . 45
2. Clearing Factor and the Mechanism of Uptake by the Tissues 46
III. Metabolism of Triglycerides in the Liver 49
1. Uptake and Release .. , .... 49
2. Synthesis of Triglycerides . . . . . . 51
3. Fatty Livers . . . . . . . . . . . 52
IV. Metabolism of Triglycerides in Adipose Tissue 53
1. Deposition of Triglycerides . 53
2. Mobilization of Triglycerides 56
References . . . . . . . . . . . 58
Biochemistry of Steroids. By D. KRITCHEVSKY (With 20 Figures)
Introduction 66
I. Biosynthesis . . . . . . . . . . 66
1. The Biosynthesis of Cholesterol 66
2. Other Sterols . . . . . . . . 75
II. Conversion of Cholesterol to Other Steroids . 76
1. Bile Acids ......... . 76
2. Adrenocortical Steroid Hormones 80
3. Sex Hormones . 81
4. Neutral Sterols 82
References • . . . . 84
Biochemistry of Phosphatides. By R. J. ROSSITER (With 7 Figures)
Introduction 93
I. Biosynthesis of Glycerophosphatides 93
1. Phosphatidic Acid . . . . . . 93
2. Phosphatidyl Choline (Lecithin) 96
3. Choline Plasmalogen 99
4. Phosphatidyl Ethanolamine 100
5. Ethanolamine Plasmalogen 101
6. Glycerol Ether Phosphatides 102
7. Phosphatidyl Serine .... 103
Contents VII
8. Phosphatidyl Inositol . 104
9. Polyphosphoinositides . 105
10. Phosphatidyl Glycerol . 107
11. Cardiolipin. • . . . . 108
II. Degradation of Glycerophosphatides 108
1. Phosphatidyl Choline (Lecithin) 109
a) Phospholipase A . . . . . . . . . 109
b) Phospholipase B (Lysophospholipa.se) 110
0) Phospholipase C . . . . 110
d) Phospholipase D . . . . 110
e) GPC Diesterase . . . . 111
f) Phosphomonoestera.ses . 111
2. Phosphatidyl Ethanolamine 112
3. Phosphatidyl Serine. . 112
4. Phosphatidyl Glycerol . 112
5. Cardiolipin. . . . . 112
6. Phosphatidic Acid 113
7. Plasmalogens. . . . . 113
8. Phosphatidyl Inositol . 113
9. Polyphosphoinositides . 114
III. Conclusion 115
References . . 116
Biochemistry or Sphingosine Containing Lipids. By R. M. BURTON (With 11 Figures)
Introduction 122
Nomenclature . . . . . . . . . . . . . . . 123
I. Studies on the Synthesis of Sphingolipide 124
Sphingosine and Dihydrosphingosine . 124
II. Studies on the Intact Animal . . . . . . 143
1. Developmental Studies . . . . . . . . 143
2. Studies Conducted in Vivo with Isotopes 145
a) Sphingosine .. .. ... 145
b) Carbohydrates . . . . . . . . . 146
c) Sulfate. . . . . . . . . . . . . 147
d) Fatty Acide . . . . . . . . . . 149
3. Cerebroside and Ceramide Metabolism 151
a) Turnover Studies . . . . . . . 153
b) Metabolic Pathways . . . . . . 155
c) Immunology of the Sphingolipide 156
d) Diseases Involving Sphingolipide 158
References . . . . . . . . . 161
Lipoproteins. By D. G. CORNWELL
Introduction . . . . . . . . . . . . . . . . . 168
Composition and Properties of Plasma. Lipoproteins 169
1. Definition of a Lipoprotein Cla.ss. . . . . . 169
2. Homogeneity: Distribution in Size and Shape 169
3. Chylomicrons . . . . . . . . . . . . . . . 171
4. Very Low Density and Low Density Lipoproteins 173
5. High Density Lipoproteins . . . . . . . . . 179
6. The Analysis of Chylomicrons and Lipoproteins 181
References . . . . . . . . . . . . . . . . . . . 182
VIII Contents
Methods lor Separation and Determination of Lipids. By H. WAGENER (With 8 Figures)
Introduction 190
I. Isolation of Lipids . . . . . . . . . . . 190
II. Quantitative Determination of Total Lipids 191
m. Separation of Lipid Classes . . . . . . . 191
a) Fractionation into Polar and Unpolar Lipids . 191
b) Fractionation into Main Lipid Classes .... 192
IV. Separation of Individual Members of Lipid Classes 195
V. Quantitative Determination of Lipid Classes 198
a) Cholesterol and Cholesterol Esters 198
b) Phospholipids . . 199
c) Glycerides. . . . 200
d) Total Fatty Acids 201
e) Free Fatty Acids . 201
f) Bile Acids. . . . 201
g) Other Lipids. . . 202
VI. Determination of Lipoproteins 202
VII. Determination of Lipoprotein Lipase Activity 202
VIII. Normal Lipid Concentrations 203
References . • . . . . . . . . • . . . . . . . 204
Part II. Lipidoses
Clinic, Pathology, Pathophysiology, Genetics
Gangliosidoses. By G. SCHETTLER and W. KABLKE (With 10 Figures)
Introduction • . . . . . . • . . . . . 213
I. Congenital Amaurotic Family Idiocy 215
Definition and Introduction 215
Clinical Manifestations 215
Pathology ....•.. 216
Results of Lipid Analyses 216
Discussion. . . . • . . 217
Diagnosis ....... 217
II. Infantile Amaurotic Family Idiocy (Tay-Sachs Disease) 217
Definition and Introduction 217
Historical Review. . . • . 217
Incidence (Age, Sex, Race) 218
Clinical Manifestations 219
Electroencephalography 219
Cerebrospinal Fluid .. 220
Serum ............... . 220
Enzymes in Plasma and Cerebrospinal Fluid 220
Pathology .. . 221
Brain .. . 221
Eye ... . 222
Other Organs 222
Histology. . .. . .... 222
Membranous Cytoplasmic Bodies 224
Histochemistry . . . . . . . . 224
Contents IX
Results of Lipid Analyses . . . . . . 227
Brain ............ . 227
The Gangliosides in Tay-Sachs Disease 228
Diagnosis ............ . 230
Pathogenetic Aspects . . . . . . . . 230
III. Late-Infantile Amaurotic Family Idiocy . 233
Definition and Introduction 233
Clinical Manifestations 234
Pathology ....... . 234
Results of Lipid Analyses . 236
IV. Juvenile Amaurotic Family Idiocy 237
Definition and Introduction 237
Incidence (Age, Sex, Race) . 238
Clinical Manifestations 238
Cerebrospinal Fluid . . 238
Electroencephalography 238
Hematology 239
Serum .... . 239
Pathology .... . 239
The Stored Material . 240
V_ Adult Amaurotic Family Idiocy 241
Definition and Introduction 241
Results of Lipid Analyses . 241
VI. Neurovisceral Gangliosidoses 242
Definition and Introduction 242
Case Reports. . . . . . . 242
Results of Lipid Analyses . 244
VII. Hurler's Disease (Gargoylism) 245
Definition and Introduction 245
Clinical Manifestations 246
Laboratory Findings .. 248
Pathology ...... . 248
Results of Lipid Analyses 249
Therapy of Gangliosidoses 250
References . . . . . . . . . 251
Gaucher's Disease. By G. SCHETTLER and W. KAHLKE (With 7 Figures)
Definition and Introduction 260
Historical Review. . . . . 260
Incidence (Age, Sex, Race) . 261
Clinical Manifestations. . . 262
Hematology ..... . 264
Other Laboratory Findings 265
Pathology ... 266
Gaucher Cells 266
Spleen .. . 269
Liver ... . 270
Lymph Nodes 270
Bones and Bone .l\-Iarrow 271
Other Organs ..... 273
Central Nervous System 273
Results of Lipid Analyses 274
Serum Lipids 274
Brain Lipids 275
Tissue Lipids 275
X Contents
Chemistry of the Stored Cerebroside . 276
Sphingosine . . . . . . 277
Fatty Acid Pattern 277
Hexose. . . . . . . . 278
Pathogenetic Considerations 278
Treatment 281
References . . . . . . . . 281
Niemann-Pick Disease. By G. SCHETTLER and W. KAHLKE (With 6 Figures)
Definition and Introduction 288
Historical Review. . . . . 288
Incidence (Age, Sex, Race) 289
Clinical Manifestations. . . 290
Neurology ..... . 291
Hematology. . . . . . . 291
Other Laboratory Findings 292
Bones .... . 292
Skin .... .. 293
Eyes .... .. 293
Course and Prognosis 293
Pathology ..... 293
Niemann.Pick Cells 294
Spleen .. . 294
Liver ... . 296
Lymph Nodes 297
Bone Marrow 297
Thymus 297
Lungs ... 298
Kidneys 298
Other Organs . . . . 299
Central Nervous System 299
Results of Lipid Analyses 299
Brain Lipids .. 300
Other Organs . . 302
Serum Lipids . . 303
Pathogenetic Aspects 303
Diagnosis 305
Treatment 305
References 306
Metachromatic Leucodystrophy. By W. KAHLKE (With 3 Figures)
Definition and Introduction 310
Historical Review. . . . . 310
Incidence (Age, Sex, Race) . 311
Clinical Manifestations . 312
Cerebrospinal Fluid 314
Blood .... . 314
Urine ...... . 314
Cholecystography . 315
Pathology ..... . 315
Central Nervous System 315
Extraneural Tissues 316
Kidneys ..... .. 316
