scope:

Preface

This book is designed as a source of practical information of use in the diagnosis and management of patients with inherited diseases of metabolism. We have kept the focus, as did Garrod, on the inborn errors. This permits a unity of theme. At the same time, the reality is that genetically-determined human variation in metabolism leads to an enormous variety of clinical expression crossing most of the boundaries of clinical subspecialty.

We want this book to be helpful to physicians at the bedside, in the intensive care unit and in the clinics and offices, as well as to biochemical geneticists and clinical chemists involved in laboratory diagnosis. The atlas format has permitted us to include very many illustrations of patients.Metabolic pathways have been shown with a reductionist or high power view of just that area most relevant to each disease. In addition, the chapters deal with individual diseases. There are introductory chapters to the organic acidemias, the disorders of the urea cycle, the disorders of fatty acid oxidation, the lactic acidemias, the glycogenoses and the mucopolysaccharidoses which provide some general considerations of these areas of metabolism and permit us to avoid some redundancy. With these exceptions each chapter represents defective activity of a single enzyme. Mutations in a single gene can lead to a very large family of different variant enzymes and accordingly very different clinical phenotypes. In general, we have considered this variation in each chapter,with emphasis on the most common expression. In three instances we have given variants separate treatments. There is historical precedent for separate consideration of the Hurler disease from the Scheie and Hurler-Scheie variants and for the separate consideration of mucolipidoses II and III. In the first edition we had chapters for complete deficiency of hypoxanthine guanine phosophoribosyltransferase (HPRT) and the other variants; now that chapter has been divided into two halves.

The rates of discovery of new or previously unrecognized diseases in this field are enormous. In the 1980s we saw for the first time descriptions of many of the currently known disorders of fatty acid oxidation; in the 1990s we saw the numbers of known discrete mitochondrial DNA mutations increase rapidly. Some of these diseases are turning out to be relatively common. Medium-chain acyl CoA dehydrogenase (MCAD) deficiency occurs in approximately 10 000 births, and most patients have the same mutation. On the other hand, although it is clear that in the aggregate the inherited diseases of metabolism make up a sizeable portion of human morbidity and mortality, each individual disease tends to be rarely encountered. Even an expert may find years have elapsed since he last saw a patient with a given disorder, reviewed the literature and ordered it in a way that would help with diagnosis or treatment. It helps to have the relevant information in one place for ready retrieval. This atlas serves that purpose for us.We are hopeful that it will do the same for our readers.

The advent of molecular biologic approaches to genetics and the increasing exploration of the human genome have changed forever the scope of human genetics and the manner in which it is practiced. In the Atlas we have endeavored to seek a balance among the molecular biology and the nature of mutation, the enzymology and intermediary metabolism and clinical practice. Our focus is on the clinician. Algorithms are provided for the logical workup of a patient with lactic acidemia, and disorders of fatty acid oxidation and a systematic approach to the diagnosis of a patient with hyperammonemia.

Medical genetics is now officially recognized in many countries among clinical and laboratory specialties. Trainees preparing themselves for board examinations might want to read the Atlas from cover to cover. We hope that in addition to medical geneticists, pediatricians, neurologists, internists, pathologists and all those who interact with patients with these disorders will find the Atlas of assistance in their practices

The field is moving so rapidly it is an experience to keep current in any disease. There is much in this book that is new, different or virtually unique. Certainly, the pictures are for us a resource. Novel mechanisms of disease have been explored. The many enzyme defects in the congenital disorders of glycosylation are becoming known and with this knowledge recognition of some quite different phenotypes. Mutations have now been identified in the genes for the very strange ethylmalonic aciduria whose petechial exacerbations lead regularly to treatment for meningococcemia. The discovery of this gene, ETHE1 by homozygosity mapping illustrates the powerful new influence of molecular biology and the data provided by the human genome project in this field. The function of this mitochondrial protein remains to be determined. Similarly the Sanjad-Sakati and Al Aqeel-Sewairi syndromes, while not metabolic in the old sense were included because they are illustrations of the way in which new molecular techniques are uncovering novel mechanisms of disease. In the Sanjad-Sakati syndrome a phenotype of endocrineopthy and dysmorphic features is caused by mutations in a tubulin-specific chaperone E (TBLE) which is required for proper folding of -tubulin, the first example to be discovered in human disease resulting from mutation inducing defective folding and assembly of the building blocks of microtubules. In the Al Aqeel-Sewairi syndrome the discovery of mutations in the matrix metalloproteinase (MMP-2) gene not only elucidates this vanishing bone syndrome, but has relevance to many disease processes, such as arthritis, tumor invasion and metastasis.

In the glutamylribose-5-phosphate storage disease the molecule that accumulates and must be detected to identify the disease does not get out of the brain. In I-cell disease and pseudohurler polydystrophy the basic defect is in the processing of lysosomal enzymes to permit their recognition and entry into cellular lysosomes. The fascinating and novel mechanism uncovered in the multiple sulfatase deficiency defect is in an enzyme which catalyzes a posttranslational change of a cysteine moiety in each of the sulfatase enzymes to an aminooxopropionic acid moiety, which change normally converts inactive sulfatase proteins to catalytically-active enzymes

Among the challenges for diagnosis and management highlighted in this volume are the disorders of fatty acid oxidation and the lactic acidemias and mitochondrial disease. The latter include the acronymic disorders resulting from mitochondrial DNA mutation and the Pearson syndrome, which may present in infancy as a pure hematologic disorder. It also includes the newly discovered deficiency of DNA polymerase, which results in a mitochondrial DNA depletion syndrome. The newly recognized disorders of creatine synthesis are a challenge for diagnosis. They are sometimes suspected when the urine is analyzed for organic acids and amino acids, and everything is high, because we base our analyses per mole of creatinine. They may be elegantly demonstrated by nuclear magnetic resonance spectroscopy (NMRS).

The chapter was written by Deborah Marsden, a former fellow at UCSD, now on the faculty at Harvard.

The Atlas was generated by our experience with patients with metabolic disease. We are grateful to the many physicians who have referred these patients to us and to those who have shared their illustrations with us.We are appreciative of the help of many of our fellows and colleagues who have helped us care for and study these patients. They include Drs. Nadia Sakati, Richard Hass, Fred Levine, Robert Naviaux, Jon Wolff and Karen McGowan.

Original artwork was done by Mrs. Frances Bakay and The Office of Learning Resources at UCSD. Images of tandem mass spectrometry were recovered by Mr. Jon Gangoiti of the Biochemical/Genetics Laboratory at UCSD. We are particularly indebted to the work of many: Mrs. Lilia Fernandez, Ms. Sandra Hoffert, Ms. Susan Allen and Ms. Linh Vuong, a medical student at UCSD, for the conversion of handwritten pages into polished typed electronic manuscript. The majority of the text was expertly typed by Ms. Debra Lin, a student at UCSD.