Genetic Disorders and the Fetus Diagnosis, Prevention, and Treatment

About 21 years ago prenatal diagnosis became part of the physician's diagnostic armamentarium against genetic defects. My first monograph in 1973 (The Prenatal Diagnosis of Hereditary Disorders) critically assessed early progress and enunciated basic principles in the systematic approach to prenatal genetic diagnosis. Six years later and under the current title, a subsequent volume provided the first major reference source on this subject. The present second (effectively third) edition, which was urged in view of the excellent reception of the two earlier volumes, reflects the remarkable growth of this new discipline and points to significant and exciting future developments. Notwithstanding these advances, the use of the new tools and techniques for the benefit of at-risk parents has taken many more years than most anticipated. Key factors have been the lack of teaching of human genetics in medical schools in the preceding decades and the difficulty of educating practicing physicians in a new scientific disci­ pline. Even today the teaching of genetics in medical schools leaves much to be desired and this will further delay the introduction of newer genetic advances to the bedside.

1 Genetic Counseling: Prelude to Prenatal Diagnosis.- 1. Introductory Perspectives.- 2. Prerequisites for Genetic Counseling.- 2.1. Introduction.- 2.2. Prerequisites for Genetic Counseling.- 3. Guiding Principles in Genetic Counseling.- 3.1. Accurate Diagnosis.- 3.2. Nondirective Counseling.- 3.3. Concern for the Individual.- 3.4. Truth in Counseling.- 3.5. Confidentiality and Trust.- 3.6. Timing of Genetic Counseling.- 3.7. Parental Counseling.- 3.8. Education.- 4. Genetic Counseling As a Prelude to Prenatal Diagnosis.- 4.1. Informed Consent.- 4.2. Carrier Detection.- 4.3. Special Cases.- 4.4. Special Considerations.- 5. Counseling for “Environmental” Exposures or Maternal Illness.- 6. Psychological Aspects of Genetic Counseling.- 7. Efficacy of Genetic Counseling.- 8. References.- 2 Amniocentesis.- 1. Introduction.- 2. Prerequisites.- 3. Technique of Amniocentesis.- 3.1. Timing.- 3.2. Surgical Aspects.- 3.3. Ultrasound prior to Amniocentesis.- 3.4. Ultrasound Concurrent with Amniocentesis.- 3.5. Multiple Gestations.- 3.6. Selective Feticide.- 3.7. Rh Isoimmunization in Amniocentesis.- 3.8. Discolored Amniotic Fluid.- 4. Safety of Genetic Amniocentesis.- 4.1. Maternal Risks.- 4.2. Fetal Risks.- 4.3. Conclusions Regarding Risks.- 5. References.- 3 Amniotic Fluid.- 1. Introduction.- 2. Amniotic Fluid Dynamics.- 2.1. Formation and Circulation.- 2.2. Volume.- 2.3. Origin.- 3. Biochemical and Other Characteristics of Amniotic Fluid.- 3.1. Proteins.- 3.2. Lipids.- 3.3. Enzymes.- 3.4. Amino Acids.- 4. The Disaccharidases.- 4.1. Introduction.- 4.2. Origin of Amniotic Fluid Disaccharidases.- 4.3. Development of Amniotic Fluid Disaccharidases.- 4.4. Clinical Use of Amniotic Fluid Disaccharidases.- 5. Miscellaneous Biochemical Constituents and Other Characteristics of Amniotic Fluid.- 5.1. Trace Elements.- 5.2. Creatinine.- 5.3. Blood Group Substances.- 5.4. Immunoglobulins.- 6. Antibacterial Activity of Amniotic Fluid.- 6.1. Bacteriostatic Effect.- 6.2. Isolation of Infectious Agents.- 7. Hormones.- 8. References.- 4 Amniotic Fluid Cell Culture.- 1. Introduction.- 2. Amniotic Fluid Cell Types.- 2.1. Cellular Contents of Native Fluids.- 2.2. Colony-Forming Cells: Morphology and Nomenclature.- 2.3. Biochemical Characterization.- 2.4. Intermediate Filament System.- 3. Origin of Colony-Forming Cell Types.- 4. Culture Technique.- 5. Enhancement of Amniotic Fluid Cell Growth.- 5.1. Enrichment Techniques.- 5.2. Growth on Extracellular Matrix Surface.- 5.3. Reduction of Oxygen Supply.- 5.4. Serum Testing.- 5.5. Defined Growth Factor Supplements.- 6. Culture Hazards.- 6.1. Syringe Toxicity.- 6.2. Contamination.- 6.3. Mycoplasma.- 6.4. Plasticware and Media Storage.- 6.5. Incubator Failure.- 7. Perspective.- 8. References.- 5 Prenatal Diagnosis of Chromosome Abnormalities.- 1. Introduction.- 2. Incidence of Chromosome Abnormalities.- 2.1. Data from Live Births.- 2.2. Midtrimester Amniocentesis Data.- 2.3. Data on Spontaneous Abortuses.- 2.4. Data on Induced Abortuses.- 2.5. Data on Stillbirths and Neonatal Deaths.- 3. Indications.- 3.1. Advanced Maternal Age.- 3.2. Advanced Paternal Age (A Disputable Indication).- 3.3. Carrier of a Balanced Structural Rearrangement.- 3.4. Previous Child with Chromosome Abnormalities.- 3.5. Antenatal Sex Determination for Prenatally Undiagnosable X-Linked Disorders.- 3.6. Other Indications.- 4. Technical Considerations for Prenatal Cytogenetic Diagnosis.- 5. Problems and Pitfalls.- 5.1. Chromosome Mosaicism.- 5.2. Maternal Cell Contamination.- 5.3. Chromosome Polymorphisms.- 5.4. De Novo Structural Rearrangement.- 5.5. Supernumerary Marker Chromosomes.- 5.6. Tetraploidy.- 5.7. Problems in Cell Cultures.- 5.8. Twin Pregnancy.- 5.9. Errors in Prenatal Cytogenetic Diagnosis.- 6. Genetic Counseling in Prenatal Cytogenetic Diagnosis.- 7. Concluding Remarks.- 8. References.- 6 The Prenatal Diagnosis of the Fragile X Syndrome.- 1. Introduction.- 1.1. First Reports of the Marker or Fragile X Chromosome.- 1.2. Characterization of the Fragile X Induction System.- 1.3. The Estimated Incidence/Prevalence of the Fragile X Syndrome.- 1.4. The Fragile X Phenotype.- 1.5. Female Carriers.- 1.6. Male Carriers.- 1.7. Histiotypic Distribution of Fragile X.- 2. Worldwide Experience in Fragile X Prenatal Testing.- 2.1. Tissues Used to Detect Positive Cases.- 2.2. Fragile X Induction Systems.- 3. The 5-Fluorodeoxyuridine Fragile X Induction System and Its Effect on Fragile X Frequency and Mitotic Index.- 3.1. Introduction.- 3.2. Temporal and Cell Density Effects on the 5-Fluorodeoxyuridine Fragile X Induction System.- 4. False-Negative and False-Positive Prenatal Fragile X Diagnoses.- 5. The Future.- 5.1. General.- 5.2. DNA Restriction Fragment Length Polymorphisms Can Complement Cytogenetic Fragile X Pre- and Postnatal Diagnoses.- 6. Conclusion.- 7. References.- 7 Disorders of Lipid Metabolism.- 1. Introduction.- 2. GM1 Gangliosidoses.- 3. GM2 Gangliosidoses.- 4. Fabry Disease (Angiokeratoma Corporis Diffusum).- 5. Gaucher Disease.- 6. Metachromatic Leukodystrophy and Multiple Sulfatase Deficiency.- 7. Krabbe Disease (Globoid Cell Leukodystrophy).- 8. Niemann-Pick Disease.- 9. Farber Disease (Acid Ceramidase Deficiency).- 10. Wolman Disease and Cholesterol Ester Storage Disease.- 11. Adrenoleukodystrophy.- 12. Refsum Disease (Phytanic Acid Storage Disease).- 13. Neuronal Ceroid-lipofuscinosis (Batten Disease).- 14. Lipoprotein-Associated Disorders.- 15. References.- 8 Disorders of Mucopolysaccharide Metabolism.- 1. Hurler Syndrome (?-L-Iduronidase Deficiency: Mucopolysaccharidosis IH).- 2. Scheie Syndrome (?-L-Iduronidase Deficiency: Mucopolysaccharidosis IS).- 3. Hurler-Scheie Compound Disease (?-L-Iduronidase Deficiency: Mucopolysaccharidosis IH/S).- 4. Hunter Syndrome (Iduronate Sulfatase Deficiency: Mucopolysaccharidosis II).- 5. Sanfillipo Syndrome (Mucopolysaccharidosis III).- 6. Morquio Syndrome (Mucopolysaccharidosis IV).- 7. Maroteaux-Lamy Syndrome (Mucopolysaccharidosis VI).- 8. ?-Glucuronidase Deficiency (Mucopolysaccharidosis VII).- 9. References.- 9 Disorders of the Metabolism of Amino Acids and Related Compounds.- 1. Introduction.- 2. Urea Cycle Disorders.- 2.1. N-Acetylglutamate Synthetase Deficiency.- 2.2. Carbamylphosphate Synthetase Deficiency.- 2.3. Ornithine Carbamyltransferase Deficiency.- 2.4. Argininosuccinate Synthetase Deficiency (Citrullinemia).- 2.5. Argininosuccinate Lyase Deficiency (Argininosuccinic Aciduria).- 2.6. Arginase Deficiency (Hyperargininemia).- 2.7. Therapy for Urea Cycle Disorders.- 3 Disorders of Ornithine Metabolism.- 3.1. Hyperornithemia, Hyperammonemia, and Homocitrullinuria (HHH Syndrome).- 3.2. Ornithine Aminotransferase Deficiency Associated with Gyrate Atrophy of the Choroid and Retina.- 4 Disorders of Lysine Metabolism.- 4.1. Periodic Hyperlysinemia with Hyperammonemia.- 4.2. Familial Hyperlysinemia.- 4.3. Saccharopinuria.- 5 Disorders of Sulfur Amino Acid Metabolism.- 5.1. Hypermethioninemia.- 5.2. Homocystinuria Due to Cystathionine ?-Synthase Deficiency.- 5.3. ?-Cystathionase Deficiency.- 5.4. Sulfite Oxidase Deficiency.- 5.5. Combined Sulfite Oxidase Deficiency and Xanthine Oxidase Deficiency (A Defect in Molybdenum Metabolism).- 6 Disorders of Phenylalanine Metabolism.- 6.1. Phenylketonuria.- 6.2. Hyperphenylalaninemia Due to Tetrahydrobiopterin Deficiency.- 7 Disorders of Tyrosine Metabolism.- 7.1. Hereditary Tyrosinemia Type I (Hepatorenal Type).- 7.2. Other Types of Tyrosinemia.- 8 Nonketotic Hyperglycinemia.- 9 Disorders of Branched-Chain Amino Acid Metabolism.- 9.1. Hypervalinemia.- 9.2. Hyperleucine-isoleucinemia.- 9.3. Maple Syrup Urine Disease.- 10 Disorders of Organic Acids.- 10.1. Introduction.- 10.2. The ?-Ketothiolase Deficiencies.- 10.3. Propionic Acidemia.- 10.4. Methylmalonic Acidemia.- 10.5. Isovaleric Acidemia.- 10.6. Biotin-Resistant ?-Methylcrotonylglycinuria.- 10.7. 3-Methylglutaconic and 3-Methylglutaric Aciduria.- 10.8. 3-Hydroxy-3-methylglutaryl-CoA Lyase Deficiency.- 10.9. 3-H