Nutrition Management of Inherited Metabolic Diseases: Lessons from Metabolic University

Preface
Disclaimer
Acknowledgments
Contents
Contributors
Part I: Background
1: Introduction to Genetics
1.1 Background
1.2 From Genes to Proteins
1.3 Genetic Variants
1.3.1 Variant Effects on Gene Structure
1.3.2 Variant Effects on Amino Acid Sequence
1.3.3 Variant Effects on the Protein
1.4 Variant Nomenclature
1.5 Genetic Testing
1.5.1 Genetic Testing Technologies
1.5.2 Interpretation of Genetic Testing
1.5.3 Purposes of Genetic Testing
1.6 Genotype and Phenotype
1.7 Single Gene Inheritance Patterns and Pedigrees
1.7.1 Single Gene Inheritance Patterns
1.7.2 Pedigrees
1.8 Summary
References
2: Newborn Screening for Inherited Metabolic Diseases
2.1 Background
2.2 Newborn Screening by Tandem Mass Spectrometry
2.3 Standardization of Newborn Screening
2.4 The Newborn Screening Process
2.5 Limitations of Newborn Screening
2.5.1 Disorders That Present Early in Life
2.5.2 Disorders That Have Risk of False Negatives
2.5.3 Metabolic Disorders Not Included on Newborn Screening
2.6 Future of Newborn Screening
References
3: Pathophysiology of Inherited Metabolic Diseases
3.1 Background
3.2 Pathophysiology of Organs
3.2.1 The Liver
3.2.2 The Muscle
3.2.3 The Kidney
3.2.4 The Brain
References
4: Metabolic Intoxication Syndrome in a Newborn
4.1 Background
4.2 Classification
4.2.1 Disorders Presenting with Intoxication Syndrome
4.2.2 Disorders of Reduced Tolerance to Fasting
4.2.3 Disorders of Mitochondrial Energy Metabolism
4.2.4 Disorders of Neurotransmission
4.2.5 Disorders with Limited Therapeutic Options in Acute Illness
4.3 Suspicion of an Inborn Error of Metabolism in a Neonate
4.4 Presentation of a Newborn with Intoxication Syndrome
4.4.1 Biochemical Diagnostics
4.5 Treating a Neonate with Intoxication Syndrome
4.5.1 Stage 1 – Provision of Glucose, Cessation of Feedings
4.5.2 Stage 2 – Medical Management
4.5.3 Stage 3 – Detoxification
4.5.4 Stage 4 – Promotion of Anabolism
4.5.5 Stage 5 – Other Supportive Treatment
4.6 Summary
References
5: Anabolism: Practical Strategies
5.1 Background
5.2 Importance of Anabolism in Metabolic Diseases
5.3 Fasting and Postprandial Metabolism
5.4 Daily Management
5.5 Acute Episodes and Hospitalization
5.5.1 Home Management
5.5.2 Hospital Management
5.6 Summary
References
6: Protein Requirements in Inherited Metabolic Diseases
6.1 Background
6.2 Biological Value and Digestibility of Protein Composition
6.3 Protein Turnover
6.4 Other Factors Influencing Protein Utilization
6.5 Protein Requirements for the General Population
6.6 Protein Requirements in Inherited Metabolic Diseases
6.6.1 Special Considerations in Protein Requirements
6.7 Medical Foods/Protein Supplements in Management of Aminoacidopathies, Organic Acidemias, and Urea Cycle Disorders
6.8 Assessing Protein Sufficiency and Plasma Amino Acids
6.9 Summary
References
7: Laboratory Evaluations in Inherited Metabolic Diseases
7.1 Background
7.2 Routine Laboratory Tests
7.2.1 Acidosis
7.2.2 Ammonia
7.2.3 Glucose and Ketones
7.2.4 Lactate
7.3 Metabolic Laboratory Tests
7.3.1 Amino Acid Analysis
7.3.2 Organic Acid Profile
7.3.3 Carnitine Profile
7.3.4 Acylcarnitine Profile
7.3.5 Metabolomics
7.4 Confirmatory Testing
References
8: Gene Therapy for Inherited Metabolic Diseases
8.1 Background
8.2 Inborn Errors of Metabolism
8.3 Overview of Gene-Based Therapy
8.4 Routes of Administration for Gene-Based Therapy
8.4.1 Ex Vivo Gene Replacement Therapy
8.4.2 In Vivo Gene Replacement Therapy
8.5 Delivery Vehicles for Gene-Based Therapy
8.5.1 Viral-Mediated Gene-Based Therapy
8.5.2 Nonviral Gene Transfer
8.6 Other Gene-Based Therapies
8.6.1 Oligonucleotide Therapy and Genome Editing
8.6.2 mRNA Therapy
8.7 Approved Gene Therapies
8.8 Clinical Trials in Inborn Errors of Metabolism (Listed in clinicaltrials.gov)
8.9 Limitations, Complications, Challenges, and Future of Gene-Based Therapy
References
Part II: Aminoacidopathies
9: Phenylketonuria: Phenylalanine Neurotoxicity
9.1 Background
9.2 Biochemistry
9.3 Genetics
9.4 Diagnosis
9.5 Clinical Presentation
9.6 Nutrition Management
9.7 Phenylalanine Neurotoxicity
9.8 White Matter Pathology
9.9 Gray Matter Pathology
9.10 Summary
References
10: Nutrition Management of Phenylketonuria
10.1 Background
10.2 Nutrition Management of an Infant with PKU
10.2.1 Overview of Nutrition Management
10.2.2 Initiating Diet for a Newly Diagnosed Neonate
10.2.3 Monitoring Blood Phenylalanine to Adjust the Diet Prescription
10.2.4 Initiating Complementary Feedings
10.2.5 Simplified Diet
10.3 Nutrition Management of PKU Beyond Infancy
10.3.1 Returning to Diet
10.3.2 Acute Management
10.4 Medical Foods for PKU
10.4.1 Glycomacropetide (GMP)-Based Medical Foods
10.5 Metabolic and Nutrition Monitoring
10.6 Large Neutral Amino Acids as an Alternative Diet Treatment for PKU
10.7 Tetrahydrobiopterin Treatment for PKU
10.8 Summary
10.9 Diet Calculation Examples for an Infant with PKU
References
11: Medical and Nutrition Management of Phenylketonuria: Pegvaliase
11.1 Background
11.2 Human Clinical Trials
11.3 Efficacy and Safety
11.4 Hypophenylalaninemia
11.5 Immunogenicity
11.6 Practical Use of Pegvaliase in Phenylketonuria
11.7 Nutrition Management of Patients with PKU Treated with Pegvaliase
11.7.1 Nutrition Management During Pegvaliase Initiation and Titration
11.7.2 Nutrition Management During Diet Normalization
11.7.3 Nutrition Management After Diet Normalization
References
12: Nutrition Management of Maternal Metabolic Disorders
12.1 Background
12.2 Maternal Phenylketonuria
12.3 Nutrition Management of MPKU
12.3.1 Phenylalanine and Tyrosine
12.3.2 Protein
12.3.3 Energy
12.3.4 Fat and Essential Fatty Acids
12.3.5 Vitamins and Minerals
12.4 Nutrition Management in Lactation and the Postpartum Period
12.5 Medical Management in Maternal PKU
12.5.1 Sapropterin Dihydrocloride
12.5.2 Pegvaliase
12.6 Monitoring
12.7 Pregnancy in Maple Syrup Urine Disease
12.8 Pregnancy in Propionic Acidemia
12.9 Pregnancy in Methylmalonic Acidemia
12.10 Pregnancy in Urea Cycle Disorders
12.11 Overview of Recommendations for the Nutrition Management for Pregnancies in Women with Disorders of Protein Metabolism
12.11.1 Maintain Normal Maternal Weight Gain During Pregnancy
12.11.2 Maintain Adequate Energy and Protein Nutriture Throughout Pregnancy
12.11.3 Maintain Plasma Amino acid Concentrations Within the Reference Range and Anticipate a Higher Intact Protein Tolerance as Pregnancy Progresses
12.11.4 Plan Ahead for Intercurrent Illness and Complications Affecting Dietary Intake
12.11.5 Refer to an Obstetric Clinic Specializing in High-Risk Pregnancy
12.11.6 Anticipate Postpartum Catabolism
12.12 Pregnancy in Fatty Acid Oxidation Disorders
12.13 Pregnancy in Disorders of Carbohydrate Metabolism
12.14 Summary
12.15 Case Reports
12.16 Diet Example for a Pregnant Woman with PKU
References
13: Hereditary Tyrosinemia
13.1 Background
13.2 Biochemistry
13.3 Diagnosis
13.4 Clinical Presentation and Natural History
13.5 Pharmaceutical Treatment of Tyrosinemia Type 1
13.6 Nutrition Management
13.7 Monitoring
13.8 Summary
References
14: Homocystinuria and Cobalamin Disorders
14.1 Homocystinuria Background
14.2 Biochemistry
14.3 Clinical Presentation
14.3.1 Eyes
14.3.2 Skeletal
14.3.3 Central Nervous System
14.3.4 Vascular System
14.3.5 Other
14.4 Natural History
14.5 Diagnosis
14.6 Pathophysiology
14.7 Management
14.8 Monitoring and Outcome
14.9 Cobalamin Disorders: Background
14.10 Clinical Presentation
14.11 Management and Outcome
References
15: Nutrition Management of Homocystinuria and Cobalamin Disorders
15.1 Background
15.2 Nutrition Management
15.2.1 Chronic Management of HCU
15.3 Adjunct Treatments for Homocystinuria
15.4 Monitoring
15.4.1 Growth
15.4.2 Laboratory Monitoring
15.5 Acute Nutrition Management
15.6 Pregnancy
15.7 Homocystinuria Summary
15.8 Background Cobalamin Disorders
15.9 Nutrition Management
15.9.1 Chronic Management Cobalamin Disorders
15.10 Adjunct Therapy for Cobalamin
15.11 Monitoring
15.12 Acute Management
15.13 Cobalamin Disorders Summary
15.14 Diet Example Diet Calculation Example for an Infant with Vitamin B6 Nonresponsive Homocystinuria
References
16: Nutrition Management of Urea Cycle Disorders
16.1 Background
16.2 Nutrition Management
16.2.1 Chronic Nutrition Management
16.2.2 Acute Nutrition Management
16.2.2.1 Nutrition Management During Hospitalization
16.2.2.2 Nutrition Management During Illness at Home
16.3 Monitoring
16.3.1 Plasma Amino Acids Related to Dietary Intake
16.3.2 Additional Plasma Amino Acids to Evaluate Based on Diagnosis
16.4 Transplantation
16.5 New Treatment Options
16.6 Summary
16.7 Diet Calculation Example
References
17: Nutrition Management of Maple Syrup Urine Disease
17.1 Background
17.2 Nutrition Management
17.2.1 Chronic Nutrition Management
17.2.2 Acute Nutrition Management
17.3 Monitoring
17.4 Transplantation
17.5 Summary
17.6 Diet Calculation Example
17.6.1 MSUD Diet Calculation Example Using Standard Infant Formula as the Source of Leucine and Intact Protein
References
Part III: Organic Acidemias
18: Organic Acidemias
18.1 Background
18.2 Clinical Presentation
18.2.1 Severe Neonatal Onset Form
18.2.2 Chronic Late Onset Form
18.2.3 Laboratory Studies and Diagnosis
18.2.4 Complications
18.3 Pathophysiology
18.4 Management
18.5 Monitoring
18.6 Summary
References
19: Glutaric Acidemia Type I: Diagnosis and Management
19.1 Background
19.2 Clinical, Genetic, and Biochemical Findings
19.3 Diagnosis and Management
19.4 Treatment
19.5 Summary
References
20: Nutrition Management of Glutaric Acidemia Type 1
20.1 Background
20.2 Nutrition Management
20.2.1 Chronic Nutrition Management
20.2.2 Acute Nutrition Management
20.3 Monitoring
20.4 Diet After the Age of 6
20.5 Summary
20.6 Diet Calculation Example
References
21: Nutrition Management of Propionic Acidemia and Methylmalonic Acidemia
21.1 Background
21.2 Nutrition Management
21.2.1 Initial Nutrition Management of the Acutely Ill Newborn
21.2.2 Chronic Nutrition Management
21.3 Adjunct Treatments for Propionic Acidemia and Methylmalonic Acidemia
21.4 Monitoring
21.4.1 Nutritional Evaluation
21.4.2 Anthropometrics
21.4.3 Laboratory Monitoring
21.5 Acute Nutrition Management During Illness
21.6 Long-Term Complications
21.7 Transplantation
21.8 Summary
21.9 Diet Case Examples
References
Part IV: Fatty Acid Oxidation Disorders
22: Fatty Acid Oxidation Disorders
22.1 Background
22.2 Biochemistry
22.2.1 Carnitine Cycle
22.2.2 Fatty Acid Beta-Oxidation
22.2.3 Ketogenesis and Ketone Utilization
22.3 Phenotypic Overview of Fatty Acid Oxidation Disorders
22.4 Diagnostic Testing
22.5 Overview of Selected Fatty Acid Oxidation Disorders
22.5.1 Medium Chain Acyl-Coenzyme A Dehydrogenase (MCAD) Deficiency
22.5.2 Long Chain 3-Hydroxyacyl-Coenzyme A Dehydrogenase (LCHAD) Deficiency
22.5.3 Very Long Chain Acyl-Coenzyme A Dehydrogenase (VLCAD) Deficiency
22.6 Overview of Ketogenesis and Ketolysis Defects
22.6.1 Ketogenesis
22.6.2 Ketolysis Defects
22.7 Summary
References
23: Nutrition Management of Fatty Acid Oxidation Disorders
23.1 Background
23.2 Management of Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD)
23.2.1 Chronic Nutrition Management
23.2.2 Treating Illness
23.2.3 Fasting
23.2.4 Diet Modifications
23.2.5 Diet After Infancy
23.2.6 Supplements
23.2.7 Diet for Exercise
23.3 Monitoring of Patients with LC-FAOD
23.4 Nutrition Management of Medium-Chain Acyl Co-A Dehydrogenase Deficiency (MCAD)
23.4.1 Chronic Management
23.5 Acute Nutrition Management in FAOD (MCAD and LC-FAOD)
23.6 Summary
23.7 Diet Calculations Examples
References
Part V: Disorders of Carbohydrate Metabolism
24: Nutrition Management of Galactosemia
24.1 Background
24.2 Nutrition Management
24.3 Monitoring
24.4 Summary
References
25: Glycogen Storage Diseases
25.1 Background
25.2 Glycogen Storage Diseases
25.2.1 Glycogen Storage Diseases Primarily Involving the Liver
25.2.1.1 Glycogen Storage Disease Type I
25.2.1.2 Glycogen Storage Diseases Type VI
25.2.2 Glycogen Storage Diseases Involving Both Liver and Muscle
25.2.2.1 Glycogen Storage Disease Type III: Debranching Enzyme Deficiency
25.2.2.2 Glycogen Storage Diseases Type IX
25.2.2.3 Glycogen Storage Disease Type IV: Branching Enzyme Deficiency
25.2.3 Selected Glycogen Storage Disease Primarily Involving the Muscle
25.2.3.1 Glycogen Storage Diseases Type II (Pompe Disease, Acid α-1,4 Glucosidase Deficiency)
25.2.3.2 Glycogen Storage Disease Type V (Muscle Phosphorylase Deficiency, McArdle Disease)
25.3 Summary
References
26: Nutrition Management of Glycogen Storage Disease
26.1 GSD Background
26.2 GSD Type I Background
26.3 Nutrition Management GSD Type I
26.3.1 Diet Principles for Infants
26.3.2 Nutrition Assessment and Diet Composition
26.3.3 Fasting and Overnight Feedings
26.3.4 Supplements for GSD Type I
26.3.5 Cornstarch Therapy for GSD Type I
26.3.6 Glycosade® Therapy for GSD Type I
26.4 Nutrition Management in Special Circumstances
26.4.1 Exercise
26.4.2 Treating Hypoglycemia and Illness
26.4.3 Monitoring
26.5 GSD Type III Background
26.6 Nutrition Management GSD Type III
26.6.1 Cornstarch Therapy for GSD Type III
26.6.2 Glycosade® Therapy for GSD Type III
26.6.3 Supplements for GSD Type III
26.6.4 Adjunct Therapy
26.7 Blood Glucose Monitoring
26.8 Summary
26.9 Diet Calculation Example
References
Appendix A. Nutrient Composition of Frequently Used Parenteral Fluids
Carbohydrate
Protein
Fat
Appendix B. Maintenance Fluid Requirements
Appendix C. Energy Needs Required for Anabolism During Acute Illness
Appendix D. Dietary Reference Intakes
Appendix E. Carnitine in Inherited Metabolic Diseases
Carnitine
The Carnitine Shuttle
L-Carnitine Food Sources and Supplementation
Appendix F. Quick Guide to Acylcarnitine Profiles
Appendix G. Simplified Diet
Appendix H. Interpreting Quantitative Fatty Acid Profiles
Plasma Fatty Acids
Appendix I. Calculation of Glucose Infusion Rate and Cornstarch Dosing for Patients with Glycogen Storage Disease
Example GIR Calculations
Example 1
Example 2
Current Dose
New Dose
Appendix J. Guide to Counting Carbohydrates for Patients with GSD Type 1
Appendix K: At-A-Glance
K-1 Glutaric Aciduria
K-2 Homocystinuria
K-3 Maple Syrup Urine Disease
K-4 Methylmalonic acidemia/ Propionic acidemia
K-5 Phenylketonuria
K-6 Tyrosinemia
K-7 Urea Cycle Disorder
K-8 Very Long-Chain Acyl-CoA Dehydrogenase Deficiency
Index