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