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  • Metabolic Disorders KNH 413
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  • Metabolic Disorders Inborn errors of metabolism group of diseases that affect a wide variety of metabolic processes; defective processing or transport of amino acids, fatty acids, sugars or metals caused by a defect in the activity of an enzyme
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  • Metabolic Disorders Inheritance Most inborn errors are autosomal recessive Carrier parents have a 25% chance of an affected child Mutations permanent, transmissible changes in the genetic material Differences in degree of stability and activity of enzyme Severity described by time of onset Classical form most severe
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  • Metabolic Disorders Impaired Metabolism - Pathophysiology Deficient or absent enzyme activity or Changes in binding site of cofactor Precursors accumulated d/t block or impaired feedback inhibition Toxic metabolites produced as a result of the build up Or deficiency of needed end product Secondary nutritional deficiencies
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  • Metabolic Disorders Diagnosis/ Newborn Screening Nonselective screening screening all newborns for a limited number of common inborn errors Selective testing of an individual known to be at increased risk (e.g. sibling) All states screen for PKU, variability in other disorders screened Tandem mass spectroscopy allows clinicians to screen for > 30 disorders
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  • Metabolic Disorders Clinical manifestations Usually appear 24 hours or more after birth, attributed to ingestion of precursor substrate of defective enzyme CNS symptoms, poor growth, failure to thrive, developmental delays, specific neurological deficits May have blatant signs (i.e. unusual odor)
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  • Metabolic Disorders Clinical manifestations diagnosis Laboratory studies Routine Hypoglycemia, acid-base balance, hyperammonemia, ketosis Specialized studies Require special lab Directed analysis for amino acids or organic acids
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  • 2007 Thomson - Wadsworth
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  • Metabolic Disorders Approaches to Treatment Acute therapy Correction of acid-base balance and hydration of immediate importance Maintenance of adequate kcal to prevent tissue catabolism Offending metabolites restricted
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  • Metabolic Disorders Approaches to Treatment Chronic Therapy Restriction of precursors Replacement of end products Providing alternate substrates for metabolism Use of scavenger drugs to remove toxic by-products Supplementation of vitamins or other cofactors
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  • Amino Acid Disorders Phenylketonuria (PKU) Isovaleric acidemia (IVA) Maple syrup urine disease (MSUD) Others
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  • 2007 Thomson - Wadsworth
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  • Amino Acid Disorders Phenylketonuria (PKU) most common Absence of phenylalanine hydroxylase enzyme Inability to convert phenylalanine to tyrosine Tyrosine becomes conditionally essential
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  • Amino Acid Disorders Phenylketonuria (PKU) Results in metal retardation, severe behavioral problems, seizures, eczema Musty or mousy odor Toxic to brain demyelination of white matter Decreased production of serotonin, epinephrine, norepinephrine, dopamine, GABA
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  • Amino Acid Disorders PKU Nutrition Interventions Restriction of dietary protein Synthetic formula supplying all essential amino acids except offending amino acids Blood phenylalanine target levels more restrictive for children up to age 12
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  • Amino Acid Disorders PKU Nutrition Interventions Assess kcal and protein needs Amount of allowed phenylalanine determined by enzymatic activity and blood levels Allow as much protein as possible for adequate growth from fruits, vegetables, limited amounts of grains Balance provided by metabolic formulas
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  • Amino Acid Disorders PKU Nutritional Concerns Risk for nutritional deficiencies Growth retardation Bone status Amino acid deficiencies Overrestriction Metabolic control during pregnancy
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  • Amino Acid Disorders PKU Adjunct Therapies Antibiotics Carnitine Sodium benzoate Sodium phenylbutyrate
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  • Urea Cycle Disorders Impaired capacity to excrete nitrogen in the form of urea Cascade of enzymatic reactions which converts ammonia to urea can be blocked Or a depletion of an amino acid essential to the function of the cycle can result Causing hyperammonemia
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  • 2007 Thomson - Wadsworth
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  • Urea Cycle Disorders Hyperammonia may cause loss of appetite, cyclical vomiting, lethargy, learning difficulties, behavioral abnormalities, severe retardation May require daily assistance, tube feedings, and wheelchairs
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  • Urea Cycle Disorders Acute Treatment Hemodialysis Sodium benzoate and sodium phenylacetate to scavenge excess ammonia IV fluids, avoiding overhydration Caloric supplementation Glucose, intralipids Complete protein restriction for 24-48 hours
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  • Urea Cycle Disorders Nutrition Interventions Protein adjustment to account for severity, age, growth rate, and individual preferences without any extra Supplemental arginine for most May use essential amino acid mixture to replace natural sources 25-30% of protein intake should be essential amino acids
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  • Urea Cycle Disorders Nutrition Concerns Amino acid intake must be balanced Risk of micronutrient deficiency Iron, zinc Adequate energy intake Nutrition support may be needed Continuous monitoring See flow sheet example
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  • Urea Cycle Disorders Adjunct therapies Liver transplantation Alternative pathway therapy
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  • Mitochondrial Disorders Results from defects either in the respiratory chain or from defects affecting overall number and function of the mitochondria MELAS or NARP
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  • 2007 Thomson - Wadsworth
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  • Mitochondrial Disorders Diagnosis DNA mutation testing Skin and muscle tissue histological and biochemical analysis Disorders include Fatty acid transport disorders Fatty acid oxidation defects Pyruvate complex disorders Respiratory chain defects
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  • Mitochondrial Disorders Respiratory Chain Five complexes that undergo changes in their oxidative state to produce ATP Defects lead to: Decreased energy production Hypotonia, developmental delay, failure to thrive
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  • Mitochondrial Disorders Nutrition Intervention No definite treatment Use of vitamin cofactors in pharmacological amounts 100-1000 times DRI for age Riboflavin and thiamin cofactors Vitamin E and lipoic acid antioxidants Vitamins C, K, CoQ 10 artificial electron receptors and transporters Frequent feedings recommended
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  • 2007 Thomson - Wadsworth
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  • Mitochondrial Disorders Adjunct therapies Carnitine and glycine conjugate with toxic metabolites, removing them from body
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  • Disorders of Vitamin Metabolism Needed as cofactors for enzymatic reactions, antioxidants, or electron receptors Pharmacologic dose may be sufficient to maintain normal enzymatic function
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  • Disorders of Vitamin Metabolism Nutritional Interventions Methylmalonic acidemia responsive to B 12 Holocarboxylase synthetase deficiency and biotinidase deficiency - responsive to biotin
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  • 2007 Thomson - Wadsworth
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  • Disorders of Vitamin Metabolism Nutritional Concerns Pharmacological doses of vitamins should be treated as drugs Use of megavitamin supplements in random fashion discouraged Toxicity a concern for fat-soluble vitamins Compliance Cost
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  • Disorders of Carbohydrate Metabolism Problems processing simple sugars galactose and fructose, or glycogen storage diseases Summary of disorders and clinical symptoms
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  • Galactosemia Enzyme defect in galactose metabolism leading to failure to thrive, hepatomegaly, life-threatening sepsis in newborn period Vomiting, jaundice upon initiation of milk feedings Anorexia, failure to gain weight or grow Cirrhosis, ascites, edema, bleeding problems, enlarged spleen if milk feedings continue
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  • Galactosemia Many states screen for it Defect is in conversion of galactose to glucose 1 phosphate G1P accumulates in tissue Clinical manifestations result
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  • Galactosemia Nutrition Interventions Exclusion of galactose/ lactose from diet Immediate reversal of symptoms results Exclusion of human milk, cows milk Substitution of casein hydrolysate-containing formula Infant soy formulas Learn other potential dietary and drug sources of galactose See Table 28.12
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  • 2007 Thomson - Wadsworth
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