Metabolic Disorders Chapter 28 1
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 2
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 3
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 4
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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 6
Metabolic Disorders Clinical manifestations Summarized in Table 28.1 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) 7
Metabolic Disorders Clinical manifestations diagnosis Laboratory studies see Table 28.2 Routine Hypoglycemia, acid-base balance, hyperammonemia, ketosis Specialized studies Require special lab Directed analysis for amino acids or organic acids 8
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 9
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 10
Amino Acid Disorders Phenylketonuria (PKU) Isovaleric acidemia (IVA) Maple syrup urine disease (MSUD) Others - see Table 28.3 11
Amino Acid Disorders Phenylketonuria (PKU) most common Absence of phenylalanine hydroxylase enzyme Inability to convert phenylalanine to tyrosine Tyrosine becomes conditionally essential See Fig. 28.2 12
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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 14
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 15
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 16
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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 18
Amino Acid Disorders PKU Adjunct Therapies Antibiotics Carnitine Sodium benzoate Sodium phenylbutyrate 19
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 See Fig. 28.3 20
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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 22
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 23
Urea Cycle Disorders Nutrition Interventions Protein adjustment to account for severity, age, growth rate, and individual preferences without any extra, see Table 28.7 Supplemental arginine for most May use essential amino acid mixture to replace natural sources 25-30% of protein intake should be essential amino acids 24
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 Table 28.8 25
Urea Cycle Disorders Adjunct therapies Liver transplantation Alternative pathway therapy 26
Mitochondrial Disorders Results from defects either in the respiratory chain or from defects affecting overall number and function of the mitochondria MELAS or NARP See Table 28.9 for related conditions 27
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 28
Mitochondrial Disorders Respiratory Chain Five complexes that undergo changes in their oxidative state to produce ATP See Figure 28.4 Defects lead to: Decreased energy production Hypotonia, developmental delay, failure to thrive 29
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Mitochondrial Disorders Nutrition Intervention No definite treatment Use of vitamin cofactors in pharmacological amounts see Table 28.10 100-1000 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 31
Mitochondrial Disorders Adjunct therapies Carnitine and glycine conjugate with toxic metabolites, removing them from body 32
Disorders of Vitamin Metabolism Needed as cofactors for enzymatic reactions, antioxidants, or electron receptors Pharmacologic dose may be sufficient to maintain normal enzymatic function 33
Disorders of Vitamin Metabolism Nutritional Interventions Methylmalonic acidemia responsive to B 12 Holocarboxylase synthetase deficiency and biotinidase deficiency - responsive to biotin 34
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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 36
Disorders of Carbohydrate Metabolism Problems processing simple sugars galactose and fructose, or glycogen storage diseases Summary of disorders and clinical symptoms see Table 28.11 37
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 38
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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 40
Galactosemia Nutrition Interventions Exclusion of galactose/ lactose from diet Immediate reversal of symptoms results Exclusion of human milk, cow s milk Substitution of casein hydrolysatecontaining formula Infant soy formulas Learn other potential dietary and drug sources of galactose See Table 28.12 41
Galactosemia Nutrition concerns Provision of alternative sources of missing nutrients: vitamin D, calcium Calcium supplements Meet kcal, protein, vitamin and mineral needs 42
Hereditary Fructose Intolerance Deficiency of fructose 1 phosphate aldolase Accumulation in tissues containing fructokinase, causing depletion of inorganic phosphate and ATP Fructose-induced hypoglycemia d/t ingestion of fructose, sucrose, or sorbitol in diet 43
Hereditary Fructose Intolerance Clinical manifestations Vomiting Poor feeding, diarrhea, failure to thrive Hepatomegaly, bleeding tendency, jaundice, edema, ascites 44
Hereditary Fructose Intolerance Nutrition Intervention With fructose-free diet vomiting and bleeding tendency disappear immediately Hepatomegaly and steatosis will disappear between 5-10 years 45
Hereditary Fructose Intolerance Nutrition Concerns Vitamin supplement may be indicated Requires strict avoidance for life of all dietary fructose and sucrose Aversion to sweets may develop 46
Glycogen Storage Diseases Deficiencies of enzymes that regulate the synthesis or degradation of glycogen (8 types) Most related to deficient activity in conversion of glycogen to glucose 6 phosphate Results in abnormal glycogen deposition in liver and muscle See Table 28.13 47
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Glycogen Storage Diseases GSD1 most commonly diagnosed Deficiency of enzyme glucose 6 phosphatase resulting in hypoglycemia Low blood glucose results in short periods of fasting (2-4 hours) Elevations in lipids, lactate, uric acid Hepatomegaly Chronic lactic acidosis, poor growth Osteoporotic bones, delayed bone age 49
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Glycogen Storage Diseases Nutrition Interventions GSD1 Frequent oral feedings, high in CHO to maintain glucose > 70 mg/dl Daytime meals followed by continuous drip nocturnal enteral feedings Cornstarch - 1-2 g/kg body weight every 3-6 hours 51
Glycogen Storage Diseases Nutrition Concerns GSD1 Availability of high-cho snacks at all times Illness can be life threatening Adjustment to decreased oral intake Multivitamin/ mineral supplement Calcium and iron supplementation 52
Disorders of Fat Metabolism Defect in enzymes which allows transport of fatty acids into the mitochondria; specific to short-, medium- or long-chain fatty acids See Table 28.14 disorders Fatty acids not utilized resulting in hypoglycemia, hyperammonemia, death MCADD most common Deficiencies of carnitine metabolism 53
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Disorders of Fat Metabolism Nutrition Intervention Prevention of fasting Limiting intake of fatty acids Providing alternate substrate for metabolism (CHO, protein) Include complex CHO vs. simple to maintain euglycemia 55
Disorders of Fat Metabolism Nutrition Intervention LCHADD restrict long-chain fatty acids to no more than 15% of kcal Supplement with MCT MCADD avoidance of fasting, feed every 3 hours Monitor blood glucose levels Do not use MCT oil 56
Disorders of Fat Metabolism Nutrition Concerns Overrestriction of fat Essential fatty acid deficiency Excessive weight gain Maximize fluid intake Carnitine used to detoxify, given as supplement 57