Metabolic Disorders - Cengage3 © 2007 Thomson - Wadsworth Metabolic Disorders • Inheritance 9Most inborn errors are autosomal recessive •Carrier parents have a 25% chance of an

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© 2007 Thomson - Wadsworth

Metabolic Disorders

Chapter 28

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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

• InheritanceMost inborn errors are autosomalrecessive• Carrier parents have a 25% chance of an

affected childMutations – 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 orChanges in binding site of cofactorPrecursors accumulated d/t block or impaired feedback inhibitionToxic metabolites produced as a result of the build upOr deficiency of needed end productSecondary nutritional deficiencies

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Metabolic Disorders

• Diagnosis/ Newborn ScreeningNonselective screening – screening all newborns for a limited number of common inborn errorsSelective – testing of an individual known to be at increased risk (e.g. sibling)All states screen for PKU, variability in other disorders screenedTandem mass spectroscopy – allows clinicians to screen for > 30 disorders

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Metabolic Disorders• Clinical manifestations

Summarized in Table 28.1Usually appear 24 hours or more after birth, attributed to ingestion of precursor substrate of defective enzymeCNS symptoms, poor growth, failure to thrive, developmental delays, specific neurological deficitsMay have blatant signs (i.e. unusual odor)

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Metabolic Disorders

• Clinical manifestations – diagnosisLaboratory studies – see Table 28.2Routine • Hypoglycemia, acid-base balance,

hyperammonemia, ketosis

Specialized studies• Require special lab• Directed analysis for amino acids or

organic acids

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Metabolic Disorders

• Approaches to TreatmentAcute 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 TreatmentChronic 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 - see Table 28.3

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• Phenylketonuria (PKU) – most common

Absence of phenylalanine hydroxylaseenzymeInability to convert phenylalanine to tyrosineTyrosine becomes conditionally essential See Fig. 28.2

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• Phenylketonuria (PKU) Results in metal retardation, severe behavioral problems, seizures, eczemaMusty or mousy odorToxic to brain – demyelination of white matterDecreased production of serotonin, epinephrine, norepinephrine, dopamine, GABA

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• PKU – Nutrition InterventionsRestriction of dietary proteinSynthetic formula supplying all essential amino acids except offending amino acidsBlood phenylalanine target levels more restrictive for children up to age 12

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• PKU – Nutrition InterventionsAssess kcal and protein needsAmount of allowed phenylalanine determined by enzymatic activity and blood levelsAllow as much protein as possible for adequate growth from fruits, vegetables, limited amounts of grainsBalance provided by metabolic formulas

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• PKU – Nutritional ConcernsRisk for nutritional deficienciesGrowth retardationBone statusAmino acid deficienciesOverrestrictionMetabolic control during pregnancy

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• PKU – Adjunct TherapiesAntibioticsCarnitineSodium benzoateSodium 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• See Fig. 28.3

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• 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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• Acute Treatment HemodialysisSodium benzoate and sodium phenylacetate to scavenge excess ammoniaIV fluids, avoiding overhydrationCaloric supplementationGlucose, intralipidsComplete protein restriction for 24-48 hours

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• Nutrition InterventionsProtein adjustment to account for severity, age, growth rate, and individual preferences without any extra, see Table 28.7Supplemental arginine for mostMay use essential amino acid mixture to replace natural sources25-30% of protein intake should be essential amino acids

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• Nutrition ConcernsAmino acid intake must be balancedRisk of micronutrient deficiency• Iron, zinc

Adequate energy intakeNutrition support may be neededContinuous monitoringSee flow sheet example – Table 28.8

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• Adjunct therapiesLiver transplantationAlternative 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• See Table 28.9 for related conditions

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• DiagnosisDNA mutation testingSkin and muscle tissue histological and biochemical analysis

• Disorders includeFatty acid transport disordersFatty acid oxidation defectsPyruvate complex disordersRespiratory chain defects

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• 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

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• Nutrition InterventionNo definite treatmentUse 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, CoQ10 – artificial electron receptors

and transporters

Frequent feedings recommended

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• Adjunct therapiesCarnitine 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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• Nutritional InterventionsMethylmalonic acidemia –responsive to B12

Holocarboxylase synthetasedeficiency and biotinidasedeficiency - responsive to biotin

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• Nutritional ConcernsPharmacological doses of vitamins should be treated as “drugs”Use of “megavitamin” supplements in random fashion discouragedToxicity a concern for fat-soluble vitaminsComplianceCost

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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 – see Table 28.11

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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 feedingsAnorexia, failure to gain weight or growCirrhosis, 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 InterventionsExclusion of galactose/ lactose from diet• Immediate reversal of symptoms results

Exclusion of human milk, cow’s milk …Substitution of casein hydrolysate-containing formulaInfant soy formulasLearn other potential dietary and drug sources of galactose• See Table 28.12

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Galactosemia

• Nutrition concernsProvision of alternative sources of missing nutrients: vitamin D, calciumCalcium supplementsMeet kcal, protein, vitamin and mineral needs

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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

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• Clinical manifestationsVomitingPoor feeding, diarrhea, failure to thriveHepatomegaly, bleeding tendency, jaundice, edema, ascites

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• Nutrition InterventionWith fructose-free diet vomiting and bleeding tendency disappear immediatelyHepatomegaly and steatosis will disappear between 5-10 years

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• Nutrition ConcernsVitamin supplement may be indicatedRequires strict avoidance for life of all dietary fructose and sucroseAversion to sweets may develop

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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

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• 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

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• Nutrition Interventions – GSD1Frequent oral feedings, high in CHO to maintain glucose > 70 mg/dLDaytime meals followed by continuous drip nocturnal enteralfeedingsCornstarch - 1-2 g/kg body weight every 3-6 hours

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• Nutrition Concerns – GSD1Availability of high-CHO snacks at all timesIllness can be life threateningAdjustment to decreased oral intakeMultivitamin/ mineral supplementCalcium and iron supplementation

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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

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• Nutrition InterventionPrevention of fastingLimiting intake of fatty acidsProviding alternate substrate for metabolism (CHO, protein)Include complex CHO vs. simple to maintain euglycemia

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• Nutrition InterventionLCHADD – restrict long-chain fatty acids to no more than 15% of kcalSupplement with MCTMCADD – avoidance of fasting, feed every 3 hoursMonitor blood glucose levelsDo not use MCT oil

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• Nutrition ConcernsOverrestriction of fatEssential fatty acid deficiencyExcessive weight gainMaximize fluid intakeCarnitine used to detoxify, given as supplement

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Metabolic Disorders - Cengage3 © 2007 Thomson - Wadsworth Metabolic Disorders • Inheritance 9Most inborn errors are autosomal recessive •Carrier parents have a 25% chance of an