Metabolic Disorders KNH 413. Metabolic Disorders Inborn errors of metabolism – group of diseases that affect a wide variety of metabolic processes; defective.

Metabolic Disorders

KNH 413

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

Metabolic Disorders

InheritanceMost inborn errors are autosomal recessive

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

Metabolic Disorders

Impaired Metabolism - PathophysiologyDeficient 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

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

Metabolic DisordersClinical 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)

Metabolic DisordersClinical manifestations – diagnosis

Laboratory studies Routine

Hypoglycemia, acid-base balance, hyperammonemia, ketosis

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

© 2007 Thomson - Wadsworth

Metabolic DisordersApproaches 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

Metabolic DisordersApproaches 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

Amino Acid Disorders

Phenylketonuria (PKU)

Isovaleric acidemia (IVA)

Maple syrup urine disease (MSUD)

Others


Amino Acid DisordersPhenylketonuria (PKU) – most common

Absence of phenylalanine hydroxylase enzyme Inability to convert phenylalanine to tyrosineTyrosine becomes conditionally essential

Amino Acid DisordersPhenylketonuria (PKU)

Results in metal retardation, severe behavioral problems, seizures, eczema

Musty or mousy odorToxic to brain – demyelination of white matterDecreased production of serotonin, epinephrine,

norepinephrine, dopamine, GABA

Amino Acid DisordersPKU – Nutrition Interventions

Restriction of dietary proteinSynthetic formula supplying all essential amino acids

except offending amino acidsBlood phenylalanine target levels more restrictive for

children up to age 12

Amino Acid DisordersPKU – Nutrition Interventions

Assess 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

Amino Acid DisordersPKU – Nutritional Concerns

Risk for nutritional deficienciesGrowth retardationBone statusAmino acid deficienciesOverrestrictionMetabolic control during pregnancy

Amino Acid DisordersPKU – Adjunct Therapies

AntibioticsCarnitineSodium benzoateSodium phenylbutyrate

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



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

Urea Cycle DisordersAcute Treatment

Hemodialysis Sodium benzoate and sodium phenylacetate to

scavenge excess ammonia IV fluids, avoiding overhydrationCaloric supplementationGlucose, intralipidsComplete protein restriction for 24-48 hours

Urea Cycle DisordersNutrition Interventions

Protein adjustment to account for severity, age, growth rate, and individual preferences without any extra

Supplemental arginine for mostMay use essential amino acid mixture to replace

natural sources25-30% of protein intake should be essential amino

acids

Urea Cycle DisordersNutrition Concerns

Amino acid intake must be balancedRisk of micronutrient deficiency

Iron, zinc

Adequate energy intakeNutrition support may be neededContinuous monitoringSee flow sheet example

Urea Cycle DisordersAdjunct therapies

Liver transplantationAlternative pathway therapy

Mitochondrial Disorders

Results from defects either in the respiratory chain or from defects affecting overall number and function of the mitochondria

MELAS or NARP



DiagnosisDNA mutation testingSkin and muscle tissue histological and biochemical

analysis

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


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


Nutrition InterventionNo definite treatmentUse of vitamin cofactors in pharmacological

amounts 100-1000 times DRI for ageRiboflavin and thiamin – cofactorsVitamin E and lipoic acid – antioxidantsVitamins C, K, CoQ10 – artificial electron receptors

and transporters

Frequent feedings recommended



Adjunct therapiesCarnitine and glycine – conjugate with toxic

metabolites, removing them from body

Disorders of Vitamin Metabolism

Needed as cofactors for enzymatic reactions, antioxidants, or electron receptors

Pharmacologic dose may be sufficient to maintain normal enzymatic function


Nutritional InterventionsMethylmalonic acidemia – responsive to B12

Holocarboxylase synthetase deficiency and biotinidase deficiency - responsive to biotin



Nutritional ConcernsPharmacological doses of vitamins should be treated

as “drugs”Use of “megavitamin” supplements in random

fashion discouragedToxicity a concern for fat-soluble vitaminsComplianceCost

Disorders of Carbohydrate Metabolism

Problems processing simple sugars galactose and fructose, or glycogen storage diseases

Summary of disorders and clinical symptoms

Galactosemia

Enzyme defect in galactose metabolism leading to failure to thrive, hepatomegaly, life-threatening sepsis in newborn periodVomiting, jaundice upon initiation of milk

feedingsAnorexia, failure to gain weight or growCirrhosis, ascites, edema, bleeding problems,

enlarged spleen if milk feedings continue

Galactosemia

Many states screen for it

Defect is in conversion of galactose to glucose 1 phosphate

G1P accumulates in tissue

Clinical manifestations result

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 galactoseSee Table 28.12


Galactosemia

Nutrition concernsProvision of alternative sources of missing nutrients:

vitamin D, calciumCalcium supplementsMeet kcal, protein, vitamin and mineral needs

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


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

ascites


Nutrition InterventionWith fructose-free diet vomiting and bleeding

tendency disappear immediatelyHepatomegaly and steatosis will disappear between

5-10 years


Nutrition ConcernsVitamin supplement may be indicatedRequires strict avoidance for life of all dietary

fructose and sucroseAversion to sweets may develop

Glycogen Storage DiseasesDeficiencies 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

Glycogen Storage DiseasesGSD1 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

Glycogen Storage DiseasesNutrition 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

Glycogen Storage DiseasesNutrition Concerns – GSD1

Availability of high-CHO snacks at all times Illness can be life threateningAdjustment to decreased oral intakeMultivitamin/ mineral supplementCalcium and iron supplementation

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

Fatty acids not utilized resulting in hypoglycemia, hyperammonemia, death

MCADD most common

Deficiencies of carnitine metabolism




Nutrition InterventionPrevention of fastingLimiting intake of fatty acidsProviding alternate substrate for metabolism (CHO,

protein) Include complex CHO vs. simple to maintain

euglycemia


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


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

Metabolic Disorders KNH 413. Metabolic Disorders Inborn errors of metabolism – group of diseases that affect a wide variety of metabolic processes; defective.

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