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
 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
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
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
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)
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
© 2007 Thomson - Wadsworth
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
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
Amino Acid Disorders
 Phenylketonuria (PKU)
 Isovaleric acidemia (IVA)
 Maple syrup urine disease (MSUD)
 Others
© 2007 Thomson - Wadsworth
Amino Acid Disorders
 Phenylketonuria (PKU) – most common
 Absence of phenylalanine hydroxylase enzyme
 Inability to convert phenylalanine to tyrosine
 Tyrosine becomes conditionally essential
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
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
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
Amino Acid Disorders
 PKU – Nutritional Concerns
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Risk for nutritional deficiencies
Growth retardation
Bone status
Amino acid deficiencies
Overrestriction
Metabolic control during pregnancy
Amino Acid Disorders
 PKU – Adjunct Therapies
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Antibiotics
Carnitine
Sodium benzoate
Sodium 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
© 2007 Thomson - Wadsworth
© 2007 Thomson - Wadsworth
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 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
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
Urea Cycle Disorders
 Nutrition Concerns
 Amino acid intake must be balanced
 Risk of micronutrient deficiency
 Iron, zinc
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Adequate energy intake
Nutrition support may be needed
Continuous monitoring
See flow sheet example
Urea Cycle Disorders
 Adjunct therapies
 Liver transplantation
 Alternative 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
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Mitochondrial Disorders
 Diagnosis
 DNA mutation testing
 Skin and muscle tissue histological and biochemical analysis
 Disorders include
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Fatty acid transport disorders
Fatty acid oxidation defects
Pyruvate complex disorders
Respiratory chain defects
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
Mitochondrial Disorders
 Nutrition Intervention
 No definite treatment
 Use of vitamin cofactors in pharmacological
amounts
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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
© 2007 Thomson - Wadsworth
Mitochondrial Disorders
 Adjunct therapies
 Carnitine 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
Disorders of Vitamin Metabolism
 Nutritional Interventions
 Methylmalonic acidemia – responsive to B12
 Holocarboxylase synthetase deficiency and
biotinidase deficiency - responsive to biotin
© 2007 Thomson - Wadsworth
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
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 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
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 Interventions
 Exclusion of galactose/ lactose from diet
 Immediate reversal of symptoms results
 Exclusion of human milk, cow’s milk …
 Substitution of casein hydrolysate-containing
formula
 Infant soy formulas
 Learn other potential dietary and drug sources of
galactose
 See Table 28.12
© 2007 Thomson - Wadsworth
Galactosemia
 Nutrition concerns
 Provision of alternative sources of missing nutrients: vitamin
D, calcium
 Calcium supplements
 Meet 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
Hereditary Fructose Intolerance
 Clinical manifestations
 Vomiting
 Poor feeding, diarrhea, failure to thrive
 Hepatomegaly, bleeding tendency, jaundice, edema,
ascites
Hereditary Fructose Intolerance
 Nutrition Intervention
 With fructose-free diet vomiting and bleeding tendency
disappear immediately
 Hepatomegaly and steatosis will disappear between 5-10
years
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
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
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
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
Glycogen Storage Diseases
 Nutrition Concerns – GSD1
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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
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
© 2007 Thomson - Wadsworth
© 2007 Thomson - Wadsworth
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
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
Disorders of Fat Metabolism
 Nutrition Concerns
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Overrestriction of fat
Essential fatty acid deficiency
Excessive weight gain
Maximize fluid intake
Carnitine used to detoxify, given as supplement