1. Metabolic Disorders
KNH 413

2. 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

3. 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

4. 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

6. 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

7. 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)

9. 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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11. 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

12. 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

13. Amino Acid Disorders Phenylketonuria (PKU) Isovaleric acidemia (IVA)
Maple syrup urine disease (MSUD)
Others

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15. Amino Acid Disorders Phenylketonuria (PKU) – most common
Absence of phenylalanine hydroxylase enzyme
Inability to convert phenylalanine to tyrosine
Tyrosine becomes conditionally essential

17. 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

18. 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

19. 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

22. Amino Acid Disorders PKU – Nutritional Concerns
Risk for nutritional deficiencies
Growth retardation
Bone status
Amino acid deficiencies
Overrestriction
Metabolic control during pregnancy

23. Amino Acid Disorders PKU – Adjunct Therapies Antibiotics Carnitine
Sodium benzoate
Sodium phenylbutyrate

24. 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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27. 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

28. 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 hours

29. 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

31. 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

33. Urea Cycle Disorders Adjunct therapies Liver transplantation
Alternative pathway therapy

34. 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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36. 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

37. 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

39. Mitochondrial Disorders
Nutrition Intervention
No definite treatment
Use of vitamin cofactors in pharmacological amounts
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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41. Mitochondrial Disorders
Adjunct therapies
Carnitine and glycine – conjugate with toxic metabolites, removing them from body

42. Disorders of Vitamin Metabolism
Needed as cofactors for enzymatic reactions, antioxidants, or electron receptors
Pharmacologic dose may be sufficient to maintain normal enzymatic function

43. Disorders of Vitamin Metabolism
Nutritional Interventions
Methylmalonic acidemia – responsive to B12
Holocarboxylase synthetase deficiency and biotinidase deficiency - responsive to biotin

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45. 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

46. Disorders of Carbohydrate Metabolism
Problems processing simple sugars galactose and fructose, or glycogen storage diseases
Summary of disorders and clinical symptoms

48. 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

50. Galactosemia Many states screen for it
Defect is in conversion of galactose to glucose 1 phosphate
G1P accumulates in tissue
Clinical manifestations result

51. 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

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53. Galactosemia Nutrition concerns
Provision of alternative sources of missing nutrients: vitamin D, calcium
Calcium supplements
Meet kcal, protein, vitamin and mineral needs

54. 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

55. Hereditary Fructose Intolerance
Clinical manifestations
Vomiting
Poor feeding, diarrhea, failure to thrive
Hepatomegaly, bleeding tendency, jaundice, edema, ascites

56. Hereditary Fructose Intolerance
Nutrition Intervention
With fructose-free diet vomiting and bleeding tendency disappear immediately
Hepatomegaly and steatosis will disappear between years

57. 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

58. 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

62. 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

64. 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 g/kg body weight every 3-6 hours

65. 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

66. 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

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69. 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

70. 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

72. 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