Metabolic Disorders · CNS symptoms, poor growth, failure to thrive, developmental delays, specific neurological deficits! May have blatant signs (i.e. unusual odor) Metabolic Disorders!

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


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

� Risk for nutritional deficiencies� Growth retardation� Bone status� Amino acid deficiencies� Overrestriction� Metabolic control during pregnancy

Amino Acid Disorders� PKU – Adjunct Therapies

� 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



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

� 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



� 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


� 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 Intervention� No definite treatment� Use of vitamin cofactors in pharmacological

amounts � 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



� 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


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


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


� Clinical manifestations� Vomiting� Poor feeding, diarrhea, failure to thrive� Hepatomegaly, bleeding tendency, jaundice, edema,

ascites


� Nutrition Intervention� With fructose-free diet vomiting and bleeding tendency

disappear immediately� Hepatomegaly and steatosis will disappear between 5-10

years


� 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

� 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




� 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


� 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


� Nutrition Concerns� Overrestriction of fat� Essential fatty acid deficiency� Excessive weight gain� Maximize fluid intake� Carnitine used to detoxify, given as supplement

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Metabolic Disorders · CNS symptoms, poor growth, failure to thrive, developmental delays, specific neurological deficits! May have blatant signs (i.e. unusual odor) Metabolic Disorders!