Inborn Errors of Metabolism Flashcards
What is the definition of inborn errors of metabolism? (IEM)
Gene mutations
which cause the dysregulation in the synthesis of enzymes and coenzymes. This causes the accumulation of toxic metabolites, and the consequential deficiency in essential metabolites.
Why does IEM concern us nutritionally?
When there is dysregulation, it will affect the transporters necessary for the metabolism of CHO, lipids and AA
How are most IEM expressed?
- Autosomal recessive
- The parents may not show the phenotype, but they carry the copy of the gene
When does IEM usually present?
Can present at any age with a wide range of severity but mostly manifest around the newborn period
-Either early (more common) or later onset
Clinical signs and symptoms?
- Global
- Affecting nearly every system; including neurological, GI, CV, Endocrine and skeleto-muscular
General signs and symptoms in IEM ?
- Overwhelming illness in the new-born period
- Recurrent vomiting
- Poor growth, failure to thrive
- Developmental delay and mental retardation
- Loss of previously acquired skills
- Cardiomyopathy
- Neuropsychiatric symptoms
When was newborn screening initiated for IEM? What was the result?
- Since the 1960s
- There was a high incidence of mental retardation prior to screening
What was the first test of IEM in newborns?
-Urinary phenyl pyruvic acid for PKU
How is testing done for IEM? In Canada, how many conditions are screened for?
- Dry blood spots collected 24-48 hours after brith to detect metabolic intermediaries
- Up to 38 conditions
In the diagnosis at screening of IEM, what can IEM help differentiate?
- In a differential diagnosis of sepsis, anoxic encephalopathy or toxic ingestion
- If we treat the symptoms, and there is no response there is likely IEM
- IEM diagnosis strengthens if typical common laboratory tests fail to determine a definitive diagnosis
How can IEM present at diagnosis? When can it occur?
As an acute or chronic, recurrent or progressive disease at ANY age
-Can occur even in the context of negative family Hx for a genetic or metabolic disorder
What may be to blame in cases of neonatal death from undetermined causes?
IEM
Which IEMs are autosomal recessive?
- Phenyl-ketonuria (PKU)
- Methylmalonic Acidemia (MMA)
- Galactosemia
Absent enzyme in PKU?
-Phenylalanine hydroxylase (PAH)
Absent enzyme in MMA?
-Methyl malonyl-CoA mutase or cobalamine co-factor deficiency
Absent enzyme in galactosemia?
GALT
Mitochondrial disorders genetic type?
X linke mtDNA mutations
When enzymes are absent, what is often affected?
Nutritional metabolism
____ babies are at more risk if they only have one copy of the X gene
Males
When there are issues with energy metabolism as a consequence of the IEM, what can it be linked to
Defects in the mitochondrial DNA which is linked to the mother
What is the model for nutritional managements for IEM?
1) Restrict the amount of substrate
2) Supplement the product to prevent deficiency
3) Supplement the cofactor to increase residual enzyme activity
4) use adjunct therapies to remove the abnormal metabolites
What is the dilemma in nutritional therapy in IEM?
- Restriction or one or more components
- Risk of nutrient deficiencies
- Supplementation required
What is the efficacy of nutritional therapy for IEM?
variable
How must nutritional therapy be designed in IEM/
Specific to the pathway, enzyme, coenzyme or transporter affected
What is the MAIN end goal of nutrition therapy for IEM?
Support adequate growth
How can we achieve appropriate growth in the nutritional management of IEM?
- Provide adequate energy, protein (complete AA profiles), vitamin and mineral intake
- Reflects the achievement of metabolic balance
What is the consequence of inadequate energy intake?
Causes an endogenous release of nitrogen and AA from muscles, which can be problematic when they accumulate due to specific enzyme deficiencies
What is important to maintain metabolic balance?
Monitoring the protein-energy ratio
Nutritional intervention for IE of protein metabolsim
- Low-protein or nitrogen free foods
- Low protein breads and pastas (sometimes GF)
- Will allow for appropriate energy intake without adding more protein to the food pattern
Protein nutritional therapy?
- Ensure that it provides an adequate amount of all essential AA
- Some AAs are not metabolized as efficiently as whole protein, recommended total protein intakes may be higher for some disorders
When is growth limited?
- When there is an AA in the shortest supply in the diet
- Inadequate nitrogen intake
In inborn errors of AA and protein metabolism, how can energy needs be met?
By increasing percentage of energy from CHO or fats
Nutritional therapy in fatty oxidation disorders?
- Other sources, such as protein and CHO must be increased to meet E needs
- Might be overwhelming considering how energy efficient fats are
How should vitamin and mineral needs be met?
-Must be met with medical foods or judicious use of supplements
(T/F) for certain IE, some vitamins are supplemented much higher than DRI levels
T
Why do vitamins have an enhancing effect on certain metabolic pathways if supplied in pharmacological doses?
-Because they are often cofactors in the affected metabolic pathways
What is PKU?
PKU results from the deficiency of PAH, which results in elevated phenylalanine levels and consequential tyrosine deficiency
What will the excess phenylalanies be shunted to?
Increase synthesis in phenylketones
Why is tyrosine important?
- Muscle protein synthesis
- Melanin
- Neurotransmitters
Sources of phenylalanine?
-Dietary and endogenous muscle protein break down
What is the normal plood Phe? When is Phe 10 times higher in the blood? At what level of Phe does not require an intervention?
- Normal: <120 umol/L
- Classical PKU presents with 10 times higher blood Phe
- Phe <360 umol does not require an intervention
4 key management strategies in PKU?
- Reduce blood Phe under 360 umol/L by fully restricting all protein sources that contain Phe
- Add little by little intact protein to cover Phe needs
- Supplementation with large, neutral AA to compete for PHE transporters
- If inadequate protein, assess deficiencies
Acute management so PKU?
- When blood levels <360 umol/L
- Use Phe-free formulas
- OK to reintroduce standard formula or breastmilk in controlled amounts
Chronic management sof PKU?
- maintain blood Phe 120-360 umol/L
- Support normal growth and developments while preventing nutrient deficiencies
How are most formulas supplemented?
-Already supplemented with tyrosine
In PKU, what are the requirements?
-Phe is lower
(NOT absent)
-Tyrosine is higher
-Energy requirements are more or less the same
what is galactosemia?
-Deficiency of GALT, which allows the conversion of galactose 1-P to glucose 1-P an UDP galactose
What are sources of galactose?
- Dietary lactose
- Galcititiol
- Galatonate
What is the consequence of lack of glucose 1-P?
No downstream substrates to continue into glycolysis
What is the consequence fo lack of UDP galactose?
-Lack of substrate required for various glycoproteins and galactolipids
Consequence of galactosemia?
- Liver damage and jaundice
- Anorexia
- May lead to sepsis
- Fatal if left untreated
Nutritional managements in galactosemia?
-Restriction of lactose and breastfeeding is contraindicated
What explains the damages caused by galactosemia?
The unmetabolized milk sugars will build up and damage the liver, eyes, kidney and brain
Acute managemet of Galactosemia?
- Soy based medical foods
- PN may be an option if PO or EN doesnt work
- Medications must be free of lactoe fillers
Chronic management of galactosemia?
- Dairy elimination
- Breastfeeding is contraindicated
- Food label reading is important
- F&V okay due to negligible amounts of Gal
- Recommended continuous monitoring of Vit D status for bone health
Is breastfeeding contraindicated in PKU?
- No
- breastmilk is low in phenylalanine, but mother may have to be mindful and consume less phenyalanine
What is contraindicated in galactosemia?
- Milk
- Casein
- Butter
- Cream
- Organ meats
- Sherbert
- Whey
- Lactalbumin
- Lactoglobulin
- Fermented soy products and fermented soy sauce
