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26/01/2016
1
Neonatale screening: behandelbare stofwisselingsziekten
prof. dr. Eva MoravaKindergeneeskunde, UZ Leuven
Inborn errors of metabolism
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Paddington station
General features of inborn errors of metabolism
A. Affected infants are usually normal at birth
B. The most frequent genetic background is: autosomal recessive inheritance
C. There is a significant intra-individual clinical variability with the same genetic diagnosis
D. All of the above
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General features of inborn errors of metabolism
A. Affected infants are usually normal at birth
B. The most frequent genetic background is: autosomal recessive inheritance
C. There is a significant intra-individual clinical variability with the same genetic diagnosis
D. All of the above
General features of inborn errors of metabolism
Neurologic abnormalitie
s
Growth Failure
Feeding intolerances
Metabolic derangemen
tHypotoniaHypertoniaSeizures
Developmental delay
Abnormal growthFailure to thrive
VomitingDiarrhea
AcidosisHyperammonemi
a
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Introduction to Inborn Errors of Metabolism
B C
D
COFACTOR
X
ENZYME1
E
ENZYME2
ENZYME2
A
Inborn errors of metabolism• Disorders of intoxication
• Disorders of energy metabolism
• Complex molecules
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Inborn errors of metabolism• Disorders of intoxication
• Disorders of energy metabolism
• Complex molecules
Intoxication
Insufficient breakdown of normal food ingredients leading to increase of partially degraded products
EXAMPLE: abnormal amino acid degradation
Metabolic acidosis, elevated lactate and ammonia
Vomiting, somnolence, seizures, hyperventillation
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Case 1
Case 1: Significant Findings
• healthy AGA newborn who became lethargic at age of 5 days over 2-3days prior to admission
• clinical: significant weight loss (dehydration), unusual odor, unresponsive, twitching, normal morphology exam
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Brief Differential Diagnosis of the Sick Infant
• infectious etiologyo sepsis vs viral encephalopathy (Herpes)
• inborn error of metabolism suggested byo unusual odoro metabolic acidosiso CNS involvemento hyperammonemia
THE PRESENTATION OF ACUTE METABOLIC DISEASES IN INFANCY IS CLINICALLY
INDISTINGUISHABLE FROM SEPSIS
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Case 1: Diagnostic Findings• pH 7.12, HC03 9, NH3 140, anion gap 28, ketones 3+, glucose 168
• laboratory: metabolic acidosis with increased anion gap, hyperammonemia, pancytopenia
• urine organic acids: massive isovalerylglycine(2752mg/gCR; nl = 0)
3-OHisovaleric acid massive ketosis
• diagnosis = isovaleric acidemia
(isovalerylCoA dehydrogenase deficiency)
An increased anion gap occurs due to
A. Elevated lactic acid levels in blood
B. Elevated ketone concentration in blood
C. Increased amount of organic acids in blood
D. All of the above
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An increased anion gap occurs due to
A. Elevated lactic acid levels in blood
B. Elevated ketone concentration in blood
C. Increased amount of organic acids in blood
D. All of the above
Anion gapDifference between positive and negative ions
Na + K – Cl - bicarbonate = 14-16 mmol/l
Abnormal anion gap: 28 mmol/lUsually contains acids: organic acids, like lactic acid, ketoacids
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Isovaleric Acidemia: Metabolic Defect
leucine
ketoisocaproic acid
isovalerylCoA
methylcrotonylCoA
IsovalerylCoAdehydrogenase(Isovaleric acidemia)
Treatment: Acute Phase
• discontinue all protein nutrients (never longer<48 hrs)
• high glucose infusion (D10 + lytes 1.5 - 2x maintenance)
• hemofiltration• I.V. carnitine 50mg/kg loading, 50mg/kg/d q6h
• intubation and bicarb. for catastrophic acidosis
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Carnitine/GlycineTherapy: Mechanism
carnitine + isovalerylCoA
isovalerylcarnitine
isovalerylcarnitine
protein leucine
leucine
transferase
freely excreted by kidneys
MITOCHONDRION
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Treatment: Recovery and later episodes
• Continue high caloric input to prevent catabolism
• Provide 1 g (0.7-1.4 g)/kg/d protein
• Leucine-free formula
• Enteral carnitine 50-100 mg/kg/d
Isovaleric Acidemia: Results of Treatment
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Disorders without acidosis
Phenylalanine
Tyrosine
Melanin
Dopamine
Phenylalanine hydroxylase
(Phenylketonuria)
Phenylpyruvic acid
BH4
Disorders without acidosis
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Treatment
Protein restrictionHigh caloric dietEssential amino acids in formula-------------------------------------------Kuvan: BH4 - PAH chaperon
Dietary treatment in PKU
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Untreated PKU
Phenylalanine ammonia lyase treatment in PKU
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Newborn Screening: Presymptomatic Diagnosis
>20 inborn metabolic diseases detected by MSMS
Newborn Screening: Presymptomatic Diagnosis
Preventable diseaseCommonKnown disease course Treatable
Reliable diagnosisCheap method
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Newborn Screening: Presymptomatic Diagnosis
Preventable (early dg.)Common (?)Known disease course !Treatable (+/-)
Reliable diagnosis!Cheap method (21 euros)
Estimated Frequency of IEMs Among Newborn Infants (before 2004)• Phenylketonuria 1 in 15,000• Organic Acidemias 1 in 20,000• MCAD deficiency 1 in 20,000• Fatty Acid Oxidation disorders 1 in 50,000• Galactosemia 1 in 60,000• Biotinidase defect 1 in 60,000• Urea Cycle Disorders 1 in 70,000• Tyrosinemia type I 1 in 100,000• Homocystinuria 1 in 470,000• MSUD 1 in 900,000
Most inborn errors of metabolism are : < 1 in 50,000 live births
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Estimated Frequency of IEMs Among Newborn Infants (before 2004)• Phenylketonuria 1 in 15,000• Organic Acidemias 1 in 20,000• MCAD deficiency 1 in 20,000• Fatty Acid Oxidation disorders 1 in 50,000• Galactosemia 1 in 60,000• Biotinidase defect 1 in 60,000• Urea Cycle Disorders 1 in 70,000• Tyrosinemia type I 1 in 100,000• Homocystinuria 1 in 470,000• MSUD 1 in 900,000
Most inborn errors of metabolism are : < 1 in 50,000 live births
Newborn screening in Belgium
Outcome in IEM