26/01/2016

1

Neonatale screening: behandelbare stofwisselingsziektenprof. dr. Eva MoravaKindergeneeskunde, UZ Leuven

Inborn errors of metabolism

26/01/2016

2

Paddington station

General features of inborn errors of metabolismA. 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

26/01/2016

3

General features of inborn errors of metabolismA. 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

26/01/2016

4

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

26/01/2016

5

Inborn errors of metabolism• Disorders of intoxication

• Disorders of energy metabolism

• Complex molecules

IntoxicationInsufficient 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

26/01/2016

6

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

26/01/2016

7

Brief Differential Diagnosis of the Sick Infant• infectious etiology

o 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

26/01/2016

8

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 toA. 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

26/01/2016

9

An increased anion gap occurs due toA. 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

26/01/2016

10

Isovaleric Acidemia: Metabolic Defect

leucine

ketoisocaproic acid

isovalerylCoA

methylcrotonylCoA

IsovalerylCoAdehydrogenase(Isovaleric acidemia)

Treatment: Acute Phase• discontinue all protein nutrients (never longer

26/01/2016

11

Carnitine/GlycineTherapy: Mechanism

carnitine + isovalerylCoA

isovalerylcarnitine

isovalerylcarnitine

protein leucine

leucine

transferase

freely excreted by kidneys

MITOCHONDRION

26/01/2016

12

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

26/01/2016

13

Disorders without acidosis

Phenylalanine

Tyrosine

MelaninDopamine

Phenylalanine hydroxylase

(Phenylketonuria)

Phenylpyruvic acid

BH4

Disorders without acidosis

26/01/2016

14

Treatment

Protein restrictionHigh caloric dietEssential amino acids in formula-------------------------------------------Kuvan: BH4 - PAH chaperon

Dietary treatment in PKU

26/01/2016

15

Untreated PKU

Phenylalanine ammonia lyase treatment in PKU

26/01/2016

16

Newborn Screening: Presymptomatic Diagnosis

>20 inborn metabolic diseases detected by MSMS

Newborn Screening: Presymptomatic Diagnosis

Preventable diseaseCommonKnown disease course Treatable

Reliable diagnosisCheap method

26/01/2016

17

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

26/01/2016

18

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