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INBORN ERRORS OF METABOLISM
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Recognize IEM in a neonate with nonspecific signs and symptoms
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Make use of simple lab tests in the
diagnosis of IEM
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Initial management of life threatening
conditions associated with IEM
An inherited enzyme deficiency leading to the
disruption of normal body metabolism
 Accumulation of a toxic substrate
(compound acted upon by an enzyme in a
chemical reaction)
 Impaired formation of a product normally
produced by the deficient enzyme
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Affects amino acid & protein, carbohydrate, and
lipid metabolism.
Most disorders are autosomal recessive in
transmission
Most disorders are evident at or soon after birth.
Early detection and treatment are essential to the
prevention of irreversible cognitive impairment and
early death
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A
B
C product deficiency
substrate excess
D
toxic metabolite
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Disorders of:
Amino acids
Carbohydrates
Fatty acid
Lysosomal and peroxisomal function
Mitochondrial
Organic acids
Metabolic Diseases Can Grouped as
Defects of Carbohydrates-Glycogen storage
disease(GSD), Galactosemia,
 Defects of amino acids-Phenylketonuria(PKU),
Alkaptonuria,Urea cycle defects(UCDs).
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Organic acidemias-isovaleric acidemia, propoinic
acidemia(PPA), methylmalonic acidemia(MMA), maple
syrup urine disease(MSUD).
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Defects of lipids-Mitochondrial fatty acid
oxidation defects, peroxisomal disorders
,lysosomal disorders ,mucopolysaccharidoses.
Defects of purines and pyrimidines-Lesh-nyhan
syndrome
 Miscellaneous –wilson disease,alpha-1-anti
trypsin deficiency.
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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)
◦ Tandem mass spectroscopy – allows clinicians to
screen for > 30 disorders
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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)
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Lens dislocation : Sulfite oxidase deficiency
Skin changes : Biotinidase deficiency
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Peroxisomal disorders :
Zellweger syndrome
Large fontanelle
 prominent forehead
 flat nasal bridge
 epicanthal folds
 hypoplastic supraorbital ridges
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Pyruvate dehydrogenase
deficiency
Epicanthal folds
 flat nasal bridge
 small nose with
anteverted flared alae nasi
 long philtrum
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Glutaric aciduria type II
Macrocephaly
 high forehead
 flat nasal bridge
 short anteverted nose
 ear anomalies
 hypospadias
 rocker-bottom feet
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Cholesterol biosynthetic
defects
 Smith-Lemli-Opitz
syndrome:
Epicanthal folds, flat nasal
bridge, toe 2/3 syndactyly,
genital abnormalities,
cataracts
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Congenital disorders of glycosylation:
Inverted nipples, lipodystrophy
Lysosomal storage
disorders:
Hurler-like phenotype
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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
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Approaches to Treatment
In most cases, treatment needs to be instituted
empirically without a specific diagnosis.
The metabolic screen helps to broadly
categorize the patient’s IEM (e.g. urea cycle
defect, organic academia,
congenital lactic acidosis etc), on the basis of
which, empirical treatment can be instituted
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Aims of treatment
1. To reduce the formation of toxic metabolites by
decreasing substrate availability (by stopping feeds and
preventing endogenous catabolism)
2. To provide adequate calories.
3. To enhance the excretion of toxic metabolites.
4. To institute co-factor therapy for specific disease and
also empirically if diagnosis not established.
5. Supportive care-Treatment of seizures (avoid sodium valproate –
may increase ammonia levels),
-Maintain euglycemia and normothermia,
-Fluid, electrolyte & acid-base balance,
-Treatment of infection,
-Mechanical ventilation if required.
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Management of hyperammonemia:
1) Discontinue all feeds. Provide adequate calories by
intravenous glucose and
lipids. Maintain glucose infusion rate 810mg/kg/min. Start intravenous lipid
0.5 g/kg/day (up to 3 g/kg/day). After
stabilization gradually add protein 0.25
g/kg till 1.5 g/kg/day.
2) Dialysis is the only means for rapid removal of
ammonia, and hemodialysis is more effective and
faster than peritoneal dialysis. Exchange transfusion is
not useful.
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3) Alternative pathways for nitrogen
excretion-:
-Sodium benzoate.
-Sodium phenylbutyrate
-L-arginine (oral or IV)
-L-carnitine (oral or IV)
4) Supportive care: Treatment of
sepsis,seizures,ventilation.
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Determine if there is metabolic acidosis
Is anion gap >16?
Is there hypoglycemia?
Is there hyperammonemia?
◦ Within 24 HOL?
◦ After 24 HOL?
Copyright ©1998 American Academy of Pediatrics
Organic acidemia
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Healthy NB rapidly ill,
◦ Ketoacidosis, poor feeding
Vomiting, dehydration
Hypotonia, lethargy
Tachypnea, seizures
Coma, unusual odors
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Labs:
Urine organic acids
Ketonuria (in the NB)- pathognomonic of IEM
Neutropenia, thrombocytopenia
+/- hyperammonemia
Abnormal acylcarnitine
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Treatment:
Stabilize
Get rid of organic acid intermediates, and
ammonia- hemodialysis
Carnitine
After stabilization, may resume oral feeds
Consult dietitian, and metabolic specialist
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No acidosis (respiratory alkalosis)
No ketones (unlike organic acidemia)
No hypoglycemia
But with hyperammonemia
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Treatment:
Remove ammonia
Hydration with D10 + electrolytes
D/C all protein x 24 hours—calories from
CHO and fat
Na phenylacetate/Na benzoate
Give arginine
Protein restriction for life
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Prognosis: guarded
Even with Treatment, many will die
Definitive treatment: liver transplant
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An inborn error of carbohydrate metabolism in
which the hepatic enzyme (galactose-1-phosphate
uridyl transferase), GALK1 or GALE, which
normally converts galactose into glucose is
absent.
Autosomal recessive pattern
Incidence It occurs in approximately 1 out of
every 60,000
Dietary Lactose
Galactose
Galactose 1-Phosphate
BRAIN
Mental retardation
LIVER
 Jaundice
 Hetaptomegaly
 Cirrhosis
Glucose
EYES
cataracts
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Galactose-1 phosphate uridyl transferase deficiency
(classic galactosemia, the most common and most
severe form)- (GALT) Type I
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Deficiency of galactose kinase – (GALK1)Type II
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Deficiency of galactose-6-phosphate –epimerase
(GALE)-Type III
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Jaundice, vomiting
poor feeding
infections
Failure to thrive
hepatomegaly
Speech disabilities,
mental retardation
Galactosemia clinical pictures
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Mild
Cataract in the
infant
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The only way to treat galactosemia is
through dietary restrictions
from the first days of life
No brest feeding
Soya- based formula
• The newborn with questionable results on newborn
screening should continue to be treated with soybased formula pending definitive results of
confirmatory testing.
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Why? If unscreened and untreated,
galactosemia is a life-threatening disorder.
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When? Neonatal period: 4th day
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How? Screening of every neonates, followed
by confirming tests. Thereby, affected infants
are treated before they become ill.
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Phenylketonuria is a genetic disorder where
the body’s enzyme, phenylalanine
hydroxylase ,is missing or malfunctioning
so that it cannot properly break down the
amino acid, phenylalanine .
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Mental Retardation
Seizures
Microcephaly (small head size)
Skin rashes
Stunted growth
Hyperactivity
“Musty or mousy” body odor from the
excess phenylalanline
Fair skin, hair, and eyes (phenylalanine is
linked to melanin production)
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PKU is usually diagnosed after birth with a
blood test taken from the infant’s heel or
the crook of their arm.
◦ If there are abnormal amounts of phe, then
further tests (blood and urine) are taken to
ensure that the child has PKU.
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Another option of diagnosis is through the
chorionic villus sampling (CVS) process.
Treatment
 Once diagnosed, babies are fed diets
containing protein without phenylalanine for
the first 7-10 days.
 Special infant formula called Lofenalac
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Recently, there’s been a special medical (pill)
formula discovered for PKU patients called
Kuvan.
It’s possible to have a wide range of PKU,
from mild to severe, but it’s suggested to
stick to a diet regiment for life.
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There’s usually a general list of foods that
should not be consumed for PKU patients like:
◦ Dairy
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 Milk, eggs, Cheese
Nuts
Beans
Peas
Meat (Poultry, beef, pork, duck etc.)
Chocolate
the sweetener aspartame can act as poisons for
people with phenylketonuria
Prevention:
Unfortunately, if PKU is already diagnosed in
an infant, there are no preventive measures
one can take for their child to not have PKU.
If a pregnant individual has PKU, then she’s
able to prevent her child from PKU symptoms
if she follows a diet low in protein.
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Inherited as an autosomal recessive trait
caused by mutations in the IDU Agene (4p16.3)
Metabolic defect: inability
◦ The body's to make an enzyme:
 lysosomal alpha-L-iduronase
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Approximately 1 in 150,000 infants
are affected
Newborn infants with this defect
appear normal at birth
By the end of the first year, signs
of impending problems begin to
develop
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© 2007 Thomson - Wadsworth
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Coarse facial features (86.4%)
Corneal clouding (70.9%)
Heaptomegaly (70.0%)
Kyphosis/gibbus (70.0%)
Hernias (58.9%)
Airway-related symptoms, such as sleep
disturbances/snoring (51.6%)
Splenomegaly (50.9%)
Cardiac valve abnormalities (48.9%)
Cognitive impairment (46.4%)
Dystosis multiplex (43.6%)
© 2007 Thomson - Wadsworth
© 2007 Thomson - Wadsworth
Hurler syndrome (type
I)
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Mucopolysaccharidosis I (MPS I) Disease
(Hurler, Hurler-Scheie, Scheie Syndromes)
Key Symptom Images
Hernia
Corneal
clouding
Coarse
facial
features
Claw hand
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 X-linked
 Coarse,
thick, facial features
 Progressive stiffness
 decreased mental development
 Hepatomegaly
 Splenomegaly
 Abnormal bone x-rays
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