In Born Error of Metabolism

(IEM)
Dr Mohammad Khassawneh
Assistant professor of pediatrics
 When to consider it
What to do quickly to determine it is
present or not
 Prospective approach for a healthy newborn
Reactive approach to a clinically abnormal
child
 Rarely a cause of disease in neonates
Hyperphenylalaninemia 1:10,000
Galactosemia 1:50,000
Homocystinurea 1:200,000
Estimated overall incidence 1:2000
Many of metabolic diseases are under
diagnosed
 Common conceptions
It should only be considered with a family
history
AR disease 2 sibs diseased 6%, 2 of 3 14%
X-linked commonly a new mutation
Hard to differentiate from sepsis
Galctosemia and e- coli
Many diseases present different from sepsis
illness
 Common Conception
Biochemical pathway are impossible to
remember
This is true for expert
Pathways are not the important part of the
evaluation
general approach is more important
It is difficult to conduct diagnostic study
Should progress from broad to specific
 Continue

Few metabolic diseases are treatable

Should give more consideration to treatable conditions
Genetic counseling sake
Gene therapy hold a promise
 Newborn Screening
Reliable screen test and low false negative
Test is simple and inexpensive
Available results soon to start effective
therapy
Definite follow up test
Outcome without treatment is very bad
Effective therapy is available
 The sick newborn infant
Cardiomegaly/cardiomyopathy
Eye anomalies / Gastrointestinal abnormalities
Hair and skin abnormalities
Hematological / Hepatic dysfunction
Sepsis
Unusual odor
PKU mousy smell
Cystiurea sulfourus smell
 Sick newborn
Cardiorespiratory, central nervous system, poor
feeding
Present in1st week of life
Lethargy and coma low tone & Seizure
Acidosis or hyperamonemia may lead to
respiratory distress
Causes:
include fatty acid, carbohydrate, organic acid,
respiratory chain, ammonia metabolism
 Example/hyperglycenemia

AR disorder
Profound hypotonia, poor feeding, hiccupping,
lethargy
Coma and Seizure with myoclonic jerk
Elevated CSF/plasma glycine
EEG findings
 Cardiomegaly and
cardiomyopathy
Beta oxidation
glycogen storage
Most common is Pompe disease (acid
maltase) generalize hypotonia and FTT
Lysosomal (cytoplasmic organelles)
MPS, sphingolipid, glycoprotein
mitochondria disorders
 Hurler Syndrome and others
AR, alfa L-idurinidase
Coarsening of feature 6-12
monthes
Cloud cornea
Deafness
Cardiomypathy
Airway obstruction
Death by early teenage
Scheie, Hunter,
Sanfilippos, Morquio
 Eye abnormalities

Cataract: galactosemia, adrenoleukodystrophy,

mucopolysacharidosis
Lens dislocation: homocystinurea, marfan
Blue sclera in oseogenesis imperfecta
Cherry red spot in lysosomal disorder (farber
disease)
 Gastrointestinal/Hair and skin
Vomiting in acidosis and urea cycle defect
Menkes disease: spares kinky scalp hair
associated with hypotonia, intractable
seizure and developmental delay
PKU: Fair hair and skin
Multiple carboxylase deficiency skin rash
and partial allopecia
 Hepatic dysfunction

Enlargement (lysosomal storage disorder)

Hypoglycemia
Galactosemia
Hereditary fructose intolerance
Hepatocellular damage, like above and adrenoleukodystrophy, fatty acid oxidase def.
Cholestatic disease
Alfa 1 antitrepsine, ZZgenotype
 Initial laboratory screening
Blood
Cell count, electrolytes, amonia, uric acid
Blood gas, lactate and pyrovate
Glucose and ketones
Urine:
smell, pH, acetone, ketone
Reducing substances
CSF: lactate pyrovate and glucose
 Specialized biochemical testing
Amino acid analysis
Maple syrup apple disease with increase leuocine,
valine and isoleuocine
Hyperglycinemia: increase glycine
Organic acid : propionic acidemia
Carnitine level
Chromatographic of glycolipid
Increased level of long chain fatty acid with
perioxysomal disorder
 galactosemia
Deficiency of galactose-1 phosphate uridyl
transferase
1/50,000
Start early after feeding
Autosomal recessive on chromosome 9p13
with male=female
Affect brain, liver, kidny and overies
 Galactosemia / clinical
No enzyme accumulation of galactose1
phosphate
Liver; cirrhosis
Kidney; fancony syndrome
Brain; mental retardation
Overy; amenorrhea
Galactose to galactitol cause cataract
 Hepatic and GI manifestation

Lethargy irritability and vomiting

Feeding difficulty and poor weight gain
Jaundice, hypoglycemia, hepatomegally
Ascites
Hepatic cirrhosis
 others
Plydypsia, polyurea
Rickets
Mental retardation
Seizure
Cataract: perinuclear haziness to complete
opacification
Fulminant e-coli sepsis
 investigation
Positive clinitest and negative clinistix
Urine galactose by chromatography
Direct hyperbilirubinemia
RBCs galactose 1 phosphate uridyl
transferase activity
Increase galactose 1phosphate in RBC
 management
Lactose free formula
Control seizure
Consult ophthalmology
Consult endocrinology
Genetic counseling
 Phenylketonurea (PKU)
Phenylalanine hydroxylase deficiency
Excess phenylalanine and its metabolites
Normal at birth and months to diagnose
Vomitting sever/ misdiagnosed pyloric
stenosis.
Fair skin and blue eyes
Eczema and skin rash
 PKUcontinue
Musty or mousey smell
Microcephaly
Growth retardation
50 point loss of IQ in the first year
Clinical feature are rarely seen Neonatal
screening

 diagnosis
Guthrie test; bacterial inhibition , positive in
4 hr old
Preferable sample at >24-48 hr of life
Positive test should be followed by
Phenylalanine and tyrosine
Increase PA, NL tyrosine, and increase PA
metabolites in urine like phenylpyrovic
 treatment
Reduce phenylalanine and metabolites in blood.
Formula low in phenylalanine
Level between 3-15mg/dl
Remember over treatment
Lethargy anorexia anemia rash diarrhea
Treatment indefinitely
Maternal PKU. Mental retarded/ microcphaly/
cardiac defect, keep level <10mg/dl