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In Born Error of Metabolism (IEM). Dr Mohammad Khassawneh Assistant professor of pediatrics . Introduction. When to consider it What to do quickly to determine it is present or not. How to identify?. Prospective approach for a healthy newborn

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in born error of metabolism iem

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

How to identify?

  • Prospective approach for a healthy newborn
  • Reactive approach to a clinically abnormal child

Common conception about IEM

  • 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
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
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
  • Few metabolic diseases are treatable
    • Should give more consideration to treatable conditions
    • Genetic counseling sake
    • Gene therapy hold a promise
newborn screening
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

Clinical presentations

  • 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
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
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
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, Sanfilippo’s, Morquio
eye abnormalities
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
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
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
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
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
  • 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
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
Hepatic and GI manifestation
  • Lethargy irritability and vomiting
  • Feeding difficulty and poor weight gain
  • Jaundice, hypoglycemia, hepatomegally
  • Ascites
  • Hepatic cirrhosis
  • Plydypsia, polyurea
  • Rickets
  • Mental retardation
  • Seizure
  • Cataract: perinuclear haziness to complete opacification
  • Fulminante-coli sepsis
  • Positive clinitest and negative clinistix
  • Urine galactose by chromatography
  • Direct hyperbilirubinemia
  • RBC’s galactose 1 phosphate uridyl transferase activity
  • Increase galactose 1phosphate in RBC
  • Lactose free formula
  • Control seizure
  • Consult ophthalmology
  • Consult endocrinology
  • Genetic counseling
phenylketonurea pku
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
pku continue
  • Musty or mousey smell
  • Microcephaly
  • Growth retardation
  • 50 point loss of IQ in the first year
  • Clinical feature are rarely seen Neonatal screening
  • 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
  • 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