Download In Born Error 0f Metabolism

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
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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
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The “sick” newborn infant
Cardiomegaly/cardiomyopathy
Eye anomalies / Gastrointestinal abnormalities
Hair and skin abnormalities
Hematological / Hepatic dysfunction
Sepsis
Unusual odor
– PKU
– Cystiurea
mousy smell
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,
Sanfilippo’s, 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
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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
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Lethargy irritability and vomiting
Feeding difficulty and poor weight gain
Jaundice, hypoglycemia, hepatomegally
Ascites
Hepatic cirrhosis
others
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Plydypsia, polyurea
Rickets
Mental retardation
Seizure
Cataract: perinuclear haziness to complete
opacification
• Fulminant e-coli sepsis
investigation
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Positive clinitest and negative clinistix
Urine galactose by chromatography
Direct hyperbilirubinemia
RBC’s galactose 1 phosphate uridyl
transferase activity
• Increase galactose 1phosphate in RBC
management
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Lactose free formula
Control seizure
Consult ophthalmology
Consult endocrinology
Genetic counseling
Phenylketonurea (PKU)
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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
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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
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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