In Born Error of Metabolism IEM

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In Born Error of Metabolism (IEM)

• Dr Mohammad Khassawneh
• Assistant professor of pediatrics

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Introduction

• When to consider it
• What to do quickly to determine it is present or
  not

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How to identify?

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

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Common conception about IEM

• Rarely a cause of disease in neonates
• Hyperphenylalaninemia 110,000
• Galactosemia 150,000
• Homocystinurea 1200,000
• Estimated overall incidence 12000
• Many of metabolic diseases are under diagnosed

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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

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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

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Continue

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

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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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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

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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

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Example/hyperglycenemia

• AR disorder
• Profound hypotonia, poor feeding, hiccupping,
  lethargy
• Coma and Seizure with myoclonic jerk
• Elevated CSF/plasma glycine
• EEG findings

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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

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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

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Eye abnormalities

• Cataract galactosemia, adrenoleukodystrophy,
  mucopolysacharidosis
• Lens dislocation homocystinurea, marfan
• Blue sclera in oseogenesis imperfecta
• Cherry red spot in lysosomal disorder (farber
  disease)

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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

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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

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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

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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

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galactosemia

• Deficiency of galactose-1 phosphate uridyl
  transferase
• 1/50,000
• Start early after feeding
• Autosomal recessive on chromosome 9p13 with
  malefemale
• Affect brain, liver, kidny and overies

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Galactosemia / clinical

• No enzyme accumulation of galactose1 phosphate
• Liver cirrhosis
• Kidney fancony syndrome
• Brain mental retardation
• Overy amenorrhea
• Galactose to galactitol cause cataract

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Hepatic and GI manifestation

• Lethargy irritability and vomiting
• Feeding difficulty and poor weight gain
• Jaundice, hypoglycemia, hepatomegally
• Ascites
• Hepatic cirrhosis

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others

• Plydypsia, polyurea
• Rickets
• Mental retardation
• Seizure
• Cataract perinuclear haziness to complete
  opacification
• Fulminant e-coli sepsis

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investigation

• Positive clinitest and negative clinistix
• Urine galactose by chromatography
• Direct hyperbilirubinemia
• RBCs galactose 1 phosphate uridyl transferase
  activity
• Increase galactose 1phosphate in RBC

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management

• Lactose free formula
• Control seizure
• Consult ophthalmology
• Consult endocrinology
• Genetic counseling

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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

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PKUcontinue

• Musty or mousey smell
• Microcephaly
• Growth retardation
• 50 point loss of IQ in the first year
• Clinical feature are rarely seen Neonatal
  screening

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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

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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

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