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In Born Error of Metabolism (IEM) PowerPoint PPT Presentation

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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)

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In born error of metabolism iem l.jpg

In Born Error of Metabolism (IEM)

Dr Mohammad Khassawneh

Assistant professor of pediatrics

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  • 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 1:10,000

    • Galactosemia 1:50,000

    • Homocystinurea 1:200,000

    • Estimated overall incidence 1:2000

  • 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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  • 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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  • 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, Sanfilippo’s, 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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  • 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

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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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  • Plydypsia, polyurea

  • Rickets

  • Mental retardation

  • Seizure

  • Cataract: perinuclear haziness to complete opacification

  • Fulminante-coli sepsis

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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

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  • 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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  • 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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  • 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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  • 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

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