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Inborn Errors of Metabolism(IEM) Lecture 1. SDK December 18 2012. Objectives. Define Inborn error of metabolism Identify the most common errors Explains the mechanism of Inborn error of metabolism. Explain the dietary plan for IEM. Inborn Errors of Metabolism.

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  • Define Inborn error of metabolism
  • Identify the most common errors
  • Explains the mechanism of Inborn error of metabolism.
  • Explain the dietary plan for IEM

SDK 2012

inborn errors of metabolism
Inborn Errors of Metabolism
  • Is a large group of hereditary biochemical diseases in which specific gene mutation cause abnormal or missing proteins that lead to alter function.
  • Class of congenital disorders caused by an inherited defect in a single specific enzyme that results in a disturbance or abnormality in a specific metabolic pathway.
      • Inborn errors of metabolism are now often referred to as
        • Congenital metabolic diseases or
        • Inherited metabolic diseases.

SDK 2012

problems arise due to
Problems arise due to
  • Accumulation of substances which are toxic or obstruct with normal function
  • The effects of reduced ability to synthesize essential compounds.
    • It leads to organ dysfunction ( brain, liver, muscle, eye, bone etc ) and damage and if left untreated

SDK 2012

common presentation of iem diseases
Common Presentation of “IEM” Diseases
  • Acute life threatening illness
          • Encephalopathy - Lethargy, Irritability, Coma
          • Vomiting
          • Respiratory Distress
          • Seizures, Hypertonia/ hypotonia
          • Hepatomegaly (enlarged liver)
          • Hepatic dysfunction / jaundice
          • Odour, Failure to thrive
          • Hiccoughs
  • Mental retardation, Macro/Microcephaly.
  • Coarse facial features/dysmorphia.
  • Developmental regression.
  • Myopathy / Cardiomyopathy.

SDK 2012

how do we can recognize iem
How do we can recognize “IEM”

Index of suspicion

  • Any full-term infant who has no
        • Antecedent maternal fever or
        • PROM (premature rupture of the membranes)
    • and who is sick enough to need a blood culture or LP, one should think for other possibilities and proceed with a few simple lab tests.
  • Simple laboratory tests
        • Glucose, Electrolytes, BUN (blood urea nitrogen), Creatinine
        • Lactate, Ammonia, Bilirubin, LFT
        • Amino acids, Organic acids, Reducing subst.

SDK 2012


Genetic Characteristic & Mode of Inheritance

  • IEM are usually Autosomal recessive.
  • Consanguinity is always relatively common.
  • Some are X-linked recessive condition including
        • Adrenoleukodystrophy
        • Agammaglobulinemia
        • Fabry’s disease
        • Granulomatous disease
        • Hunter’s Syndrome
        • Lesch – Nyhan Syndrome
        • Menke’s Syndrome
  • A few inherited as Autosomal dominant trait including:
        • Porphyria,
        • Hyperlipedemia
        • Hereditary angioedema
classification of diseases due to iem
Small molecule disease


Amino acid /Protein


Nucleic Acids

Organelle disease





Classification of diseases due to IEM
screen able iem
Screen able IEM
  • Organic acidemia
    • PropionicAcidemia
    • Methylmalonicacidemia
  • Urea cycle defects
    • Argininosuccinicaciduria and others
  • Amino acid disorders
    • Maple syrup urine disease
    • PKU
    • Homocystinuria
  • Carbohydrate disorders
    • Galactosemia

SDK 2012

1 organic acidemia
1. Organic Acidemia
  • The term "organic acidemia" or "aciduria" applies to a group of disorders characterized by the excretion of organic acids in urine.

Organic refer to amino acids and certain odd-chained fatty acids.

  • Well at birth and for the first few days of life.
  • Toxic encephalopathy.
  • All are autosomal recessive, the commonest MMA, MSUD

Clinical presentationsOrganic Acidemia,

  • Signs of Toxic encephalopathy includes :
    • Vomiting, poor feeding, neurologic symptoms such as seizures and abnormal tone, and lethargy progressing to coma.
    • May attributed to sepsis or neonatal asphyxia.

Laboratory findings

  • Metabolic acidosis
  • Hyperammonemia
  • Hypoglycemia
  • Lactic acidosis
  • Anemia, ± thrombocytopenia ± neutropenia
  • Definite diagnosis. Urine organic acid analysis by mass spectrometry.
2 maple syrup urine disease msud
2. Maple syrup urine disease(MSUD)
  • Inherited disease
  • Occurs in infants within the first few days of birth
  • Results in mental retardation/death
  • Urine has “burning sugar/maple syrup” odor
  • Symptoms
    • Vomiting, dehydration, lethargy, seizures, pancreatitis
  • Unable to process amino acids
    • Leucine, isoleucine, valine
    • Products build up, as well as their toxic by-products in blood and urine

-If untreated, will lead to death, coma, neurological decline

what genes are affected
What genes are affected?
  • Autosomal recessive
  • deficiency of BCKDHA (chr 19)
    • Branched chain ketoacid



3. Urea Cycle Defects.

  • causes hyperammonemia but without acidosis
  • Others causes of hyperammonemia without acidosis:
        • liver impairment
              • Generalized Infections
argininosuccinate lyase deficiency asa
Argininosuccinatelyase deficiency (ASA)
  • Initial clinical presentation, Sepsis-like features CNS depression ( i.e. decreased feeding, lethargy, apnea, seizure, coma)
    • Hyperammonemia ( recurrent)
    • No acidosis or hypoglycemia
    • Hepatomegaly
4 amino acid disorders 4 1 phenylketonuria
4. Amino Acid Disorders4.1. Phenylketonuria
  • Autosomal Recessive Disorder.
  • Inherited error of metabolism caused by deficiency in the enzyme phenylalanine hydroxylase (PAH).
    • Mutation in both alleles of the gene for the enzyme.
    • Chromosome 12.
    • Recessive allele carried by 1 out of every 60 individuals.

Clinical features of PKU

  • Hyperactivity, athetosis, vomiting.
  • Blond.
  • Seborric dermatitis or eczema skin.
  • Hypertonia.
  • Seizures.
  • Severe mental retardation.
  • Unpleasant odor of phenyl acetic acid
4 4 homocystinuria
4.4 Homocystinuria
  • homocysteine is an intermediate in the metabolism of methionine to cysteine but can also be used to reform methionine.
  • homocystine is formed by joining 2 homocysteines
  • homocysteine is linked to both folate and vitamin B12 metabolism
  • excessive accumulation of homocystine leads to homocystinuria and is caused by
    • decreased metabolism of homocysteine through either its link to folate Metabolism or through its link to cysteine formation

SDK 2012

homocystinuria cbs def
Homocystinuria (CBS def)

• Mental retardation

• Ectopialentis

• Skeletal abnormalities

• Thromboembolism



  • Inborn errors of metabolism (IEMs) individually are rare but collectively are common. Presentation can occur at any time, even in adulthood.
  • Diagnosis does not require extensive knowledge of biochemical pathways or individual metabolic diseases.
  • An understanding of the broad clinical manifestations of IEMs provides the basis for knowing when to consider the diagnosis.
  • Most important in making the diagnosis is a high index of suspicion.
  • Successful emergency treatment depends on prompt institution of therapy aimed at metabolic stabilization.
thank you
Thank You

SDK 2012