
a single gene defect causes
a clinically significant block in a
metabolic pathway resulting either in
accumulation of substrate behind the
block or deficiency of the product
IEM arises from a damaged gene which
leads to abnormal enzyme.
 May be autosomal or sex-linked.
 May be recessive or dominant in
expression.
 Heterozygote will have both normal and
abnormal alleles. But homozygote will
have two alleles the same on each
chromosome.

An accumulation of the substrate before the enzyme
defect*.
 A decrease in the amount of the product is observed.
 An increased concentration of the alternative
metabolites*.
 A decrease or absence of the enzyme activity.

Screening for IEM who do not have the
symptoms
 Investigations of the patient with
symptoms of the IEM


It is the process of detecting a patient
with an IEM before they show overt
symptoms of the disease.
› Allow the treatment to begin
› Counseling to be given
Screening is done for high risk group which
includes
All newborn infants
Family of affected children
Expectant mothers who have history of
affected children. (prenatal diagnosis)
Suitable treatment for disease
 Life threatening disease
 High incidence of disease
 A suitable test is available
 Acceptable cost.

› PKU
› Congenital hypothyroidism
Test to identify carriers of the disease
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Failure to thrive
Poor feeding
Persistent vomiting
Unexplained jaundice
Unexplained hypoglycemia
Ketosis
Lactic acidosis
Convulsions and coma
Lethargy
Hypotonia
hyperventilation

Some may present later (within first few
years)
› Abnormal liver function tests
› Mental retardation
Front line tests
 Plasma

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Electrolytes
Acid base balance
Blood gases
Glucose
Liver function tests
calcium

Plasma
› Insulin
› Lactic acid
› Ammonia
› Ketones

Urine
› Amino acids
› Organic acids
› Sugars

History of affected individual
› Amniocentesis (15th week of gestation -20th
week)
fibroblast extracted from amniotic fluid.
fibroblasts are cultured and specific enzyme
studies are done

Cvs (9th week completed within 10 days)
›
›
›
›
DNA analysis (cystic fibrosis)
Down syndrome
Hemoglobinopathies
Tay sachs disaease
Autosomal recessive disorder
 1 in 15,000 live births in America.
 Deficiency of phenylalanine hydroxylase

Deficiency
May be carried out in three stages:
a. Diagnosis of Broad Category: Saudubray
et al (2002)* suggested a battery of simple
and routine tests for identification of the
broad category of the disorders. These tests
include plasma electrolytes, ABGs, blood
ammonia and lactic acid etc.
*Saudubray JM, Nasoogne MC, Lonlay PD, Touati G. Clinical approach to
inherited metabolic disorders in neonates: an overview. Smin Neonatol 2002; 7: 3-15.
May be carried out in three stages:
b. Diagnosis of the exact disorder
• It requires very sophisticated equipment
e.g. HPLC, tandem mass spectrometry,
GC-MS and ion exchange
chromatography.
May be carried out in three stages:
b. Diagnosis of the exact disorder (cont)
• These techniques also require elaborate
infrastructure of trained manpower,
proper back-up service for the
instruments and regular supply of
reagents.
May be carried out in three stages:
b. Diagnosis of the exact disorder (cont)
• AKU hospital has taken an initiative to
establish the first-ever lab in the country
for the pin-point diagnosis of some of the
IEM.
May be carried out in three stages:
c. Determination of deficient enzyme or
protein Although a few laboratories in the
world provide this facility, this is only of
academic and research interest. Diagnosis of
the genetic defect provides another
promising pathway for some of these
disorders.