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Inborn error of metabolism
1.
2. Inborn Error of Metabolism
Single gene mutations
Alteration of primary protein structure
Alteration of the amount of protein synthesized
Mild to lethal
3. Inheritance:
• Most IEM…… autosomal recessive genetic traits
• Urea cycle disorder ornithine transcarbamylase
deficiency…….. X linked
• Some are mitochondrial inheritance
4. Metabolic disorders can be classified using a
variety of schemes based on:
the clinical presentation
the age of onset
the tissues or organ systems involved
the defective metabolic pathways
6. Group 1
Anabolism/
catabolism
Lysosomal,
Peroxisomal,
glycosylation, and
cholesterol synthesis
defects
some Lysosomal
disorders can be
efficiently treated by
enzyme replacement
or substrate
reduction therapies
Group 2
intermediary
metabolism
Aminoacidopathies,
organic acidurias, urea
cycle disorders, sugar
intolerances, metal
disorders and
porphyrias
Acute or chronic
intoxications
Neonatal to adulthood
Most …. treatable
emergency removal of
the toxin by special diets,
extracorporeal
procedures, cleansing
drugs or vitamins
Group 3
energy production/
utilization
Cytoplasmic defects
encompass those affecting
glycolysis, glycogenosis,
gluconeogenesis,
hyperinsulinisms, and
creatine and pentose
phosphate pathways; the
latter are untreatable.
Mitochondrial defects
include respiratory chain
disorders, and Krebs cycle
and pyruvate oxidation
defects, mostly untreatable,
and
disorders of fatty acid
oxidation and ketone bodies
that are treatable
41. Treatment
Prevent Catabolism:
Administration of calories is used in the treatment of
acute episodes to try to slow down catabolism.
Limit the Intake of the Offending Substance:
the basis of treatment in Galactosemia, fructose
intolerance and PKU.
Increase Excretion of Toxic Metabolites:
by exchange transfusion, peritoneal dialysis (PD),
hemodialysis, forced diuresis, using alternative
pathways for the excretion of toxic metabolites. For
example, carnitine is useful in the elimination of organic
acids in the form of carnitine esters. Sodium benzoate
and phenylacetate are useful in treating
hyperammonemia.
42. Enzyme Replacement Therapy:
Human alpha glucosidase enzyme (pompe’s disease)-
Laronidase (Aldurazyme) enzyme(MPS I)patients-
Fabry-specific enzyme replacement therapy (ERT) with
recombinant alpha-Gal A (Fabrazyme) is safe and
effective, Imiglucerase (Gaucher disease)
Increase the Residual Enzyme Activity:
B12 decreases the urinary levels of methyl malonate by
enhancing activity of Trans Cobalmin II
Reduce Substrate Synthesis:
Inhibition of substrate synthesis has been used as a
strategy for treating glycolipid Lysosomal storage
disease.
43. Replacement of the End Product:
Hypoglycaemia can be prevented by frequent feeds
during the day and continuous nasogastric feeding
at night, in infancy and early childhood. Raw
cornstarch (2 g/kg every six hours) has been shown
to be effective in preventing hypoglycaemia in older
children with glycogen storage disease type I as
well as decreasing the hyperlipidaemia,
hyperuricaemia, and lactic acidaemia
44. Transplantation and Gene Therapy:
For the last 25 years, hematopoietic cell
transplantation (HCT) has been used as effective
therapy for selected inborn errors of metabolism
(IEMs), mainly Lysosomal storage diseases and
Peroxisomal disorders. The main rational for HCT in
IEMs is based on the provision of correcting
enzymes by donor cells within and outside the blood
compartment
45. Prevention
Genetic counselling and prenatal diagnosis:
The samples required are chorionic villus tissue or
amniotic fluid. Modalities available are:
• Substrate or metabolite detection: useful in
phenylketonuria, peroxisomal defects.
• Enzyme assay: useful in lysosomal storage
disorders like Niemann-Pick disease, Gaucher
disease.
• DNA based (molecular) diagnosis: Detection of
mutation in proband/ carrier parents is a
prerequisite.
Neonatal screening: tandem mass spectrometry
46. Selective screening for inborn errors of metabolism
by tandem mass spectrometry in Egyptian children:
A 5 year report
• A relatively high number of patients (203/3380 (6%))
were confirmed with 17 different types of IEMs.
Averages for age at diagnosis for different disorders
ranged from 2.5 months to 6.6 years with general
developmental delay and irreversible neurological
damage being the most common presenting features
(75.9% and 65.5%, respectively). Amino acid disorders
(127/203 (62.6%)), mainly phenylketonuria (100/203
(49.3%)), were the most encountered, followed by
organic acidemias (69/203 (34%)), while fatty acid
oxidation defects (7/203 (3.4%)) were relatively rare.
88% of patients were born t consanguineous parents.
47. References
• Talkad S. Raghuveer and et.al. Inborn Errors of
Metabolism in Infancy and Early Childhood: An
Update. American Family Physician j.2006:
17:1981-1990
• Atlas of Metabolic Diseases, 2nd edition
• Ananth N Rao, J Kavitha, Minakshi Koch and
Suresh Kumar V. Inborn Errors of Metabolism:
Review and data from a tertiary care center.
Indian Journal of Clinical Biochemistry, 2009: 24
(3) 215-222
• Anju Gupta. To Err is Genetics: Diagnosis and
Management of Inborn Errors of Metabolism
(IEM)
48. • Laila A. Selim and et.al. Selective screening for
inborn errors of metabolism by tandem mass
spectrometry in Egyptian children: A 5 year
report. Clinical Biochemistry 47 (2014) 823–828