GENETIC
BASIS OF
DISEASE- part 2
Genetic basis of disease part 2
objectives
a. Define inborn errors of metabolism
b. Describe the common characteristic features
of inborn errors of metabolism.
c. Correlate the patho physiological basis of
prototypical and common inborn errors of
metabolism with biochemical abnormalities.
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Inborn Errors of Metabolism- IEM
Introduction
• Also called,
•
Inherited Metabolic Diseases
or Congenital Metabolic Diseases
•
Large group of genetic disorders, resulting in metabolic
defects due to a genetically determined specific defects in
a protein.
•
IEM caused by a single gene mutation (reduced or absent
gene), which leads defects in proteins result from to
production or abnormal function.
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a. Define inborn errors of
metabolism
A groups of mainly Autosomal recessive
diseases, sharing the following characteristic:
1.
Occurs when both copies of genes are mutated.
2.
Both sexes are affected equally.
3.
Onset usually EARLY in life.
4.
Frequently involved enzyme protein Metabolic
pathway block Pathological consequences.
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Common characteristic features of IEM
1. Inheritance of Inborn Errors of Metabolism
Most of the inborn errors of metabolism are
inherited as: Autosomal recessive.
There are also X-linked, and mitochondrial inherited.
A Few are inherited as Autosomal dominant.
2.
Racial and ethnic groupsthe incidence varies with predominance of certain
inborn errors of metabolism within particular
groups.
Some of these diseases occur in large numbers in
communities in which consanguinity is common.
3.Defect in an enzyme or transport protein, which
results in a disruption in a metabolic pathway.
may result in toxic accumulations of substrates before
the disruption+ accumulations intermediates from
alternative metabolic pathways.
4. Onset usually EARLY in life :
•
Carbohydrate or protein metabolism=present in the
neonatal period or early infancy and tend to be rapidly
progressive.
•
Fatty acid oxidation, glycogen storage, and lysosomal
storage disorders less severe present later in infancy
or childhood and tend to be episodic.
General Outcomes of Inborn Errors of
Metabolism
1.
Accumulation of a substrate or its metabolic
derivatives that are harmful or may interfere with
normal function of cells. (S)
2.
Accumulation of intermediates
metabolic pathways. (C)
3.
Decreased ability to synthesize essential compounds
(P)- Deficiency of products
4.
Defects in energy production.
from
alternative
Single Gene Mutation (of gene for enzyme 1)
enzyme 1
s
Reaction 2
(absent
Reaction 1
or no function)
P
Enzyme 1 is absent or not functioning
Reaction 1 is stopped
Reaction 2 is activated
P is absent or decrease
S & C are increased
C
Any one of these (S,C,P) may have pathological effects.
How to diagnose
Relevant history .
 Age of presentation of disease.
 Family History.
Prenatal Diagnosis: Chrorinic villus biopsy is carried out
in the first trimester and Amniocentesis in the second
trimester
Biochemical screening –
 Basic investigations: (CHO, LIPID AND PROTEINS)
Confirmatory test



Metabolic tests. (HPLC, Tandem mass spectrometry)
Sequencing of the specific gene (molecular genetic techniques)PCR, Karyotyping, etc..
Prevention: Program for screening all newborns for certain
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metabolic disorders
c. Correlate the patho-physiological basis of
prototypical and common inborn errors of
metabolism with biochemical abnormalities
Example-PKU
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IEM:
the patho-physiological basis of
Phenylketonuria (PKU)
Single gene defects result in abnormalities in the synthesis
or catabolism of proteins, carbohydrates, fats, or complex
molecules.
PKU- Commonest inherited inborn error disease , specially
Scandinavian descent commonest cause of mental retardation.
PKU- Single gene defects , Autosomal recessive- caused by lack of
enzyme phenylalanine hydroxylase and consequent inability to
metabolize phenylalanine.
Homozygous variants of disease has severe lack of phenylalanine
hydroxylase leading hyperphenylalaninemia.
PKU- affected infants are normal at birth.
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Normal Biochemical pathway for phenylalanine
50% of the dietary phenylalanine Protein synthesis.
50% of the reminder  Tyrosine (precursor of melanin)
PKU-Biochemical abnormalities
Increased phenylpyruvic acid

*E*
Increased phenylalanine (Phe)  Decreased tyrosine
Block
Phenylketonuria –
mutant enzyme is usually phenylalanine hydroxylase(E*)
synthesize less tyrosine (often fair skinned), have 
plasma levels of (Phe), excrete phenylpyruvate and
metabolites
PKU-Biochemical abnormalities
Phenylketonuria –
Increase plasma levels of phenylalanine and its
metabolites:
1.
Induces brain damage.
Lack of tyrosine, (precursor of melanin), is
responsible for light color of hair and skin
(Hypopigementation).
2.
3. Increase plasma level of phenylalanine
Lead to excretion in large amount in urine
and sweat- give strong mousy odor.
Clinical features of PKU.
PKU – raised Plasma level of phenylalanine& its
metabolites in early life if untreated;

- Impaired brain development

- Severe mental retardation (after 6 months)& low IQ.

- Neurological deficit- unable to walk and 2/3 can’t talk.

- Seizures + strong mousy odor in urine& sweat of infants.

- Tyrosine levels  deficiency of melanin formation --- decreased
pigmentation (hypopigmentation) in hair & eyes.
These complications can be delayed by:


Restriction of diet phenylalanine early in life.
Several screening procedures in antenatal and immediate in postnatal
period.
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