Inherited Metabolic

Disorders I

Prof. A. Amayo
INBORN ERRORS OF METABOLISM

Metabolism comprises all the processes

by which living matter is built up
(anabolism) or broken down(catabolism).

Metabolic processes are controlled by two

integrated inputs:-
· Genes which limit the capacity of
any given cell and
· Environment which determines how
those genes will be expressed.

Metabolic disorders result from

disturbance in the interaction between
genetic and environmental factors.
Classification

• Chromosomal disorders –
lack, excess or abnormal
arrangement of one or more
chromosomes. Many genes are
affected.

• Monogenic disorders –
single mutant gene defects,
display simple (Mendelian) mode
of inheritance.
• Complex diseases –
interaction of multiple genes
and environmental factors.
Monogenic Disorders:

Patterns of inheritance
- Autosomal dominant
- Autosomal recessive
- Sex linked (X-linked)

The common feature is a

qualitative or quantitative
change in synthesis of a protein
which has enzymic or other
functional properties.
• Overall global prevalence:
50.9 per 100,000 live births
Waters D. J Glob Health 2018
Class No. of Incidence
disorders
known

Critical, life 70-80 ~1:5,000

threatening
disorders of
infancy

Serious >300 ~1:1,000

disorders
in infants
and adults

Common >300 ~1:50

disorders
Effects of genetic changes on
protein synthesis

(a) No protein is synthesized

premature chain termination.
(nonsense mutation)
No m-RNA is detectable.
(b) Reduced concentration
of protein of normal
structure –
reduced rate of transcription or
processing.
(c) Synthesis of protein with
abnormal structure –
common with point mutations.
Effects of inherited
metabolic diseases
The effect of any given genetic
alteration on cellular
metabolism depends on :
• the role that the mutant
protein plays and

• the severity of the defect.

Model metabolic pathway

Ta Ea Eb Ec
A A B C D

F G

A-B-C-D Are substrate and products

of a major metabolic pathway.
Ta - transport system for A
FG - products of minor pathway
Ea, Eb, Ec - Are enzymes
Interference in pathway can lead to
several clinical abnormalities.
1. Precursor deficiency –
maybe due to
defective receptor or
carrier systems e.g.
Hartnup disease –
intestinal transport of
tryptophan is defective.
Since tryptophan is
converted to nicotinamide
intracellulary, there is a
deficiency which may lead to
pellagra.
2. Precursor (substrate)
accumulation:
If substrate is toxic it
will lead to clinical
manifestations e.g:
• Gaucher’s disease,
accumulation of lysosomal
glucocerebroside.
• Galactosaemia –
Increased galactose in
tissues.
3. Product deficit:-
A block in the reaction sequence
results in inadequate synthesis of
the end product. If :
• the product is essential,
• no alternative pathway for its
synthesis, clinical features will
arise.
Examples:
- Congenital adrenal
hyperplasia- block in cortisol
synthesis.
- Congenital hypothyroidism
Block in thyroid hormone
synthesis.
4. Alternate pathway
utilisation:-
Reduced enzyme activity will not
only lead to precursor
accumulation, but a usually
minor alternate pathway may
become prominent. If product is
toxic, will lead to symptoms
• Example – phenyl ketonuria.
Reduced activity of phenylalanine
hydroxylase leads to
overproduction of phenyl pyruvic,
phenylacetic and phenyllactic
acids.
• Congenital adrenal
hyperplasia there is
overproduction of androgens by
adrenal cortex.
Suspicion of inherited disease
in children
• If routine diagnostic tests
normal
• symptoms not in keeping with
suspected diagnosis.
• Response to treatment
inappropriate.
• Mental retardation without
known history of prenatal
morbidity, meningitis or trauma.
• Failure to thrive with no known
cause – Not attributable to
psychosocial deprivation, GIT or
renal disease, hormonal
disturbance.
 Laboratory evaluation of
suspected of suspected
metabolic disorders

• Plasma electrolytes
• Glucose
• Calcium
• Liver enzymes
• Urinalysis
• Blood gases
• Complete blood count and
differential
Additional tests

• Plasma lactate
• Urine organic acid analysis
• Plasma amino acid
analysis/urine amino acid
(TLC).
Specimen collection
important. Take in neonates
>2days of age.
• Urine reducing substances
non-glucose reducing
substances.
• Plasma ammonia
Specific diagnostic tests
• Analytic techniques e.g.
HPLC, GC, or GC/MS for
identification of abnormal
metabolites esp organic
acids.
• Specific assays of enzyme
activity in tissue samples or
body fluids e.g in
galactosaemia.
• Molecular biological
techniques for gene defects
(DNA based techniques)
DNA diagnosis of Genetic
Disorders:
Necessary when:
• The gene is not expressed in
cultured cells or leucocytes
• There is no biochemically
detectable phenotype
• Disease has delayed onset of
presentation

Types of DNA based diagnostic

tests
• Direct gene evaluation (PCR
based)
• Linkage analysis (RFLP)
• DNA probe analysis

Dot-blot analysis
If there is a specific mutation
that characterises the
condition e.g Sickle Cell
Disease.

Multiplex PCR
If there is a variety of
mutations causing variants of
same disease e.g cystic
fibrosis.
Screening for metabolic
disorders

a) Neonatal screening:-
Search in population for babies
possessing certain genetic
diseases.
Principles of Neonatal
screening:
• Disease must be a significant
cause of morbidity and
mortality
• Treatment must be readily
available and effective in
decreasing complications of
the disorder.
• Screening test must be easy
to perform and cheap.
• Test should have few false
positives and no false
negatives.
Screening programs
available for:-
• Phenylketonuria
• Congenital hypothyroidism
• Cystic fibrosis
• Galactosaemia
• Maple syrup urine disease
Use Guthrie test systems. False
negative – antibiotics. Sample
>2days.
Fluorometric methods, GC/MS
for rapid simultaneous testing
of >30 analytes.
Prenatal diagnosis:-
Screening done while baby is
in utero or pre-implantation
in IVF programs.
Suitable for conditions with no
“cure” (untreatable)
• High risk groups – women
with previously affected
infant. Those in whom carrier
state is more common than
general population.
• E.g Sickle cell anaemia.
• Carrier screening is
meaningful in prenatal
diagnosis where termination
is considered if affected
fetuses are identified. There
are ethical and religious
implications.
• Diagnosis may be
biochemical or DNA based
• Use of circulating fetal DNA.
• Prenatal screening may also
be used to plan appropriate
place and method of delivery
for infants well being.
Principles of management of
genetic disorders
• Requires accurate diagnosis
• Early intervention before
irreversible tissue damage
occurs.

a) Treatment of clinical
phenotype
- Patient education, drugs, surgery
- Not aimed at correcting primary
defect but avoiding the
complications.
 b. Biochemical
(metabolic) level
- Nutritional or
pharmacological intervention
at metabolite level.

i) Precursor toxicity –
dietary restriction of
substrate. Started soon after
birth and continued for life.
Monitoring to ensure just
sufficient intake for normal
growth.
ii) Alternate pathway
utilisation –
May be used to remove toxic
metabolites e.g. in urea cycle
disorders. Use of benzoate
and phenylacetate –
hippurate reduces ammonia
accumulation.
iii) Inhibition of
overactive pathways
e.g. inhibition of xanthine
oxidase by allopurinol in
gout.
iv) Product deficit –
replacement therapy e.g in
Congenital hypothyroidism
 Treatment at protein
level
• Activation of mutant
protein
• Protein replacement
therapy

Gene transfer
Germ line therapy – not yet
fully applied in humans
 Further reading

• Clinical Chemistry (Marshall)

• Clinical Chemistry and
Metabolic Medicine (Crook
M.A )