Aminoaciduria
Overview of Amino Acid Catabolism
1st phase
Removal of the α-amino groups
2nd phase
Carbon skeletons of the α-ketoacids are converted to common intermediates
of energy producing and other metabolic pathways
1st phase of catabolism of amino acids:
Removal of the α-amino groups
With
production
of
Free
Ammonia
In Liver
Small amount excreted in
urine
Urea
2nd phase of A. A. catabolism
Breakdown of the resulting carbon skeletons of amino acids
Giving 7 intermediates
Oxalacetate, a-ketoglutarate, Pyruvate, Fumarate, Succinyl CoA
Acetyl CoA & Acetoacetyl CoA
• ATP, CO2 & H2O: by Citric acid cycle intermediates)
• Glucose: from Gluconeogenesis intermediates)
• Fatty Acids: from acetyl CoA & Acetoacetyl CoA)
• Ketone Bodies : from acetyl CoA & Acetoacetyl CoA)
Amino Acids
Metabolism
Glucogenic & Ketogenic Amino Acids
Glucogenic Amino Acids
Amino acids whose catabolism
yields pyruvate or one of the
intermediates of citric acid cycle
i.e. substrates of gluconeogenesis
& therefore can give rise to GLUCOSE
Ketogenic Amino Acids
Amino Acids whose catabolism
Yields acetyl CoA or acetoactyl CoA
i.e. finally give rise to ketone bodies
Leucine& lysine are the only
exclusively ketogenic amino acids
& therefore cannot give rise to glucose
Inborn Errors of Amino Acid Metabolism
Inborn Errors of Metabolism
also called,
Inherited metabolic diseases
or Congenital metabolic diseases

They are a large group of genetic disorders, resulting in metabolic defects due to
a genetically determined specific defects in a protein.

Defects in proteins result from a single gene mutation which leads to reduced or
absent gene product or production of a different protein with abnormal
function.
General effects of
inborn errors of metabolism
•
Accumulation of a substrate or its metabolic derivatives that are harmful or may
interfere with normal function of cells.
•
Accumulation of intermediates from alternative metabolic pathways
•
Decreased ability to synthesize essential compounds
•
Defects in energy production
Inheritance of
inborn errors of metabolism
•
Most of the inborn errors of metabolism are inherited as autosomal recessive or
X-linked disorders in nuclear DNA.
•
Few are inherited as autosomal dominant.
•
Some may involve mitochondrial functions as they are linked to mitochondrial DNA
•
The incidence of these diseases within different racial & ethnic groups 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.
Detection of inborn errors of metabolism
Inherited disorders may be detected in different stages during life
•
Heterozygote carriers of a disease
may be found during screening (as such performed on family members of a patient
with muscular dystrophy).
•
Before birth (intrauterine)
some inherited disorders can be detected before birth (as cystic fibrosis).
•
Neonatal screening (in first days of life)
As for phenylketonuria
•
In neonates (in first weeks of life)
Many disorders involving single gene defects become apparent clinically (give
symptoms & signs).
•
Some disorders such as familial hypercholesterolemia may not be recognized until
adult life.
Neonatal Screening
• Programs for screening all newborns for certain metabolic disorders are
performed with the following criteria:
1- The disease should not be clinically apparent at the time of screening
2- The disease should have a relatively high incidence in the population screened.
3- The disease should be treatable & so results of screening test must be obtained before
irreversible damage is likely to have occurred.
4- Screening test should be simple & reliable.
•
Examples of screening programs:
Phenylketonuria
Galactossemia
Congenital hypothyroidism
Cystic fibrosis
•
A positive result of a screening test should be confirmed by quantitative analysis or identifying the
enzyme defect..
•
In a second positive test, the individual might be required to be reassessed after a period of time
in some cases.
Inborn Errors of Amino Acid Metabolism
1- Phenylketonuria (PKU)
Phenylketonuria
•
•
is the commonest cause of inborn errors of amino acid metabolism
is the commonest inherited cause of mental retardation
•
It is mainly caused by deficiency of phenylalanine hydroxylase of liver (which
converts phenylalanine to tyrosine).
Causes of Phenylketonuria (PKU)
1- Deficiency of phenylalanine hydroxylase
Causes of Phenylketonuria (PKU) cont.
2- Deficiency in enzymes that synthesize or reduce the coenzyme dihydrobiobterin
(DHBP synthetase & DHBP reductase)
In this case, simply restricting dietary phenylalanine will not reverse CNS defects
due to deficiency of neurotransmitters
Metabolic & clinical effects of phenylketonuria
• Elevated blood phenylalanine & its metabolites
Phenylalanine & its metabolites phenylpyruvic, phenylacetate &
phenyllactate accumulates resulting in their rise in blood
& excretion in urine (phenylketonuria).
• CNS symptoms:
Persistent postnatal hyperphenylalaninemia causes irreversible brain
damage ending in mental retardation (by age of one year) & convulsions.
Most untreated patients show IQ below 50
• Hypopigmentation:
Tyrosine levels are reduced ending in deficiency of melanin formation resulting in
decreased pigmentation (hypopigmentation) in hair & eyes.
Also, the hydroxylation of tyrosine by tyrosinase (the first step in melanin
pigment formation) is competitively inhibited by high levels phenylalanine.
Diagnosis of Phenylketonuria
Neonatal diagnosis
Early diagnosis of PKU is important because the disease is treatable by dietary means.
Newborn with PKU frequently has normal blood levels of phenylalanine (PA) at birth
As the mother clears increased blood PA in her fetus through placenta. So, test performed at
birth may show false –ve results.
PA begins to be elevated when newborn takes milk (containing proteins) for at least 24 hours
Accordingly, feeding with milk for 48 hours is sufficient to raise the newborn blood PA to
levels that can be used for diagnosis.
Diagnosis of Phenylketonuria
cont.
Neonatal Screening Program for PKU
•
Must be made within one month of birth, if mental retardation is to be prevented.
•
Screening program for neonate (6 –14 days of life) using Guthrie test is performed:
- A disk of a filter paper containing blood from a heel
prick is placed on plates impregnated with a microorganism, Bacillus subtilis,
which requires phenylalanine for growth, the only source being the
blood spot.
- The growth of the organism is a positive test.
•
Test has to be confirmed by measuring blood phenylalanine
Treatment of phenylketonuria
Principles of treatment of PKU
•
.
•
Treatment must begin during first 7-10 days of life to prevent mental retardation.
•
Treatment should be continued for many years (at least till age of 8) as high blood levels of
phenylalanine between 4 – 8 years leads to mental retardation.
However, life-long treatment by diet restriction of phenylalanine is preferred
•
Avoiding low levels of phenylalanine in blood as it is an essential amino acid and therefore is
essential for physical & mental growth.
•
Tyrosine is must be supplied in diet as it cannot be synthesized from phenylalanine in cases of
PKU
Treatment aims at maintaining blood phenylalanine levels close to normal range.
Protocol of treatment:
• By feeding synthetic amino acid preparations low in phenylalanine
• Supplemented with some natural foods such as vegetables, fruits & certain cereals selected for
their low phenylalanine content & rich in tyrosine.
Maternal PKU
•
•
•
Pregnant women with PKU & are not on low PA diet, the offspring are affected
with maternal PKU syndrome.
High blood PA levels in the mother cause microcephaly, mental retardation &
congenital heart abnormalities in the fetus
Accordingly, dietary control of PA must begin prior to pregnancy & must be
maintained throughout pregnancy.
Inborn Errors of Amino Acid Metabolism
2- Maple Syrup Urine Disease (MSUD)
•
Due to deficiency of the branched chain a-ketoacid dehydrogenase enzyme which
decarboxylates the branched-chain amino acids leucine, isoleucine & valine.
•
Metabolic & clinical effects :
1- Accumulation of these amino acids & their metabolites (a-ketoacids) in
blood lead to toxic CNS effects.
2- Characteristic maple syrup odor in urine (due to the amino acid isoleucine)
•
Diagnosis:
Elevated branched-chain amino acids & their metabolites in blood & urine
Newborns suspected to have MSUD should be tested within 24 hours of birth to start treatment
early (to avoid toxic effects)
•
Treatment:
Synthetic formula that contains limited amounts of leucine, isoleucine & valine
sufficient to provide amino acids necessary for normal growth & development
without producing toxic effects.
Inborn Errors of Amino Acid Metabolism
3- Disorders of tyrosine amino acid metabolism
Disorders of tyrosine amino acid metabolism lead to the following consequences:
1- Deficiency of melanin pigments (Albinism)
Tyrosine is the precursor of melanin (by tyrosinase enzyme)
Deficiency of tyrosine leads to albinism.
Albinism refers to a group of conditions in which a defect in tyrosine metabolism
(deficiency of tyrosinase) results in deficiency in the production of melanin resulting in the
partial or full absence of pigment from the skin, hair & eyes.
2- Deficiency of neurotransmitters:
Tyrosine is the precursor of DOPA
DOPA is converted to dopamine & catecholamine (neurotransmitters)
Disturbance of these neurotransmitters may cause Parkinson’s disease.
Inborn Errors of Amino Acid Metabolism
4- Disorders of tyrosine amino acid metabolism
Alkaptonuria
•
•
Caused by deficiency of homgentisic acid oxidase
( enzyme in tyrosine metabolism)
Homgentisic acid (metabolite of tyrosine metabolism)
cannot be further metabolized & thus accumulates resulting in:
1- Excretion of homogentisic acid in urine in excessive amounts
(homogentisic aciduria) which is oxidized to dark pigments
on standing.
2- Homogentisic acid is deposited in connective tissue ending in
degenerative changes in large joints (arthritis).
Inborn Errors of Amino Acid Metabolism
5- Homocystinuria
•
•
Deficiency of the enzyme cytathionine synthetase (for methionine amino acid
metabolism) resulting in inability to metabolize amino acid methionine & homocysteine
Elevated methionine & homocysteine may cause:
- CNS manifestations: mental retardation, seizures, etc
- Vascular thrombosis (complicated by CHD & strokes)
•
Treated by diet deficient in methionine & giving large dose of vitamin B6 ,B12 & folate