Aminoaciduria

Overview of Amino Acid Catabolism

1st phase

Removal of the α-amino groups

2

nd

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

2

nd

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 aims at maintaining blood phenylalanine levels close to normal range. 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 • •

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 B 6 ,B 12 & folate