CLINICAL BIOCHEMISTRY SECOND STAGE LECTURE 7 DRTHANA ALSEWEDY INBORN

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Inborn error in metabolism of amino acids

Clinical biochemistry second stage CLINICAL BIOCHEMISTRY SECOND STAGE LECTURE 7 DRTHANA ALSEWEDY INBORN lecture 7 Dr.Thana Alsewedy

Inborn error in metabolism of amino acids

Inborn errors of amino acid metabolism are metabolic disorders of in which impair the synthesis and degradation .amino acids .

Abnormality in phenylalanine and Tyrosine metabolism

PHENYL KETONURIA (PKU)

Deficiency of phenyl alanine hydroxylase (Fig.17.1) is the cause for this disease. The genetic mutation may be such that either the enzyme is not synthesized, or a non-functional enzyme is synthesized.

Phenyketonuria (PKU) is a genetic disorder that is characterized by an inability of the body to metabolize phenylalanine, caused by a deficiency in Phenylalanine Hydroxylase (PAH) enzyme or The defect is due to deficiency of dihydrobiopterin reductase.an enzyme that catalyzes the regeneration of tetrahydrobiopterin (cofactor of PAH)

CLINICAL BIOCHEMISTRY SECOND STAGE LECTURE 7 DRTHANA ALSEWEDY INBORN

4. Biochemical Abnormalities

A. Phenylalanine could not be converted to tyrosine. So phenylalanine accumulates. Phenylalanine level in blood is elevated.

B. So alternate minor pathways are opened accumulation of too much phenylalanine and its toxic metabolities phenylpyruvic acid, phenyllactic acid and phenylacetic acid. which becomes a major donor of amino groups in aminotransferase activity and depletes neural tissue of α-ketoglutarate. Absence of α-ketoglutarate in the brain shuts down the TCA cycle and the associated production of aerobic energy, which is essential to normal brain development.

Phenyl ketone (phenyl pyruvate), phenyl lactate and phenyl acetate are excretedin urine.

Clinical Manifestations

A. The classical PKU child is mentally retarded

B. Agitation, hyperactivity, tremors and convulsions are often manifested. This may be because phenylalanineinterferes with neurotransmitter synthesis. Since tetrahydrobioptrerin is the co-enzyme

required for serotonin and dopamine, the decreased level of these neurotransmitters may also result in the neurological symptoms.

C. The child often has hypopigmentation, explained by the decreased level of tyrosine.

D. Phenyl lactic acid in sweat may lead to mousy body odor.

CLINICAL BIOCHEMISTRY SECOND STAGE LECTURE 7 DRTHANA ALSEWEDY INBORN

6. Laboratory Diagnosis

Blood phenylalanine: Normal level is 1 mg/dl. In PKU, the level is >20 mg/dl.

2-Tyrosinemia

Tyrosine is an amino acid which is found in most animal and plant proteins. The metabolism of tyrosine in humans takes place in liver Tyrosinemia is caused by an absence of the enzyme fumarylacetoacetate hydrolase (FAH) which is essential in the metabolism of tyrosine. The absence of FAH leads to an accumulation of toxic metabolic products in various body tissues, which in turn results in progressive damage to the liver and kidneygiving a raised level of tyrosine in blood and urine clinical symptoms include moderate mental retardation, characteristic eye and skin lesions and disturbance in fine coordination.

3-Alkaptonuria (Black urine disease)

An inherited defect in the phenyl a lanine – tyrosine pathway involves a deficiency in the enzyme that catalyses the oxidation of homogentisic acid (an intermediate in the metabolic breakdown of tyrosine and phenyalanin).

Alkaptonuria is caused by the lack of an enzyme called homogentisic dioxygenase (HGD). This condition occurs 1 in 1,000,000 live birth homogentisic acid accumulates and gets excreted in urine where the urine turns black on standing. There is a form of arthritis in late cases and generalized pigmentation of connective tissues; this is believed to be due to the oxidation of homogentisic acid by polyphenol oxidase

forming benzoquinone acetate that polymerises and binds to connects tissues molecules.High doses of ascorbic acid have been used in some patients, to help reduces the deposition of pigment on collagen, but progress of the disease has not been significantly affected by this strategy. Patients usually lead a normal life. It is compatible with fairly normal life. The only abnormality is the blackening of urine onstanding. The homogentisic acid is oxidized by polyphenol oxidase to benzoquinone acetate (Fig.17.6). It is then polymerized to black colored alkaptone bodies.

CLINICAL BIOCHEMISTRY SECOND STAGE LECTURE 7 DRTHANA ALSEWEDY INBORN

4-ALBINISM

1. The Greek word, albino means white. Albinismis an autosomal recessive disease with an incidence of 1 in 20,000 population (Fig.17.7).

Albinism – genetically determined lack or deficit of enzyme tyrosinase

Tyrosinase is completely absent, leading to defective synthesis of melanin.

3. The ocular fundus is hypopigmented and iris may be grey or red. There will be associated photophobia, nystagmus and decreased visualacuity.

4. The skin has low pigmentation, and so skin is sensitive to UV rays. The skin may show presence of naevi and melanomas. Hair is also white.

CLINICAL BIOCHEMISTRY SECOND STAGE LECTURE 7 DRTHANA ALSEWEDY INBORN

Branched chain amino acids Abnormality

Maple syrup urine disease (MSUD)

The normal metabolism of the branched chain amino acids Leucine, Isoleucine, and valine Valine. (Val) (V) is glucogenic; Leucine (Leu) (L)

is ketogenic while Isoleucine (Ile) (I) is both ketogenicand glucogenic. All the three are essential amino acids. Leucine is the major ketogenic amino acid.These amino acids serve as an alternate source of fuel for the brain especially under conditions of starvation.metabolism of these amino acid involves loss of the α-amino acid by transamination followed by oxidative decarboxylation of the respective keto acids. . The decarboxylation step is catalysed by branched chain α keto acid decarboxylase. In approximately 1 in 300,000 live birth in the general US population are affected by this enzyme defect leading to ketoaciduria. When untreated this condition may lead to both physical and mental retardation of the newborn and a distinct maple syrup odor of the urine.

This defect can be partially managed with a low protein or modified diet. In some instances,supplementation with high doses of thiamine pyrophosphate is recommended Thisis because the decarboxylation

requires thiamine..

CLINICAL BIOCHEMISTRY SECOND STAGE LECTURE 7 DRTHANA ALSEWEDY INBORN

Homocystinuria

Norepinephrine

Genetic defects for both the synthase and the lyase enzymes involved in conversion of methionine amino acid into cysteine amino acid. . Missing or impaired cystathionine synthase leads to homocystinuria. High concentration of homocysteine and methionine in the urine. Homocysteine is highly reactive molecule. Disease is often associated with mental retardation, multisystemic disorder of connective tissue, muscle, CNS, and cardiovascular system

CLINICAL BIOCHEMISTRY SECOND STAGE LECTURE 7 DRTHANA ALSEWEDY INBORN

Cystinuria

Cystinuria is one of the inborn errors of metabolism. The disorder is attributed to

the deficiency in transport of amino acids is an inherited autosomal recessive disease that is characterized by the formation of cystine(cysteine-S-S cysteine) stones in the kidneys, ureter, and bladder. Cystinuria is a cause of persistent kidney stones. It is a disease involving the defective transepithelial transport of cystine and dibasic amino acids in the kidney and intestine, and is one of many causes of kidney stones.

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