Protein And Amino Acid Metabolism

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PKU

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Five types of hyperphenylalaninaemias have been described.

The five types of hyperphenylalaninaemias along with the corresponding enzyme

Classical type of phenyl ketonuria (PKU): An inherited disorder with incidence of 1 in 10,000 live births.

Enzyme deficiency Phenyl alanine hydroxylase is absent.

Metabolic changes due to absence of phenylalanine hydrodylase:

Phenyl alanine cannot be converted to tyrosine, as a result alternative catabolites are produced.

Phenyl alanine accumulates in the blood;

phenyl alanine undergoes transamination to form phenyl pyruvic acid and its products as phenyl lactic acid and phenyl acetic acid are produced.

Phenyl acetic acid is conjugated with glutamine and excreted as phenyl acetyl glutamine in urine (responsible for “mousy odour” of urine).

Accumulation of phenylalanine leads to

• Defective “serotonin” formation.

• Also impairs melanin synthesis, Children with the defect tend to have flair skin and fair hair.

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What are the 5 types of PkU and their probable causes?

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I.Classical type of phenyl ketonuria(PKU)

Phenyl alanine hydroxylase enzyme absent

Low phenyl alanine diet

II.Persistent hyperphenylalaninaemia

Decreased Phenyl alanine hydroxylase enzyme

None but temporary dietary therapy

III.Transient mild hyperphenylalaninaemia

Maturational delay of phenyl alanine hydroxy-

Tx is same as for type 2

IV.Dihydropteridine reductase deficience

Deficient or absent dihydropteridine reductase

Dopa, 5-OH tryptophan, carbi Dopa

V.Abnormal dihydrobiopterin function

Clinical features:

Child is mentally retarded, other features include seizures, Psychoses and eczema.

Blood: Increased levels of phenyl alanine.

Normal level in bloodis 1 to 2 mg%. It increases to 15 to 65 mg%.

Urine•Excretion of phenyl alanine, and its catabolites: Phenylpyruvic acid, and phenyl lactic acid.

•Phenyl acetic acid excreted as phenyl acetyl glutamine which produces ‘mousy’ odour.

•Also abnormal O-hydroxy derivative is formed, whose metabolites may also be found in urine.

Diagnosis

•By estimation of plasma Phenyl alanine level.

•“Screening test”: for presence of phenyl pyruvate withFeCl3 (In urine).

Administration of phenyl alanine to a phenylketonuric patient should result in prolonged elevation of the level of this amino acid in blood (“phenyl alanine tolerance test”).

Treatment By giving diet having very low levels of phenyl alanine.

The diet can be terminated at 6 years of age, when high concentration of phenyl alanine and its derivatives are no longer injurious to brain.

Note In phenylketonurias, tyrosine constitutes as an essential amino acid and must be provided in the diet.

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Alkoptunuria

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Alkaptonuria

A rare inborn error or hereditary defect in metabolism of Phenyl alanine and Tyrosine.

It is of historical interest Garrod’s ideas concerning heritable metabolic disorders was proposed.

Inheritance: Autosomal recessive.

Incidence: Estimated incidence 2 to 5 per million live births.

Over 600 cases have been reported in literature.

Enzyme deficiency: Lack of the enzyme homogentisate oxidase. Homogentisic acid accumulates in the tissues and blood and appears in urine.

Most striking clinical manifestation—is occurrence of dark urine on standing in air.

Homogentisic acid like many derivatives of tyrosine is readily oxidised to black pigments (alkapton).

Urine when exposed to air slowly turns black from top to bottom

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Onchronosis

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In long-standing cases, deposition of homogentisic acid derivatives in cartilages of ears and other exposed parts leads to generalised pigmentation of connective tissues and deposition in joints leads to arthritis, a condition called Ochronosis.

Mechanism of Ochronosis The precise mechanism of ochronosis is not known.

It probably involves oxidation of homogentisate by Polyphenol oxidase, forming benzoquinone acetate, which polymerizes and binds to connective tissue macromolecules.

Note

• Alkaptonuria may also occur in premature infants on account of vitamin C deficiency.

Condition is improved in premature infants by administration of vit. C.

• Experimental alkaptonuria may be produced by “α-α’ dipyridyl”-chelating agent of Fe. 3.

Tyrosinaemia Type I (Also called Tyrosinosis) A rare inherited disorder. Tyrosinosis is characterised by accumulation of metabolites that adversely affect the activities of several enzymes and transport systems.

Pathophysiology of this disorder is complex.

Enzyme deficiency: There is lack of the enzyme Fumaryl acetoacetate hydrolase and possibly also Maleyl acetoacetate isomerase.

Types: Both acute and chronic forms are known.

1. In acute tyrosinosis: Infants exhibit diarrhoea, vomiting, a “cabbage”-like odour. They do not thrive well, and there

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Albinism

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It includes a spectrum of clinical syndromes characterized by hypomelanosis, arising from inherited defects in the pigment cells (melanocytes) of eye and skin.

There are various forms of the disease. But can be divided into two major groups:

(a) Oculocutaneous albinism: More than ten forms are known. In this there is decreased pigmentation of skin and eyes.

They can be differentiated by clinical presentation and biochemical and other features.

Such ‘albinos’ can be biochemically of two types:

(i) ‘Tyrosinase’ negative albinos

(ii) ‘Tyrosinase’ positive albinos