Disorders of the Metabolism

Inherited deficiencies in the enzymes of phenylalanine and tyrosine metabolism lead to the diseases phenylketonuria and alkaptonuria .

because their clinical management is different.15).000). For example. caused by a deficiency of phenylalanine hydroxylase (Figure 20.Phenylketonuria (PKU). may also be caused by deficiencies in the enzymes that synthesize or reduce the coenzyme biopterin is frequently important to distinguish among the various forms of hyperphenylalaninemia. is the most common clinically encountered inborn error of amino acid metabolism (prevalence 1:11. a small fraction of PKU is a result of a deficiency in either reductase or synthetase .

Antenatal diagnosis of PKU: Classic PKU is a family of diseases caused by any of forty or more different mutations in the gene that codes for phenylalanine hydroxylase {PAH). and blue eyes). microcephaly. These metabolites give urine a characteristic musty("mousey") odor. and phenylpyruvate. tremor. Neonatal diagnosis of PKU: Early diagnosis of phenylketonuria is important because the disease is treatable by dietary means. seizures.Characteristics of PKU a. hyperactivity. light skin color. and failure to grow are characteristic findings in PKU. are also elevated in PKU. CNS symptoms: Mental retardation. . Elevated phenylalanine: Phenyllactate. Hypopigmentation: Patients with phenylketonuria often show a deficiency of pigmentation (fair hair. which are not normally produced in significant amounts in the presence of functional phenylalanine hydroxylase.phenylacetate. failure to walk or talk.

The illness has three characteristic symptoms: homogentisic aciduria (the patient's urine contains elevated levels of homogentisic acid. large joint arthritis. resulting in the accumulation of gentisic acid. which is oxidized to a dark pigment on standing.Alkaptonuria is a rare metabolic disease involving a deficiency in acid oxidase. and black ochronotic pigmentation of and collagenous tissue .

but usually no symptoms are present until later in life. Dark staining of the diapers sometimes can indicate the disease in infants. and decrease the amount of pigment deposited in body tissues. Although alkaptonuria is not life-threatening. .Patients with alkaptonuria are usually asymptomatic until about age forty. the associated arthritis may be severely crippling. Diets low in in phenylalanine and reduce the levels of homogentisic acid.

but gout is usually preceded by hyperuricemia. as a result of either over-production or underexcretion of uric acid.Gout: Gout is a disorder characterized by high levels of uric acid in the blood. Hyperuricemia results in the deposition of crystals of sodium end product of purine tissues. especially the kidney and causing first acute and progressing To [Note: Hyperuricemia does not always lead to gout.] .


in which tophi (nodular masses of urate crystals) are deposited in the soft tissues of the body. A definitive diagnosis requires aspiration andexamination of synovial fluid using polarized light microscopy toconfirm the presence of monosodium urate crystals (Figure 22.17) .shows a patient with an index finger showing tophaceous gout. This process generates oxygen metabolites that damage tissue. resulting in the release of lysosomal enzymes that evoke an inflammatory response. The deposition of needle-shaped monosodium urate crystals initiates an inflammatory process involving the infiltration of granulocytes that phagocytize the urate crystals.

Types of Gout Primary gout: is caused by the underexcretion of uric acid due to defective renal secretion. This is defined as "primary gout. in patients with chronic renal insufficiency." Secondary hyperuricemia: This form of gout is caused by a variety of disorders and lifestyles. overproduction of uric acid may occur because of an inherited abnormality in the enzymes of purine metabolism. However. . and those who consume excessive amounts of alcohol or purine-rich foods. those with myeloproliferative disorders. those undergoing chemotherapy. for example.

therefore. and is reserved for those patients whose hyperuricemia is a result of overproduction of urate. such as probenecid or are used in most patients with because most are "underexcretors" of uric acid. which inhibits xanthine oxidase. thus preventing the deposition of urate crystals. . resulting in an accumulation of hypoxanthine and xanthine more soluble than uric acid and. such as aspirin. and with anti-inflammatory drugs. less likely to initiate an inflammatory response. Uricosuric agents. Allopurinol is converted in the body to oxypurinol. inhibitor of uric acid more toxic. to provide pain relief. Most therapeutic strategies for gout involve lowering the uric acid level below the saturation point.Treatment for gout: Acute attacks are treated with colchicine to decrease movement of granulocytes into the affected area.

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