Galactokinase deficiency, an autosomal recessive disorder, also leads to the accumulation of galactose in body fluids (see Fig. 52-2), which results in the formation of galactitol (dulcitol) through the action of aldose reductase. Galactitol, acting as an osmotic agent, can be responsible for cataract formation and, rarely, for increased intracranial pressure. These are the only clinical manifestations. Individuals homozygous for galactokinase deficiency usually develop cataracts after the neonatal period, whereas heterozygous individuals may be at risk for cataracts as adults.
Hereditary fructose intolerance, in many ways, is analogous to galactosemia. When fructose is ingested, deficiency of fructose-1-phosphate aldolase leads to the intracellular accumulation of fructose 1-phosphate with resultant emesis, hypoglycemia, and severe liver and kidney disease. Elimination of fructose and sucrose from the diet prevents clinical disease. Fructosuria is caused by fructokinase deficiency, but its deficiency is not associated with clinical consequences.
Disorders of amino acid metabolism are the result of the inability to catabolize specific amino acids derived from protein. Usually a single amino acid pathway is involved. This amino acid accumulates in excess and is toxic to various organs, such as the brain, eyes, skin, or liver. Treatment is directed at the specific pathway and usually involves dietary restriction of the offending amino acid and supplementation with special medical foods (formulas) that provide the other amino acids and other nutrients. Confirmatory testing includes quantitative specific plasma amino acid profiles along with specific mutation testing and sometimes enzymology.
Phenylketonuria (PKU), an autosomal recessive disease, primarily affects the brain and occurs in 1 in 10,000 persons.Classic PKU is the result from a defect in the hydroxylationof phenylalanine to form tyrosine (Fig. 53-1); the activity ofphenylalanine hydroxylase in the liver is absent or greatlyreduced. Affected infants are normal at birth, but if untreated, severe mental retardation (IQ 30) develops in the first year oflife. A positive newborn screening test must be followed up byperforming quantitative plasma amino acid analysis. A plasmaphenylalanine value of greater than 360 μM (6 mg/dL) is consistent with the diagnosis of one of the hyperphenylalaninemiasand demands prompt evaluation and treatment. Untreated,classic PKU is characterized by blood phenylalanine concentrations higher than 600 μM. Milder forms of hyperphenylalaninemia are indicated by values of plasma phenylalanine lowerthan this but higher than 360 μM. A significant percentage ofpremature infants and a few full-term infants have transientelevations in phenylalanine. Short-term follow-up usuallyidentifies these infants promptly. A small percentage of infantsdiagnosed with PKU (≤2% in the United States) have a defectin the synthesis or metabolism of tetrahydrobiopterin, thecofactor for phenylalanine hydroxylase and for other enzymesinvolved in the intermediary metabolism of aromatic aminoacids. Such disorders in biopterin metabolism are diagnosedby measuring dihydrobiopterin reductase in erythrocytes andby analyzing biopterin metabolites in urine. This testing shouldbe carried out in all hyperphenylalaninemic infants.
Treatment is designed to maintain plasma phenylalanine values in the therapeutic range of 120 to 360 mM using a diet specifically restricted in phenylalanine but otherwise nutritionally complete. Since the early 1980s, treatment for life is recommended to reduce the risks of long-term neuropsychiatric problems and reduce the risk of maternal PKU syndrome.