These single gene disorders, a subset of the inborn errors of metabolism, are caused by mutations that generally result in abnormal proteins, most often enzymes. The inherited defects may be expressed as a total loss of enzyme activity or, more frequently, as a partial deficiency in catalytic activity. Without treatment, the amino acid disorders almost invariably result in intellectual disability or other developmental abnormalities as a consequence of harmful accumulation of metabolites. Although >50 of these disorders have been described, many are rare, occurring in <1 per 250,000 in most populations (Fig. 20.14). Collectively, however, they constitute a very significant portion of pediatric genetic diseases (Fig. 20.15).
boxes. Classification of amino acids is color coded: Red = glucogenic; brown = glucogenic and ketogenic; green = ketogenic. Compounds in BLUE ALL CAPS are the seven metabolites to which all amino acid metabolism converges. CoA = coenzyme A; NAD(H) = nicotinamide adenine dinucleotide.
A. Phenylketonuria
PKU is the most common clinically encountered inborn error of amino acid metabolism (incidence 1:15,000). It is caused by a deficiency of PAH (Fig. 20.16). Biochemically, PKU is characterized by hyperphenylalaninemia. Phenylalanine is present in high concentrations (ten times normal) not only in plasma but also in urine and body tissues. Tyrosine, which normally is formed from phenylalanine by PAH, is deficient. Treatment includes dietary restriction of phenylalanine and supplementation with tyrosine. [Note: Hyperphenylalaninemia may also be caused by rare deficiencies in any of the several enzymes required to synthesize BH4 or in dihydropteridine reductase, which regenerates BH4 from BH2 (Fig. 20.17). Such deficiencies indirectly raise phenylalanine concentrations, because PAH requires BH4 as a coenzyme. BH4 is also required for tyrosine hydroxylase and tryptophan hydroxylase, which catalyze reactions leading to the synthesis of neurotransmitters, such as serotonin and the catecholamines. Simply restricting dietary phenylalanine does not reverse the central nervous system effects due to deficiencies in neurotransmitters. Supplementation with BH4 and replacement therapy with L-3,4 dihydroxyphenylalanine and 5-hydroxytryptophan (products of the affected tyrosine hydroxylase– and tryptophan hydroxylase–catalyzed reactions) improves the clinical outcome in these variant forms of hyperphenylalaninemia, although the response is unpredictable.]
Screening of newborns for a number of treatable disorders, including inborn errors of amino acid metabolism, is done by tandem mass spectrometry of blood obtained from a heel prick. By law, all states must screen for >20 disorders, with some screening for >50. All states screen for PKU.
1. Additional characteristics: As the name suggests, PKU is also characterized by elevated levels of a phenylketone in the urine.
a. Elevated phenylalanine metabolites: Phenylpyruvate (a phenylketone), phenylacetate, and phenyllactate, which are not normally produced in significant amounts in the presence of functional PAH, are elevated in PKU (Fig. 20.18). These metabolites give urine a characteristic musty (“mousy”) odor.
b.