[excerpt starts]

Abnormal proteins, typically enzymes, caused by mutations are responsible for these single gene disorders, which are a subgroup of inborn errors of metabolism. The mutations generally lead to either a complete loss of enzyme activity or a partial deficiency in catalytic activity. If left untreated, these amino acid disorders almost always result in intellectual disability or other developmental abnormalities due to the harmful buildup of metabolites. Although over 50 of these disorders have been identified, many are rare, occurring in less than 1 in 250,000 individuals in most populations. However, collectively, they make up a significant portion of pediatric genetic diseases.

Classification of amino acids is color-coded: Red represents glucogenic amino acids, brown represents glucogenic and ketogenic amino acids, and green represents ketogenic amino acids. The seven metabolites that all amino acid metabolism converges to are highlighted in BLUE ALL CAPS. CoA refers to coenzyme A, and NAD(H) represents nicotinamide adenine dinucleotide.

A. Phenylketonuria (PKU)
PKU is the most commonly encountered inborn error of amino acid metabolism, with an incidence of 1 in 15,000. It is caused by a deficiency of the enzyme PAH. Biochemically, PKU is characterized by high levels of phenylalanine in the blood (hyperphenylalaninemia). Phenylalanine concentrations are not only elevated in plasma but also in urine and body tissues. The conversion of phenylalanine to tyrosine, which is normally catalyzed by PAH, is impaired. Treatment involves restricting dietary intake of phenylalanine and supplementing with tyrosine. [Note: Rare deficiencies in enzymes involved in the synthesis of BH4 or in dihydropteridine reductase, which regenerates BH4 from BH2, can also cause hyperphenylalaninemia by indirectly increasing phenylalanine concentrations. PAH requires BH4 as a coenzyme. BH4 is also necessary for the synthesis of neurotransmitters such as serotonin and the catecholamines, which are produced by tyrosine hydroxylase and tryptophan hydroxylase. Merely restricting dietary phenylalanine does not reverse the effects on the central nervous system caused by deficiencies in neurotransmitters. In these variant forms of hyperphenylalaninemia, supplementation with BH4 and replacement therapy with L-3,4 dihydroxyphenylalanine and 5-hydroxytryptophan (products of the affected tyrosine hydroxylase and tryptophan hydroxylase reactions) can improve clinical outcomes, although the response is unpredictable.]

Tandem mass spectrometry of blood obtained from a heel prick is used to screen newborns for various treatable disorders, including inborn errors of amino acid metabolism. All states are required by law to screen for more than 20 disorders, with some screening for over 50. PKU screening is performed in all states.

1. Additional characteristics: As the name suggests, PKU is also characterized by increased levels of a phenylketone in the urine.
a. Elevated phenylalanine metabolites: PKU results in elevated levels of phenylpyruvate (a phenylketone), phenylacetate, and phenyllactate, which are not typically produced in significant amounts when PAH is functional. These metabolites give the urine a distinctive musty or "mousy" odor.
b.

[excerpt ends]
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.