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Hyperphenylalaninemia causes chronic toxic encephalopathy, depending on the timing, extent, and length of exposure to increased phenylalanine concentrations. Severe hyperphenylalaninemia leading to phenylketonuria (PKU) has a distinct role in the field of inherited metabolic disorders: PKU is the first genetic disease that could be treated exclusively by dietary manipulation and that could be entirely prevented by universal newborn screening and presymptomatic dietary intervention. This has had a huge impact on pediatric medicine, on the evolution of neonatal screening, and on the concept of gene-environment interaction. Genetic defects associated with hyperphenylalaninemia can be regarded as a strong risk factor for neurodisability, but the clinical outcome is more determined by the quality of metabolic treatment than by genetic variability.


Metabolic Derangement

Hyperphenylalaninemia is caused by impaired hydroxylation of phenylalanine to tyrosine (Fig. 130-1). The enzyme phenylalanine 4-hydroxylase (PAH) is predominantly expressed in the liver and requires tetrahydrobiopterin (BH4) as a cofactor. A lack of PAH activity leads to accumulation of phenylalanine, with levels usually exceeding 20 mg/dL (1200 μmol/L); increased excretion of its metabolites phenylacetate and phenylpyruvate; and decreased availability of the product tyrosine, which is needed for synthesis of protein, neurotransmitters, and melatonin. The phenylalanine pool is a function of dietary intake and losses through excretion, residual metabolic activity, and net protein synthesis.

Figure 130-1

Pathway of phenylalanine and tyrosine degradation. Phenylalanine from dietary protein or endogenous proteolysis is hydroxylated by phenylalanine hydroxylase (PAH) using tetrahydrobiopterin (BH4) as a cofactor. BH4 is thereby oxidized in 2 steps to dihydrobiopterin (qBH2). BH2 needs to be reduced back to BH4 by dihydropterin reductase (DHPR). In severe PAH deficiency, phenylalanine accumulates and is deaminated to phenylpyruvic acid, which can be further metabolized. Phenylalanine and its alternative metabolites can then be found in urine.

Tyrosine stems from dietary protein or endogenous proteolysis or is synthesized from phenylalanine. The first and rate-limiting step is its deamination to 4-OH-phenylpyruvic acid by the enzyme tyrosine aminotransferase (TAT). This step is reversible. 4-OH-phenylpyruvic acid is then oxidized via 4-OH-phenylpyruvic dioxygenase (HPD) to homogentisic acid. Deficiency of TAT and deficiency or inhibition of HPD both lead to accumulation of tyrosine. Homogentisic acid is further oxidized by homogentisate dioxygenase (HGD) to maleylacetoacetic acid (MAA) and fumarylacetoacetic acid (FAA). Fumarylacetoacetate hydrolase (FAH) cleaves FAA to fumaric acid and acetoacetic acid. In FAH deficiency, MAA and FAA accumulate and are converted to succinylacetoacetate, which is decarboxylated to succinylacetone. Succinylacetone inhibits both HPD, causing hypertyrosinemia, and porphobilinogen synthase, causing symptoms of acute intermittent porphyria. 2(2-Nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexane dione (NTBC) is a strong inhibitor of HPD and is used to avoid accumulation of MAA and FAA in FAH deficiency.

The damage to the brain is believed to result from direct toxicity of phenylalanine and depletion ...

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