Hyperphenylalaninemia is broadly defined as the presence of blood phenylalanine levels that exceed the limits of the upper reference range (2 mg/dL or 120 mmol/L) but trail the levels found in patients with phenylketonuria (PKU). Phenylalanine levels that exceed 20 mg/dL (1200 mmol/L) are considered diagnostic for PKU (see Phenylketonuria). This article describes nonphenylketonuric hyperphenylalaninemia, which includes phenylalanine levels of 2-20 mg/dL.
Phenylalanine levels of 6 mg/dL (360 mmol/L) or less in patients consuming an unrestricted diet generally indicate a benign condition. No dietary phenylalanine restrictions are usually recommended for individuals with levels in this range. In contrast, dietary restriction may be indicated for patients whose phenylalanine levels are more than 12 mg/dL (725 mmol/L); chronic phenylalanine levels in this range reportedly cause measurable intellectual impairment in children.
Dietary treatment is somewhat controversial for children with phenylalanine levels in the intermediate range of 7-11 mg/dL (425-660 mmol/L). For example, one study noted that most centers in the United States recommend restricting dietary phenylalanine when levels exceed 10 mg/dL (600 mmol/L). Many also recommend treatment for levels that exceed 8-9 mg/dL (480-545 mmol/L). The British Medical Research Council Working Party on PKU recommends dietary phenylalanine restriction when levels consistently exceed 6.6-10 mg/dL (400-600 mmol/L).
Hyperphenylalaninemia is caused by defects in the gene that encodes the enzyme phenylalanine hydroxylase, impairing the conversion of phenylalanine to tyrosine.  Defects in the same gene also result in classic PKU. Broad genotype/phenotype correlations have been made (ie, mild or hyperphenylalaninemia alleles vs severe or PKU alleles), although phenylalanine tolerance may vary in unrelated individuals with identical mutations. A small percentage of individuals with elevated phenylalanine levels have normal phenylalanine hydroxylase activity but lack tetrahydrobiopterin, a crucial cofactor. This is generally a more severe deficiency involving neurotransmitters, as well as phenylalanine metabolism. See the image below.
Frequency is approximately 15-75 cases per 1,000,000 births.
The condition is less prevalent than classic PKU and shows less variation in incidence among populations.
Most individuals with hyperphenylalaninemia have normal life expectancy. Several studies have identified a linear relationship between the phenylalanine level and intelligence testing and performance. Intelligence quotients seem less affected by benign hyperphenylalaninemia than by PKU, even at seemingly the same levels of serum phenylalanine. This effect may be due to smaller fluctuations of serum phenylalanine concentration.
Hyperphenylalaninemia occurs in all races.
Both sexes are equally affected because deficiency in phenylalanine hydroxylase activity is inherited as an autosomal-recessive trait. Pregnant women with phenylalanine levels that exceed 6 mg/dL risk having children with microcephaly, mental retardation, and birth defects (eg, maternal hyperphenylalaninemia). 
Hyperphenylalaninemia most is commonly diagnosed by newborn screening and must be distinguished from classic PKU by confirmatory testing at an experienced center.  Some cases in adult women have been detected using maternal screening programs or following birth of children with birth defects. Elevated phenylalanine levels are associated with neuropsychological effects.
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