Hyperphenylalaninemia

Updated: May 18, 2017
  • Author: Eric T Rush, MD, FAAP, FACMG; Chief Editor: Luis O Rohena, MD, FAAP, FACMG  more...
  • Print
Overview

Background

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) without treatment but that are below the level found in patients with phenylketonuria (PKU). Phenylalanine levels that exceed 20 mg/dL (1200 mmol/L) are considered typical of classic PKU (see Phenylketonuria). In 2014, the American College of Medical Genetics and Genomics released a practice statement that recommended that PKU and hyperphenylalaninemia both be considered part of the spectrum of phenylalanine hydroxylase (PAH) deficiency.

Phenylalanine levels of 6 mg/dL (360 mmol/L) or less in patients consuming an unrestricted diet are generally considered to be a benign condition. No dietary phenylalanine restrictions are usually recommended in this instance. In contrast, dietary restriction is generally indicated among 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.

Practices of dietary treatment vary in children with phenylalanine levels in the intermediate range of 7-11 mg/dL (425-660 mmol/L). Most centers in the United States recommend restricting dietary phenylalanine when levels exceed 10 mg/dL (600 mmol/L). Some 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).

Next:

Pathophysiology

Hyperphenylalaninemia is the term used to describe the mildest manifestation of phenylalanine hydroxylase deficiency, with classic PKU representing the more severe end of this spectrum. [15] Broad genotype/phenotype correlations have been made for mild versus severe disease, 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. These patients generally have a more severe phenotype with more pronounced neurological involvement and a less consistent response to therapy. See the image below.

Phenylalanine hydroxylase converts phenylalanine t Phenylalanine hydroxylase converts phenylalanine to tyrosine.
Previous
Next:

Epidemiology

Frequency

United States

Frequency is approximately 15-75 cases per 1,000,000 births.

International

The condition is less prevalent than classic PKU and shows less variation in incidence among populations.

Mortality/Morbidity

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 the same levels of serum phenylalanine. This effect may be due to smaller fluctuations of serum phenylalanine concentration.

Race

Hyperphenylalaninemia occurs in all races.

Sex

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). [1]

Age

Hyperphenylalaninemia most is commonly diagnosed by newborn screening and must be distinguished from classic PKU by confirmatory testing at an experienced center. [2] 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.

Previous