Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine (Phe) metabolism caused by variants in the gene PAH, which encodes the enzyme phenylalanine hydroxylase (PAH). These variants lead to complete or partial deficiency of PAH enzymatic activity, resulting in inability to metabolize the amino acid Phe.
As the PAH enzyme catalyzes the hydroxylation of Phe to tyrosine (Tyr), conversion of Phe to Tyr is impaired. This causes the amino acid Phe to build up in the blood and brain, leading to a range of intellectual disabilities, as well as neurological, neuropsychiatric, and psychosocial consequences.4
If not adequately controlled, excess levels of Phe, which are toxic to the brain, disrupt normal neurophysiology. High Phe levels may lead to serious neurological and neuropsychological complications, affecting the way people with PKU think, feel, and act.1,2,6,7
In the United States, the estimated prevalence of PKU is 1 case per 15,000 births.4
The American College of Medical Genetics and Genomics released guidelines in 2014 on the diagnosis and management of PKU: management should be started as early as possible and maintained for life; blood Phe levels should be maintained at ≤360 µmol/L throughout life; and any combination of therapies that helps keep blood Phe levels in the recommended range is appropriate.3
The effects of high Phe are felt throughout a patient’s life.3,7
Young adults and adults with uncontrolled Phe can experience neurologic, psychiatric, and cognitive symptoms, including:
The burden of PKU extends beyond the brain and into many aspects of adult life. Adults with PKU have an increased risk of several multisystemic comorbidities.8
Phe control typically drops off during adolescence, increasing the severity of neuropsychological symptoms and negatively impacting life trajectory.2,3
Young adults and adult patients can become trapped in a cycle of decline making dietary compliance and PKU management more difficult.6,9
The mainstay of PKU management is lifelong dietary management with a Phe-restricted diet.3,10
A low-Phe diet consists of 3 main parts:3,10
While a Phe-restricted diet remains the cornerstone of care for patients with PKU, there are challenges which may make strict adherence difficult for patients.3,11
Lowering Phe is recognized as the key strategy in managing PKU.3
Elevated levels of the amino acid Phe correlates with neuropsychological symptom severity, which generally improves with Phe reductions.3
Emerging clinical evidence suggests that additional benefits may be attained when Phe is below recommended levels.12,13
The American College of Medical Genetics and Genomics (ACMG) recommends starting management as early as possible and maintaining Phe levels ≤360 µmol/L.3
Globally, the approach for PKU management has been a highly Phe-restricted diet, medical nutritional therapy, and low-protein foods. In combination with a low-Phe diet, prescription medications are also available.3,10
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