Phenylalanine hydroxylase deficiency treatment and management: A systematic evidence review of the American College of Medical Genetics and Genomics (ACMG)

In 2014, for the first time ever, the American College of Medical Genetics (ACMG) completed an in-depth review of PKU treatment and research literature.  The committee consisted of PKU experts from the United States and Canada and their published recommendations provide insight on the best way to manage this diverse disorder.

It is a long document and worth reading thoroughly. In summary, the experts after a thorough review of the available information determined that:

• PAH genotyping is recommended for all patients, for improved therapy planning;
• Response to Kuvan is not accurately predicted by genotype and thus should be documented by formal testing;
• Any combination of therapies that facilitate in lowering blood-phe levels is appropriate: therapies may be combined and should be individualized;
• Reduction in blood-phe levels, increase in dietary PHE tolerance or improvement in clinical symptoms are all valid indications for continuation of therapy;
• Patients who have discontinued therapy will likely experience neuropsychological improvements once therapy is restarted;
• Patients with late diagnosed or untreated PKU may benefit from starting therapy;
• Treatment should be lifelong for all patients with untreated PHE levels above 360 umol/l (6 mg/dl);
• Maintaining a treated PHE level of 120-360 umol/l (2-6 mg/dl) is recommended for all patients of all ages;
• Achievement of maternal PHE levels lower than 360 umol/l (6 mg/dl) prior to conception is recommended;
• Elevated blood-PHE levels in the first 8-10 weeks of gestation are associated with an increased risk of congenital heart defects and poor fetal growth;
• Kuvan is a Class C medication and may be used during pregnancy following discussion of the benefit and risks to mother and fetus;
• Mothers with PKU should maintain treatment postpartum for optimal maternal/infant outcomes;
• Intelligence in patients with optimally treated PKU is in the normal range but lower than sibling controls;
• The incidence of non-intellectual psychological symptoms, especially impairment of executive function, is increased;
• Appropriate intellectual and mental health assessments are an important component of care for individuals affected with PKU;
• Treatment for life mandates the need for funding of medications and medical foods regardless of age.