Phenylketonuria (PKU) is a recessively inherited metabolic disorder that occurs in 1 of 10,000 to 15,000 newborns in the United States.  Early implementation of a phenylalanine-restricted diet has long been the primary treatment method used to avoid severe intellectual disabilities. (1) This means that patients with the disease must control their intake of products such as soy, chicken, turkey, lamb, seafood, dairy, eggs, and even wholegrain.  Such dietary restrictions can quickly limit a patient’s diet to a bland range of foods.

Luckily, new medical technologies have allowed scientists to see mutations in the protein structure of the disease, which has lead to drug development that could lessen strict dietary restrictions.
Improving Treatment for the Disease Phenylketonuria

Dietary Management for Phenylketonuria

Phenylketonuria is caused by the accumulation of excess amounts of phenylalanine (Phe),  an essential amino acid that cannot be synthesized by our bodies.  Dietary management of the disease was established over half a century ago and has rendered an immense amount success in the prevention of severe intellectual disability in its patients.

The PKU diet restricts the intake of natural proteins in order to minimize the amount of Phe in the body, and it requires carefully balanced supplementation of essential amino acids, vitamins, and minerals. In order for the diet to be successful in preventing intellectual disability, it is crucial to start the diet within the first few weeks of the patient’s life. Therefore, neonatal screening programs must be involved if early disease identification is to be attained. (2)

Although crucial for the avoidance of neurological effects, the strict low-Phe diet has several shortcomings, not the least of which is the burden it imposes on patients and their families.  Nutritional deficiencies and the disruption to normal life are reason enough to seek alternative PKU treatment options.

Phenylketonuria Treatment Research

Recent studies have given scientists a new view of the protein structure phenylalanine hydroxylase (PAH), a liver enzyme that is mutated and misfolded in patients with PKU.  In a healthy patient, PAH will catalyze the hydroxylation of excess phenylalanine in the diet to tyrosine, a nonessential amino acid, which keeps Phe from reaching neurotoxic levels in the body.  Patients with PKU suffer from an altered catalyzation process causing excess amounts of Phe to build up in the body.  More in-depth knowledge of the misfolding of the protein has introduced new opportunities for the design and discovery of therapeutic pharmacological chaperones; proteins that act as cellular guards and facilitate protein folding.

Pharmacologic chaperones, including the naturally occurring cofactor 5,6,7,8-tetrahydrobiopterin (BH4), are involved in the hydroxylation of Phe, which can help stabilize misfolded mutant enzymes.  A lack of BH4 can give rise not only to the dysfunction of PAH (and therefore create hyperphenylalaninemia), but also to the dysfunction of brain tyrosine hydroxylases, leading to severe neurologic neurotransmitter deficiencies. (3)

Using new protein analysis technologies, scientists now understand that BH4 can act as a molecular chaperone and increase the stability of partially misfolded PAH proteins. (4) Over the past decade, BH4 has been used as a cofactor of PAH to treat a subset of PKU patients under experimental conditions. In the past several years, BH4 has been commercialized in the form of Sapropterin Dihydrochloride, a synthetic form of BH4. The widespread use of pharmaceuticals like Sapropterin Dihydrochloride could dramatically change the way PKU patients manage their disease.

Many questions regarding existing therapies remain unanswered and more research must be done before new medicines can reach the patient, but the future of PKU treatment has never seemed more promissory.  It is now clear that new technologies will continue to enhance our understanding of protein folding in a way that will lead to a more balanced individual treatment of Phenylketonuria.

  1. Koch R, de la Cruz F. Historical aspects and overview of research on phenylketonuria. Ment Retard Dev Disabil Res Rev 1999; 5 101–3.
  2. National institutes of health consensus development conference statement: phenylketonuria: screening and management. Pediatrics. 2000;108:972–982
  3. Hyghland K. Tetrahydrobiopterin deficiencies with hyperphenylalaninemia. In: Blau N, editor. PKU and BH4. Advances in Phenylketonuria and Tetrahydrobiopterin. SPS Publications; 2006.
  4. Erlandsen H, Pey AL, Gámez A, Pérez B, Desviat LR, Aguado C, Koch R, Surendran S, Tyring S, Matalon R, Scriver CR, Ugarte M, Martínez A, Stevens RC. Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations. Proc. Natl. Acad. Sci. U. S. A. 2004;101:16903–16908