Could It Be Untreated PKU?


Patients may have been told they would ‘grow out of’ PKU, and consequently go off-diet, with consequences such as cognitive deficit.

Patients with phenylketonuria (PKU) who have gone off-diet are at a high risk for attention issues, focus issues, anxiety, and depression. Mental health clinicians can aid patients by remembering to ask patients if they could possibly have untreated PKU, research suggests.

PKU affects about 1 in 10,000 to 15,000 individuals and is more common among those with Northern European and Chinese ancestry than Hispanics and people of African descent. Every newborn in the United States. is screened at birth for the condition, and because the threshold for testing is so low, it cannot be missed, explained Johns Hopkins pediatrics professor Ada Hamosh, MD, MPH, in an interview with MD Magazine®.

Previously, it was thought that a patient with PKU could be treated, following a diet with a strictly limited amount of protein, just for the first few years of life, as their brains were developing; however, it is now known that this is not the case, Dr. Hamosh said. And, adult patients who are off-diet and present with tremors, anxiety and depression, focus issues, and more know that they have PKU.

“They know they have PKU,” Dr. Hamosh said. “They’ve been taken off, or they took themselves off [diet]. [Either] they don’t care, or they’re busy adults and they forgot. [But,] they still need to be treated.”

The most common cognitive deficits in functioning adult patients with PKU appear in vigilance, working memory, and motor skills, according to the results of a meta-analysis of relevant studies by Hofman et al.1 The investigators suggested that understanding the development of the cognitive deficits would be best served by further research from larger, international, multicenter studies.

In one study from 2017, investigators monitored 57 early-treated adult patients with PKU and healthy matched controls.2 The investigators performed IQ tests to determine the cognitive profile and mental health of the patients. Patients with PKU were found to perform worse than the matched controls on tests of working memory, inhibitory control, and sustained attention tasks.

“Adult patients had lower IQ and poorer executive functions than controls, resembling problems observed in younger patients with phenylketonuria, as well as more internalizing problems,” the study authors wrote.

There are currently 2 US Food and Drug Administration (FDA)-approved therapies for treating PKU: Kuvan, which was approved in 2007, and Palynziq, which was approved in October 2018. According to Dr. Hamosh, she has not yet offered Palynziq in her clinic, because of a high risk of anaphylaxis, which means that users must have access to epinephrine auto-injectors. As patients adapt to the drug, Barbara K. Burton, MD, professor of pediatrics at the Northwestern University Feinberg School of Medicine, and director of the PKU clinic at the Ann & Robert H. Lurie Children’s Hospital of Chicago, in Illinois, stated that the adverse effects will dissipate. “They all decline in frequency very significantly after about 6 months of treatment,” she said.

Because the primary treatment for PKU is a modified diet of extremely low protein, patient adherence is typically low, according to many published papers on the topic. A small Australian study from 2014 examined the diets of eight young adults and measures of PKU.3 They observed a strong correlation between lifetime phenylalanine (Phe) levels and anxiety and stress in the patients.

Furthermore, a study out of Italy showed that adults inadequately managed their diets.4

“[This is] likely due to inappropriate perception and knowledge of the disease, and lack of awareness of the negative impact of poor metabolic control in adult life,” the authors wrote. “Clinicians should consider implementing more intense and tailored educational measures, as well as structured transitional care processes.”

The organization National PKU News published diet intervention guidelines which suggest reducing Phe intake to the minimum required for “normal physiological functioning, without any excess.”5

“The diet also includes measured amounts of lower protein foods such as fruits, vegetables, and limited amounts of grain products; and Phe-free or nearly Phe-free foods such as special low protein products, and other foods that are mainly composed of fat or carbohydrate,” the California and Washington-based authors wrote. “All high-protein foods are usually eliminated from the diet to achieve blood Phe levels in the desired range. These include dairy products, eggs, fish, meats, poultry, legumes, and nuts. In some instances where the adult has a relatively higher tolerance for phenylalanine, very small amounts of the higher protein foods might be suitable for the diet, but this is not typical.”

All told, the PKU diet involves a major change in eating patterns that have been established over a lifetime, according to the authors.

Other treatment considerations include antipsychotics, behavioral support for anxiety, changing food attitudes, and considerations about aging with PKU.

A new British study surveyed 631 participants with PKU, either adults with PKU or parents or caregivers to children with PKU, in order to determine the practical, social and psychological factors of living with the illness.6

“Adults with PKU or caregivers/parents of children identified significant neurocognitive, mental health and general health issues,” the study authors wrote. “Limits on socialization, perception of social isolation and dietary stigma are major obstacles which are difficult to overcome with conventional dietary management.”

Half of the children involved in the study reported difficulties in maintaining focus, while about a third reported each of the following: educational difficulties, anxiety or depression, gastrointestinal symptoms. Half of the children also described social exclusion, while some reported difficult relationships with friends or family.

Among the adult respondents, depression and anxiety was present in half, while difficulty maintaining focus and low mood was also observed. Difficulties in relationships, social exclusion, and gastrointestinal symptoms were also present. Many were taking antidepressants, while some were taking anxiolytics, the researchers reported.

“We believe the diet should be considered whenever it is feasible. In adults who are untreated, the major goals are positive health, and emotional and behavioral stability,” the authors of the National PKU guidelines wrote, adding that the general consensus among clinicians is that the “diet for life” approach is the best approach.


  1. Hofman DL, Champ CL, Lawton CL, Henderson M, Dye L. A systematic review of cognitive functioning in early treated adults with phenylketonuria. Orphanet J Rare Dis. 2018 Aug 30;13(1):150. doi: 10.1186/s13023-018-0893-4.
  2. Jahja, R, Huijbregts, SCJ, de Sonneville, LMJ, et al. Cognitive profile and mental health in adult phenylketonuria: A PKU-COBESO study. Neuropsychology. 2017 May;31(4):437-447. doi: 10.1037/neu0000358.
  3. Clacy A, Sharman R, McGill J. Depression, anxiety, and stress in young adults with phenylketonuria: associations with biochemistry. J Dev Behav Pediatr. 2014 Jul-Aug;35(6):388-91. doi: 10.1097/DBP.0000000000000072.
  4. Cazzorla C, Bensi G, Biasucci G, et al. Living with phenylketonuria in adulthood: The PKU ATTITUDE study. Mol Genet Metab Rep. 2018;16:39-45. Published 2018 Jul 11. doi:10.1016/j.ymgmr.2018.06.007.
  5. Dolan, BE, Koch R, Bekins C, Schuett V. PKU News. Diet Intervention Guidelines For Adults With Untreated PKU. Updated August 2000. Accessed November 5, 2018.
  6. Ford S, O'Driscoll M, MacDonald A. Living with Phenylketonuria: Lessons from the PKU community. Mol Genet Metab Rep. 2018;17:57-63. Published 2018 Oct 18. doi:10.1016/j.ymgmr.2018.10.002.
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