Phenylketonuria (PKU) is a rare genetic disorder that causes harmful levels of the dietary protein phenylalanine (Phe), an essential amino acid and a fundamental building block of protein, to build up in the body. If left untreated PKU can have serious neurocognitive and neurobehavioural consequences, some of which are irreversible.
The condition was initially identified in the 1930s and became the first metabolic condition diagnosable via lab test.1 With the development of diets low in protein and medical food that were Phe-free in the 1950s and 60s, it became the became the first metabolic disease for which an effective therapeutic intervention was developed. Researchers found that in children who began diets low in dietary Phe behaviour improved and development exceeded prior expectations.2 Also in the 1960s, with the development of the Guthrie bacterial inhibition assay to screen for the condition, PKU screening became the genesis of modern newborn screening programs.3 More recently, pharmaceutical treatment for PKU has been introduced that lower blood phenylalanine (Phe) levels or improve metabolic tolerance.
For decades, however, despite being burdensome, difficult to adhere to, and linked to numerous comorbidities,4,5 a lifetime low-protein diet remained the principal therapeutic intervention for PKU. And even as newborn screening for PKU and early intervention have become the norm, it seems that people with PKU still experience cognitive deficits when compared to the general population and many mysteries about the condition remain.
In our recent systematic literature review, “Intelligence quotient scores among early‑treated phenylketonuria patients: results from a systematic literature review” published in Orphanet Journal of Rare Diseases, we sought to synthesize published data on the impact of PKU on cognition in early-treated PKU to better understand unmet treatment need. We focused on studies which measured IQ using standard tests such as the Wechsler, Culture Fair, or Stanford‑Binet tests. Twenty-five studies met our inclusion criteria and were included in the synthesis. We found that the evidence consistently showed that people with PKU tended to have lower IQ scores than those without PKU (Figure 1). Additionally, higher Phe levels were generally linked to lower IQ, although differences between the studies made direct comparisons difficult. Even with early treatment, individuals who struggled to maintain their diets or had higher Phe levels often showed poorer cognitive ability.
Figure: Figure: Mean (SD) Wechsler Intelligence Full scale IQ scores in restricted subgroups of children with PKU vs external control groups.
Note: Dotted line (—-) indicates the standardized ‘average intelligence’ score
Source: O’Sullivan et al. 2025
Our review findings confirm that PKU continues to affect cognitive abilities even when treatment begins early. While PKU research has led to a lot ‘firsts’ in rare disease research, there is still a lot that can be done to make the lives of people with PKU better. Pharmaceutical treatments have the potential to make it easier to sustain low blood Phe levels, thus lowering the risk of cognitive impairments. Beyond that, with lower blood Phe levels people can potentially have less restrictive diets which would bring the benefit of lower comorbidity risks and generally make life easier.
References
1. Blau N, van Spronsen FJ, Levy HL. Phenylketonuria. The Lancet. 2010;376(9750):1417-1427.
2. Bickel H, Gerrard J, Hickmans E. Preliminary Communication. The Lancet. 1953;262(6790):812-813.
3. Cao J, Pasquali M, Jones PM. Newborn Screening: Current Practice and Our Journey over the Last 60 Years. The Journal of Applied Laboratory Medicine. 2024;9(4):820-832.
4. Yagudina R, Kulikov A, Serpik V, Protsenko M, Kopeyka K. Factors Affecting Adherence to a Low Phenylalanine Diet in Patients with Phenylketonuria: A Systematic Review. Nutrients. 2024;16(18):3119.
5. Whitehall KB, Rose S, Clague GE, et al. Systematic literature review of the somatic comorbidities experienced by adults with phenylketonuria. Orphanet journal of rare diseases. 2024;19(1):293.
6. O’Sullivan F, Tomazos I, van Spronsen FJ, et al. Intelligence quotient scores among early-treated phenylketonuria patients: results from a systematic literature review. Orphanet journal of rare diseases. 2025;20(1):314.