Cognitive outcomes in early-treated adults with phenylketonuria (PKU): A comprehensive picture across domains.

Abstract

Objective: Phenylketonuria (PKU) is an inherited metabolic disease which affects cognitive functions due to an inability to metabolize phenylalanine which leads to the accumulation of toxic by-products (Phe) in the brain. PKU can be effectively treated with a low phenylalanine diet, but some cognitive deficits remain. Studies have reported impairments, especially for processing speed and executive functions, but there is a lack of comprehensive assessment across cognitive domains. Moreover, it is important to establish outcomes in early treated adults with PKU (AwPKU) who have better metabolic control than groups previously reported in the literature. Method: We tested 37 AwPKU with an unprecedented number of tasks (N = 28) and measures (N = 44) and compared results with 30 controls matched for age and education. Results: We found (a) group impairments, particularly in tasks tapping speed of processing and complex executive functions; (b) high variability across participants, with a sizable number of AwPKU with completely normal performance (about 38%); (c) but also a sizable number of participants who were clearly impaired (about 24%); and (d) good performance in tasks tapping verbal learning, verbal memory and orthographic processing, indicating no generalized learning impairment. Conclusion: Our results indicate good outcomes, but also that deficits are still present with current treatment policies.

The neurological and psychological phenotype of adult patients with early‐treated phenylketonuria: A systematic review

“…A number of well‐controlled studies reported statistically significant deficits in patients compared with healthy control groups or normative populations across a range of neuropsychological and executive functions, including sustained and selective attention, working memory, response inhibition, and letter fluency . Two studies that performed extensive analyses on the same cohort of patients reported impairments in patients with ETPKU vs healthy controls, in the higher order executive functions, visuo‐spatial attention and visuo‐motor coordination, with significant variability across patients . Additionally, a recent study reported that compared with a control group, patients with ETPKU showed deficits in complex language tasks and were slower and less accurate in tasks requiring planning and strategic abilities .…”

Cognitive impairments in inherited metabolic diseases: Promises and challenges

“…Studies have shown that EFs are commonly affected across metabolic diseases. In this issue, Crowe et al have Palermo et al, 2017). Finally, Bergeron et al have reported impairments in Niemann-Pick C, again, in the Trail Making B and in span tasks involving monitoring.…”

“…In addition, not only language but also memory and learning (including spelling, which requires memorization of irregular words in English) appear relatively preserved. These functions may be sub-optimal in individuals with poor dietary control, but they do not show the significant group impairment shown in tasks requiring visual attention and executive functions (EFs; see Palermo et al, 2017;Romani et al, 2017). A similar pattern-with more severe impairments in visual attention than in language tasks (particularly lexical-retrieval tasks)-is seen in ageing, which is also characterized by a degradation of the myelin sheet, important for the speed of axonal transmission (e.g., see Jenkins, Myerson, Joerding, & Hale, 2000).…”

Phenylketonuria, co‐morbidity, and ageing: A review

“…Despite treatment, subtle cognitive deficits are still observed in ETAwPKU. [28][29][30] Underlying mechanisms are still under debate, and there is wide inter-individual variability, but such deficits have been associated with observed disruptions in brain pathophysiology (eg, demyelination and disturbed neurotransmitter synthesis). Some observed disruptions are similar to those seen in healthy ageing, but occur at a younger age in ETAwPKU (see Box 2).…”