The Effect of Improved Dietary Control on Cognitive and Psychiatric Functioning in Adults With Phenylketonuria: The ReDAPT Study

Abstract

Background Phenylketonuria (PKU) is an autosomal recessive inherited disorder characterised by a deficiency in phenylalanine hydroxylase (PAH). Untreated, PKU is associated with a wide range of cognitive and psychiatric sequelae. Contemporary management guidelines recommend lifetime dietary control of phenylalanine (Phe) levels, however many individuals may – due to erroneous treatment recommendations or patient factors – discontinue dietary control and subsequently suffer symptoms of anxiety, depression and disturbances to cognition. We undertook a prospective cohort study of patients with early-treated phenylketonuria who had ceased dietary control to test the hypothesis that resumption of dietary control of PKU is associated with improvements in measures of psychiatric morbidity and cognitive functioning. Methods We re-initiated dietary control for early-treated patients with PKU and monitored cognitive and psychiatric outcomes over a twelve-month period. Assessments included objective cognitive function (measured by cognitive proficiency index (CPI)), anxiety and depression scales. General linear mixed model (GLMM) analyses were performed to assess change in psychometric variables from baseline over twelve months after resumption of dietary control. Results A total of nine patients were recruited. Mean age was 34 years, five were female. Mean time off dietary control was 20.4 years, and mean baseline phenylalanine (Phe) levels were 1108 µmol/L. GLMM analysis demonstrated a positive relationship between CPI and time on diet (b = 0.56 [95% CI = 0.17, 0.95]). Age, time off diet, Phe levels and depression scores were not associated with cognitive function. There was a negative relationship between time on diet and anxiety (b = -0.88 95% CI = [-1.26, -0.50]) and depression ratings (b = -0.61, 95% CI = [-0.95, -0.26]). Conclusions This study demonstrated improvements in cognitive function, anxiety, and depression ratings associated with resumption of dietary control of PKU. Raw Phe levels were not strongly associated with psychiatric or cognitive scores in this cohort. These findings support the importance of lifelong treatment for PKU, and demonstrate the reversibility of cognitive and psychiatric sequelae of the disease.

Cognitive Functioning in Adults with Phenylketonuria in a Cohort of Spanish Patients

“…In the present study, no correlations or significant scores were obtained related to the BDI-II, being these results consistent with Brumm et al [21] and Palermo et al [10], who showed the same data where no clinically significant results for depression (BDI-II) were present and no relation between Phe levels and emotional health was found. Burgess et al [19] findings suggest that these psychiatric deficits can be positive modified in AwPKUs, and that they are possible if the dietary control is followed up or improved.…”

“…Adults with this metabolic disease, usually present slight results below healthy control groups in intelligence (Anderson et al, [17,18,50]), also in reduced processing speed and dysfunction in executive functioning tasks (Anderson et al,(18)(19)(20)50]). Bartus et al [4] also mention a reduced processing speed, difficulties with working memory, reduced IQ, and attention problems.…”

Improved attention linked to sustained phenylalanine reduction in adults with early‐treated phenylketonuria

“…Understanding the contribution to adult functioning of recent fluctuations in Phe levels compared to lifetime Phe levels is confounded by the high correlation between these two Phe values. Additionally, the high burden associated with resuming a Phe‐restricted diet may minimize the benefits imparted by sustained Phe reduction on adult executive functioning (Burgess et al, 2021).…”