Abstract
BackgroundPhenylketonuria (PKU) is an autosomal recessive inherited disorder characterised by a deficiency in phenylalanine hydroxylase. 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 who discontinue dietary control 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.MethodsWe 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.ResultsA total of nine patients were recruited. Mean age was 33 years (SD = 8.75), five were female. Mean time off dietary control was 19.1 years (SD = 11.3), and mean baseline phenylalanine (Phe) levels were 1108 µmol/L (SD = 293). 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]).ConclusionsThis 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 in improving the cognitive and psychiatric sequelae of the disease.
Highlights
Phenylketonuria (PKU) is an autosomal recessive inherited disorder characterised by a deficiency in phenylalanine hydroxylase (PAH) associated with a wide range of Burgess et al Orphanet J Rare Dis (2021) 16:35 cognitive and psychiatric sequelae [1]
Phe competes with other large neutral amino acids (LNAA) -tyrosine, tryptophan, valine, isoleucine, leucine, threonine, methionine, and histidine—at the L-type amino acid transporter (LAT1) for transport to the brain across the blood–brain barrier (BBB)
Two patients were on antidepressant medications, and one of these was taking a mood stabiliser, these patients did not demonstrate trends that differed to other participants
Summary
Phenylketonuria (PKU) is an autosomal recessive inherited disorder characterised by a deficiency in phenylalanine hydroxylase (PAH) associated with a wide range of Burgess et al Orphanet J Rare Dis (2021) 16:35 cognitive and psychiatric sequelae [1]. Phe levels are elevated in patients with PKU due to deficiencies in PAH activity, resulting in toxic accumulation of Phe in brain tissues. In PKU, disruption of relative concentrations of amino acids (hyperPhe and depletion of other LNAAs) results in saturation of the transporter by Phe, and reduced transport of other LNAAs [3]. Phenylketonuria (PKU) is an autosomal recessive inherited disorder characterised by a deficiency in phenylalanine hydroxylase. 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
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