Sleep Disturbances in Phenylketonuria: An Explorative Study in Men and Mice

Abstract

Sleep problems have not been directly reported in phenylketonuria (PKU). In PKU, the metabolic pathway of phenylalanine is disrupted, which, among others, causes deficits in the neurotransmitters and sleep modulators dopamine, norepinephrine, and serotonin. Understanding sleep problems in PKU patients may help explain the pathophysiology of brain dysfunction in PKU patients. In this explorative study, we investigated possible sleep problems in adult treated PKU patients and untreated PKU mice. In the PKU patients, sleep characteristics were compared to healthy first degree relatives by assessment of sleep disturbances, sleep–wake patterns, and sleepiness with the help of four questionnaires: Holland sleep disorder questionnaire, Pittsburgh sleep quality index, Epworth sleepiness scale, and Munich Chronotype Questionnaire. The results obtained with the questionnaires show that PKU individuals suffer more from sleep disorders, a reduced sleep quality, and an increased latency to fall asleep and experience more sleepiness during the day. In the PKU mice, activity patterns were recorded with passive infrared recorders. PKU mice switched more often between active and non-active behavior and shifted a part of their resting behavior into the active period, confirming that sleep quality is affected as a consequence of PKU. Together, these results give the first indication that sleep problems are present in PKU. More detailed future research will give a better understanding of these problems, which could ultimately result in the improvement of treatment strategies by including sleep quality as an additional treatment target.

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

“…Of the 643 articles retrieved from the initial search, 83 met criteria for inclusion in this review (Figure ). Patients had been maintained on a Phe‐restricted diet during early childhood, although this did not necessarily equate to strict treatment; overall adherence to diet throughout their lifetime was not consistently reported and was variable between studies.…”

“…One study did find that patients with PKU experienced only internalizing disturbances (emotional problems such as depression and anxiety), while healthy controls exhibited both internalizing and externalizing disturbances (interpersonal problems such as antisocial behavior) equally . Regarding sleep behavior, one study reported that adult patients with ETPKU presented more sleep disorders, reduced sleep quality, increased latency to fall asleep, and more daytime sleepiness compared with first degree relatives …”

Prevalence of sleep disorders in early-treated phenylketonuric children and adolescents. Correlation with dopamine and serotonin status

“…All patients showed subjectively good sleep quality, 15 very good and 10 fairly good. By contrast, Bruinenberg et al, 19 found more sleep disorders (specially insomnia and circadian rhythm sleep disorders) and reduced sleep quality in 25 treated adult PKU patients (mean age: 30 ± 9) compared to controls, but they did not assess metabolic control or provide the age when treatment was started in these patients. Bilder et al, 18 reported a sleep disorder prevalence of 14.4% in 3714 adult PKU patients (aged 20 to >80 years, mean age: 38.5 years) versus 6.9% in general population controls, which fell to 9% in the age range of 20e39 years (n ¼ 2247) (the authors supposed that this adult cohort were most likely to have had early and continuous treatment).…”

“…6,15 Regarding the serotoninergic deficit, references to its repercussions on sleep quality have been described in the literature but are scarce, 16 even studies in which sleep is evaluated. In that sense, our group has performed a previous study in early-treated PKU young adult patients in which alterations in sleep quality were not found 17 ; however, recent studies have been published in PKU adults 18,19 reporting more sleep disorders than in controls.…”

Salivary serotonin does not correlate with central serotonin turnover in adult phenylketonuria (PKU) patients

“…In turn, this neurotransmitter deficiency is associated with depression (serotonin deficiency) and behavioural disturbances (especially frontal lobe dysfunction in dopamine deficiency) [ 35 ]. Sleep disturbances in PKU patients have been also well documented [ 11 ]. Bioavailability of tyrosine due to changes in intestinal microbiota and altered metabolism of tryptophan via the kynurenine pathway in patients who are ingesting medical foods also contribute to the bioamine defects [ 32 ].…”