Effectiveness of methylphenidate in adults with phenylketonuria and attention-deficit/hyperactivity disorder: An N-of-1 series

Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism. In patients who have not been diagnosed by newborn screening, so called ‘late-diagnosed’ patients, symptoms include severe neurodevelopmental disorders including intellectual disabilities and attention-deficit/hyperactivity disorder (ADHD). It is hypothesized that ADHD symptoms in late-diagnosed PKU patients typically present as behavioral problems. These may be caused by low levels of prefrontal dopamine, as a result of impaired monoamine synthesis. Targeting the dopamine imbalance may improve ADHD symptoms and even a broader domain of functioning in late or untreated PKU. Currently, behavioral problems in PKU are mainly treated with antipsychotic drugs that may induce or aggravate parkinsonian features. Methylphenidate (MPH), a dopamine reuptake inhibitor, may be beneficial in treating ADHD symptoms and behavioral problems in PKU by raising brain dopamine availability. The goal of the project is to investigate the effectiveness of methylphenidate for ADHD symptoms in late-diagnosed PKU.

The N-of-1 study is a series of double-blind randomized and placebo-controlled multiple cross-over trials within five participants with a minimum age of 18 years old who are diagnosed with PKU as well as ADHD. Each N-of-1 trial consists of a baseline period, a dose titration phase, three cycles of alternating two 7-day intervention periods each followed by a 7-day washout period, and a follow-up measurement. During the intervention periods, participants will receive twice daily methylphenidate (doses based on age and body weight) or placebo. The primary outcome measure includes the personalized ‘Goal Attainment Scaling’(GAS). Secondary outcome measures are the Strengths and Difficulties Questionnaire (SDQ) (subscale hyperactivity/inattention), the shortened version of the Emotion Dysregulation Inventory (EDI) reactivity index, the personal questionnaire (PQ), and adverse effects.

We hypothesize that methylphenidate improves ADHD manifestations in adults with (late-diagnosed) PKU.

At the end of each seven-day interventional period, primary caregivers will be contacted to evaluate GAS scores (primary outcome measure), to go through the personal questionnaire (PQ), to discuss any change in diet, and to discuss possible side effects by using a standardized checklist of side effects of methylphenidate. Also, a dried blood spot will be conducted at the end of each interventional period. The other secondary outcome measures (SDQ and EDI) will be measured at the end of each period (weekly). Both questionnaires will be filled out digitally by primary caregivers using the app m-Path, Castor Electronic Data Capture (EDC) or by using paper forms. Three and six months after terminating the third cycle of the N-of-1 trial, an optional contact moment will take place for follow-up measurements in which the questionnaires will be filled out and the goals and items of GAS and PQ will be discussed again.

Participants will receive twice daily methylphenidate or placebo.