Phenylketonuria, co‐morbidity, and ageing: A review

Abstract

Phenylketonuria (PKU) is a metabolic condition which, left untreated, results in severe and irreversible brain damage. Newborn screening and the development of the low phenylalanine (Phe) diet have transformed the outcomes for people with PKU. Those who have benefited from early treatment are now approaching their fifth and sixth decade. It is therefore timely to consider multi‐morbidity in PKU and the effects of ageing, in parallel with the wider benefits of emerging treatment options in addition to dietary relaxation. We have conducted the first literature review of co‐morbidity and ageing in the context of PKU. Avenues explored have emerged from limited study of multi‐morbidity to date and the knowledge and critical enquiry of the authors. Findings suggest PKU to have a wider impact than brain development, and result in several intriguing questions that require investigation to attain the best outcomes for people with PKU in adulthood moving through to older age. We recognise the difficulty in studying longitudinal outcomes in rare diseases and emphasise the necessity to develop PKU registries and cohorts that facilitate well‐designed studies to answer some of the questions raised in this review. Whilst awaiting new information in these areas we propose that clinicians engage with patients to make personalised and well‐informed decisions around Phe control and assessment for co‐morbidity.

Implementing a Transition Program from Paediatric to Adult Services in Phenylketonuria: Results after Two Years of Follow-Up with an Adult Team

“…Early diagnosis and implementation of a Phe restricted diet have drastically improved clinical prognosis [1], and the PKU European guidelines state that treatment and follow-up should be maintained in adulthood [2]. However, the growing adult population with PKU is still understudied and the impact of PKU in the ageing process is unknown [3]. PKU in adulthood has been associated with neurological and neuropsychiatric issues such as deficits in executive function, tremor, depression, anxiety, and white matter abnormalities [4][5][6], but comorbidities affecting other body systems are also reported [7][8][9].…”

Mental health diagnoses in adults with phenylketonuria: a retrospective systematic audit in a large UK single centre

“…This study has a wider age range which may allow for better appreciation of changes in mental health diagnoses in older PKU patients but may still have missed those PKU patients whose diagnosis may have been missed before the introduction of Guthrie testing in the late 1960s. Ageing in treated PKU patients is currently an area with little evidence available as treated patients are only just reaching their fifth and sixth decade [ 21 ]. This study used a larger population of patients than previous studies, giving the study greater power to find relationships between the exposure and outcome.…”

Engineering Organoids for in vitro Modeling of Phenylketonuria

“…At the cellular level, high L-Phe concentrations were shown to affect dendritic branching and decrease synaptic density, plasticity, and excitability (Hörster et al, 2006;González et al, 2016;Saudubra and Garcia-Cazorla, 2018). Hypomyelination, demyelination, oxidative stress damage and brain energy impairment are also recognized as drivers of PKU-associated neuropathology, being triggered by a direct neurotoxic effect of L-Phe and neurotransmitter deficiency (Pilotto et al, 2018;Vardy et al, 2019). (McKean, 1972;Butler et al, 1981;Pilotto et al, 2018).…”

“…Consequently, a greater susceptibility to age-related neurodegenerative diseases should be contemplated in PKU patients. Some of the observed disruptions naturally occurring in healthy aging individuals could then emerge at a younger age in early treated adults with PKU ( Sirtori et al, 2005 ; Pilotto et al, 2018 ; Vardy et al, 2019 ). To which degree of exposure to high L-Phe levels, chronic or acute, and poor dietary compliance at some point of a patient’s life, impacts such predisposition is still to be determined.…”