Morphometric analysis of gray matter integrity in individuals with early-treated phenylketonuria

Biogenic amines synthesis in phenylketonuria (PKU) patients with high phenylalanine (Phe) concentration is thought to be impaired due to inhibition of tyrosine and tryptophan hydroxylases and competition with amino acids at the blood-brain barrier. Dopamine and serotonin deficits might explain brain damage and progressive neuropsychiatric impairment in adult PKU patients. Ten early treated adult PKU patients (mean age 38.2 years) and 15 age-matched controls entered the study.

Section: Discussionsupporting

confidence: 93%

“…When treated early, children and young adults with PKU may present mild cognitive deficits, especially in executive and attention functions . Early reports in animal models and small series have shown that increased Phe levels in PKU patients cause reduced availability of serotonin and dopamine in the brain …”

Section: Introductionmentioning

confidence: 99%

Cerebrospinal fluid biogenic amines depletion and brain atrophy in adult patients with phenylketonuria

Padovani

Blau

Leks

et al. 2019

“…Although routine MRI data currently have limited use in informing treatment decisions, future research may use regular examinations to monitor white matter changes in people with PKU as they age. Furthermore, a recent morphometric MRI study in a mixed population of adults and children showed gray matter volume reductions in the parietal and occipital cortex of patients with ETPKU . This indicates that brain MRI changes in patients with ETPKU are not only confined to the white matter, highlighting the importance of performing brain MRI to better understand the disease.…”

Section: Discussionmentioning

confidence: 96%

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

Burlina

Lachmann

Manara

et al. 2019

Newborn screening for phenylketonuria (PKU) and early introduction of dietary therapy has been remarkably successful in preventing the severe neurological features of PKU, including mental retardation and epilepsy. However, concerns remain that long‐term outcome is still suboptimal, particularly in adult patients who are no longer on strict phenylalanine‐restricted diets. With our systematic literature review we aimed to describe the neurological phenotype of adults with early‐treated phenylketonuria (ETPKU). The literature search covered the period from 1 January 1990 up to 16 April 2018, using the NLM MEDLINE controlled vocabulary. Of the 643 records initially identified, 83 were included in the analysis. The most commonly reported neurological signs were tremor and hyperreflexia. The overall quality of life (QoL) of ETPKU adults was good or comparable to control populations, and there was no evidence for a significant incidence of psychiatric disease or social difficulties. Neuroimaging revealed that brain abnormalities are present in ETPKU adults, but their clinical significance remains unclear. Generally, intelligence quotient (IQ) appears normal but specific deficits in neuropsychological and social functioning were reported in early‐treated adults compared with healthy individuals. However, accurately defining the prevalence of these deficits is complicated by the lack of standardized neuropsychological tests. Future research should employ standardized neurological, neuropsychological, and neuroimaging protocols, and consider other techniques such as advanced imaging analyses and the recently validated PKU‐specific QoL questionnaire, to precisely define the nature of the impairments within the adult ETPKU population and how these relate to metabolic control throughout life.

“…100 **evidence for this came from a single cross-sectional study 98 and, therefore, observed deficits in cognitive performance may be due to individual differences and do not necessarily reflect the trajectory of cognitive ageing in PKU. 82 increased ROS production 51,83,84 inhibition of antioxidant enzymes 51,85 reduced gray matter volume [86][87][88][89] • Decreased Tyr and Trp r and other LNAA 1 decreased dopamine and norepinephrine (Tyr) and serotonin (Trp) 1 disruptions in protein synthesis 90…”

Section: Gastrointestinal Pathologymentioning

confidence: 99%

Phenylketonuria, co‐morbidity, and ageing: A review

Vardy

MacDonald

Ford³

et al. 2020

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.