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

Padovani, Alessandro; Blau, Nenad; Leks, Edytha; Schulte, Claudia; Deuschl, Christian; Zipser, Carl Moritz; Piel, David; Freisinger, Peter; Gramer, Gwendolyn; Kölker, Stefan; Haas, Dorothea; Burgard, Peter; Nawroth, Peter P.; Hoffmann, Georg; Scheffler, Klaus; Berg, Daniela; Trefz, Friedrich K.

doi:10.1002/jimd.12049

Cited by 43 publications

(51 citation statements)

References 35 publications

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“…For example, Bodner et al [ 34 ] reported ETPKU-related differences in putamen volume. Christ et al [ 36 ] documented decreased parietal and occipital GM volumes in a sample of individuals with ETPKU as compared to individuals without PKU. Most recently, Pilotto et al [ 36 ] found that higher CSF phe levels were correlated with GM atrophy in right parietal and bilateral frontal regions in a small sample of individuals with ETPKU.…”

Section: Discussionmentioning

confidence: 99%

The effects of early-treated phenylketonuria on volumetric measures of the cerebellum

Aldridge

Cole

Gunn

et al. 2020

Molecular Genetics and Metabolism Reports

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Past murine studies of phenylketonuria (PKU) have documented significant effects on cerebellum at both the gross and cellular levels. The profile of neurocognitive and motor difficulties associated with early-treated PKU (ETPKU) is also consistent with potential cerebellar involvement. Previous neuroanatomical studies of cerebellum in patients with PKU, however, have yielded mixed results. The objective of the present study was to further examine potential differences in cerebellar morphometry between individuals with and without ETPKU. To this end, we analyzed high resolution T1-weighted MR images from a sample of 20 individuals with ETPKU and an age-matched comparison group of 20 healthy individuals without PKU. Measurements of whole brain volume, whole cerebellum volume, cerebellar gray matter volume, and cerebellar white matter volume were collected by means of semiautomatic volumetric analysis. Data analysis revealed no significant group differences in whole brain volume, whole cerebellar volume, or cerebellar white matter volume. A significant reduction in cerebellar gray matter volume, however, was observed for the ETPKU group compared to the non-PKU comparison group. These findings expand on previous animal work suggesting that cerebellar gray matter is impacted by PKU. It is also consistent with the hypothesis that the cognitive difficulties experienced by individuals with ETPKU may be related to disruptions in gray matter. Additional studies are needed to fully elucidate the timing and extent of the impact of ETPKU on cerebellum and the associated neurocognitive consequences.

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Section: Discussionmentioning

confidence: 99%

The effects of early-treated phenylketonuria on volumetric measures of the cerebellum

Aldridge

Cole

Gunn

et al. 2020

Molecular Genetics and Metabolism Reports

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“…40 A single study looked at the pathological hallmarks of AD, tau and amyloid, in the cerebrospinal fluid of 15 AwPKU (mean age 38.2 years), though, given the research targets and young age of participants, results are inconclusive. 41 There has been no study of tau, amyloid or synuclein in PKU, presumably as numbers of those studied at post mortem are small and tend to be younger. Huttenlocher 31 particularly raised the paucity of neuropathological study of the brain in AwPKU.…”

Section: Brain Healthmentioning

confidence: 99%

Phenylketonuria, co‐morbidity, and ageing: A review

Vardy

MacDonald

Ford³

et al. 2020

J of Inher Metab Disea

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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.

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“…Separation was achieved in 5 min by applying isocratic elution (40% mobile phase A: 0.1% formic acid in MilliQ water and 60% mobile phase B: 100% methanol), at a flow rate of 0.6 mL/min and a column temperature of 40 • C. Detection was achieved using positive-ion electrospray ionization in multiple reaction monitoring mode, using the following transitions: m/z 295.2 > 235. 3…”

Section: Analysesmentioning

confidence: 99%

“…This leads to a diminished or sometimes even blocked conversion of Phe into tyrosine (Tyr). The resulting high Phe concentrations in blood and brain are detrimental for neurological development [3]. Therefore, the treatment of PKU and some other hyperphenylalaninemic disorders largely consists in dietary Phe restriction.…”

Section: Introductionmentioning

confidence: 99%

Aspartame and Phe-Containing Degradation Products in Soft Drinks across Europe

et al. 2020

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Phenylketonuria and tyrosinemia type 1 are treated with dietary phenylalanine (Phe) restriction. Aspartame is a Phe-containing synthetic sweetener used in many products, including many ‘regular’ soft drinks. Its amount is (often) not declared; therefore, patients are advised not to consume aspartame-containing foods. This study aimed to determine the variation in aspartame concentrations and its Phe-containing degradation products in aspartame-containing soft drinks. For this, an LC–MS/MS method was developed for the analysis of aspartame, Phe, aspartylphenylalanine, and diketopiperazine in soft drinks. In total, 111 regularly used soft drinks from 10 European countries were analyzed. The method proved linear and had an inter-assay precision (CV%) below 5% for aspartame and higher CVs% of 4.4–49.6% for the degradation products, as many concentrations were at the limit of quantification. Aspartame and total Phe concentrations in the aspartame-containing soft drinks varied from 103 to 1790 µmol/L (30–527 mg/L) and from 119 to 2013 µmol/L (20–332 mg/L), respectively, and were highly variable among similar soft drinks bought in different countries. Since Phe concentrations between drinks and countries highly vary, we strongly advocate the declaration of the amount of aspartame on soft drink labels, as some drinks may be suitable for consumption by patients with Phe-restricted diets.

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

Cited by 43 publications

References 35 publications

The effects of early-treated phenylketonuria on volumetric measures of the cerebellum

The effects of early-treated phenylketonuria on volumetric measures of the cerebellum

Phenylketonuria, co‐morbidity, and ageing: A review

Aspartame and Phe-Containing Degradation Products in Soft Drinks across Europe

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