Determining factors of the cognitive outcome in early treated PKU: A study of 39 pediatric patients.
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ABSTRACT:
SUBMITTER: Herenger Y
PROVIDER: S-EPMC6664159 | biostudies-literature | 2019 Sep
REPOSITORIES: biostudies-literature
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Determining factors of the cognitive outcome in early treated PKU: A study of 39 pediatric patients.
Herenger Yvan Y Maes Emmanuelle E François Laurent L Pasco Jeremy J Bouchereau Juliette J Pichard Samia S Ogier de Baulny Hélène H Schiff Manuel M
Molecular genetics and metabolism reports 20190725
Phenylketonuria (PKU) is a disorder of phenylalanine metabolism, characterized by a neurotoxic phenylalanine (Phe) accumulation, and treatable with a life-long Phe-restricted diet. Though early and continuously treated PKU (ETPKU) patients exhibit normal IQ, their cognitive outcome remains suboptimal. In this longitudinal study, we aimed at assessing the determinants of IQ subscales and quality of metabolic control in ETPKU children. We collected blood Phe levels, numbers of blood samples for Ph ...[more]
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Project description:OBJECTIVE:Early treatment of phenylketonuria (ET-PKU) prevents mental retardation, but many patients still show cognitive and mood problems. In this study, it was investigated whether ET-PKU-patients have specific phenylalanine (Phe-)related problems with respect to social-cognitive functioning and social skills. METHODS:Ninety five PKU-patients (mean age 21.6?±?10.2 years) and 95 healthy controls (mean age 19.6?±?8.7 years) were compared on performance of computerized and paper-and-pencil tasks measuring social-cognitive abilities and on parent- and self-reported social skills, using multivariate analyses of variance, and controlling for general cognitive ability (IQ-estimate). Further comparisons were made between patients using tetrahydrobiopterin (BH4, N?=?30) and patients not using BH4. Associations with Phe-levels on the day of testing, during childhood, during adolescence and throughout life were examined. RESULTS:PKU-patients showed poorer social-cognitive functioning and reportedly had poorer social skills than controls (regardless of general cognitive abilities). Quality of social-cognitive functioning was negatively related to recent Phe-levels and Phe-levels between 8 and 12 years for adolescents with PKU. Quality of social skills was negatively related to lifetime phenylalanine levels in adult patients, and specifically to Phe-levels between 0 and 7, and between 8 and 12 years. There were no differences with respect to social outcome measures between the BH4 and non-BH4 groups. CONCLUSION:PKU-patients have Phe-related difficulties with social-cognitive functioning and social skills. Problems seem to be more evident among adolescents and adults with PKU. High Phe-levels during childhood and early adolescence seem to be of greater influence than current and recent Phe-levels for these patients.
| S-EPMC4851698 | biostudies-literature
Project description:ObjectivePhenylketonuria (PKU) is an inherited metabolic disease which affects cognitive functions due to an inability to metabolize phenylalanine which leads to the accumulation of toxic by-products (Phe) in the brain. PKU can be effectively treated with a low phenylalanine diet, but some cognitive deficits remain. Studies have reported impairments, especially for processing speed and executive functions, but there is a lack of comprehensive assessment across cognitive domains. Moreover, it is important to establish outcomes in early treated adults with PKU (AwPKU) who have better metabolic control than groups previously reported in the literature.MethodWe tested 37 AwPKU with an unprecedented number of tasks (N = 28) and measures (N = 44) and compared results with 30 controls matched for age and education.ResultsWe found (a) group impairments, particularly in tasks tapping speed of processing and complex executive functions; (b) high variability across participants, with a sizable number of AwPKU with completely normal performance (about 38%); (c) but also a sizable number of participants who were clearly impaired (about 24%); and (d) good performance in tasks tapping verbal learning, verbal memory and orthographic processing, indicating no generalized learning impairment.ConclusionOur results indicate good outcomes, but also that deficits are still present with current treatment policies. (PsycINFO Database Record
| S-EPMC5328133 | biostudies-literature
Project description:BACKGROUND:The implementation of neonatal screening and the early initiation of lifelong therapy have helped to prevent severe complications and enabled much more favorable outcomes for early-treated phenylketonuria (ETPKU) patients. However, PKU patients tend to develop subtle cognitive and psychosocial abnormalities and the strict dietary therapy can present financial and social burden. Thus, PKU is expected to affect the quality of life (QoL) of these patients. There is insufficient evidence regarding the relationship between metabolic control and Health-Related QoL (HRQoL). We aimed to assess the effect of short- and long-term therapy on QoL among Hungarian adult PKU patients using the standardized PKU-specific PKU-QoL questionnaire. Methods: We conducted a single-centre, cross-sectional, observational study in Hungary. We included adult PKU patients treated with diet and amino acid supplements only. Patients reported HRQoL using the standardized adult PKU-QoL questionnaire and mean blood Phe concentrations were assessed for three different time periods: the previous 10 years, the previous year and concentration at the time of completing the questionnaire. The correlation between patients' QoL scores and their Phe levels was assessed. The classical PKU group was further divided into "good" and "suboptimal" adherence groups based on individual mean Phe levels in the examined time period. We evaluated differences in QoL among the two subgroups of classical PKU patients. QoL scores between classical and non-classical patients were also compared. Results: Data from 88 adult patients were analysed (66 had classical PKU). No median PKU-QoL score reached major or severe impact/frequent symptoms in any domain. The highest scores (meaning larger burden) were mostly related to emotional impact of PKU and disease management. When performing correlation analysis between Phe levels and QoL scores by all patients we found weak to fair positive correlation in several domains either short or long term. Patients with classical PKU reported greater financial impact of PKU than patients with less severe PKU. Classical PKU patients with good therapy adherence tended to report better HRQoL scores than patients with suboptimal adherence. Conclusion: We conclude that patients showed good HRQoL using the PKU-specific questionnaire. Our study demonstrates that suboptimal metabolic control is negatively associated with patients' HRQoL.
| S-EPMC7183227 | biostudies-literature
Project description:PurposeMacular structure is poorly evaluated in early-treated phenylketonuria (ETPKU). To evaluate potential changes, we aimed to examine retinas of PKU patients using optical coherence tomography (OCT) with additional OCT angiography (OCTA) and compare the results to healthy controls.MethodsA total of 100 adults were recruited in this monocentric, case-control study: 50 patients with ETPKU (mean age: 30.66 ± 8.00 years) and 50 healthy controls (mean age: 30.45 ± 7.18 years). Macular thickness, vessel density and flow area of the right eye was assessed with spectral domain OCT angiography SD-OCT(A). Macular microstructural data between the ETPKU and control group was compared. In the ETPKU group, the relationship between visual functional parameters (best corrected visual acuity [VA], spherical equivalent [SE], contrast sensitivity [CS] and near stereoacuity) and microstructural alterations was examined. The dependency of OCT(A) values on serum phenylalanine (Phe) level was analysed.ResultsThere was significant average parafoveal and perifoveal total retinal layer thinning in ETPKU patients compared to healthy controls (p < 0.016 and p < 0.001, respectively), while the foveal region remained unchanged in the ETPKU group. Whole macular and parafoveal superficial capillary plexus density was significantly decreased in ETPKU compared to controls (p < 0.001). There were no significant differences in the foveal avascular zone, nonflow area, macular superficial and deep capillary plexus between the groups. The temporal parafoveal inner retinal layer thickness was found to negatively correlate with individual Phe levels (r = -0.35, p = 0.042). There was no difference in vascular density and retinal thickness in the subgroup analysis of patients with good therapy adherence compared to patients on a relaxed diet.ConclusionsDurable elevation in Phe levels are only partially associated with macular retinal structural changes. However, therapy adherence might not influence these ophthalmological complications.
| S-EPMC8121983 | biostudies-literature
Project description:Purposethis systematic review aimed to assess the effects of dietary liberalization following tetrahydrobiopterin (BH4) treatment on anthropometric measurements, nutritional biomarkers, quality of life, bone density, mental health and psychosocial functioning, and burden of care in PKU patients.Methodsthe PubMed, Cochrane, and Embase databases were searched on 7 April 2022. We included studies that reported on the aforementioned domains before and after dietary liberalization as a result of BH4 treatment in PKU patients. Exclusion criteria were: studies written in a language other than English; studies that only included data of a BH4 loading test; insufficient data for the parameters of interest; and wrong publication type. Both within-subject and between-subject analyses were assessed, and meta-analyses were performed if possible.Resultstwelve studies containing 14 cohorts and 228 patients were included. Single studies reported few significant differences. Two out of fifteen primary meta-analyses were significant; BMI was higher in BH4-treated patients versus controls (p = 0.02; standardized mean difference (SMD) (95% confidence interval (CI)) = -0.37 (-0.67, -0.06)), and blood cholesterol concentrations increased after starting BH4 treatment (p = 0.01; SMD (CI) = -0.70 (-1.26, -0.15)).Conclusionthere is no clear evidence that dietary liberalization after BH4 treatment has a positive effect on anthropometric measurements, nutritional biomarkers, or quality of life. No studies could be included for bone density, mental health and psychosocial functioning, and burden of care.
| S-EPMC9504284 | biostudies-literature
Project description:PurposeRetinal changes are poorly described in early treated phenylketonuria (ETPKU). We aimed to investigate possible visual functional and ocular microstructural changes in adult patients with ETPKU. Optical coherence tomography (OCT) and its angiography (OCTA) data from patients with PKU were compared to healthy controls.MethodsIn this prospective, monocentric, cross-sectional, case-control study 50 patients with ETPKU and 50 healthy subjects were evaluated with OCT and OCTA. Measurements were performed on right eyes. The following visual function parameters were studied: best corrected visual acuity (BCVA), spherical equivalent (SE), contrast sensitivity and near stereoacuity; microstructural parameters: retinal nerve fiber layer thickness (RNFLT), ganglion cell layer (GCC) thickness, focal loss of volume (FLV), global loss of volume (GLV), peripapillary, papillary vessel density (VD), ocular axial length (AL) and intraocular pressure (IOP).ResultsAmong functional tests there were significant differences in contrast sensitivity at 1.5 (p < 0.001), 6 (p < 0.013), 12 (p < 0.001), 18 (p < 0.003) cycles per degree, in near stereoacuity (Titmus Wirt circles, p < 0.001) and in best corrected visual acuity (BCVA, p < 0.001). A statistically significant, moderate positive linear correlation was observed between BCVA and average Phe levels over the last ten years (β = 0.49, p < 0.001). The average (p < 0.001), superior (p < 0.001) inferior GCC (p < 0.001), the FLV (p < 0.003), GLV (p < 0.001) and the average RNFLT (p < 0.004) values of the PKU group were significantly lower than the controls. The serum phenylalanine level (Phe) in the PKU group negatively correlated with inferior (-0.32, p < 0.007), superior (r = -0.26, p < 0.028) and average (-0.29 p < 0.014) RNFL and with AL (-0.32, p < 0.026). In AL we detected a significant difference (p < 0.04) between the good and suboptimal dietary controlled group. There was no significant difference between the ETPKU and control group in the measured vessel density parameters and in IOP.ConclusionsOur results suggest that functional and ocular microstructural defects are present in patients with PKU, and some of them may depend on dietary control. The mechanism is unclear, but the correlation indicates the importance of strict dietary control in terms of preservation of retinal functions.
| S-EPMC7516291 | biostudies-literature
Project description:Background: Phenylketonuria (PKU) is an inborn error of metabolism caused by phenylalanine hydroxylase (PAH) deficiency. Patients with mild or moderate PKU can be successfully treated with sapropterin dihydrochloride (SD) which since recently is registered for usage from the age of 4 months. SD is a pharmaceutical version of tetrahydrobiopterin (BH4), a cofactor of PAH. Similar BH4 concentrations to those observed in plasma have been found in CSF of patients after a single oral administration thus proving that SD crosses the BBB. Hyperactivity has recently been reported as a post-marketing observation in some PKU patients treated with SD. Methods: 60 or 120 ng/ml sepiapterin, a stable precursor of BH4, were applied to study the effects of BH4 on developing brain cells in 3D organotypic rat brain cell cultures at two developmental stages. Immunohistochemistry, western blotting, metabolomics and RNA sequencing were performed. Findings: BH4 and BH2 measurements confirmed a successful conversion of sepiapterin to the active form BH4. In the earlier developmental stage, brain cell specific markers showed swollen astrocytes and diminished astrocytic fibres, delayed differentiation of oligodendrocytes and perturbation of axonal elongation. Immunofluorescence for activated caspase-3 revealed an increased apoptosis rate. We also found signs of perturbated GABAergic neurotransmission. RNAseq analyses revealed a number of significantly affected genes. GO enrichment allowed to identify key biological processes. Interestingly, none of these effects was observed in the later developmental stage. We show deleterious effects of SD on developing brain cells in a rat in vitro model. This observation raises the question whether the use of SD can be recommended in very young PKU patients as currently licensed.
2021-03-20 | GSE112108 | GEO
Project description:PurposeDespite the risk of anaphylaxis, oral food challenges (OFCs) are performed clinically for various indications, particularly to confirm tolerance development. This study aimed to assess OFCs by relevant indications and build an outcome prediction model to help determine when to perform OFCs in children who are likely to have developed immune tolerance.MethodsIn total, 432 pediatric OFCs were retrospectively analyzed according to indications. Clinical characteristics, serum total immunoglobulin (Ig) E, blood eosinophils, and specific IgE and IgG4 levels for food allergens were noted and compared. Machine learning was utilized to select the most important variables in determining the passage of the OFCs, and prediction models were constructed using the selected variables.ResultsOFCs were most commonly performed to confirm tolerance development (number, %; 267, 61.8%). The most common food allergens tested were egg (191, 44.2%) and milk (135, 31.3%). Children who passed the egg challenges for confirming tolerance acquisition had significantly lower egg white-specific IgE level (P = 0.008). Similarly, those who passed milk challenges had significantly lower cow's milk-specific IgE (P = 0.002) and casein-specific IgE levels (P = 0.005). We developed a nomogram to predict the outcome of OFCs to determine the tolerance acquisition with the selected variables; lower food-specific IgE, higher total IgE, and younger age indicated a higher probability of passage. The area under the curve (95% confidence interval) was 0.623 (0.503-0.743) for egg and 0.734 (0.628-0.840) for milk.ConclusionsSerum total IgE and food-specific IgE combined with age showed trends toward passing OFCs for confirming tolerance development. The constructed model may be used by clinicians as a practical guide for minimizing the risks of OFCs and a timely reintroduction for children with food allergies.
| S-EPMC10973639 | biostudies-literature
Project description:BackgroundPneumonia is one of the leading causes of morbidity and mortality in under fives. We carried out a comprehensive study to identify factors influencing both mortality and morbidity for children less than 5 years of age hospitalized with severe pneumonia.Methods200 hospitalized children aged 2-60 months with World Health Organization (WHO) defined severe pneumonia were enrolled in the study. The children were managed using a standard protocol. They were closely followed up for need for change in antibiotics, prolonged hospital stay, need for mechanical ventilation and mortality. Data on the factors influencing the outcome were collected.ResultsOf 200 children enrolled in the study, 113 (56.5%) needed a change in antibiotics, 102 (51%) stayed for more than 5 days in the hospital, 41 (20.5%) needed mechanical ventilation and 21 (10.5%) died. On multivariate analysis, lack of exclusive breastfeeding [RR (95%CI) 2.63 (2.16-2.86)], overcrowding [RR (95%CI) 1.94 (1.35-2.38)] and an abnormal chest x-ray [RR (95%CI) 2.29 (1.22-3.44)] were associated with the need for change of antibiotics. Lack of exclusive breastfeeding [RR (95%CI) 2.56 (2.0-2.93)], overcrowding [RR (95%CI) 2.59 (1.78-3.23)] and an abnormal chest x-ray [RR (95%CI) 2.99 (1.65-4.38)] were identified as determinants for prolonged hospital stay. Head nodding [RR (95%CI) 8.34 (2.71-12.77)], altered sensorium [RR (95%CI) 5.44 (1.34-17.56)], abnormal leukocyte counts [RR (95%CI) 5.85(1.36-17.14)] and pallor [RR (95%C) 10.88 (2.95-20.40)] were associated with mortality. Head nodding (RR (95% CI) 4.73 (1.50-6.36)] and cyanosis (RR (95%CI) 5.06 (1.80-11.34)] were the determining factors for mechanical ventilation. In radiographically confirmed pneumonia, the determining factors for change of antibiotics were: lack of exclusive breast feeding [RR (95% CI) 2.05 (1.69-2.2)] and low birth weight [RR (95% CI) 1.59 (1.1-1.89)]. For prolonged hospital stay, the factors identified were mothers' education less than graduation [RR (95% CI) 1.5 (1.19-1.7)], lack of exclusive breast feeding [RR (95% CI) 1.77 (1.19-2.09)] and oxygen saturation of < 90% at time of presentation [RR (95% CI) 2.06 (1.42-2.42)]. Determinants for mechanical ventilation were mothers' education less than graduation [RR (95% CI) 3.6 (1.15-6.3)] and cyanosis at presentation [RR (95% CI) 10.9 (1.56-18.9)]. For mortality, the only determinant was pallor [RR (95% CI) 10.54 (1.8-21.79)].ConclusionChildren hospitalized with severe community acquired pneumonia [as defined by World Health Organization (WHO)] who had not received exclusive breast feeding, had stayed in an overcrowded homes and had an abnormal chest radiograph were more likely to fail to respond with primary antibiotic regimen and require change of antibiotics and prolonged hospital stay. In children with radiographically confirmed pneumonia, lack of breast feeding and low birth weight was associated with need for change in antibiotics.
| S-EPMC2651138 | biostudies-literature
Project description:Early dietary treatment of phenylketonuria (PKU), an inborn error of phenylalanine (Phe) metabolism, results in normal cognitive development. Although health-related quality of life (HRQoL) of PKU patients has been reported as unaffected in high-income countries, there are scarce data concerning HRQoL and adherence to treatment of PKU children and adolescents from Brazil. The present study compared HRQoL scores in core dimensions of Brazilian early-treated PKU pediatric patients with those of a reference population, and explored possible relationships between adherence to treatment and HRQoL. Early-treated PKU pediatric patient HRQoL was evaluated by self- and parent-proxy reports of the Pediatric Quality of Life Inventory (PedsQL) core scales. Adherence to treatment was evaluated by median Phe levels and percentage of results within the therapeutic target range in two periods. Means for total and core scales scores of PedsQL self- and parent proxy-reports of PKU patients were significantly lower than their respective means for controls. Adequacy of median Phe concentrations and the mean percentage of values in the target range fell substantially from the first year of life to the last year of this study. There was no significant difference in mean total and core scale scores for self- and parent proxy-reports between patients with adequate and those with inadequate median Phe concentrations. The harmful consequences for intellectual capacity caused by poor adherence to dietary treatment could explain the observed decrease in all HRQoL scales, especially in school functioning. Healthcare system and financial difficulties may also have influenced negatively all HRQoL dimensions.
| S-EPMC5731329 | biostudies-literature