The Impact of Phenylketonuria on Body Composition in Adults.

INTRODUCTION: Patients with phenylketonuria (PKU) must follow a lifelong phenylalanine (Phe)-restricted diet with additional amino acid supplementations, and this may put them at risk for nutritional disturbances. However, the body composition and nutritional status of adult patients with PKU has only been partially explored. The current study aims to assess the body composition of adult patients with PKU using multifrequency bioimpedance analysis (MF-BIA) and to reveal potential correlations between therapy adherence and body composition. Additionally, we compared body composition of patients with healthy controls. METHODS: Fifty adult patients with early-treated PKU (27 female and 23 male) and 40 healthy, age- and gender-matched controls were included in this single-center, cross-sectional study. MF-BIA was performed on all subjects. Additionally, we determined serum nutritional markers for all patients. In the PKU patient group, correlation analyses were performed between body composition parameters and therapy adherence. We compared body composition of patients with PKU and controls using BIA. RESULTS: The proportion of overweight was 56% among all patients with PKU. Female patients with PKU had significantly higher body fat percentage compared with controls. In parallel with higher fat content, we observed lower muscle mass, protein, and mineral content among female patients with PKU compared to controls. Such findings were not observed in male patients. Female patients with PKU had decreased therapy adherence and had significantly lower prealbumin levels compared with males. There was no significant correlation observed between body composition parameters and therapy adherence over the last 10 years in the PKU patient group. CONCLUSION: Although female patients had less optimal therapy adherence over the last 10 years compared with male patients, our results suggest that this does not influence body composition fundamentally. Our results suggest that obesity is an important comorbidity in young adult patients with PKU, especially in females. We advocate that nutritional assessments and weight management should be additional objectives of PKU management to provide optimal care.

The Association of Therapy Adherence and Thyroid Function in Adult Patients with Phenylketonuria.

BACKGROUND: The standard, lifelong therapy of phenylketonuria (PKU) is a natural protein-restricted diet complemented with phenylalanine (Phe)-free L-amino acid mixtures that provide the daily necessary micronutrients. OBJECTIVE: To assess thyroid function and structure and the iodine status of early-treated adult PKU (ETPKU) patients in Hungary. METHODS: Sixty-nine PKU patients (aged 18-41 years) and 50 healthy controls were enrolled in the study. Thyroid hormones, serum thyroglobulin, thyroid antibodies, urinary iodine, and selenium concentrations were measured, and thyroid ultrasound was performed. RESULTS: The incidence of thyroid dysfunction was infrequent (n = 2). Blood Phe was negatively correlated with thyroid-stimulating hormone (TSH), and PKU patients had higher free thyroxine and lower TSH levels than healthy controls. Although optimal iodine status was found in the entire PKU population, by dividing the patients according to their therapy compliance, we observed that lower therapy adherence was associated with mild iodine deficiency and lower urinary selenium levels. CONCLUSIONS: The results of this study suggest that iodine status is strongly influenced by the adherence to therapy in ETPKU patients. No or not enough medical food consumption combined with a low-Phe diet can lead to subclinical iodine deficiency.

[Adult phenylketonuria]. / Phenylketonuria felnottkorban.

Starting from 1975 phenylketonuria is part of the newborn screening program in Hungary. Since then a generation, treated with special diet and medical foods right after neonatal diagnosis has reached adulthood. Thanks to early treatment initiation, children with phenylketonuria are able to lead life to the full. Consequently, phenylketonuria is no longer considered a pediatric disease. Follow up of adult patients with phenylketonuria is performed in internal medicine centers specialized in metabolic diseases. The outcome of the lifelong special treatment, and the particularities of phenylketonuria in adulthood are yet to be determined. The aim of our review is to present recent findings in phenylketonuria focusing mainly on the adult care. After long time the first international guidelines appeared, new therapies were put in use, and these current developments are expected to be implemented in daily practice in the near future. New challenges must be met such as maternal phenylketonuria, long term effects of dietotherapy and the sequelae of untreated phenylketonuria in adulthood. Orv Hetil. 2017; 158(46): 1857-1863.

[Bone metabolism in adults with phenylketonuria - Hungarian data]. / Csontanyagcsere felnott phenylketonuriás pácienseknél ­ hazai adatok.

INTRODUCTION: Patients with phenylketonuria have lower bone mineral density compared to healthy people, however, the ethiology of these alterations is not clear. Hungarian data were missing in this topic. AIM: The main aim of our study was to survey the correlation between metabolic control and change of bone mineral density in early treated Hungarian adult patients with phenylketonuria. METHOD: In this monocentric study bone mineral density of 59 adult PKU patients have been repeatedly measured in a 4-year interval using dual-energy X-ray absorptiometry. Two subgroups have been established based on average blood phenylalanine levels. The correlation between the change in bone mineral density and average phenylalanine, tyrosine concentrations have been determined while initial bone mineral density and change have also been examined in the subgroups. RESULTS: Mean phenylalanine concentration was 614 (182-1222) micromol/L, whereas mean tyrosine concentration was 49 (24-99) micromol/L and the calculated ratio was 16 (4,5-35). Three patients have had severely decreased bone mineral density in either localisation while 22 have had mild decrease. Low bone mineral density compared to cronological age has been found by 9 patient. The mean change was +0.0380 (-0.1550-0.7800) g/cm2 in femur, and +0.0120 (-0.57300-0.3130) g/cm2 in the lumbar spine. There was a correlation in the change in Z-score neither with mean phenylalanine nor with tyrosine concentration. CONCLUSIONS: Bone mineral density was not changed and hardly influenced by the metabolic control in early-treated young adult phenylketonuria patients in a few years interval. Orv Hetil. 2017; 158(47): 1868-1872.

Long-Term Renal Function in Adult Patients with Phenylketonuria.

INTRODUCTION: In phenylketonuria (PKU), toxic phenylalanine (Phe) can harm other organs beyond the brain. Furthermore, the lifelong therapy of PKU consists of consumption of increased amounts of amino-acid mixture that provoke hyperfiltration in the glomeruli. Therefore, the adherence to therapy in PKU might influence the long-term kidney function in PKU patients. METHODS: Data from 41 adult, early treated PKU patients were analyzed in this 10-year, retrospective, monocentric study. Two subgroups were created according to their therapy adherence: one with long-term blood Phe levels in the therapeutic range (<600 µmol/L), and one with suboptimal blood Phe levels. Renal function and metabolic parameters were collected over 10 years. Kidney function parameters were compared between the two groups and associations between blood Phe levels and kidney function were tested. RESULTS: After 10 years, serum creatinine levels (p = 0.369) and estimated glomerular filtration rate (eGFR) (p = 0.723) did not change significantly from baseline in the good therapeutic group. The suboptimal therapeutic group's eGFR decreased in the same period (from 110.4 ± 14 mL/min/1.73 m2 to 94.2 ± 16 mL/min/1.73 m2, p = 0.017). At 10 years, the suboptimal therapeutic group had an increased serum creatinine level (81 ± 14.4 µmol/L vs. 71.5 ± 13 µmol/L, p = 0.038), and a decreased eGFR (94.2 ± 16 mL/min/1.73 m2 vs. 103.3 ± 13 mL/min/1.73 m2p = 0.031) compared to the good adhering group. Significant negative correlation between Phe levels and eGFR (r = -0.41, p = 0.008) was observed. CONCLUSION: Long-term suboptimal therapy adherence in PKU patients with high blood Phe levels may lead to deterioration in kidney function.

Reduced macular thickness and macular vessel density in early-treated adult patients with PKU.

PURPOSE: Macular 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. METHODS: A 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. RESULTS: There 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. CONCLUSIONS: Durable elevation in Phe levels are only partially associated with macular retinal structural changes. However, therapy adherence might not influence these ophthalmological complications.

Altered visual functions, macular ganglion cell and papillary retinal nerve fiber layer thickness in early-treated adult PKU patients.

PURPOSE: Retinal 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. METHODS: In 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). RESULTS: Among 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 (ß = 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. CONCLUSIONS: Our 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.

Health Related Quality of Life assessment among early-treated Hungarian adult PKU patients using the PKU-QOL adult questionnaire.

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.

Metabolic and catecholamine response to sympathetic stimulation in early-treated adult male patients with phenylketonuria.

PURPOSE: Defective function of phenylalanine hydroxylase in phenylketonuria (PKU) results in the accumulation of phenylalanine (Phe) and the reduction of tyrosine (Tyr) in the blood, interfering in the normal development and function of organs and tissues in the body. Tyr is the precursor of catecholamines, secreted in response to stress by the adrenal medulla and paraganglia. The aim of this study was to evaluate plasma catecholamine and amino acid response to an escalating series of sympathetic stress tests in PKU patients. METHODS: Twelve males with classical PKU (aged 18-41 years) and ten healthy male controls were included in this study. The subjects were exposed to three different sympathetic stress stimulations: cold pressor, isometric handgrip, and peak treadmill tests to exhaustion. Physiological, metabolic, and hormonal changes were determined. RESULTS: Aerobic capacity (VO2max) was significantly lower in the PKU group (p = 0.018); however, relative VO2max was similar in the two groups during the spiroergometric test. No significant differences in norepinephrine or in epinephrine response were found between the two groups during the different stimulation tests. Blood Phe increased significantly in the PKU group compared with controls (p = 0.027) during the spiroergometric test, while Tyr levels remained stable in both groups. CONCLUSION: PKU itself might not influence stress-induced catecholamine changes. Only strenuous exercise increased blood Phe levels in PKU subjects.

Comprehensive DNA Methylation and Mutation Analyses Reveal a Methylation Signature in Colorectal Sessile Serrated Adenomas.

Colorectal sessile serrated adenomas (SSA) are hypothesized to be precursor lesions of an alternative, serrated pathway of colorectal cancer, abundant in genes with aberrant promoter DNA hypermethylation. In our present pilot study, we explored DNA methylation profiles and examined selected gene mutations in SSA. Biopsy samples from patients undergoing screening colonoscopy were obtained during endoscopic examination. After DNA isolation and quality analysis, SSAs (n = 4) and healthy controls (n = 5) were chosen for further analysis. DNA methylation status of 96 candidate genes was screened by q(RT)PCR using Methyl-Profiler PCR array system. Amplicons for 12 gene mutations were sequenced by GS Junior Instrument using ligated and barcoded adaptors. Analysis of DNA methylation revealed 9 hypermethylated genes in both normal and SSA samples. 12 genes (CALCA, DKK2, GALR2, OPCML, PCDH10, SFRP1, SFRP2, SLIT3, SST, TAC1, VIM, WIF1) were hypermethylated in all SSAs and 2 additional genes (BNC1 and PDLIM4) were hypermethylated in 3 out of 4 SSAs, but in none of the normal samples. 2 SSAs exhibited BRAF mutation and synchronous MLH1 hypermethylation and were microsatellite instable by immunohistochemical analysis. Our combined mutation and DNA methylation analysis revealed that there is a common DNA methylation signature present in pre-neoplastic SSAs. This study advocates for the use of DNA methylation as a potential biomarker for the detection of SSA; however, further investigation is needed to better characterize the molecular background of these newly recognized colorectal lesions.