The Adult Phenylketonuria (PKU) Gut Microbiome.
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ABSTRACT:
SUBMITTER: Mancilla VJ
PROVIDER: S-EPMC8001843 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Phenylketonuria (PKU) is a rare metabolic disorder characterized by impaired conversion of phenylalanine (Phe) to tyrosine. If left untreated, the resultant accumulation of excess blood Phe can cause physiological, neurological, and intellectual disabilities. The National PKU Alliance (NPKUA) conducted a survey of its membership to assess current health status and interest in new treatments for PKU. Of the 625 survey respondents, less than half (46.7%) reported blood Phe within (120-360 ?mol/L) - the range recommended by the American College of Medical Genetics and Genomics (ACMG). The survey results also showed that younger (? 18 years) individuals were about 3-times as successful in keeping their blood Phe concentrations within the recommended clinical range compared with adults. Blood Phe over 360 ?mol/L was reported in one-quarter (25.5%) of ? 18 year old individuals and almost two-thirds (61.5%) of adults. A little more than half (51.7%) of respondents reported having difficulty in managing their PKU, including the maintenance of a Phe-restricted diet. Individuals with PKU desire new treatments that would allow them to increase their intake of natural protein, discontinue or reduce their intake of medical foods (medical formula and foods modified to be low in protein), improve their mental health (including a reduction in depression and anxiety), and a reduction of their blood Phe concentrations. Respondents preferred oral administration of any newly developed therapies and, in general, disliked therapeutic injections. Injections at home were preferred over injections at a clinic. Payers, government agencies, clinicians, and industry partners should consider patient input when developing and approving new therapies and treatments for PKU.
| S-EPMC4789336 | biostudies-literature
Project description:Phenylketonuria (PKU) was the first inherited metabolic disease in which dietary treatment was found to prevent the disease's clinical features. Treatment of phenylketonuria remains difficult due to progressive decrease in adherence to diet and the presence of neurocognitive defects despite therapy. This review aims to summarize the current literature on new treatment strategies. Additions to treatment include new, more palatable foods based on glycomacropeptide that contains very limited amount of aromatic amino acids, the administration of large neutral amino acids to prevent phenylalanine entry into the brain or tetrahydropterina cofactor capable of increasing residual activity of phenylalanine hydroxylase. Moreover, human trials have recently been performed with subcutaneous administration of phenylalanine ammonia-lyase, and further efforts are underway to develop an oral therapy containing phenylanine ammonia-lyase. Gene therapy also seems to be a promising approach in the near future.
| S-EPMC4279156 | biostudies-literature
Project description:Cognitive and mental health problems in individuals with the inherited metabolic disorder phenylketonuria (PKU) have often been associated with metabolic control and its history. For the present study executive functioning (EF) was assessed in 21 PKU patients during childhood (T1, mean age 10.4 years, SD?=?2.0) and again in adulthood (T2, mean age 25.8 years, SD?=?2.3). At T2 additional assessments of EF in daily life and mental health were performed. Childhood (i.e. 0-12 years) blood phenylalanine was significantly related to cognitive flexibility, executive motor control, EF in daily life and mental health in adulthood (i.e. at T2). Patients with a greater increase in phenylalanine levels after the age of 12 performed more poorly on EF-tasks at T2. Group-based analyses showed that patients with phenylalanine <360 µmol/L in childhood and phenylalanine ?360 µmol/L from age 13 onwards (n?=?11) had better cognitive flexibility and executive motor control than those who had phenylalanine ?360 µmol/L throughout life (n?=?7), supporting the notion that phenylalanine should be below the recommended upper treatment target of 360 µmol/L during childhood for better outcome in adulthood. Despite some results indicating additional influence of phenylalanine levels between 13 and 17 years of age, evidence for a continued influence of phenylalanine levels after childhood on adult outcomes was largely lacking. This may be explained by the fact that the patients in the present study had relatively low phenylalanine levels during childhood (mean: 330 µmol/L, range: 219-581 µmol/L) and thereafter (mean Index of Dietary Control at T2: 464 µmol/L, range: 276-743 µmol/L), which may have buffered against transitory periods of poor metabolic control during adolescence and early adulthood.
| S-EPMC5574956 | biostudies-literature
Project description:BACKGROUND: Parents of children with chronic conditions are known to be at risk of impairment in their quality of life (QoL). Studies considering other chronic conditions proposed diverse factors to have an impact on the parent's QoL. So far, there has been little research on parents who have a child with phenylketonuria (PKU). This study was designed to evaluate the parental quality of life (PQoL) of parents of children and adolescents who have PKU and identify possible predictors of PQoL. METHODS: In this cross-sectional study 89 parents completed self-report measures of PQoL, family stress, social support, and parental coping. To determine the impact of these potential predictors on PQoL, regression and mediation analyses were performed. RESULTS: Most parents coped well with their children's metabolic disorder. Family stress (??=?-0.42; p?<?0.001) and perceived social support (??=?0.33; p?=?0.001) were proven to be the most powerful predictors, accounting together for 45% of the variance of PQoL. Social support mediated the association between family stress and PQoL. CONCLUSIONS: The current study indicates that parents of younger children are an especially vulnerable group. Members of health-care teams should be able to identify and empower vulnerable parents to seek and maintain social support.
| S-EPMC3626680 | biostudies-literature
Project description:BACKGROUND: Phenylketonuria (PKU) is an autosomal recessive disorder of phenylalanine metabolism. The inability to convert phenylalanine (Phe) into tyrosine causes Phe to accumulate in the body. Adherence to a protein restricted diet, resulting in reduced Phe levels, is essential to prevent cognitive decline. Frequent evaluation of plasma Phe levels and, if necessary, adjustment of the diet are the mainstay of treatment. We aimed to assess whether increased self-management of PKU patients and/or their parents is feasible and safe, by providing direct online access to blood Phe values without immediate professional guidance. METHODS: Thirty-eight patients aged ≥ 1 year participated in a 10 month randomized controlled trial. Patients were randomized into a study group (1) or a control group (2). Group 2 continued the usual procedure: a phone call or e-mail by a dietician in case of a deviant Phe value. Group 1 was given a personal "My PKU" web page with a graph of their recent and previous Phe values, online general information about the dietary treatment and the Dutch PKU follow-up guidelines, and a message-box to contact their dietician if necessary. Phe values were provided on "My PKU" without advice. Outcome measures were: differences in mean Phe value, percentage of values above the recommended range and Phe sample frequency, between a 10-month pre-study period and the study period in each group, and between the groups in both periods. Furthermore we assessed satisfaction of patients and/or parents with the 'My PKU' procedure of online availability. RESULTS: There were no significant differences in mean Phe value, percentage of values above recommended range or in frequency of blood spot sampling for Phe determination between the pre-study period and the study period in each group, nor between the 2 groups during the periods. All patients and/or parents expressed a high level of satisfaction with the new way of disease management. CONCLUSIONS: Increased self-management in PKU by providing patients and/or parents their Phe values without advice is feasible and safe and is highly appreciated. TRIAL REGISTRATION: The trial was registered with The Netherlands National Trial Register (NTR #1171) before recruitment of patients.
| S-EPMC3133536 | biostudies-other
Project description:Urea cycle disorders (UCDs) are a group of rare inherited metabolic diseases causing hyperammonemic encephalopathy. Despite intensive dietary and pharmacological therapy, outcome is poor in a subset of UCD patients. Reducing ammonia production by changing faecal microbiome in UCD is an attractive treatment approach. We compared faecal microbiome composition of 10 UCD patients, 10 healthy control subjects and 10 phenylketonuria (PKU) patients. PKU patients on a low protein diet were included to differentiate between the effect of a low protein diet and the UCD itself on microbial composition. Participants were asked to collect a faecal sample and to fill out a 24 h dietary journal. DNA was extracted from faecal material, taxonomy was assigned and microbiome data was analyzed, with a focus on microbiota involved in ammonia metabolism.In this study we show an altered faecal microbiome in UCD patients, different from both PKU and healthy controls. UCD patients on dietary and pharmacological treatment had a less diverse faecal microbiome, and the faecal microbiome of PKU patients on a protein restricted diet with amino acid supplementation showed reduced richness compared to healthy adults without a specific diet. The differences in the microbiome composition of UCD patients compared to healthy controls were in part related to lactulose use. Other genomic process encodings involved in ammonia metabolism, did not seem to differ. Since manipulation of the microbiome is possible, this could be a potential treatment modality. We propose as a first next step, to study the impact of these faecal microbiome alterations on metabolic stability.Take home messageThe faecal microbiome of UCD patients was less diverse compared to PKU patients and even more compared to healthy controls.
| S-EPMC8433284 | biostudies-literature
Project description:Phenylketonuria (PKU), a rare metabolic disorder, causes cognitive impairment unless treated with a strict, protein-restricted diet, but few studies have examined the relationship between treatment compliance and parental wellbeing. In the present study, 46 primary caregivers of children with PKU completed measures of psychological distress, parenting stress (related to caring for a child with an illness), resilience, perceived social support and child dependency. Treatment adherence was assessed using the proportion of blood phenylalanine concentrations within target range in the preceding year. Results indicated that 59% of caregivers showed clinical levels of psychological distress, which was predicted by their parenting stress and resilience. Whilst the proportion of blood phenylalanine concentrations in range was not associated with parental distress, it was predicted by child age and caregiver's perceived support from family. Despite experiencing high levels of distress, the results indicated that caregivers' ability to adhere to treatment was not affected. Interventions to reduce parenting stress and boost caregiver resilience may have a positive effect on parental wellbeing. Additionally, interventions to promote treatment adherence benefit parents of older children, with a focus on promoting support from family members. Further research with larger sample sizes and longitudinal designs is needed to further establish causal mechanisms.
| S-EPMC5740045 | biostudies-literature
Project description:IntroductionPhenylketonuria (PKU) is a rare, metabolic genetic disorder that can cause various neuropsychological symptoms that often affect patients' health-related quality of life, even for patients with good metabolic control. To date, no patient-reported outcomes (PRO) instrument combines the measurement of neuropsychological and dietary concepts to capture the broad impact of PKU on quality of life. This article presents the development of the PKU Symptom Severity and Impacts Scale (PKU-SSIS), a PRO instrument that is designed to evaluate neuropsychological symptoms and impacts in early-treated patients with PKU.MethodsA draft instrument was developed based on a targeted literature review, PKU expert physician interviews, and an advisory board consisting of patients with PKU. Qualitative interviews combining concept elicitation/cognitive interviews were conducted with patients with classic PKU aged at least 15 years old. A separate sample of 20 patients with PKU completed the draft PKU-SSIS in a paper survey format, to enable preliminary assessment of any floor and ceiling effects.ResultsPatient interviews elicited four key symptom themes: neurocognitive function, emotional and behavioral, physical functioning, and physical health. Four impact themes were also identified: social function, physical health, emotions, and level of independence. No floor or ceiling effects were identified.ConclusionThe final instrument included 22 items, covering three symptom domains (1. emotional, mood, and psychological; 2. (neuro)cognitive, executive, and intellectual function; and 3. physical health), and four impact domains (1. social relations, 2. level of independence, 3. general well-being, and 4. self-care). The PKU-SSIS will help to address an important gap in the evaluation of existing and future treatments for PKU.
| S-EPMC8684342 | biostudies-literature
Project description:BackgroundPhenylketonuria (PKU; OMIM#261600) is a rare metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene resulting in high phenylalanine (Phe) in blood and brain. If not treated early this results in intellectual disability, behavioral and psychiatric problems, microcephaly, motor deficits, eczematous rash, autism, seizures, and developmental problems. There is a controversial discussion of whether patients with PKU have an additional risk for atherosclerosis due to interference of Phe with cholesterol synthesis and LDL-cholesterol regulation. Since cholesterol also plays a role in membrane structure and myelination, better insight into the clinical significance of the impact of Phe on lipoprotein metabolism is desirable. In 22 treated PKU patients (mean age 38.7 years) and 14 healthy controls (mean age 35.2 years), we investigated plasma with NMR spectroscopy and quantified 105 lipoprotein parameters (including lipoprotein subclasses) and 24 low molecular weight parameters. Analysis was performed on a 600 MHz Bruker AVANCE IVDr spectrometer as previously described.ResultsConcurrent plasma Phe in PKU patients showed a wide range with a mean of 899 μmol/L (50-1318 μmol/L). Total cholesterol and LDL-cholesterol were significantly lower in PKU patients versus controls: 179.4 versus 200.9 mg/dL (p < 0.02) and 79.5 versus 104.1 mg/dL (p < 0.0038), respectively. PKU patients also had lower levels of 22 LDL subclasses with the greatest differences in LDL2 Apo-B, LDL2 Particle Number, LDL2-phospholipids, and LDL2-cholesterol (p < 0.0001). There was a slight negative correlation of total cholesterol and LDL-cholesterol with concurrent Phe level. VLDL5-free cholesterol, VLDL5-cholesterol, VLDL5-phospholipids, and VLDL4-free cholesterol showed a significant (p < 0.05) negative correlation with concurrent Phe level. There was no difference in HDL and their subclasses between PKU patients and controls. Tyrosine, glutamine, and creatinine were significantly lower in PKU patients compared to controls, while citric and glutamic acids were significantly higher.ConclusionsUsing NMR spectroscopy, a unique lipoprotein profile in PKU patients can be demonstrated which mimics a non-atherogenic profile as seen in patients treated by statins.
| S-EPMC7047385 | biostudies-literature