Introduction. Phenylketonuria (PKU), a genetic disease with autosomal dominant transmission, is the most frequent inborn error in aminoacidic metabolism. The variations in phenylalanine-hydroxylase ...(PAH) gene lead to a lowered enzymatic activity causing hyperphenylalaninemia. PKU has a mean European prevalence of 1:10,000 newborns, with a large variation in different ethnicities and geographic regions. The large genetic variability (over 1200 genetic variants known) as well as other factors determines a wide spectrum of metabolic phenotypes. Untreated, PKU leads to irreversible intellectual disability, low stature, hypopigmentation, motor deficits, seizures, but the early diagnosis and treatment enables almost normal somatic and mental development. Aim. The aim of this study is the determination of the impact of non-genetic factors over the clinical phenotype of PKU patients in a region of north-west Romania. Material and method. The study group is formed from 44 patients diagnosed with phenylketonuria in the 1981 – 2021 period, found in the database of Bihor Regional Center for Medical Genetics, Emergency Clinical County Hospital, Oradea, Romania. The collected data was referring to the age, sex and domicile of the patients, the age of the diagnosis and the beginning of the treatment, also the metabolic control over the years, the metabolic phenotype of the patients and its impact on the clinical phenotype (IQ, the presence or absence of intellectual disability or the existence of a specific clinical phenotype). Results. The majority of patients (66%) were diagnosticated with phenylketonuria in the first 4 months of life, although there were cases with a late diagnosis, 20.5% of the patients were diagnosticated after the age of 1 year. Based on the pre-treatment plasmatic levels of phenylalanine, the majority of cases (72.7%) had a severe metabolic phenotype (classic PKU - cPKU), 20.5% of cases had a milder form of PKU (mPKU) and 6.8% of patients were found with a mild hyperphenylalaninemia (HPA). In the case of 23 patients, an optimal metabolic control was not obtained. The specific phenotype (blonde hair, light skin, blue eyes) was found in 22.7% of cases, 77.3% not having these features. At 68.2% of cases intellectual disability was found, with different levels of severity: 5 patients (11.5%) had liminal intellect, 9 patients (20.5%) had mild mental retardation, 6 patients (13.6%) had moderate mental retardation, 9 cases (20.5%) were with severe mental retardation and 1 patient (2.3%) had profound mental retardation; 31.8% of cases had normal intellect. The prevalence in Bihor county is 1:7,843 newborns. Discussions. A partial or, in rare cases, total lack of dietetic treatment was observed in all patients over 20 years old (current age). The delay in treatment initiation or an insufficient treatment, with a suboptimal metabolic control, will affect patient’s intellect, regardless of metabolic phenotype. If in 20 years old patients, or older, the main reason for mental retardation is the lack of dietetic treatment availability in the first years of life, for the younger patients the reason for mental retardation is usually a lack of compliance with the treatment. The majority of metabolic phenotypes is cPKU, in concordance with the literature data; the mild phenotype (HPA) was observed in a small percentage of patients, smaller than the data reported in the literature. In the first two studied decades the mild phenotypes were seldom observed. In the absence of screening tests or suggestive clinical manifestation it can be assumed that HPA patients remained undiagnosed, which would explain the small HPA percentage in the study group. A significant improvement in metabolic control in younger patients compared with older ones was observed, which denotes a better access to specific alimentation on one side, and o the other side, a better understanding of the disease from the patients and their families. Also, this study confirms a known fact that the diet in PKU is of great importance in the disease evolution. In this study there were included patients with severe metabolic phenotype with good metabolic control which reached adulthood without intellectual deficits, with higher education, social integrated and also patients with mild metabolic phenotype but with a poor metabolic control which developed intellectual deficiency. Conclusions. The PKU prevalence in Bihor county is higher than the estimated national value. The late diagnosis and treatment or the poor metabolic control led to intellectual disability, regardless of the metabolic phenotype. PKU screening and the better access to treatment allows younger generations of patients to enjoy a superior quality of life than the patients from the first two studied decades.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
This study aims to analyze the regeneration of ulama in North Sumatra carried out by pesantren and Pendidikan Kader Ulama (PKU). This research uses the literature study method by collecting written ...sources in the form of authoritative books and journals. The theory used in this study is the theory put forward by Azyumardi Azra, that the function of pesantren in the past was the transmission and transfer of Islamic sciences, preserving Islamic traditions, and being a place to reproduce ulama. Currently, there seems to have been a shift towards the theory that pesantren can no longer be expected as a forum for cadre ulama, so the alternative solution is to establish an independent clerical cadre institution. The results of this study show that there is currently a scarcity of ulama. Many pesantren that once functioned as appropriate reproducing ulama can no longer be expected because they have been contaminated with the current of modernization. Pesantren can reformulate the curriculum as before and also it can develop Ma'had 'Aly. PKU is an alternative solution that can be used as an effort to regenerate ulama. Then, another important thing is that the mastery of the yellow book for prospective ulama must be strengthened because it is an absolute qualification for ulama. The real contributions from this research are to provide recommendations for pesantren to reinstate their original function, namely producing clerical cadres. Then, the efforts to regenerate ulama must be supported by Islamic mass organizations as a legacy of ulama which are also responsible for establishing clerical regeneration institutions.
Background and Aim:Phenylketonuria is a type of autosomal recessive congenital and genetically induced fungal disease that has not been converted to tyrosine by the lack or lack of the phenylalanine ...hydroxylase enzyme and has been shown to increase phenylalanine levels in the blood, especially in the brain. The aim of this study was to compare the IQ scores of children with phenylketonuria and healthy children referring to Besat hospital clinic in Sanandaj in 2017-2018.Methods:This historic cohort study wasperformed on all of the patients at the time of birth, referred to PKU and pediatric clinics, as well as healthy children (for phenylketonuria) referred to other clinics of the children's hospital. The control group was done.Goodinow’s intelligence test was used to measure cognitive, mental and children's intelligence. Finally, the results of the two groups were analyzed by the statistical consult.Results:The results showed that 46 (69.7%) were male and 20 (30.3%) were female. The mean age of the subjects was 6.34±2.52of years. Result from the current study showed that there was not significant differences between IQ mean in two groups of study(p>0.05).Conclusion:According to the results of this study, the timely identification and treatment of patients with phenylketonuria has been able to prevent the complications of this disease to a large extent, and keep the children's IQs intact, thereby providing timely andaccurate identification and treatment of this disease is necessary among children.
Insufficient metabolic control during pregnancy of mothers with phenylketonuria (PKU) leads to maternal PKU syndrome, a severe embryo-/fetopathy. Since maintaining or reintroducing the strict ...phenylalanine (Phe) limited diet in adults with PKU is challenging, we evaluated the most important dietary and psychosocial factors to gain and sustain good metabolic control in phenylketonuric women throughout pregnancy by a questionnaire survey with 38 questions concerning therapy feasibility. Among them, the key questions covered 5 essential items of PKU care as follows: General information about maternal PKU, PKU training, diet implementation, individual metabolic care, personal support. In addition, all participating PKU mothers were asked to estimate the quality of their personal metabolic control of the concluded pregnancies. 54 PKU mothers with 81 pregnancies were approached at 12 metabolic centers in Germany and Austria were included. According to metabolic control, pregnancies of PKU women were divided in two groups: group "ideal" (not more than 5% of all blood Phe concentrations during pregnancy > 360 µmol/l; n = 23) and group "suboptimal" (all others; n = 51).
The demand for support was equally distributed among groups, concerning both amount and content. Personal support by the direct social environment (partner, family and friends) ("suboptimal" 71% vs "ideal" 78%) as well as individual metabolic care by the specialized metabolic center (both groups around 60%) were rated as most important factors. The groups differed significantly with respect to the estimation of the quality of their metabolic situation (p < 0.001). Group "ideal" presented a 100% realistic self-assessment. In contrast, group "suboptimal" overestimated their metabolic control in 53% of the pregnancies. Offspring of group "suboptimal" showed clinical signs of maternal PKU-syndrome in 27%.
The development of training programs by specialized metabolic centers for females with PKU in child bearing age is crucial, especially since those mothers at risk of giving birth to a child with maternal PKU syndrome are not aware of their suboptimal metabolic control. Such programs should provide specific awareness training for the own metabolic situation and should include partners and families.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
•This White Paper offers a neurocognitive assessment platform for clinical trials in PKU.•It describes 5 neuropsychological domains relevant to outcomes in PKU.•Criteria for measures to be included ...in the Assessment Platform are defined.•Both Performance and Patient Reported Outcome measures are recommended.•Once implemented, this Platform may accelerate approval of new PKU treatments.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Infants born to mothers with phenylketonuria (PKU) may develop congenital abnormalities because of elevated phenylalanine (Phe) levels in the mother during pregnancy. Maintenance of blood Phe levels ...between 120 and 360 μmol/L reduces risks of birth defects. Sapropterin dihydrochloride helps maintain blood Phe control, but there is limited evidence on its risk–benefit ratio when used during pregnancy. Data from the maternal sub‐registries—KAMPER (NCT01016392) and PKUDOS (NCT00778206; PKU‐MOMs sub‐registry)—were collected to assess the long‐term safety and efficacy of sapropterin in pregnant women in a real‐life setting. Pregnancy and infant outcomes, and the safety of sapropterin were assessed. Final data from 79 pregnancies in 57 women with PKU are reported. Sapropterin dose was fairly constant before and during pregnancy, with blood Phe levels maintained in the recommended target range during the majority (82%) of pregnancies. Most pregnancies were carried to term, and the majority of liveborn infants were reported as ‘normal’ at birth. Few adverse and serious adverse events were considered related to sapropterin, with these occurring in participants with high blood Phe levels. This report represents the largest population of pregnant women with PKU exposed to sapropterin. Results demonstrate that exposure to sapropterin during pregnancy was well‐tolerated and facilitated maintenance of blood Phe levels within the target range, resulting in normal delivery. This critical real‐world data may facilitate physicians and patients to make informed treatment decisions about using sapropterin in pregnant women with PKU and in women of childbearing age with PKU who are responsive to sapropterin.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Screening for phenylketonuria (PKU) is a public health strategy that is used to diagnose and treat patients with PKU to prevent severe neurological diseases. The purpose of this study was to ...determine the incidence of phenylketonuria based on the results of the newborn screening program and to evaluate the indicators of this program at Kerman University of Medical Sciences, southeast Iran.
In this study, infants referred to sampling centers for screening in the cities covered by the Kerman University of Medical Sciences were investigated during the years 2012–2019. The screening information was obtained from the data recorded in the newborn screening program and the information about the patients from the national form of the epidemiological survey of the occurrence of genetic diseases in the Kerman health department. Excel software was used to analysis descriptive statistics, draw diagrams.
The screening coverage was 96.07%. 83.9% of infants were screened during the 3rd to 5th day of birth. The incidence of phenylketonuria was 1.27 per 10,000 live births. The highest incidence was related to the cities of Erzuye (11.5 per 10 thousand live births) and Baft (5.2 per 10 thousand live births). In total, 0.45% of the samples were inappropriate. In 72% of sick babies, the treatment was started before 21 days, 100% of patients identified in screening were the first child of the patient in the family and 64.5% of the parents of the patients were consanguineous.
The incidence of phenylketonuria in Kerman is in line with the national average. The implementation of the screening program had a significant impact on the timely diagnosis and the timely initiation of treatment. It is necessary to increase the level of awareness of households regarding the consequences of consanguineous marriages, especially in areas with a high prevalence of phenylketonuria.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Phenylketonuria (PKU), caused by variants in the phenylalanine hydroxylase (PAH) gene, is the most common autosomal-recessive Mendelian phenotype of amino acid metabolism. We estimated that globally ...0.45 million individuals have PKU, with global prevalence 1:23,930 live births (range 1:4,500 Italy–1:125,000 Japan). Comparing genotypes and metabolic phenotypes from 16,092 affected subjects revealed differences in disease severity in 51 countries from 17 world regions, with the global phenotype distribution of 62% classic PKU, 22% mild PKU, and 16% mild hyperphenylalaninemia. A gradient in genotype and phenotype distribution exists across Europe, from classic PKU in the east to mild PKU in the southwest and mild hyperphenylalaninemia in the south. The c.1241A>G (p.Tyr414Cys)-associated genotype can be traced from Northern to Western Europe, from Sweden via Norway, to Denmark, to the Netherlands. The frequency of classic PKU increases from Europe (56%) via Middle East (71%) to Australia (80%). Of 758 PAH variants, c.1222C>T (p.Arg408Trp) (22.2%), c.1066−11G>A (IVS10−11G>A) (6.4%), and c.782G>A (p.Arg261Gln) (5.5%) were most common and responsible for two prevalent genotypes: p.Arg408Trp;Arg408Trp (11.4%) and c.1066−11G>A;1066−11G>A (2.6%). Most genotypes (73%) were compound heterozygous, 27% were homozygous, and 55% of 3,659 different genotypes occurred in only a single individual. PAH variants were scored using an allelic phenotype value and correlated with pre-treatment blood phenylalanine concentrations (n = 6,115) and tetrahydrobiopterin loading test results (n = 4,381), enabling prediction of both a genotype-based phenotype (88%) and tetrahydrobiopterin responsiveness (83%). This study shows that large genotype databases enable accurate phenotype prediction, allowing appropriate targeting of therapies to optimize clinical outcome.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
To evaluate effects of sapropterin dihydrochloride on blood phenylalanine (Phe) and symptoms of neuropsychiatric impairment in children and adolescents with phenylketonuria (PKU).
PKU subjects ...8-17 years of age (n = 86) were randomized to double-blind treatment with sapropterin (n = 43) or placebo (n = 43) for 13 weeks, then all received open-label sapropterin therapy for an additional 13 weeks. Blood Phe and symptoms of inattention, hyperactivity/impulsivity (Attention-Deficit/Hyperactivity Disorder Rating Scale IV ADHD RS-IV), executive functioning (Behavior Rating Inventory of Executive Function), depression (Hamilton Rating Scale for Depression), and anxiety (Hamilton Rating Scale for Anxiety) were assessed.
Following the 13-week randomization phase, the sapropterin and placebo groups had mean changes in blood Phe of −20.9% and +2.9%, respectively. Corresponding least square mean differences in ADHD RS-IV scores were significantly greater for the sapropterin vs the placebo group: Total (−3.2 points, P = .02), Inattention subscale (−1.8 points, P = .04), and Hyperactivity/Impulsivity subscale (−1.6 points, P = .02). Forest plots favored sapropterin treatment over placebo for all ADHD RS-IV and Behavior Rating Inventory of Executive Function indices. There were no significant differences in reported problems with attention or executive function between the 2 groups at baseline or at week 26 following the 13-week open-label treatment period. Anxiety and depression scores did not differ significantly between cohorts at any time. Sapropterin was well tolerated, with a favorable safety profile.
Sapropterin reduced blood Phe and was associated with significant improvement in parent-reported symptoms of inattention, hyperactivity/impulsivity, and executive functioning in children and adolescents with PKU.
ClinicalTrials.gov, NCT01114737. Registered 27 April 2010, https://clinicaltrials.gov/ct2/show/NCT01114737.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Background: In 2011, a European phenylketonuria (PKU) survey reported that the blood phenylalanine (Phe) levels were well controlled in early life but deteriorated with age. Other studies have shown ...similar results across the globe. Different target blood Phe levels have been used throughout the years, and, in 2017, the European PKU guidelines defined new targets for blood Phe levels. This study aimed to evaluate blood Phe control in patients with PKU across Europe. Methods: nine centres managing PKU in Europe and Turkey participated. Data were collected retrospectively from medical and dietetic records between 2012 and 2018 on blood Phe levels, PKU severity, and medications. Results: A total of 1323 patients (age range:1–57, 51% male) participated. Patient numbers ranged from 59 to 320 in each centre. The most common phenotype was classical PKU (n = 625, 48%), followed by mild PKU (n = 357, 27%) and hyperphenylalaninemia (HPA) (n = 325, 25%). The mean percentage of blood Phe levels within the target range ranged from 65 ± 54% to 88 ± 49% for all centres. The percentage of Phe levels within the target range declined with increasing age (<2 years: 89%; 2–5 years: 84%; 6–12 years: 73%; 13–18 years: 85%; 19–30 years: 64%; 31–40 years: 59%; and ≥41 years: 40%). The mean blood Phe levels were significantly lower and the percentage within the target range was significantly higher (p < 0.001) in patients with HPA (290 ± 325 μmol/L; 96 ± 24%) and mild PKU (365 ± 224 μmol/L; 77 ± 36%) compared to classical PKU (458 ± 350 μmol/L, 54 ± 46%). There was no difference between males and females in the mean blood Phe levels (p = 0.939), but the percentage of Phe levels within the target range was higher in females among school-age children (6–12 years; 83% in females vs. 78% in males; p = 0.005), adolescents (13–18 years; 62% in females vs. 59% in males; p = 0.034) and adults (31–40 years; 65% in females vs. 41% in males; p < 0.001 and >41 years; 43% in females vs. 28% in males; p < 0.001). Patients treated with sapropterin (n = 222) had statistically significantly lower Phe levels compared to diet-only-treated patients (mean 391 ± 334 μmol/L; percentage within target 84 ± 39% vs. 406 ± 334 μmol/L; 73 ± 41%; p < 0.001), although a blood Phe mean difference of 15 µmol/L may not be clinically relevant. An increased frequency of blood Phe monitoring was associated with better metabolic control (p < 0.05). The mean blood Phe (% Phe levels within target) from blood Phe samples collected weekly was 271 ± 204 μmol/L, (81 ± 33%); for once every 2 weeks, it was 376 ± 262 μmol/L, (78 ± 42%); for once every 4 weeks, it was 426 ± 282 μmol/L, (71 ± 50%); and less than monthly samples, it was 534 ± 468 μmol/L, (70 ± 58%). Conclusions: Overall, blood Phe control deteriorated with age. A higher frequency of blood sampling was associated with better blood Phe control with less variability. The severity of PKU and the available treatments and resources may impact the blood Phe control achieved by each treatment centre.
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