Search Results (45)

Since January 2023, the Russian Federation has implemented expanded neonatal screening for 36 hereditary disorders, which has changed the diagnostic algorithm for hyperphenylalaninemia/phenylketonuria (HPA/PKU) by introducing tandem mass spectrometry (MS/MS) on the second day of life, followed by confirmatory biochemical and molecular testing in newborns at risk. We analyzed 1247 newborns aged 5–15 days with elevated phenylalanine levels (≥120 µmol/L) and a phenylalanine to tyrosine ratio of at least 1 detected during the first stage of screening using MS/MS. At the reference center, newborns underwent repeat biochemical testing and stepwise molecular analysis of HPA-associated genes. Two pathogenic variants in HPA-associated genes were identified in 538 newborns, including 534 newborns with biallelic pathogenic variants in PAH and 4 with BH4-deficient forms (PTS, QDPR). The incidence of molecularly confirmed HPA was 1:4518 newborns (95% CI: 1:4152–1:4925). The PAH variant spectrum was dominated by p.Arg408Trp (c.1222C>T) (33.4%). Genotype-based analysis indicated that 73 newborns (13.7%) were likely responsive to cofactor therapy, whereas 222 (41.6%) were potentially responsive. These findings define the molecular epidemiology of HPA in Russia and support early genetic stratification for diagnosis and treatment. Full article

Phenylketonuria (PKU) is an autosomal recessive disorder characterised by an inborn error of phenylalanine (Phe) metabolism. Such errors are attributed to pathogenic gene variants causing phenylalanine hydroxylase (PAH) deficiency, impairing the hydroxylation of phenylalanine to tyrosine in the Phe metabolic pathway. This defect leads to plasma Phe concentrations above the normal range. If untreated, hyperphenylalaninemia can adversely affect brain function, leading to severe intellectual disability and seizures. Since 1969, the newborn dried blood spot test has remained the main method of early screening and diagnosis for PKU. The primary therapeutic management is a lifelong phenylalanine-restricted diet with the aim of decreasing plasma Phe levels. The recommended diet consists of avoiding high-protein foods such as meat, fish, eggs and nuts, and can be supplemented with high-protein medical formulas which are low in phenylalanine. Pharmacological interventions such as sapropterin, sepiapterin and pegvaliase can also be used as treatment adjuncts in patients with PKU. Currently, small-molecule inhibitors reducing renal phenylalanine reabsorption are being explored as a potential therapeutic intervention. Furthermore, novel gene-editing techniques are under evaluation as potential curative strategies, with preclinical studies showing promising results in correcting pathogenic phenylalanine hydroxylase variants. This non-systematic review synthesises current literature on the management of PKU, with a focus on dietary interventions and recommendations. Full article

Mouse models of genetic diseases are important research tools. However, the genetic background of the mouse strain can significantly influence how a genetic mutation is expressed. Studies on preclinical models of phenylketonuria (PKU), an inherited metabolic disorder, have used two strains, BTBR and C57Bl/6, created via a chemically induced point mutation in the gene encoding the enzyme phenylalanine hydroxylase (BTBR^enu2 and C57^enu2, respectively). Despite having the same levels of hyperphenylalaninemia (HPA), published results indicate differences in neural and behavioral phenotypes between the two backgrounds. To explore this difference further, the current study examines the genome-wide transcriptome of the prefrontal cortex (pFC), the brain region which is the most vulnerable to the negative effects of HPA. Regardless of the strain, the enu2 mutation upregulated the expression of several aminoacyl-tRNA synthetases and eukaryotic translation initiation factors, suggesting an essential modification in the protein translation process and supporting the downregulation of gene programs related to myelination. Accordingly, we deepened the exploration of cognitive dysfunctions in C57^enu2− mice, showing a previously unreported working memory impairment under increasing information load. These findings identify convergent pFC molecular and cognitive alterations induced by HPA across distinct genetic backgrounds, providing clinically relevant insights into mechanisms that may contribute to executive dysfunctions in PKU. Full article

Background: Fetal growth restriction (FGR) is a significant obstetric complication associated with increased perinatal morbidity and long-term developmental risks. Despite advances in prenatal diagnosis, the genetic etiology of isolated FGR remains incompletely characterized, complicating genetic counseling and clinical management. Objective: This study aimed to systematically evaluate the genetic causes of isolated FGR by integrating karyotyping, chromosomal microarray analysis (CMA), and trio-based whole exome sequencing (trio-WES) and to assess the incremental diagnostic yield of this sequential approach. Methods: A retrospective cohort of 153 fetuses with isolated FGR (diagnosed by ultrasound between February 2018 and July 2024) underwent karyotyping and CMA. Cases with normal results from both tests (n = 50) were subsequently analyzed by trio-WES. Results: Karyotyping identified chromosomal abnormalities in three cases (2.0%). CMA detected pathogenic/likely pathogenic copy number variations (CNVs) or uniparental disomy (UPD) in twelve cases (7.8%), including the three karyotypic abnormalities and nine additional cases (5.9% incremental yield). Trio-WES performed on 50 CMA-negative cases identified pathogenic or likely pathogenic variants in 12 cases (24%). Among these, seven cases (14% of the WES subgroup) harbored variants directly causative of FGR, including one case of UPD(6) missed by CMA alone. Additionally, trio-WES revealed seven incidental pathogenic/likely pathogenic variants not directly linked to FGR and identified one case in which FGR was attributed to maternal hyperphenylalaninemia. Conclusions: The sequential application of CMA and trio-WES significantly improves the diagnostic yield for isolated FGR. Trio-WES proved particularly valuable in detecting UPD and single-gene variants missed by CMA alone and in revealing contributory maternal genetic conditions. These findings support the integration of advanced genetic testing into the diagnostic workup for isolated FGR to enhance etiological diagnosis, facilitate comprehensive genetic counseling, and inform multidisciplinary management. Full article

Background/Objectives: Skeletal impairment has been reported as a common finding in Hyperphenylalaninemia (HPA)/Phenylketonuria (PKU) patients regardless of age and method of diagnosis, both in children and adults. Quantitative Ultrasound (QUS) is a radiation-free and low-cost method for assessing bone quality, used in various chronic conditions. Methods: Bone quality was evaluated using a calcaneal QUS device. Auxological parameters, nutritional intakes, and plasma levels of key bone biomarkers were also registered. The population was divided into four groups: PKU patients under diet therapy and HPA patients on a free diet, both divided into receiving or not receiving single vitamin D supplementation. Results: All HPA/PKU patients had median bone quality index (BQI) Z- and T-score values lower than −1, with slightly better values in HPA children and PKU-supplemented adults. Dietary vitamin D intake in PKU patients was significantly higher than in HPA subjects (p < 0.001), due to protein substitute supplementation. However, plasma 25(OH) vitamin D levels, although increased compared to baseline, were still overlapping among groups (p = 0.845) after supplementation. Approximately a quarter of both pediatric and adult non-supplemented PKU patients had Z-score and T-score levels below −2, and this percentage decreased with vitamin D supplementation in all groups. In PKU-supplemented patients, the Broadband Ultrasound Attenuation (BUA) was significantly higher than in the other groups (p = 0.040). Conclusions: The improvement in BUA may represent preliminary evidence of the effect of vitamin D on bone architecture, which could encourage this supplementation to prevent the worsening of bone structure and reduce the risk of fractures. Full article

Background/Objectives: Phenylketonuria (PKU) is an inborn error of metabolism (IEM) that requires a specialized medical nutrition therapy (MNT) to maintain blood phenylalanine concentrations within a safe range. This study aimed to assess nutrition practices, knowledge, and PKU diet adherence in patients with PKU. Methods: This cross-sectional study included 27 patients (n = 19 women) with PKU, recruited from clinics of IEM in Greece, ranging in age between 14 and 60 years, with PKU diagnosis via neonatal screening. Each participant completed the questionnaire independently. For the two patients with age below 18 years old, caregivers provided written informed consent. All participants were questioned regarding their dietary practices, nutritional knowledge, and perceptions. Results: More than half (66.7%) of patients complied with the PKU diet and the recommended daily protein substitutes. However, 25.9% reported being unaware of their blood phenylalanine levels, and 40.7% didn’t know how many PKU exchanges they consumed daily. Most patients (88.8%) perceived the recommended PKU diet as “healthy”, and reported feeling well when adhering to it. Several concerns were raised regarding protein substitutes, with 10.5% of patients feeling that the amount of prescribed protein substitutes was too high, while 25.9% perceived it as being too low. Additionally, 14.8% of patients expressed concerns regarding the protein amount required for building muscle mass. Overall, the majority of participants perceived the PKU diet as being adequate in energy, carbohydrates, lipids, and protein. Conclusions: Although patients with PKU generally possess a good understanding of PKU nutritional principles, significant potential for improvement in dietary education is apparent. To support optimal management of blood phenylalanine concentrations, it is essential to implement novel communication strategies that facilitate patient adherence to the MNT for PKU. Such strategies should also empower caregivers to provide effective support, including the proper use of protein substitutes and accurate protein exchanges. Full article

Background: Phenylketonuria (PKU) is a rare autosomal recessive metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene, leading to hyperphenylalaninemia (HPA). Untreated, elevated phenylalanine (Phe) levels cause severe neurocognitive, developmental, and psychiatric complications. Management relies on a Phe-restricted diet, which is challenging to maintain, particularly in adolescents and adults. Sapropterin dihydrochloride, a synthetic form of tetrahydrobiopterin (BH4), can enhance residual PAH activity, lowering blood Phe levels and increasing dietary tolerance in responsive patients. However, real-world alignment with best practices remains underexplored. This study aims to report a tertiary referral center’s experience with sapropterin treatment in PKU and assess adherence to international guidelines. Methods: We retrospectively analyzed 23 PKU patients treated with sapropterin from 2007 to 2025. Patients with baseline Phe levels of 360–2000 µmol/L underwent a 10 mg/kg/day loading test over two weeks. Responsiveness was defined as a ≥30% reduction in blood Phe levels. Phe levels were measured pre- and post-test, and dietary tolerance was evaluated. Adherence to best practices was critically reviewed. Results: All patients showed significant Phe reductions (mean 71.43%, p < 0.0001), exceeding responsiveness thresholds. Most achieved substantial increases in dietary Phe tolerance, with three patients partially responsive (800–1200 mg/day). Responsiveness was unrespectful of the patient’s genotype, for those individuals for whom this was known (8/23 patients). Although effective, the test dose and duration differed from guideline recommendations (20 mg/kg/day). Neuropsychological and QoL assessments were not systematically performed, representing a key limitation. Conclusions: Sapropterin dihydrochloride effectively identified responders and improved dietary flexibility even with lower dosing protocols. Greater adherence to international standards, particularly regarding long-term neuropsychological monitoring, is needed to optimize patient care. Full article

Background/Objectives: Dietary treatment in phenylketonuria consists of a phenylalanine-restricted diet supplemented with a phenylalanine-free medical formula (Phe-FF). During the first six months of life, phenylalanine requirements can be met with breast milk (BM) or infant formula (IF). Despite all the benefits breastfeeding confers, it is often discontinued upon diagnosis of phenylketonuria, so more evidence is needed to support it. This study aimed to compare the assessments of nutritional status and metabolic control in infants with hyperphenylalaninemia/phenylketonuria who received BM, IF, or a combination of both as sources of intact protein, in addition to Phe-FF. Methods: A retrospective observational study was conducted in hyperphenylalaninemia/phenylketonuria patients between 0 and 6 months of age. Three groups were compared depending on the source of intact protein ingested: (1) BM + Phe-FF; (2) IF + Phe-FF; (3) mixture of BM and IF (BM + IF + Phe-FF). At each clinic visit, an anthropometric assessment and phenylalanine blood levels were analyzed. Results: 185 nutritional and metabolic assessments were included. The lowest median phenylalanine blood concentration was observed in the BM + Phe-FF group (129 µmol/L, interquartile range [IQR]: 39.5–232.5). In the BM + Phe-FF group all assessments were classified as eutrophic: −0.09 (SD ± 0.78); a statistically significant difference was observed between the BMI Z-Score of BM + Phe-FF and BM + IF-Phe-FF (p = 0.036). No statistically significant differences were observed in length/age Z-Score. Conclusions: Our results indicate that BM is the best option as a source of intact protein for children under 6 months of age with hyperphenylalaninemia/phenylketonuria, to maintain an adequate nutritional status and metabolic control. Full article

Background: Phenylketonuria (PKU) is an autosomal recessive disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene, leading to impaired amino acid metabolism. Early diagnosis through newborn screening (NBS) enables prompt treatment, preventing neurological complications. This study aims to describe the genetic and phenotypic spectrum of PKU and mild hyperphenylalaninemia (m-HPA) in patients diagnosed at the Department of Inborn Errors of Metabolism and Newborn Screening, Hospital G. Rodolico-S. Marco, Catania, over four decades (1987–2023). Materials and Methods: The retrospective analysis included 102 patients with elevated blood phenylalanine (Phe) levels born in Sicily and followed at the Institute. The phenotype evaluation comprised the Phe levels at birth/diagnosis, dietary tolerance, and sapropterin dihydrochloride responsiveness. The dietary compliance and Phe/Tyr ratios were assessed and compared across phenotypic classes and age groups. Results: Of 102 patients, 34 were classified as having classic PKU, 9 as having moderate PKU, 26 as having mild PKU, and 33 as having m-HPA, with a median age of 21.72 years. Common PAH variants included c.1066-11G>A (26/204 alleles), c.782G>A (18/204 alleles), and c.165delT (13/204 alleles). The phenotypes sometimes diverged from the genotype predictions, emphasizing dietary tolerance over the initial Phe levels for classification: m-HPA was statistically associated with a higher dietary tolerance (p < 0.001) compared to the classic, moderate, or mild forms of PKU. Conclusions: This study highlights the importance of large databases (e.g., BioPKU) for phenotype prediction and treatment optimization. Regular assessment of Phe/Tyr ratios is crucial for monitoring adherence and health. Phenotype determination, dietary management, and emerging therapies (Pegvaliase and gene therapy) are key to improving outcomes for PKU patients. Full article

DNAJC12 deficiency is a recently described inherited metabolic disorder resulting in hyperphenylalaninemia and neurotransmitter deficiency. The effect of treatment on the prevention of neurological manifestations in this newly reported and heterogenous disorder is not fully understood, and the optimal treatment strategy remains to be elucidated. The global or regional incidence of the disease is yet to be estimated. Here, we report the first individual diagnosed with DNAJC12 deficiency in Hong Kong; the condition was picked up by newborn screening due to hyperphenylalaninemia after ruling out phenylalanine hydroxylase deficiency and other tetrahydrobiopterin related disorders. Compound heterozygous variants in the DNAJC12 gene were identified, which included a novel missense change and a nonsense pathogenic variant. Treatment with neurotransmitter precursors (tetrahydrobiopterin, levodopa, and oxitriptan) was initiated at four months of age, and dietary protein restriction was started at four years and six months of age. He remains asymptomatic at four and a half years of age, apart from having mildly impaired socio-communication and language development. In this report, we discuss the current diagnostic approach to hyperphenylalaninemia in newborn screening and the uncertainties that exist in the clinical outcome from earlier detection, treatment, and monitoring of DNAJC12-deficiency patients. Full article

In phenylketonuria (PKU), natural protein intake is thought to increase with age, particularly during childhood and adolescence. Longitudinal dietary intake data are scarce and lifelong phenylalanine tolerance remains unknown. Nine centres managing PKU in Europe and Turkey participated in a retrospective study. Data were collected from dietetic records between 2012 and 2018 on phenylalanine (Phe), natural protein, and protein substitute intake. A total of 1323 patients (age range: 1–57 y; 51% male) participated. Dietary intake data were available on 1163 (88%) patients. Patient numbers ranged from 59 to 320 in each centre. A total of 625 (47%) had classical PKU (cPKU), n = 357 (27%) had mild PKU (mPKU), n = 325 (25%) had hyperphenylalaninemia (HPA), and n = 16 (1%) were unknown. The mean percentage of blood Phe levels within target ranged from 65 ± 54% to 88 ± 49%. When intake was expressed as g/day, the mean Phe/natural protein and protein equivalent from protein substitute gradually increased during childhood, reaching a peak in adolescence, and then remained consistent during adulthood. When intake was expressed per kg body weight (g/kg/day), there was a decline in Phe/natural protein, protein equivalent from protein substitute, and total protein with increasing age. Overall, the mean daily intake (kg/day) was as follows: Phe, 904 mg ± 761 (22 ± 23 mg/kg/day), natural protein 19 g ± 16 (0.5 g/kg/day ± 0.5), protein equivalent from protein substitute 39 g ± 22 (1.1 g/kg/day ± 0.6), and total protein 59 g ± 21 (1.7 g/kg/day ± 0.6). Natural protein tolerance was similar between males and females. Patients with mPKU tolerated around 50% less Phe/natural protein than HPA, but 50% more than cPKU. Higher intakes of natural protein were observed in Southern Europe, with a higher prevalence of HPA and mPKU compared with patients from Northern European centres. Natural protein intake doubled with sapropterin usage. In sapropterin-responsive patients, 31% no longer used protein substitutes. Close monitoring and optimisation of protein intake prescriptions are needed, along with future guidelines specifically for different age groups and severities. Full article

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. Full article

Morphofunctional assessment was developed to evaluate disease-related malnutrition. However, it can also be used to assess cardiometabolic risk, as excess adiposity increases this risk. Phenylketonuria (PKU) is the most prevalent inherited metabolic disease among adults, and obesity in PKU has recently gained interest, although fat mass correlates better with cardiometabolic risk than body mass index. In this systematic review, the objective was to assess whether adult patients with PKU have higher fat mass than healthy controls. Studies of adult PKU patients undergoing dietary treatment in a metabolic clinic reporting fat mass were included. The PubMed and EMBASE databases were searched. Relevance of articles, data collection, and risk of bias were evaluated by two independent reviewers. Ten articles were evaluated, six with a control group, including 310 subjects with PKU, 62 with mild hyperphenylalaninemia, and 157 controls. One study reported a significant and four a tendency towards an increased fat mass in all patients or only females with PKU. Limitations included not having a healthy control group, not reporting sex-specific results and using different techniques to assess fat mass. Evaluation of fat mass should be included in the morphofunctional assessment of cardiometabolic risk in adult patients with PKU. Full article

The published data on the vitamin status of patients with phenylketonuria (PKU) is contradictory; therefore, this systematic review and meta-analysis evaluated the vitamin status of PKU patients. A comprehensive search of multiple databases (PubMed, Web of Sciences, Cochrane, and Scopus) was finished in March 2024. The included studies compared vitamin levels between individuals diagnosed with early-treated PKU and healthy controls while excluding pregnant and lactating women, untreated PKU or hyperphenylalaninemia cases, control groups receiving vitamin supplementation, PKU patients receiving tetrahydrobiopterin or pegvaliase, and conference abstracts. The risk of bias in the included studies was assessed by the Newcastle–Ottawa scale. The effect sizes were expressed as standardised mean differences. The calculation of effect sizes with 95% CI using fixed-effects models and random-effects models was performed. A p-value < 0.05 was considered statistically significant. The study protocol was registered in the PROSPERO database (CRD42024519589). Out of the initially identified 11,086 articles, 24 met the criteria. The total number of participants comprised 770 individuals with PKU and 2387 healthy controls. The meta-analyses of cross-sectional and case–control studies were conducted for vitamin B12, D, A, E, B6 and folate levels. PKU patients demonstrated significantly higher folate levels (random-effects model, SMD: 1.378, 95% CI: 0.436, 2.320, p = 0.004) and 1,25-dihydroxyvitamin D concentrations (random-effects model, SMD: 2.059, 95% CI: 0.250, 3.868, p = 0.026) compared to the controls. There were no significant differences in vitamin A, E, B6, B12 or 25-dihydroxyvitamin D levels. The main limitations of the evidence include a limited number of studies and their heterogeneity and variability in patients’ compliance. Our findings suggest that individuals with PKU under nutritional guidance can achieve a vitamin status comparable to that of healthy subjects. Our study provides valuable insights into the nutritional status of PKU patients, but further research is required to confirm these findings and explore additional factors influencing vitamin status in PKU. Full article