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Phenylketonuria is an inherited metabolic disease that can be treated if detected early and can easily be screened with phenylalanine as a biomarker. Phenylketonuria is included in the National Neonatal Screening Program. We aimed to investigate the possible effects of the pandemic on phenylketonuria screening in our country during coronavirus disease 2019 (COVID-19) era. We retrospectively evaluated patients who were referred to our center due to elevated blood phenylalanine levels detected by national screening program retrospective- and prospectively within one-year as of 11 March 2020, the date when first COVID-19 case was detected in our country. Multivariate analysis showed birth region and phenylalanine levels to be independently associated with the time period until the first admission to hospital, but none of the parameters were significantly associated with the pandemic. There was no evidence that the COVID-19 pandemic affected the screening of newborn phenylketonuria, however since the data was limited to our center and to draw generalized conclusions larger scaled multicentric studies are needed. [ABSTRACT FROM AUTHOR]

Background 6-Pyruvoyl-tetrahydropterin synthase (PTS) is the key enzyme in BH4 synthesis. PTS deficiency is classified as severe type and mild type, and the prognosis and treatment differ for these types. Distinguishing between two types in the early stage is difficult. Reference to reported cases is needed for interpretation of the correlation between genotype and prognosis. Case report: We report a full-term female newborn with mild PTS deficiency. On the day 21 after birth, the phenylalanine level was 859.6 mmol/L (reference range: 30–117 mmol/L). After 1 year of observation, the patient was found to be in a healthy condition without treatment. Conclusions: Although the phenylalanine level is high in mild PTS deficiency patients after birth, some of them may have few symptoms with no treatment. We review 19 cases and find 8 mutations of PTS that may be associated with mild PTS deficiency. [ABSTRACT FROM AUTHOR]

• The SNaPshot assay achieved the sensitivity and specificity of 91.6% and 100.0%, respectively. • The carrier rate was 1 in 58 (1.73%), and c.728G > A was the most common variant. • SNaPshot can accurately and rapidly detect PAH gene variants at a comparable performance and lower cost as compared with NGS. Hyperphenylalaninemia (HPA) is a common autosomal recessive disorder of phenylalanine metabolism, mainly caused by the deficiency of phenylalanine hydroxylase gene (PAH). A simple, fast, and accurate assay to achieve early diagnosis for children with HPA is required. In the present study, we established a SNaPshot-based assay that allows the simultaneous genotyping of 96 hotspot variants in the PAH gene. First, 18 Chinese HPA patients were analyzed by next generation sequencing (NGS) and SNaPshot in parallel. Then, the SNaPshot assay was performed to analyze the mutational spectrum of the PAH in 4,276 individuals in Eastern China. A total of 36 variants in the PAH gene were successfully identified by NGS, while the SNaPshot assay identified 34 PAH variants in these patients. Thus, the SNaPshot assay achieved the sensitivity and specificity of 91.6% and 100.0%, respectively. Furthermore, the carrier rate was approximately 1 in 58 (1.73%) in 4,276 individuals, and c.728G > A was the most common variant. In summary, SNaPshot can accurately and rapidly detect PAH gene variants at a comparable performance and lower cost as compared with NGS. Our results suggest that SNaPshot may serve as a promising approach for a routine genetic test in clinical practice. [ABSTRACT FROM AUTHOR]

Abstract Background Phenylketonuria (PKU) is an inherited metabolic disorder characterized by reduced activity of phenylalanine hydroxylase resulting in elevated blood phenylalanine (Phe) concentration. Despite some obvious ocular changes, the disorder has been poorly recognized by ophthalmologists. Neurophysiologic tests imply prolonged reaction time correlating with increased phenylalanine blood concentrations. We aimed to test saccadic reaction time in PKU patients in dependency of blood phenylalanine concentrations. Methods Nineteen biochemically diagnosed PKU patients and 100 controls completed comprehensive ophthalmologic and orthoptic examinations including saccadometry by infrared based video-oculography. Peak velocity, gain, and particularly latency of reflexive saccades were compared to controls, and regression analysis was performed. Results Latency of reflexive saccades was not associated with the current phenylalanine concentration. Although in 10 out of 19 patients phenylalanine concentrations were outside the age-related therapeutic range, latency differed little between PKU patients and the controls, as well as peak velocity and gain. Ocular findings occurred as partial hypopigmentation of the iris in one late diagnosed patient aged 36 years, and as bilateral cataracts (possibly due to steroid intake) with refractive amblyopia, strabismus, high myopia, and glaucoma in another late diagnosed patient aged 46 years. Visual acuity was reduced in eight PKU patients. Conclusions Saccadometry, particularly saccadic reaction time, is not useful in the monitoring of phenylketonuria. Ophthalmic examination is recommended in PKU patients, as the occurrence of ocular pathologies was relatively high.

Background: Hyperphenylalaninemia (HPA) is defined as blood phenylalanine (Phe) levels exceeding the normal values (>120 μmol/L or >2 mg/dL) and is caused by a deficiency in the enzyme phenylalanine hydroxylase (PAH). The widespread screening of Phe levels in newborn screening programs has led to a very high number of patients with HPA., Methods: The samples were collected at various ages, not at the point of diagnosis. Nine pterin derivatives, including isoxanthopterin, sepiapterin, xanthopterin, primapterin, biopterin, neopterin, 7,8-dihydrobiopterin, 7,8-dihydroneopterin, and tetrahydrobiopterin (BH4), were analyzed in different HPA classes in serum, dried blood spots (DBS), and urine samples. A total of 18 patients, including six classical phenylketonuria (PKU), eight BH4-responsive PKU, and four mild HPA patients, were included in the study., Results: Among the nine pterin derivatives measured, a significant increase was observed in the levels of isoxanthopterin, biopterin, and 7,8-dihydrobiopterin in serum, dried blood spots (DBS), and urine samples of patients with HPA compared to the control group. However, elevations in isoxanthopterin, biopterin, and 7,8-dihydrobiopterin were observed in all HPA groups, although the extent of elevation varied among the different disease groups. There were also significant differences between HPA subgroups among these high values., Conclusion: In this study, it might be suggested that pterin profiling shows promising potential for its effective utilization in the differential diagnosis of HPA. Pterin profiling demonstrated its efficacy in accurately categorizing patients into distinct subtypes. This approach offers several notable advantages, including the ability to simultaneously screen multiple HPA subtypes through a single test, establish disease decision limits for pterins, shorten the time required for HPA differential diagnosis, reduce the risk of misdiagnosis, and increase overall diagnostic accuracy. This study is the most comprehensive study examining the association between HPA pterin in the literature. In our study, samples obtained from BH4-responsive PKU patients were on treatment. This may have affected the results. Preliminary findings on pterin profiles may need to be replicated in a prospective cohort of samples collected at the time of diagnosis to confirm the results., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 S. Karger AG, Basel.)

Women with phenylketonuria (PKU) should maintain blood phenylalanine (phe) concentration within the recommended range before and during pregnancy to prevent maternal PKU syndrome (MPKUS) in their offspring. Women who gave birth to children with MPKUS symptoms were more likely to report elevated phe concentration before pregnancy, and barriers to accessing components of their dietary management during pregnancy, including blood phe testing, medical food, modified low-protein foods, and healthcare visits with PKU specialists., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors.)

This study aimed to evaluate the biochemical factors, genetic mutations, outcome of treatment, and clinical follow-up data of Iranian patients with tetrahydrobiopterin (BH4) deficiency from April/2016 to March/2020. Forty-seven BH4 deficiency patients were included in the study and underwent biochemical and genetic analyses. The clinical outcomes of the patients were evaluated after long-term treatment. Out of the 47 (25 females and 22 males) BH4 deficiency patients enrolled in the study, 23 were Dihydropteridine reductase (DHPR) deficient patients, 23 were 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficient patients, and one was GTP-Cyclohydrolase 1 deficiency (GTPCH-1) patient. No clinical symptoms were observed in 10 of the DHPR deficient patients (before and after the treatment). Also, most patients diagnosed at an early age had a proper response to the treatment. However, drug therapy did not improve clinical symptoms in three of the patients diagnosed at the age of over 10 years. Also, 16 PTPS deficiency patients who were detected within 6 months and received treatment no clinical symptoms were presented. One of the patients was detected with GTPCH deficiency. Despite being treated with BH4, this patient suffered from a seizure, movement disorder, mental retardation, speech difficulty, and hypotonia. The study results showed that neonatal screening should be carried out in all patients with hyperphenylalaninemia because early diagnosis and treatment can reduce symptoms and prevent neurological impairments. Although the BH4 deficiency outcomes are highly variable, early diagnosis and treatment in the first months of life are crucial for good outcomes. [ABSTRACT FROM AUTHOR]

Phenylketonuria (PKU) is one of the most frequent autosomal recessive diseases caused by inherited deficiency of phenylalanine hydroxylase (PAH), which is accompanied by intellectual disability. The PAH gene mutations lead to a complete or partial loss of activity in the PAH enzyme, resulting in an increase in the serum phenylalanine level and phenotypic PKU manifestations. The study includes an analysis of the spectrum of PAH mutations among patients with PHU from West Ukrainian regions. Molecular genetic analyses were performed in 158 nonrelative PKU patients, including a cohort of 101 patients with hyperphenylalaninemia (HPA) diagnosed by neonatal screening. DNA of the PKU patients was isolated by the salting-out method from peripheral blood lymphocytes. We used the method of polymerase chain reaction with restriction fragment length polymorphism (RFLP–PCR, ACRS–PCR) to study 316 alleles. According to the results of the study, the R408W mutation has been identified with high degree homozygosity (35.44%) in 58.54% of mutant alleles. The frequencies of other identified mutations were as follows (in parentheses): IVS10nt-11G>A (4.35%), R158Q (4.17%), Y414C (2.78%), and R252W (1.25%). The most spread mutation among PKU patients from the western region of Ukraine was R408W. The spectrum and the frequency of mutations in the studied sample correlated with the frequency shown by the general population of Ukraine and corresponded to the spectrum of mutations in Western Europe. [ABSTRACT FROM AUTHOR]

In addition to tetrahydrobiopterin deficiencies and phenylalanine hydroxylase deficiency (phenylketonuria) due to PAH variants, the deficiency of the co-chaperone protein DNAJC12 was identified in 2017 as a novel cause of inherited hyperphenylalaninemia, revealing the genetic etiology in previously unresolved cases. In this study, we aimed to investigate DNAJC12 deficiency in non-tetrahydrobiopterin-deficient persistent hyperphenylalaninemia cases without biallelic PAH variants in a single pediatric metabolic center. It was determined retrospectively that 471 patients with non-tetrahydrobiopterin deficiency-hyperphenylalaninemia had undergone PAH gene sequencing and 451 patients had biallelic variants in PAH. DNAJC12 sequencing was performed in the remaining 20 patients, identifying a previously reported homozygous splice-site variant (c.158-2A > T) in one patient with axial hypotonia and developmental delay, and a novel, homozygous c.404del (p.Arg135Lysfs*21) frameshift variant in an asymptomatic patient. In segregation analysis, the asymptomatic patient's both parents were also found to be homozygous for this variant and hyperphenylalaninemic. The parents may have had academic difficulties but intellectual disability could not be confirmed due to lack of cooperation. The symptomatic patient significantly benefited from treatment with sapropterin dihydrochloride and neurotransmitter precursors. DNAJC12 deficiency might be responsible for approximately 10% or more of cases with unexplained hyperphenylalaninemia. The phenotypic spectrum is broad, ranging from early infantile hypotonia to incidental diagnosis in adulthood. Similar to tetrahydrobiopterin deficiencies, early diagnosis and treatment with sapropterin dihydrochloride and neurotransmitter precursors can be beneficial, supporting the analysis of DNACJ12 gene in patients with unexplained hyperphenylalaninemia. [ABSTRACT FROM AUTHOR]

We retrospectively examined the relationship between blood biomarkers, in particular the historical mean phenylalanine to tyrosine (Phe:Tyr) ratio, and cerebral glucose metabolism. We hypothesized that the historical mean Phe:Tyr ratio would be more predictive of cerebral glucose metabolism than the phenylalanine (Phe) level alone. We performed a retrospective case series analysis involving 11 adult classical phenylketonuria/hyperphenylalaninemia patients under the care of an Inherited Metabolic & Neuropsychiatry Clinic who had complained of memory problems, collating casenote data from blood biochemistry, and clinical [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG PET). The Phe:Tyr ratio was calculated for individual blood samples and summarized as historical mean Phe:Tyr ratio (Phe:Tyr) and historical standard deviation in Phe:Tyr ratio (SD-Phe:Tyr), for each patient. Visual analyses of [18F]FDG PET revealed heterogeneous patterns of glucose hypometabolism for eight patients. [18F]FDG PET standardized uptake was negatively correlated with Phe in a large cluster with peak localized to right superior parietal gyrus. Even larger clusters of negative correlation that encompassed most of the brain, with frontal peaks, were observed with Phe:Tyr, and SD-Phe:Tyr. Our case series analysis provides further evidence for the association between blood biomarkers, and cerebral glucose hypometabolism. Mean historical blood Phe:Tyr ratio, and its standard deviation over time, appear to be more indicative of global cerebral glucose metabolism in patients with memory problems than Phe.

Abstract Introduction: Any abnormal newborn screening (NBS) test should be subjected to appropriate diagnostic tests and should be followed. Once the newborn has been diagnosed and treated, the family should receive comprehensive genetic services. Aim: To present the experience of studying older siblings of patients with inborn errors of metabolism (IEM) identified by NBS in a single-national follow-up reference center. Methods: A retrospective analysis of medical files of the IEM patients detected by NBS was conducted. All those older siblings who tested positive for the same IEM of the patient detected by newborn screening were included. Results: A total of 26 positive siblings from 18 families with seven different IEM were found (phenylketonuria, argininemia, glucose-6-phosphate dehydrogenase deficiency, 3-methylcrotonyl-CoA carboxylase deficiency, dihydropteridine reductase deficiency, tyrosinemia type 3, and medium chain acyl-CoA dehydrogenase deficiency). The age range of the affected siblings was 2 to 19 years old, with a mean age of 8.5 years. Ten older siblings (38.5%) had clinical consequences for the disease, including severe intellectual disability. Conclusions: It is necessary to study older siblings, and family history and genetic counseling of all NBS-detected families should be recommended, especially in countries where expanded NBS programs are beginning.

We retrospectively examined the relationship between blood biomarkers, in particular the historical mean phenylalanine to tyrosine (Phe:Tyr) ratio, and cerebral glucose metabolism. We hypothesized that the historical mean Phe:Tyr ratio would be more predictive of cerebral glucose metabolism than the phenylalanine (Phe) level alone. We performed a retrospective case series analysis involving 11 adult classical phenylketonuria/hyperphenylalaninemia patients under the care of an Inherited Metabolic & Neuropsychiatry Clinic who had complained of memory problems, collating casenote data from blood biochemistry, and clinical [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG PET). The Phe:Tyr ratio was calculated for individual blood samples and summarized as historical mean Phe:Tyr ratio (Phe:Tyr) and historical standard deviation in Phe:Tyr ratio (SD-Phe:Tyr), for each patient. Visual analyses of [18F]FDG PET revealed heterogeneous patterns of glucose hypometabolism for eight patients. [18F]FDG PET standardized uptake was negatively correlated with Phe in a large cluster with peak localized to right superior parietal gyrus. Even larger clusters of negative correlation that encompassed most of the brain, with frontal peaks, were observed with Phe:Tyr, and SD-Phe:Tyr. Our case series analysis provides further evidence for the association between blood biomarkers, and cerebral glucose hypometabolism. Mean historical blood Phe:Tyr ratio, and its standard deviation over time, appear to be more indicative of global cerebral glucose metabolism in patients with memory problems than Phe. [ABSTRACT FROM AUTHOR]

Background: Phenylalanine hydroxylase (PAH) deficiency is an autosomal recessive disorder that results in elevated concentrations of phenylalanine (Phe) in the blood. If left untreated, the accumulation of Phe can result in profound neurocognitive disability. The objective of this systematic literature review and meta-analysis was to estimate the global birth prevalence of PAH deficiency from newborn screening studies and to estimate regional differences, overall and for various clinically relevant Phe cutoff values used in confirmatory testing.Methods: The protocol for this literature review was registered with PROSPERO (International prospective register of systematic reviews). Pubmed and Embase database searches were used to identify studies that reported the birth prevalence of PAH deficiency. Only studies including numeric birth prevalence reports of confirmed PAH deficiency were included.Results: From the 85 publications included in the review, 238 birth prevalence estimates were extracted. After excluding prevalence estimates that did not meet quality assessment criteria or because of temporal and regional overlap, estimates from 45 publications were included in the meta-analysis. The global birth prevalence of PAH deficiency, estimated by weighting regional birth prevalences relative to their share of the population of all regions included in the study, was 0.64 (95% confidence interval [CI] 0.53-0.75) per 10,000 births and ranged from 0.03 (95% CI 0.02-0.05) per 10,000 births in Southeast Asia to 1.18 (95% CI 0.64-1.87) per 10,000 births in the Middle East/North Africa. Regionally weighted global birth prevalences per 10,000 births by confirmatory test Phe cutoff values were 0.96 (95% CI 0.50-1.42) for the Phe cutoff value of 360 ± 100 µmol/L; 0.50 (95% CI 0.37-0.64) for the Phe cutoff value of 600 ± 100 µmol/L; and 0.30 (95% CI 0.20-0.40) for the Phe cutoff value of 1200 ± 200 µmol/L.Conclusions: Substantial regional variation in the birth prevalence of PAH deficiency was observed in this systematic literature review and meta-analysis of published evidence from newborn screening. The precision of the prevalence estimates is limited by relatively small sample sizes, despite widespread and longstanding newborn screening in much of the world. [ABSTRACT FROM AUTHOR]

Tetrahydrobiopterin (BH 4) deficiency is caused by genetic variants in the three genes involved in de novo cofactor biosynthesis, GTP cyclohydrolase I (GTPCH/ GCH1), 6-pyruvoyl-tetrahydropterin synthase (PTPS/ PTS), sepiapterin reductase (SR/ SPR), and the two genes involved in cofactor recycling, carbinolamine-4α-dehydratase (PCD/ PCBD1) and dihydropteridine reductase (DHPR/ QDPR). Dysfunction in BH 4 metabolism leads to reduced cofactor levels and may result in systemic hyperphenylalaninemia and/or neurological sequelae due to secondary deficiency in monoamine neurotransmitters in the central nervous system. More than 1100 patients with BH 4 deficiency and 800 different allelic variants distributed throughout the individual genes are tabulated in database of pediatric neurotransmitter disorders PNDdb. Here we provide an update on the molecular-genetic analysis and structural considerations of these variants, including the clinical courses of the genotypes. From a total of 324 alleles, 11 are associated with the autosomal recessive form of GTPCH deficiency presenting with hyperphenylalaninemia (HPA) and neurotransmitter deficiency, 295 GCH1 variant alleles are detected in the dominant form of L-dopa-responsive dystonia (DRD or Segawa disease) while phenotypes of 18 alleles remained undefined. Autosomal recessive variants observed in the PTS (199 variants), PCBD1 (32 variants), and QDPR (141 variants) genes lead to HPA concomitant with central monoamine neurotransmitter deficiency, while SPR deficiency (104 variants) presents without hyperphenylalaninemia. The clinical impact of reported variants is essential for genetic counseling and important for development of precision medicine. [ABSTRACT FROM AUTHOR]

Objective Phenylketonuria (PKU) is one of the most common inherited metabolic diseases, which is classified into classic and non-classic types. It is estimated that 2% of children with PKU develop a severe and progressive neurological disease, called non-classic (malignant) PKU. This study aimed to demonstrate the clinical features, laboratory findings, and diagnostic/therapeutic characteristics of non-classic PKU patients referred to a tertiary referral center for children in Tehran, Iran. Materials & Methods In this study, background information, such as gender and age, clinical manifestations, laboratory findings, and response rate to conventional treatment, was investigated in patients with non-classic PKU, who were referred to Mofid Children's Hospital in Tehran, Iran, through neonatal screening. Results Twenty patients with a diagnosis of non-classic PKU were included in this study. The mean age of the patients was 6.00±2.81 years (range: 2-12 years), and 45.0% were male. In patients with a late diagnosis, the most common presentations were motor developmental delay (15.0%), skin and cutaneous manifestations (15.0%), seizure (5.0%), and restlessness (5.0%). The overall response rate to treatment was 85.0%. Factors that predict good response to treatment included female gender, higher neopterin level, and lower age at diagnosis and management. Conclusion In conclusion, about half of patients with non-classic PKU remain asymptomatic, which is due to early diagnosis via neonatal screening. Also, higher age at diagnosis and treatment, besides low neopterin levels, may be useful as prognostic factors. [ABSTRACT FROM AUTHOR]

Phenylketonuria (PKU) is an inborn error of metabolism caused by phenylalanine hydroxylase (PAH) deficiency and characterized by elevated plasma levels of phenylalanine (hyperphenylalaninemia-HPA). In severe cases, PKU patients present with neurological dysfunction and hepatic damage, but the underlying mechanisms are not fully elucidated. Other forms of HPA also characterized by neurological symptoms occur in rare instances due to defects in the metabolism of the PAH cofactor tetrahydrobiopterin. This review aims to gather the knowledge acquired on the phenylalanine-induced toxicity focusing on findings obtained from pre-clinical studies. Mounting evidence obtained from PKU genetic mice, rats submitted to different HPA models, and cell cultures exposed to phenylalanine has shown that high levels of this amino acid impair mitochondrial bioenergetics, provoke changes in oxidative and inflammatory status, and induce apoptosis. Noteworthy, some data demonstrated that phenylalanine-induced oxidative stress occurs specifically in mitochondria. Further studies have shown that the metabolites derived from phenylalanine, namely phenylpyruvate, phenyllactate, and phenylacetate, also disturb oxidative status. Therefore, it may be presumed that mitochondrial damage is one of the most important mechanisms responsible for phenylalanine toxicity. It is expected that the findings reviewed here may contribute to the understanding of PKU and HPA pathophysiology and to the development of novel therapeutic strategies for these disorders. [ABSTRACT FROM AUTHOR]

Background: Hyperphenylalaninemia (HPA) is the most common amino acid metabolic disease involving phenylalanine hydroxylase (PAH, OMIM*612,349) deficiency or coenzyme tetrahydrobiopterin (BH4) deficiency. Patients with severe HPA often have a difficult life. Early diagnosis of HPA before the development of symptoms is possible via neonatal screening, facilitating appropriate treatment and reducing mortality and disability rates. This study revealed the prevalence, mutational and phenotypic spectrum, and prognosis of HPA by neonatal screening from January 2001 to September 2020 in Nanjing, Jiangsu Province, China.Methods: Through a retrospective analysis of the information available in the neonatal screening database, the clinical presentations, laboratory data, molecular characteristics and treatment follow-up data of HPA patients detected by neonatal screening were evaluated.Results: We diagnosed 181 patients with HPA from 1 to 957 newborns, giving an incidence of 1:6873. Among these patients, 177 were identified as PAH deficient and four patients were BH4 deficient. The average current age of the patients was 6.38 years old. The most common mutations of PAH were c.728 C > A/ p.Arg243Gln (13.83 %), c.158G > A/ p.Arg53His (9.57 %), c.611 A > G/ p.Tyr204Cys (7.44 %), and c.721 C > T/ p.Arg241Cys (6.38 %).Conclusions: This study revealed the prevalence, phenotype-genotype, and prognosis of HPA in China and contributes to the updating of PAHD data for China and worldwide. Our study not only expanded the spectrum of phenotypes and genotype but also provided a valuable tool for improved genetic counseling and management of future cases. [ABSTRACT FROM AUTHOR]

Abstract Background Phenylketonuria (PKU) is an inherited deficiency in the enzyme phenylalanine hydroxylase (PAH), which, when poorly-managed, is associated with clinical features including deficient growth, microcephaly, seizures, and intellectual impairment. The management of PKU should start as soon as possible after diagnosis to prevent irreversible damage and be maintained throughout life. The aim of this study was to assess the burden of illness in PKU patients in general and in PKU patients born before and after the introduction of newborn screening in Germany. Methods This retrospective matched cohort analysis used the Institut für angewandte Gesundheitsforschung Berlin (InGef) research database containing anonymized healthcare claims of approximately 4 million covered lives. PKU patients were compared with matched controls from the general population within the same database (1:10 ratio via direct, exact matching on age and gender without replacement). PKU patients were included if they were aged ≥18 years on 01/01/15 and were continuously enrolled from 01/01/10 to 31/12/15. The 50 most commonly reported comorbidities and 50 most commonly prescribed medications in the PKU population were analyzed. Differences between groups were tested using 95% confidence interval (CI) of prevalence ratio (PR) values. Results The analysis included 377 adult PKU patients ( 1.5 vs controls included major depressive disorders (PR = 2.3), chronic ischemic heart disease (PR = 1.7), asthma (PR = 1.7), dizziness and giddiness (PR = 1.8), unspecified diabetes mellitus (PR = 1.7), infectious gastroenteritis and colitis (PR = 1.7), and reaction to severe stress and adjustment disorders (PR = 1.6). The most commonly prescribed Anatomical Therapeutic Chemical (ATC) subcodes among PKU patients (vs the control population) are for systemic antibacterials (34.7% vs 32.8%), anti-inflammatory and antirheumatic (29.4% vs 27.5%), renin-angiotensin agents (30.0% vs 27.0%), acid-related disorders (29.4% vs 20.2%), and beta-blockers (24.9% vs 19.9%). Conclusion The overall clinical burden on patients with PKU is exacerbated by a significantly higher risk of numerous comorbidities and hence, prescribing of the requisite medication, both for recognized (e.g. major depressive disorders) and more unexpected comorbidities (e.g. ischemic heart disease).

INTRODUCTION: Classical phenylketonuria (PKU) is an inherited disorder of amino acid metabolism disorder. The basis of treatment is a life-long phenylalanine restricted diet. In this study, we aimed evaluate the the effect of phenylalanine restricted diet on anthropometric parameters of patients with PKU. METHODS: This study was conducted retrospectively in the pediatric nutrition and metabolism clinic between 2007 and 2015 by reviewing the charts of 40 patients with PKU followed by dietary therapy and 78 patients with mild hyperphenylalanine (HPA) without dietary therapy. Body weight, height, weight standard deviation score (SDS), height SDS, Body mass index (BMI) SDS of the patients were assessed at the birth, sixth, twelfth, eighteenth, twenty fourth, thirtieth and thirty-sixth months of life. RESULTS: In the analysis of anthropometric parameters of patients at birth. 6th month. 12th month. 18th month. 24th month. 30th month and 36th month of life there was no differences in weight gain (p=0.516). In the evaluation of height with six months interval, at the end of the 3 years of life, height growth rate was higher in HPA group than PKU group (F(1,33)=3.443,p=0.037). Height growth rate of PKU patients with diet therapy was slower than HPA patients in the first three years of life, but there was no significant difference between the two groups in terms of BMI. DISCUSSION AND CONCLUSION: We can conclude that the height growth rate is lower in PKU patients than HPA patients. We think that the lower height growth rate of PKU patients is the result of Phe and natural protein-restricted diet.

Lifelong dietary treatment is recommended in the management of phenylketonuria (PKU). Accordingly, an increasing adult population require age-specific PKU guidelines on protein requirements to support changing metabolic demands across the lifespan. Given that protein intake for dietary management of PKU is primarily (52–80%) derived from protein substitutes, the prescribing practice of protein substitutes must be underpinned by robust evidence. Whilst dietary guidelines for PKU management is evolving to incorporate adult specific protein recommendations, the scientific evidence underpinning these guidelines is currently limited. Instead, the determination of protein requirements for people with PKU have previously been extrapolated from estimates derived from the general healthy population, based on arguably outdated nitrogen balance methodology. Furthermore, a compensatory factor of 20–40% has been incorporated to account for the reduced uptake and utilisation of the elemental amino acids contained in protein substitutes. However, research informing this compensatory factor has been conducted in younger adults, with the majority of studies in non-PKU individuals. Given extensive evidence that the muscle anabolic response to ingested protein is impaired in older vs. young adults, the validity of current dietary protein recommendations for adults and older adults with PKU has been challenged. This narrative review aims to critically evaluate the existing scientific evidence underpinning current guidelines on protein requirements for adults with PKU, highlighting existing gaps in knowledge and directions for future research. We argue that current guidelines on protein requirements need updating to optimise long-term physical and functional outcomes in older adults with PKU. [ABSTRACT FROM AUTHOR]

Phenylalanine hydroxylase deficiency (PAHD) is an autosomal recessive inborn error that affects phenylalanine (Phe) metabolism. It has a complex phenotype with many variants and genotypes among different populations. Shanxi province is a high-prevalence area of PAHD in China. In this study, eighty-nine PAHD patients were subjected to genetic testing using Sanger sequencing, followed by multiplex ligation-dependent probe amplification analysis (MLPA). Allelic and genotypic phenotype values (APV and GPV, respectively) were used for genotype-based phenotypic prediction. Fifty-one types of variants, including three novel forms, were identified. The predominant variant was p.R243Q (22.09%), followed by p.R53H (10.47%), p.EX6-96A > G (9.30%), p.V399V (5.23%) and p.R413P (3.49%). Notably, mild hyperphenylalaninemia (MHP) has a high prevalence in this region (up to 45.76%), and the variant p.R53H was solely observed in patients of MHP. According to the genotype–phenotype prediction, the APV/GPV system was well correlated with the metabolic phenotype of most PAHD patients. We have systematically constructed the mutational and phenotypic spectrum of PAH in Shanxi province. Hence, this study will help to further understand the genotype-phenotype associations in PAHD patients, and it may offer more reliable genetic counseling and management. [ABSTRACT FROM AUTHOR]

Importance: Sapropterin hydrochloride, a natural coenzyme (6R‐tetrahydrobiopterin) of phenylalanine hydroxylase, was first approved as a treatment for tetrahydrobiopterin deficiency in 1992 in Japan, and was then approved as a treatment for a tetrahydrobiopterin‐responsive hyperphenylalaninemia in 2007 and 2008, in the USA and Japan, respectively. Guidelines are required on the proper use of sapropterin hydrochloride for tetrahydrobiopterin‐responsive hyperphenylalaninemia. Observations: It is recommended that tetrahydrobiopterin‐responsive hyperphenylalaninemia should be diagnosed in all cases of hyperphenylalaninemia, including phenylketonuria, by tetrahydrobiopterin administration tests rather than by phenotype or blood phenylalanine levels. Conclusions and Relevance: If tetrahydrobiopterin‐responsive hyperphenylalaninemia is diagnosed, all ages can be treated with sapropterin hydrochloride. Although there are reports that sapropterin hydrochloride is effective and safe for the prevention of maternal phenylketonuria, further investigation is required. [ABSTRACT FROM AUTHOR]

Hyperphenylalaninemia (HPA), the most common amino acid metabolism disorder, is caused by defects in enzymes involved in phenylalanine metabolism, with the consequent accumulation of phenylalanine and its secondary metabolites in body fluids and tissues. Clinical manifestations of HPA include mental retardation, and its early diagnosis with timely treatment can improve the prognosis of affected patients. Due to the genetic complexity and heterogeneity of HPA, high-throughput molecular technologies, such as next-generation sequencing (NGS), are becoming indispensable tools to fully characterize the etiology, helping clinicians to promptly identify the exact patients’ genotype and determine the appropriate treatment. In this review, after a brief overview of the key enzymes involved in phenylalanine metabolism, we represent the wide spectrum of genes and their variants associated with HPA and discuss the utility of genomic testing for improved diagnosis and clinical management of HPA.

Pyruvoyl Tetrahydropterin Synthase (PTPS) Deficiency is the most common form of BH4 deficiency resulting in hyperphenylalaninemia. It can have variable clinical severity and there is limited information on the clinical presentation, natural history and effectiveness of newborn screening for this condition. Retrospective data (growth and clinical parameters, biochemical and genetic testing results, treatment) were collected from 19 patients with PTPS deficiency in different centers, to evaluate biochemical and clinical outcomes. Descriptive statistics was used for qualitative variables, while linear regression analysis was used to correlate quantitative variables. Patients with PTPS deficiency had an increased incidence of prematurity (4/18) with an average gestational age only mildly reduced (37.8 ± 2.4 weeks) and low birth weight (−1.14 ± 0.97 SD below that predicted for gestational age). With time, weight and height approached normal. Values. All patients were identified by newborn screening for an elevated phenylalanine level. However, phenylalanine levels were normal in two whose testing was performed at or before 24 h of age. Sapropterin dihydrochloride treatment normalized phenylalanine levels. Molecular testing identified novel variants in the PTS gene, some of which present in more than one affected family. The neurotransmitter derivatives 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) in the CSF were decreased in most cases except in 2 families with the peripheral form of PTPS deficiency. With time, HVA and 5HIAA became abnormally low in two of these patients requiring therapy. Prolactin (whose secretion is inhibited by dopamine) levels were elevated in several patients with PTPS deficiency and inversely correlated with the z-scores for height (p < 0.01) and weight (p < 0.05). Most patients with PTPS deficiency had delayed development early in life, improving around school age with IQs mostly in the normal range, with a small decline in older individuals. From a neurological standpoint, most patients had normal brain MRI and minor EEG anomalies, although some had persistent neurological symptoms. Patients with PTPS deficiency have not only an increased incidence of prematurity, but also decreased birth weight when corrected for gestational age. Hyperphenylalaninemia can be absent in the first day of life. Therapy with sapropterin dihydrochloride normalizes phenylalanine levels and neurotransmitter precursors can improve CSF neurotransmitter metabolites levels. Insufficient dopaminergic stimulation (as seen from elevated prolactin) might result in decreased height in patients with PTPS deficiency. Despite early delays in development, many patients can achieve independence in adult life, with usually normal neuroimaging and EEG. [ABSTRACT FROM AUTHOR]

Subtle executive function deficits, particularly regarding inhibitory control, have been reported in patients with phenylketonuria (PKU) despite early dietary treatment. Purpose of this study was to assess whether young female adults with PKU exhibit altered neural activity underlying such deficits, particularly in a fronto-parietal cognitive control network (CCN). Behavioural data and functional magnetic resonance imaging (fMRI) data were acquired during a Go-NoGo task in 16 young adult patients with PKU and 17 control subjects. Hypothesis-driven analyses of behavioural and fMRI data in the CCN were supplemented by exploratory whole brain activation analyses. PKU patients exhibited a trend towards higher errors of commission. Patients exhibited marginally increased activation associated with inhibitory control in only one CCN core region (right middle frontal gyrus, p = .043). Whole brain analyses revealed widespread relatively increased activation in adults with PKU in the main task contrast (NoGo > Go). This increased activation was mainly observed outside the CCN and largely overlapped with the default mode network (DMN). In conclusion, only subtle inhibitory control deficits and associated brain activity differences were observed in young adults with PKU. Thus, this work adds to the notion that this particular population seems to be only slightly affected by such cognitive deficits. While there were also only minimal increases when compared to healthy subjects in brain activity in a cognitive control network, we observed more widespread activation increases outside this network. These results support the assumption of DMN dysfunction in PKU. [ABSTRACT FROM AUTHOR]

Phenylketonuria (PKU) is the most common inborn error of amino acids metabolism. PKU management aims to keep as soon as possible blood phenylalanine (Phe), a non-acutely neurotoxic metabolite, within safe ranges through a dietary Phe restriction tailored to individual dietary Phe tolerance. Information on initial neonatal management of PKU, when Phe tolerance is still unknown, is scanty. We reviewed the metabolic data from 304 patients with PAH deficiency detected at newborn screening within the last 37 years. In keeping with the general neonatal management of intoxication-type inborn errors of metabolism, initial management consisted in a Phe wash-out through the exclusive administration of normocaloric Phe-free formulas until normalization of blood Phe. Based on genotype and Phe tolerance assessed at follow-up, 55 patients had classic PKU (18%), 50 mild PKU (17%), and 199 non-PKU hyperphenylalaninemia (HPA) (65%). The duration of Phe wash-out amounted to 7 ± 2 days in classic PKU, 4 ± 2 days in mild PKU, and < 24 h in non-PKU HPA (p < 0.001). After the wash-out, dietary Phe re-introduction and its upwardly titration allowed the assessment of individual metabolic phenotype. During the first 6 years of life, Phe tolerance was stable in classic PKU (~ 200 mg/day) but increased in milder forms, allowing unrestricted diet in non-PKU HPA. Neonatal Phe wash-out in PKU ensures the earliest correction of HPA. This metabolic reset also facilitates the prompt definition of individual Phe tolerance, allowing anticipation of dietary personalization and optimization of longitudinal metabolic control. [ABSTRACT FROM AUTHOR]

Abstract Background Recently hyperphenylalaninemia (HPA) caused by variants in DNAJC12 was reported and this suggested a new strategy for diagnosis. But DNAJC12‐associated HPA is a rare in Chinese population so far. Methods The clinical information and blood samples from the patient and his family members were collected and analyzed. Whole‐exome sequencing (WES) was used to identify the causative gene. Results We reported a newborn patient with HPA, having excluded the causes in common genes associated with HPA. By using whole‐exome sequencing, novel compound heterozygosity mutations in DNAJC12 were found, namely c.306C>G (p.His102Gln) and c.182delA (p.Lys61Argfs*6). Administering a diet with low phenylalanine combined with tetrahydrobiopterin and neurotransmitter precursors were shown to be effective in preventing neurodevelopmental delay for these patients. Conclusion Our finding confirms the diagnosis of DNAJC12‐associated HPA and suggests that genetic detection of DNAJC12 should be considered when newborn screening results are positive for HPA.

Phenylketonuria (PKU) and Hyperphenylalaninemia (HPA) are inborn errors of metabolism (IEM) due to mutations in the PAH gene resulting in increased blood phenylalanine (Phe) concentrations. Depending on the Phe levels, a lifelong dietary intervention may be needed. During the COVID-19 pandemic, finding new strategies to ensure follow-up and metabolic control for such patients became mandatory and telehealth was identified as the most eligible tool to provide care and assistance beyond barriers. The aim of this study was to evaluate how telehealth use may have impacted disease follow-ups. Seven hundred and fifty-five patients affected by PKU/HPA in follow-ups at the Clinical Department of Pediatrics (San Paolo Hospital, ASST Santi Paolo e Carlo, University of Milan, Italy) were included in this study. The data regarding the used telehealth model, type of performed consultations and patients’ perspectives were retrospectively collected and analyzed after a one-year experience of implemented follow-ups. The results demonstrated that telehealth seemed to be a useful tool to improve the adherence to treatment and that it could guarantee continuous assistance and care beyond the surrounding epidemiological status. Patients expressed great satisfaction with the offered services and requested that they were implemented in standards of care on a long-term basis. Our results suggested the implementation of telehealth in the management guidelines for PKU/HPA patients.

6-Pyruvoyl-tetrahydropterin synthase deficiency (PTPSd) is a rare autosomal recessive disorder of synthesis of biogenic amines, which is characterized by variable neurological impairment and hyperphenylalaninemia. We aimed to assess the long-term clinical outcome of this disorder and the factors affecting it. At total of 28 PTPSd patients (aged 19.9 ± 10.9 years) underwent clinical (neurological and psychiatric) and neuropsychological assessment (BRIEF, VABS-II, and IQ). Based on CSF homovanillic (HVA) and 5-hydroxyindolacetic acid (5-HIAA) and pterin concentrations at diagnosis, patients were classified as having either a severe [SF; low level of CSF, HVA, and 5-HIAA with altered neopterin/biopterin (Neo/Bio)] or mild form (MF; normal HVA and 5-HIAA with altered Neo/Bio) of PTPSd. Approximately 36% of patients had MF PTPSd. At the last examination, 43% of patients had movement disorders (2 MF, 10 SF), 43% of patients had variable degrees of intellectual disability (SF only), 39% met the criteria for a psychiatric disorder (3 MF, 9 SF). Applying a linear regression model, we found that HVA and phenylalanine levels at birth had a significant influence on IQ, BRIEF, and VABS-II variability. Lastly, 5-HIAA further contributed to VABS-II variability. The disease showed a self-limiting clinical course and its treatment, although delayed, is effective in improving the neurological status. Neurodevelopmental impairment due to PTPSd shows a self-limiting course. A continuous improvement in the neurological condition has been observed in patients receiving treatment, even when delayed. The severity of brain biogenic amine depletion at diagnosis predicts neurological and psychiatric outcomes. • Data about the clinical outcome of PTPS deficiency are lacking. • Distinguishing mild from severe form of PTPSd has relevant prognostic implications. • Neurotransmitters depletion predicts neurological and psychiatric outcomes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Recently hyperphenylalaninemia (HPA) caused by variants in DNAJC12 was reported and this suggested a new strategy for diagnosis. But DNAJC12‐associated HPA is a rare in Chinese population so far. Methods: The clinical information and blood samples from the patient and his family members were collected and analyzed. Whole‐exome sequencing (WES) was used to identify the causative gene. Results: We reported a newborn patient with HPA, having excluded the causes in common genes associated with HPA. By using whole‐exome sequencing, novel compound heterozygosity mutations in DNAJC12 were found, namely c.306C>G (p.His102Gln) and c.182delA (p.Lys61Argfs*6). Administering a diet with low phenylalanine combined with tetrahydrobiopterin and neurotransmitter precursors were shown to be effective in preventing neurodevelopmental delay for these patients. Conclusion: Our finding confirms the diagnosis of DNAJC12‐associated HPA and suggests that genetic detection of DNAJC12 should be considered when newborn screening results are positive for HPA. [ABSTRACT FROM AUTHOR]

Biallelic variants of the gene DNAJC12, which encodes a cochaperone, were recently described in patients with hyperphenylalaninemia (HPA). This paper reports the retrospective genetic analysis of a cohort of unsolved cases of HPA. Biallelic variants of DNAJC12 were identified in 20 patients (generally neurologically asymptomatic) previously diagnosed with phenylalanine hydroxylase (PAH) deficiency (phenylketonuria [PKU]). Further, mutations of DNAJC12 were identified in four carriers of a pathogenic variant of PAH. The genetic spectrum of DNAJC12 in the present patients included four new variants, two intronic changes c.298‐2A>C and c.502+1G>C, presumably affecting the splicing process, and two exonic changes c.309G>T (p.Trp103Cys) and c.524G>A (p.Trp175Ter), classified as variants of unknown clinical significance (VUS). The variant p.Trp175Ter was detected in 83% of the mutant alleles, with 14 cases homozygous, and was present in 0.3% of a Spanish control population. Functional analysis indicated a significant reduction in PAH and its activity, reduced tyrosine hydroxylase stability, but no effect on tryptophan hydroxylase 2 stability, classifying the two VUS as pathogenic variants. Additionally, the effect of the overexpression of DNAJC12 on some destabilizing PAH mutations was examined and a mutation‐specific effect on stabilization was detected suggesting that the proteostasis network could be a genetic modifier of PAH deficiency and a potential target for developing mutation‐specific treatments for PKU. [ABSTRACT FROM AUTHOR]

Background: Tetrahydrobiopterin (BH4) deficiencies comprise a group of six rare neurometabolic disorders characterized by insufficient synthesis of the monoamine neurotransmitters dopamine and serotonin due to a disturbance of BH4 biosynthesis or recycling. Hyperphenylalaninemia (HPA) is the first diagnostic hallmark for most BH4 deficiencies, apart from autosomal dominant guanosine triphosphate cyclohydrolase I deficiency and sepiapterin reductase deficiency. Early supplementation of neurotransmitter precursors and where appropriate, treatment of HPA results in significant improvement of motor and cognitive function. Management approaches differ across the world and therefore these guidelines have been developed aiming to harmonize and optimize patient care. Representatives of the International Working Group on Neurotransmitter related Disorders (iNTD) developed the guidelines according to the SIGN (Scottish Intercollegiate Guidelines Network) methodology by evaluating all available evidence for the diagnosis and treatment of BH4 deficiencies.Conclusion: Although the total body of evidence in the literature was mainly rated as low or very low, these consensus guidelines will help to harmonize clinical practice and to standardize and improve care for BH4 deficient patients. [ABSTRACT FROM AUTHOR]

Background: Phenylketonuria (PKU) is an inherited metabolic disorder characterized by reduced activity of phenylalanine hydroxylase resulting in elevated blood phenylalanine (Phe) concentration. Despite some obvious ocular changes, the disorder has been poorly recognized by ophthalmologists. Neurophysiologic tests imply prolonged reaction time correlating with increased phenylalanine blood concentrations. We aimed to test saccadic reaction time in PKU patients in dependency of blood phenylalanine concentrations.Methods: Nineteen biochemically diagnosed PKU patients and 100 controls completed comprehensive ophthalmologic and orthoptic examinations including saccadometry by infrared based video-oculography. Peak velocity, gain, and particularly latency of reflexive saccades were compared to controls, and regression analysis was performed.Results: Latency of reflexive saccades was not associated with the current phenylalanine concentration. Although in 10 out of 19 patients phenylalanine concentrations were outside the age-related therapeutic range, latency differed little between PKU patients and the controls, as well as peak velocity and gain. Ocular findings occurred as partial hypopigmentation of the iris in one late diagnosed patient aged 36 years, and as bilateral cataracts (possibly due to steroid intake) with refractive amblyopia, strabismus, high myopia, and glaucoma in another late diagnosed patient aged 46 years. Visual acuity was reduced in eight PKU patients.Conclusions: Saccadometry, particularly saccadic reaction time, is not useful in the monitoring of phenylketonuria. Ophthalmic examination is recommended in PKU patients, as the occurrence of ocular pathologies was relatively high. [ABSTRACT FROM AUTHOR]

Phenylketonuria (PKU) is an autosomal recessive disease caused by mutations in the PAH gene, resulting in deficiency of phenylalanine hydroxylase (PAH), an enzyme that converts phenylalanine (Phe) to tyrosine (Tyr). The purpose of this study was to capture real-world data associated with managing PKU under current standard of care and to characterize a representative population for a planned gene therapy trial. A retrospective chart review was conducted at two U.S. clinics for individuals 10–40 years old diagnosed with PKU-related hyperphenylalaninemia (HPA). Demographics, medical history, treatments and blood Phe data were collected from electronic medical records spanning a five-year period ending in November 2017. 152 patients were enrolled (65.8% had classical PKU). Although >95% of patients were prescribed a Phe-restricted diet, blood Phe concentrations remained substantially elevated, particularly in patients diagnosed with classical PKU. As the Phe threshold was lowered (Phe < 600, 360, 120 or 30 μmol/L), the number of patients with consecutive lab values below the threshold decreased, suggesting that many patients' Phe levels are inadequately controlled. 62.5% of patients were reported as having a history of at least one neuropsychiatric comorbidity, and adults were more likely than adolescents (69.5% vs. 54.3%). 92 of 98 PAH genotypes collected were distinct mutations; the 6 null-null genotypes were associated with classical PKU. Overall the demographics and clinical data were consistent across both sites. Despite dietary restrictions, mean Phe concentrations were > 360 μmol/L (a level considered well-controlled based on current U.S. treatment guidelines) for mild, moderate, and classical PKU patients. There remains an unmet need for therapies to control Phe concentrations. [ABSTRACT FROM AUTHOR]

Background: The Sapropterin dihydrochloride enzyme cofactor, a synthetic analog form of 6R-BH4, was offered as an oral treatment for hyperphenylalaninemia. The sapropterin dihydrochloride role in patients with phenylketonuria (PKU) is to activate the endogenous phenylalanine hydroxylase (PAH) and to restore partially the oxidative metabolism of phenylalanine (Phe), when patients have insufficiency or lack of tetrahydrobiopterin. The sapropterin dihydrochloride anticipated to restore PAH activity through providing an exogenous source of the lost or deficient cofactor. Aim of Study: This study aims to evaluate the effects and clinical significance of tetrahydrobiopterin supplementation in hyperphenylalaninemia. Patients and Methods: This study describes the use of tetrahydrobiopterin in 58 patients with hyperphenylalaninemia treated before the age of 15 years with the use of tetrahydrobiopterin loading test. More than 30% decrement in Phe consider positive. Results: Fifty-eight patient been enrolled in this prospective study as follows; seven patient non PKU hyperphenylalaninemia (Phe level <600 μM), 13 patients mild to moderate PKU (Phe level between 600 and 1200 μM) and 38 with classic PKU (Phe level equal or above 1200 μM). The mean of Phe at the diagnosis was 377.00 ± 150.240 μM, 843.00 ± 133.899 μM and 1513.736 ± 274.372 μM sequentially. The response to treatment with tetrahydrobiopterin was inversely related to the level of Phe where its 100% in non PKU hyperphenylalaninemia, 70% in mild-to-moderate PKU and 16% in classic PKU. Tetrahydrobiopterin therapy significantly enhanced dietary Phe tolerance and permitted a Phe-free medical formula to be discontinued in a significant number of patients in whom phenylalaninemia within therapeutic target (120-300 μM) were achieved. Tetrahydrobiopterin displays the safety and usefulness of this treatment for patients mild PKU. Conclusions: Tetrahydrobiopterin therapy should be tried in all patients with hyperphenylalaninemia and/or PKU as it may significantly decrease the Phe level and improvement his milestone moreover safe in mild PKU. [ABSTRACT FROM AUTHOR]

Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism caused by pathogenic variants in the phenylalanine hydroxylase gene (PAH). The correlation between genotype and phenotype can be complex and sometimes variable but often very useful for categorizing and predicting dietary tolerance and potential outcome. We reviewed medical records for 367 patients diagnosed with PKU or persistent mild hyperphenylalaninemia (MHP) between 1950 and 2015 who had PAH genotyping. In 351 we had the full PAH genotype as well as phenotypic characteristics such as phenylalanine (Phe) concentrations (at newborn screening, confirmation, and highest known), and dietary Phe tolerance. On 716 mutant chromosomes, including 14 in genotypes with only one identified variant, we identified 114 different pathogenic variants. The most frequent, p.R408W, was present in 15.4% of the alleles; other frequent variants were c.1315 + 1G > A (6.1%), p.I65T (5.7%), and p.R261Q (5.7%). Three variants, c.142 T > G (p.L48 V), c.615G > C (p.E205D), and c.1342_1345delCTCC, were novel. We used the phenotypic parameters of variants paired with null alleles (functional hemizygotes) to assign the variants as classic PKU, moderate PKU, mild PKU, MHP-gray zone, or MHP. We also included the phenotype association(s) for all of the full genotypes. In 103 patients, we also could assign sapropterin dihydrochloride responsiveness, which is a synthetic form of the tetrahydrobiopterin (BH 4) PAH cofactor. This compilation from a single metabolic center provides further information on PAH variants in the United States and the correlations between genotype and phenotype. [ABSTRACT FROM AUTHOR]

This study presents further research into the spectrum of variants in genes responsible for the development of phenylketonuria (PKU) and hyperphenylalaninemia (HPA) in patients in Russia. After a study of 25 frequent variants, 293 patients (327 chromosomes without detected variants) from among 1265 probands still had no confirmed diagnosis. A study involving methods of next generation sequencing (NGS) of PAH, PTS, GCH1, PCBD1, QDPR, SPR and DNAJC12 genes to search for point mutations and multiplex ligation-dependent probe amplification (MLPA) methods to search for gross deletions were conducted for these patients. Among 327 chromosomes without identified variants, variants in the PAH gene were found on 260 chromosomes, and variants in the PTS gene were found on 10 chromosomes. On 10 chromosomes gross deletions by the MLPA method were detected. 104 rare variants of the РАН gene, including 10 variants not previously described, and 6 variants of the PTS gene were revealed. The NGS method revealed additional РАН gene variants on 10.3% of chromosomes and PTS gene variants on 0.4%. Gross deletions of the РАН gene were revealed in 0.5% of chromosomes. Thus, the most complete understanding of the spectrum of variants leading to the development of the PKU and HPA in Russia with the use of all methods available today has been obtained. Such a detailed study of the spectrum of rare variants on the genetic material from Russia was undertaken for the first time. [ABSTRACT FROM AUTHOR]

Phenylketonuria (PKU) is a metabolic disorder accumulating phenylalanine (Phe) and its metabolites in plasma and tissues of the patients. Regardless of the mechanisms, which Phe causes brain impairment, are poorly understood, energy deficit may have linked to the neurotoxicity in PKU. It is widely recognized that creatine is involved in maintaining of cerebral energy homeostasis. Because of this, in a previous work, we incorporated it into liposomes and this increased the concentration of creatine in the cerebral cortex. Here, we examined the effect of creatine nanoliposomes on parameters of oxidative stress, enzymes of phosphoryl transfer network, and activities of the mitochondrial respiratory chain complexes (RCC) in the cerebral cortex of young rats chemically induced hyperphenylalaninemia (HPA). HPA was induced with l-phenylalanine (5.2 µmol/g body weight; twice a day; s.c.), and phenylalanine hydroxylase inhibitor, α-methylphenylalanine (2.4 µmol/g body weight; once a day; i.p.), from the 7th to the 19th day of life. HPA reduced the activities of pyruvate kinase, creatine kinase, and complex II + III of RCC in the cerebral cortex. Creatine nanoliposomes prevented the inhibition of the activities of the complexes II + III, caused by HPA, and changes oxidative profile in the cerebral cortex. Considering the importance of the mitochondrial respiratory chain for brain energy production, our results suggesting that these nanoparticles protect against neurotoxicity caused by HPA, and can be viable candidates for treating patients HPA. [ABSTRACT FROM AUTHOR]

In this study, we evaluated the incidence and genetic characteristics of hyperphenylalaninemia (HPA) in Xiamen, China. We analyzed the newborn screening data of HPA, obtained using a fluorometric method and tandem mass spectrometry (MS/MS), from 2013 to 2017. The suspected positive samples were further diagnosed using MassArray technology, multiplex ligation-dependent probe amplification (MLPA), and Sanger sequencing. A total of 418,831 newborns were screened, of whom 19 were diagnosed as HPA patients, with an incidence of 1:22,044. Of these HPA patients, 15 tested positive for phenylketonuria (PKU, 1:27922), and 4 tested positive for tetrahydrobiopterin deficiency (BH4D, 1:104,708). A total of 17 mutations were identified among 38 alleles in the 19 patients, with a detection rate of 94.74%, including 13 PAH and 4 PTS mutations. Among these, the c.721C>T, c.728G>A, c.1197A>T, c.611A>G and c.331C>T mutations, and the c.259C>T and c.155A>G mutations were the most prevalent PAH and PTS mutations in Xiamen, respectively. Therefore, this study systematically demonstrated the incidence and mutation spectrum of HPA in Xiamen. This information would contribute to genetic counseling, prenatal diagnosis, and management of HPA patients. Moreover, combining MS/MS technology with molecular genetic diagnosis is an effective strategy for future newborn HPA screening in Xiamen. • The incidence of hyperphenylalaninemia (HPA) in Xiamen is about 1 in 22,044 newborns. • The overall incidence of phenylketonuria (PKU) is 1:27922 in Xiamen. • Tetrahydrobiopterin deficiency (BH4D) has an incidence of 1:104,708 in Xiamen. • The study has clearly elucidated the mutations of PAH and PTS gene in this region. [ABSTRACT FROM AUTHOR]

Fresh urine sample is required for measurement of pterins in patients with hyperphenylalaninemia (HPA) for detection of tetrahydrobiopterin (BH4) coenzyme deficiency. The present study aimed to measure the levels of neopterin and biopterin in the urine of patients with HPA using manganese dioxide (MnO2) and iodine oxidation methods. The levels of neopterin and biopterin in the urine of 124 patients were measured using two methods of oxidation (MnO2 and iodine) and the results were statistically analyzed using correlation test, Roc-Curve and ANOVA in SPSS-20 software. The level of significant was determined to be P > 0.05. Patients age mean ± SD = 4.96 year, neopterin and biopterin mean ± SD in 124 patients were 2.75 mmol/molcr and 2.49 mmol/molcr. Correlation regression between two methods (iodine and MnO2 oxidation) was 0.99. There was no significant difference between the two oxidation methods (P > 0.05). The results of this study showed that MnO2 oxidation can be a suitable alternative method instead of iodine oxidation for measurement of urine neopterin, biopterin and diagnosis of BH4 deficiency. [ABSTRACT FROM AUTHOR]

Abstract Background Hyperphenylalaninemia (HPA) can be classified into phenylketonuria (PKU) which is caused by mutations in the phenylalanine hydroxylase (PAH) gene, and BH4 deficiency caused by alterations in genes involved in tetrahydrobiopterin (BH4) biosynthesis pathway. Dietary restriction of phenylalanine is considered to be the main treatment of PKU to prevent irreversible intellectual disability. However, the same dietary intervention in BH4 deficiency patients is not as effective, as BH4 is also a cofactor in many neurotransmitter syntheses. Method We utilized next generation sequencing (NGS) technique to investigate four unrelated Thai patients with hyperphenylalaninemia. Result We successfully identified all eight mutant alleles in PKU or BH4-deficiency associated genes including three novel mutations, one in PAH and two in PTS, thus giving a definite diagnosis to these patients. Appropriate management can then be provided. Conclusion This study identified three novel mutations in either the PAH or PTS gene and supported the use of NGS as an alternative molecular genetic approach for definite diagnosis of hyperphenylalaninemia, thus leading to proper management of these patients in Thailand.

We report a 16-year-old man with disorders of tetrahydrobiopterin metabolism due to dihydropteridine reductase (DHPR) deficiency. He revealed moderate mental retardation, parkinsonism, and spastic paralysis with levodopa and 5-hydroxytryptophan (5-HTP) supplementation from the age of 2 months. Brain MRI showed high intensity areas in bilateral frontal and posterior deep white matter on fluid-attenuated inversion recovery (FLAIR). Coronal FLAIR image showed a high signal in bilateral pyramidal tracts. Single photon computed tomography (SPECT) imaging of the dopamine transporter was normal. This imaging indicates no dopaminergic cell loss. Our patient had no motor fluctuations or dyskinesias. Early diagnosis and replacement treatment might lead to a favorable outcome.