Hyperphenylalaninemia and serotonin deficiency in Dnajc12-deficient mice.

Serotonin exerts numerous neurological and physiological actions in the brain and in the periphery. It is generated by two different tryptophan hydroxylase enzymes, TPH1 and TPH2, in the periphery and in the brain, respectively, which are members of the aromatic amino acid hydroxylase (AAAH) family together with phenylalanine hydroxylase (PAH), degrading phenylalanine, and tyrosine hydroxylase (TH), generating dopamine. In this study, we show that the co-chaperone DNAJC12 is downregulated in serotonergic neurons in the brain of mice lacking TPH2 and thereby central serotonin.

High prevalence of low bone mineral density in young adults with phenylketonuria.

Background: It has been reported that phenylalanine (Phe)-restricted diets may have negative effects on bone health in patients with classical phenylketonuria (cPKU). We aimed to evaluate bone mineral density (BMD) in adults with cPKU and determine the risk factors associated with low BMD.

Methods: Eighty adult patients with cPKU were examined, including 41 women and 39 men.

The Prevention of Maternal Phenylketonuria (PKU) Syndrome: The Development and Evaluation of a Specific Training Program.

Background: Maternal phenylketonuria (PKU) syndrome, leading to severe psychomotor retardation, microcephaly, cardiac defects and undergrowth, affects the unborn children of mothers with PKU with insufficient metabolic control during pregnancy. To improve long-term outcomes, a specific prevention program was developed.

Methods: We designed a group training program for young women with PKU (>14 years) and their partners.

Oral health care knowledge among Phenylketonuria patients in the Latvian population.

Background: Phenylketonuria (PKU) is an autosomal recessive inherited disorder of phenylalanine (Phe) metabolism that results from a deficiency of phenylalanine hydroxylase (PAH). Patients with PKU rely on amino acid mixtures and low-protein diets, which often exhibit an acidic nature and pose various challenges to oral health. The objective of the study was to evaluate oral care habits of PKU patients in Latvia and the impact of the recommendations developed on improving oral care.

Spectrum analysis of inborn errors of metabolism for expanded newborn screening in Xinjiang, China.

To determine the disease spectrum and genetic characteristics of inborn errors of metabolism (IEM) in Xinjiang province in the northwest of China, 41,690 newborn babies were screening by tandem mass spectrometry from November 2018 to December 2021. Of these, 57 newborn babies were referred for genetic analysis by next-generation sequencing, which was validated by Sanger sequencing. A total of 36 newborn babies and one relative were diagnosed with IEM, and the overall positive predictive value was 29.

Neuropsychological profile of French adults with early-treated phenylketonuria: a multicenter study.

Background And Objective: Adult patients with early-treated phenylketonuria (AwET-PKU) may present some subtle neurocognitive deficits. The aim of the study was to investigate 1) neurocognitive functions in a large group of AwET-PKU 2) the influence of plasma phenylalanine (Phe).

Methods: Participants: 187 AwET-PKU (classic PKU [cPKU] 81%, mild PKU [mPKU] 14%, and mild persistent hyperphenylalaninemia [MPH] 5%).

Cognition and wellbeing in middle-aged early treated people with phenylketonuria: Preliminary results and methodological lessons.

The first cohort of early-treated adults with phenylketonuria (PKU) is reaching middle-age and moving towards old age. We do not know if and how the effects of an aging brain may interact with the effect of PKU. This study compared wellbeing and cognition in 19 middle-aged adults with PKU (age 40+ mean = 45.

Patient voices on PKU care: Insights from focus groups with current and former patients.

Many adults with phenylketonuria (PKU) were discharged from clinics before lifelong treatment guidelines and new therapies. As part of the PKU lost to clinical care study, moderated focus groups were conducted to understand why individuals become lost to care and how to maintain patient engagement. Focus groups involved active clinic patients and those lost to PKU care.

Reversible white matter changes following a 4-week high phenylalanine exposure in adults with phenylketonuria.

Alterations in brain structure are frequently observed in adults with early-treated phenylketonuria (PKU) compared to healthy controls, with cerebral white matter (WM) being particularly affected. The extent to which temporary elevation of phenylalanine (Phe) levels impacts WM remains unclear. We conducted a double-blind, randomised, placebo-controlled crossover trial to investigate the effects of a 4-week high Phe exposure on cerebral WM and its relationship to cognitive performance and metabolic parameters in adults with PKU.

Rapid determination of phenylalanine and tyrosine in volumetrically collected dried blood spots using fully automated processing and analysis by capillary electrophoresis.

An off-the-shelf Agilent 7100 capillary electrophoresis (CE) instrument was employed for the automated processing and analysis of dried blood spots (DBSs) collected by Capitainer®B volumetric devices. Solutions for DBS elutions were transferred directly into CE vials through a separation capillary by the application of an auxiliary nitrogen gas connected to the external pressure line of the CE instrument. This allowed for liquid handling at pressures up to 15 bar and enabled the use of a single capillary for rapid DBS processing and efficient CE separations.

Co-occurrence of two rare diseases: a child with phenylketonuria and WNT1 osteoporosis.

Introduction: Phenylketonuria (PKU), an inborn error of metabolism, when inadequately treated, may lead to nutritional deficits, which could affect bone health. This remains a controversial issue, given that in the majority of PKU cases, bone mineral density is within normal limits. On the other hand, WNT1 mutations are detrimental for bone, as they lead to primary osteoporosis.

Amelioration of metabolic and behavioral defects through base editing in the Pah phenylketonuria mouse model.

Phenylketonuria (PKU) is a liver metabolic disorder mainly caused by a deficiency of the hepatic phenylalanine hydroxylase (PAH) enzyme activity, often leading to severe brain function impairment in patients if untreated or if treatment is delayed. In this study, we utilized dual-AAV8 vectors to deliver a near PAM-less adenine base editor variant, known as ABE8e-SpRY, to treat the Pah PKU mouse model carrying a frequent R408W mutation in the Pah gene. Our findings revealed that a single intravenous injection in adult mice and a single intraperitoneal injection in neonatal mice resulted in 19.

A Phase 1 Study to Assess the Pharmacokinetics, Food Effect, Safety, and Tolerability of Sepiapterin in Healthy Japanese and Non-Japanese Participants.

Background: Sepiapterin is a natural precursor of tetrahydrobiopterin (BH), a key cofactor for phenylalanine hydroxylase. It is being developed for the treatment of patients with phenylketonuria. In this study, the ethnic differences in pharmacokinetics and safety of sepiapterin in Japanese and non-Japanese participants and food effects were evaluated.

Amyloid inspired single amino acid (phenylalanine)-based supramolecular functional assemblies: from disease to device applications.

In the evolving landscape of biomolecular supramolecular chemistry, recent studies on phenylalanine (Phe) have revealed important insights into the versatile nature of this essential aromatic amino acid. Phe can spontaneously self-assemble into fibrils with amyloid-like properties linked to the neurological disorder phenylketonuria (PKU). Apart from its pathological implications, Phe also displays complex phase behavior and can undergo structural changes in response to external stimuli.

Expanding diversity within phenylketonuria in ecuadorian patients: genetic analysis and literature review of newborn screenings.

Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by a deficiency in the phenylalanine hydroxylase (PAH) enzyme, leading to the accumulation of phenylalanine and its metabolites, which are toxic to the central nervous system. Without treatment, PKU can result in severe intellectual disability and neurological issues. This study aims to present the first cohort of clinically described Ecuadorian PKU patients, analyzing genotype-phenotype correlations and comparing these variants with global databases to improve diagnosis and treatment in Ecuador.

Do early-treated adults with phenylketonuria sense high phenylalanine levels?

This study aimed to analyze whether early-treated adults with phenylketonuria (PKU) can subjectively sense high phenylalanine (Phe) concentrations and whether a possible impact of Phe on objective measures of cognitive performance and mood reflects patients' self-perception. Data from the PICO study, a randomized, placebo-controlled, double-blind, crossover trial, were analyzed. Twenty-eight adults with PKU received either Phe capsules or placebo in two 4-week intervention periods in a randomized order, with a 4-week washout in between.

Safety assessment of sapropterin dihydrochloride: real-world adverse event analysis based on the FDA adverse event reporting system (FAERS).

Objective: Sapropterin dihydrochloride is the first drug for the therapy of phenylketonuria, which is a rare disease that occurs one of 10,000-15,000 newborns. As a result, detailed and comprehensive reports on the safety of sapropterin in large, real-world populations are required. The purpose of this study is to undertake a complete analysis of sapropterin's adverse events (AEs) using the FDA Adverse Event Reporting System (FAERS) database.

A Qualitative Investigation into the Determinants of Unfulfilled Needs in Caregivers of Patients with Phenylketonuria.

Objective: To conduct an in-depth exploration of the factors influencing unfulfilled needs in caregivers of patients with phenylketonuria.

Methods: A rapid qualitative analysis approach was used to conduct semi-structured interviews with 16 caregivers of patients with phenylketonuria undergoing specialized dietary interventions, along with 5 medical professionals, within a designated phenylketonuria diagnosis and treatment center in Shanxi Province. Interview data were systematically organized, analyzed, and thematically extracted.

Neurocognitive functioning remained unchanged in adults with phenylketonuria: Report of a 15-year follow-up.

Aim: The long-term prognosis of treated phenylketonuria (PKU) is a controversial issue. A controlled long-term study was performed to assess the neuropsychological outcome in adult patients with early treated PKU.

Methods: We investigated 27 patients aged 34-55 years (median age: 47 years) and 19 healthy controls, matched for age and socio-economic status.

SLC6A19 inhibition facilitates urinary neutral amino acid excretion and lowers plasma phenylalanine.

BACKGROUNDThe toxic accumulation of phenylalanine (Phe) in the brain underlies the neurological presentation of phenylketonuria (PKU). Solute carrier family 6 member 19 (SLC6A19) is the major transporter responsible for the (re)absorption of Phe in the kidney and intestine. Here, we describe the characterization of the first small molecule SLC6A19 inhibitor to enter clinical development for the treatment of PKU.