Initial results from the PHEFREE longitudinal natural history study: Cross-sectional observations in a cohort of individuals with phenylalanine hydroxylase (PAH) deficiency.

Over fifty years have passed since the last large scale longitudinal study of individuals with PAH deficiency in the U.S. Since then, there have been significant changes in terms of treatment recommendations as well as treatment options.

Adherence to PKU guidelines among patients with phenylketonuria: A cross-sectional national multicenter survey-based study in Argentina, Brazil, and Mexico.

Objective: To characterize adherence to Phenylketonuria (PKU) management practices among PKU patients treated at reference sites around Argentina, Brazil, and Mexico.

Methods: This is a retrospective, observational, multicenter, and multinational survey-based study using aggregate data. From an initial list of 40 sites, 22 clinicians expressed interest in completing the survey, with 20 clinicians from 20 unique sites fulfilling all the study criteria.

Neuropsychiatric Function Improvement in Pediatric Patients with Phenylketonuria.

Objective: To evaluate effects of sapropterin dihydrochloride on blood phenylalanine (Phe) and symptoms of neuropsychiatric impairment in children and adolescents with phenylketonuria (PKU).

Study Design: PKU subjects 8-17 years of age (n = 86) were randomized to double-blind treatment with sapropterin (n = 43) or placebo (n = 43) for 13 weeks, then all received open-label sapropterin therapy for an additional 13 weeks. Blood Phe and symptoms of inattention, hyperactivity/impulsivity (Attention-Deficit/Hyperactivity Disorder Rating Scale IV [ADHD RS-IV]), executive functioning (Behavior Rating Inventory of Executive Function), depression (Hamilton Rating Scale for Depression), and anxiety (Hamilton Rating Scale for Anxiety) were assessed.

Burden of phenylketonuria in Latin American patients: a systematic review and meta-analysis of observational studies.

Background: Phenylketonuria (PKU) is an inborn error of metabolism caused by a deficiency of the enzyme phenylalanine hydroxylase. If untreated, the complications of PKU lead to significant neucognitive and neuropsychiatric impairments, placing a burden on both the individual's quality of life and on the healthcare system. We conducted a systematic literature review to characterize the impact of PKU on affected individuals and on healthcare resources in Latin American (LATAM) countries.

Measuring Burden of Illness in Phenylketonuria (PKU): Development of the PKU Symptom Severity and Impacts Scale as a Robust Patient-Reported Outcome.

Introduction: Phenylketonuria (PKU) is a rare, metabolic genetic disorder that can cause various neuropsychological symptoms that often affect patients' health-related quality of life, even for patients with good metabolic control. To date, no patient-reported outcomes (PRO) instrument combines the measurement of neuropsychological and dietary concepts to capture the broad impact of PKU on quality of life. This article presents the development of the PKU Symptom Severity and Impacts Scale (PKU-SSIS), a PRO instrument that is designed to evaluate neuropsychological symptoms and impacts in early-treated patients with PKU.

Improved attention linked to sustained phenylalanine reduction in adults with early-treated phenylketonuria.

Pegvaliase is approved to reduce phenylalanine (Phe) levels for people with phenylketonuria (PKU). PRISM-1 (NCT01819727) and PRISM-2 (NCT01889862) data were analyzed to evaluate the relationship between Phe and inattention in adult participants with PKU. In the modified-intent-to-treat population (N = 156), baseline mean (SE) plasma Phe was 1263 (29) μmol/L and the Attention Deficit Hyperactivity Disorder Rating Scale-IV Inattentive (IA) symptoms score was 9.

A non-interventional observational study to identify and validate clinical outcome assessments for adults with phenylketonuria for use in clinical trials.

Introduction: Current clinical outcome assessments (COAs) are not effectively capturing the complex array of symptoms of adults with phenylketonuria (PKU). This study aimed to identify concepts of interest relevant to adults with PKU. Based on these concepts, COAs for patient-reported outcomes (PROs), observer-reported outcomes (ObsROs), and clinician-reported outcomes (ClinROs) were selected or developed and content validity was assessed.

Long-term comparative effectiveness of pegvaliase versus standard of care comparators in adults with phenylketonuria.

Phenylketonuria (PKU) is caused by phenylalanine hydroxylase (PAH) deficiency, resulting in high blood and brain Phenylalanine (Phe) concentrations that can lead to impaired brain development and function. Standard treatment involves a Phe-restricted diet alone or in conjunction with sapropterin dihydrochloride in responsive patients. The Food and Drug Administration approved pegvaliase enzyme substitution therapy for adults with blood Phe >600 μmol/L in the US.

Neuropsychiatric comorbidities in adults with phenylketonuria: A retrospective cohort study.

Adults with phenylketonuria (PKU) may experience neurologic and psychiatric disorders, including intellectual disability, anxiety, depression, and neurocognitive dysfunction. Identifying the prevalence and prevalence ratios of these conditions will inform clinical treatment. This nested, case-controlled study used International Classification of Diseases, Ninth Revision (ICD-9) codes from the MarketScan® insurance claims databases from 2006 to 2012 and healthcare claims data for US-based employer and government-sponsored health plans.

Development of the US English version of the phenylketonuria - quality of life (PKU-QOL) questionnaire.

Background: Phenylketonuria (PKU) is a rare genetic disorder caused by a defect in the metabolism of phenylalanine (PHE) resulting in elevated blood and brain PHE levels, and leading to cognitive, emotional, and psychosocial problems. The phenylketonuria - quality of life (PKU-QOL) questionnaire was the first self-administered disease-specific instrument developed to assess the impact of PKU and its treatment on the health-related quality of life (HRQL) of patients and their caregivers. Available in four versions (child, adolescent, adult and parent), the PKU-QOL was simultaneously developed and validated in seven countries [i.

Adherence to clinic recommendations among patients with phenylketonuria in the United States.

Objective: Assess current management practices of phenylketonuria (PKU) clinics across the United States (US) based on the key treatment metrics of blood phenylalanine (Phe) concentrations and blood Phe testing frequency, as well as patient adherence to their clinic's management practice recommendations.

Methods: An online survey was conducted with medical professionals from PKU clinics across the US from July to September 2015. Forty-four clinics participated in the survey and account for approximately half of PKU patients currently followed in clinics in the US (Berry et al.

Impact of long-term elosulfase alfa treatment on respiratory function in patients with Morquio A syndrome.

Objective: To present long-term respiratory function outcomes from an open-label, multi-center, phase 3 extension study (MOR-005) of elosulfase alfa enzyme replacement therapy (ERT) in patients with Morquio A syndrome.

Methods: In part 1 of MOR-005, patients initially randomized to ERT in the 24-week pivotal study (MOR-004) remained on their regimen (2.0 mg/kg/week or every other week); placebo patients were re-randomized to one of the two regimens.

Long-term endurance and safety of elosulfase alfa enzyme replacement therapy in patients with Morquio A syndrome.

Long-term efficacy and safety of elosulfase alfa enzyme replacement therapy were evaluated in Morquio A patients over 96weeks (reaching 120weeks in total from pre-treatment baseline) in an open-label, multi-center, phase III extension study. During this extension of a 24-week placebo-controlled phase III study, all patients initially received 2.0mg/kg elosulfase alfa either weekly or every other week, prior to establishment of 2.

Sapropterin Dihydrochloride Mixed With Common Foods and Beverages.

Sapropterin dihydrochloride is used to lower blood phenylalanine levels in tetrahydrobiopterin-responsive phenylketonuria in conjunction with a phenylalanine-restricted diet. This study investigated the solubility and stability of sapropterin tablets and a sapropterin powder formulation when mixed in selected beverages and foods. Solubility was partial for the tablets and complete for the powder.

Long-term developmental progression in infants and young children taking sapropterin for phenylketonuria: a two-year analysis of safety and efficacy.

Purpose: Sapropterin is an oral synthetic formulation of tetrahydrobiopterin prescribed as adjunctive therapy for phenylketonuria. The efficacy of sapropterin in reducing blood phenylalanine levels has been demonstrated in clinical studies of individuals with phenylketonuria older than 4 years of age. Its effect on neurocognitive functioning in younger children has not been examined.

Newborn screening 50 years later: access issues faced by adults with PKU.

Fifty years after the implementation of universal newborn screening programs for phenylketonuria, the first disease identified through newborn screening and considered a success story of newborn screening, a cohort of adults with phenylketonuria treated from birth provides valuable information about effects of long-term treatment for inborn errors of metabolism in general, and phenylketonuria specifically. For phenylketonuria, newborn screening allows early implementation of the phenylalanine-restricted diet, eliminating the severe neurocognitive and neuromotor impairment associated with untreated phenylketonuria. However, executive function impairments and psychiatric problems are frequently reported even for those treated early and continuously with the phenylalanine-restricted diet alone.

Recommendations for the use of sapropterin in phenylketonuria.

Phenylketonuria (PKU) is an inherited disorder of phenylalanine (Phe) metabolism. Until recently, the only treatment for PKU was a Phe-restricted diet. Increasing evidence of suboptimal outcomes in diet-treated individuals, inconsistent PKU management practices, and the recent availability of tetrahydrobiopterin (BH(4)) therapy have fueled the need for new management and treatment recommendations for this metabolic disorder.

Evolving patient selection and clinical benefit criteria for sapropterin dihydrochloride (Kuvan®) treatment of PKU patients.

Purpose: To understand current patient selection, dosing, and response criteria used for sapropterin dihydrochloride (sapropterin, Kuvan®) to treat phenylketonuria (PKU).

Methods: Results of a 2010 survey of twenty-nine academic medical centers are reported to describe practice patterns in comparison to results of a survey done in 2008 and to what is reported in the literature.

Results/conclusions: In addition to reduction in blood phenylalanine (Phe) levels, clinicians report using broader disease-management approaches when evaluating clinical benefit of sapropterin, including consideration of increased Phe tolerance and behavioral changes.

Tetrahydrobiopterin therapy for phenylketonuria in infants and young children.

Objective: To describe patient selection, treatment administration, response evaluation, and side effect management associated with sapropterin therapy in infants and children aged <4 years.

Study Design: Six case reports are presented from 4 US metabolic clinics treating phenylketonuria with sapropterin in patients aged 7 months to 4 years. Outcomes included blood phenylalanine (Phe) levels before and during treatment.

Suboptimal outcomes in patients with PKU treated early with diet alone: revisiting the evidence.

Background: The National Institute of Health (NIH) published a Consensus Statement on the screening and management of Phenylketonuria (PKU) in 2000. The panel involved in the development of this consensus statement acknowledged the lack of data regarding the potential for more subtle suboptimal outcomes and the need for further research into treatment options. In subsequent years, the approval of new treatment options for PKU and outcome data for patients treated from the newborn period by dietary therapy alone have become available.

Nutrient intakes and physical growth of children with phenylketonuria undergoing nutrition therapy.

Objective: To evaluate nutrient intakes, plasma phenylalanine (PHE) and tyrosine (TYR) concentrations, and physical growth of children with phenylketonuria undergoing nutrition management.

Design: Children were fed three different medical foods during a one-year study. Subjects/setting Children were evaluated at baseline and every three months in metabolic clinics.

Prenatal diagnosis of holocarboxylase synthetase deficiency by assay of the enzyme in chorionic villus material followed by prenatal treatment.

Deficiency of holocarboxylase synthetase leads to multiple carboxylase deficiency, which is fatal in the absence of prompt diagnosis and treatment with biotin. In a pregnancy at risk for deficiency of holocarboxylase synthetase, prenatal diagnosis was performed by assay of the enzyme in chorionic villus material. The Km for biotin was 220.

Isovaleric acidemia: response to a leucine load after three weeks of supplementation with glycine, L-carnitine, and combined glycine-carnitine therapy.

Objective: To assess the effectiveness of glycine and carnitine therapy on isovaleryl conjugate excretion in isovaleric acidemia (IVA).

Study Design: Urinary isovalerylglycine (IVG) and isovalerylcarnitine (IVC) were measured from 12-hour urine specimens collected overnight from an 8-year-old patient with IVA (who had no residual activity of isovaleryl-CoA dehydrogenase in fibroblasts) before and during 3-week courses of supplementation with glycine alone (250 mg/kg per day), L-carnitine alone (100 mg/kg per day) therapy, and both of these agents combined, with a 2 gm leucine challenge performed at the end of each treatment period.

Results: Isovalerylglycine was the predominant metabolite excreted throughout the study, and its mean value doubled with glycine treatment.