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BackgroundSanfilippo type B is a mucopolysaccharidosis (MPS) with a major neuronopathic component characterized by heparan sulfate (HS) accumulation due to mutations in the NAGLU gene encoding alfa-N-acetyl-glucosaminidase. Enzyme replacement therapy for neuronopathic MPS requires efficient enzyme delivery throughout the brain in order to normalize HS levels, prevent brain atrophy, and potentially delay cognitive decline.MethodsIn this phase I/II open-label study, patients with MPS type IIIB (n = 22) were treated with tralesinidase alfa administered i.c.v. The patients were monitored for drug exposure; total HS and HS nonreducing end (HS-NRE) levels in both cerebrospinal fluid (CSF) and plasma; anti-drug antibody response; brain, spleen, and liver volumes as measured by MRI; and cognitive development as measured by age-equivalent (AEq) scores.ResultsIn the Part 1 dose escalation (30, 100, and 300 mg) phase, a 300 mg dose of tralesinidase alfa was necessary to achieve normalization of HS and HS-NRE levels in the CSF and plasma. In Part 2, 300 mg tralesinidase alfa sustained HS and HS-NRE normalization in the CSF and stabilized cortical gray matter volume (CGMV) over 48 weeks of treatment. Resolution of hepatomegaly and a reduction in spleen volume were observed in most patients. Significant correlations were also established between the change in cognitive AEq score and plasma drug exposure, plasma HS-NRE levels, and CGMV.ConclusionAdministration of tralesinidase alfa i.c.v. effectively normalized HS and HS-NRE levels as a prerequisite for clinical efficacy. Peripheral drug exposure data suggest a role for the glymphatic system in altering tralesinidase alfa efficacy.Trial registrationClinicaltrials.gov NCT02754076.FUNDINGBioMarin Pharmaceutical Inc. and Allievex Corporation.

Previous studies have suggested that cognitive and psychosocial underfunctioning in early-treated adults with PKU may be explained by suboptimal adherence to dietary treatments, however these studies often employ small samples, with different outcome measures, definitions and cut-offs. Samples have also tended to comprise participants with a limited range of blood phenylalanine concentrations, and often individuals who may not have been treated early enough to avoid neurological damage. In this study, we explore the impact of lifetime dietary control, as indicated by blood phenylalanine concentrations in childhood, adolescence and adulthood, on long-term cognitive and psychosocial outcomes in a large sample of adults with PKU who were diagnosed by neonatal screening and commenced on dietary treatment within the first month of life. 154 participants underwent cognitive testing, assessing attention, learning, working memory, language, executive functioning and processing speed. 149 completed measures of psychosocial functioning, documenting educational, occupational, quality of life, emotional and social outcomes which were compared with a group of healthy controls. Many adults with PKU demonstrated cognitive impairments, most frequently affecting processing speed (23%), executive function (20%) and learning (12%). Cognitive outcomes were related to measures of historic metabolic control, but only processing speed was significantly related to phenylalanine concentration at the time of testing after controlling for historic levels. Adults with PKU did not, however, differ from controls in educational, occupational, quality of life or emotional outcomes, or on a measure of family functioning, and showed only minor differences in relationship style. These findings have implications for patient counselling and decisions regarding the management of PKU in adulthood. This article is protected by copyright. All rights reserved.

Background: Sapropterin dihydrochloride, a synthetic formulation of BH4, the cofactor for phenylalanine hydroxylase (PAH, EC 1.14.16.1), was initially approved in Europe only for patients ≥4 years with BH4-responsive phenylketonuria. The aim of the SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) trial was to assess the efficacy (improvement in daily phenylalanine tolerance, neuromotor development and growth parameters), safety and pharmacokinetics of sapropterin dihydrochloride in children <4 years. Results: In total, 109 male or female children <4 years with confirmed BH4-responsive phenylketonuria or mild hyperphenylalaninemia and good adherence to dietary treatment were screened. 56 patients were randomly assigned (1:1) to 10 mg/kg/day oral sapropterin plus a phenylalanine-restricted diet or to only a phenylalanine-restricted diet for 26 weeks (27 to the sapropterin and diet group and 29 to the diet-only group; intention-to-treat population). Of these, 52 patients with ≥1 pharmacokinetic sample were included in the pharmacokinetic analysis, and 54 patients were included in the safety analysis. At week 26 in the sapropterin plus diet group, mean phenylalanine tolerance was 30.5 (95% confidence interval 18.7-42.3) mg/kg/day higher than in the diet-only group (p < 0.001). The safety profile of sapropterin, measured monthly, was acceptable and consistent with that seen in studies of older children. Using non-linear mixed effect modelling, a one-compartment model with flip-flop pharmacokinetic behaviour, in which the effect of weight was substantial, best described the pharmacokinetic profile. Patients in both groups had normal neuromotor development and stable growth parameters. Conclusions: The addition of sapropterin to a phenylalanine-restricted diet was well tolerated and led to a significant improvement in phenylalanine tolerance in children <4 years with BH4-responsive phenylketonuria or mild hyperphenylalaninemia. The pharmacokinetic model favou, SCOPUS: ar.j, info:eu-repo/semantics/published

To avoid potentially severe outcomes, phenylketonuria (PKU) must be detected as soon as possible after birth and managed with life-long treatment. A questionnaire-based survey was performed to document diagnosis and management practices for PKU in a region of Southern and Eastern Europe. Prevalence and management data were obtained from 37/59 (63 %) centres within 19/22 (86%) contacted countries (N = 8600 patients). The main results' analysis was based on completed questionnaires obtained from 31 centres (53%) within 15 countries (68%). A median of 10 % of patients per centre had been diagnosed after the newborn period. Metabolic dieticians and specialised adult PKU clinics were lacking in 36 and 84% of centres, respectively. In 26% of centres, treatment initiation was delayed until >15 days of life. Blood phenylalanine (Phe) thresholds to start treatment and upper Phe targets were inconsistent across centres. Ten percent of centres reported monitoring Phe every 2 weeks for pregnant women with PKU, which is insufficient to minimise risk of neonatal sequalae. Sapropterin dihydrochloride treatment was available in 48% of centres, with 24-h responsiveness tests most common (36%). Only one centre among the five countries lacking newborn screening provided a completed questionnaire. CONCLUSION: Targeted efforts by health care professionals and governments are needed to optimise diagnostic and management approaches for PKU in Southern and Eastern Europe. WHAT IS KNOWN: PKU must be detected early and optimally managed throughout life to avoid poor outcomes, yet newborn screening is not universal and diagnostic and management practices for PKU are known to vary widely between different centres and countries. Targeted efforts by health care professionals and governments are needed to optimise diagnostic and management approaches. WHAT IS NEW: PKU management practices are documented in 19 South and Eastern European countries indicating a heterogeneous situation across the reg

Phenylketonuria (PKU) is an inborn error of amino acid metabolism. It occurs in approximately 1 in 10,000 of the United Kingdom population and follows an autosomal recessive pattern of inheritance. The disease results from a deficiency or defect of the enzyme phenylalanine hydroxylase which converts phenylalanine (phe) to tyrosine (tyr). In PKU there is an accumulation of phenylalanine that is toxic to the developing brain and causes mental retardation, spasticity and seizures. The treatment of PKU is the adherence to a special phe-restricted diet with amino acid, vitamin and mineral supplements. There are guidelines for the duration of dietary therapy in the United Kingdom produced by the Medical Research Council (MRC) Steering Committee on Phenylketonuria. These guidelines have been reviewed recently and lifelong diet is now recommended. This study began prior to the publication of these recommendations at a time when many centres discontinued diet in early adolescence. The rationale for stopping diet in adolescence is that the majority of brain development is complete by the end of childhood. The risks to the brain of the subsequent rise in phe levels in adolescence and adulthood after diet cessation remain unclear. The impetus to this study was the emergence of reports of adults with PKU (who had discontinued diet after childhood) developing new neurological signs such as spasticity of the limbs. Magnetic resonance imaging (MRI) of the brain in these patients showed an abnormal signal in the cerebral white matter and it was initially suggested that the MRI changes depicted the structural abnormalities causing the loss of function in these individuals. It was postulated by these authors that elevated phe levels in later life had a toxic effect on myelin and that adults with PKU were at risk of later onset neurological damage. This study was designed to obtain more information about brain function in adults with PKU who had stopped dietary treatment and to attempt

Phenylketonuria (PKU) is an inborn error of amino acid metabolism. It occurs in approximately 1 in 10,000 of the United Kingdom population and follows an autosomal recessive pattern of inheritance. The disease results from a deficiency or defect of the enzyme phenylalanine hydroxylase which converts phenylalanine (phe) to tyrosine (tyr). In PKU there is an accumulation of phenylalanine that is toxic to the developing brain and causes mental retardation, spasticity and seizures. The treatment of PKU is the adherence to a special phe-restricted diet with amino acid, vitamin and mineral supplements. There are guidelines for the duration of dietary therapy in the United Kingdom produced by the Medical Research Council (MRC) Steering Committee on Phenylketonuria. These guidelines have been reviewed recently and lifelong diet is now recommended. This study began prior to the publication of these recommendations at a time when many centres discontinued diet in early adolescence. The rationale for stopping diet in adolescence is that the majority of brain development is complete by the end of childhood. The risks to the brain of the subsequent rise in phe levels in adolescence and adulthood after diet cessation remain unclear. The impetus to this study was the emergence of reports of adults with PKU (who had discontinued diet after childhood) developing new neurological signs such as spasticity of the limbs. Magnetic resonance imaging (MRI) of the brain in these patients showed an abnormal signal in the cerebral white matter and it was initially suggested that the MRI changes depicted the structural abnormalities causing the loss of function in these individuals. It was postulated by these authors that elevated phe levels in later life had a toxic effect on myelin and that adults with PKU were at risk of later onset neurological damage. This study was designed to obtain more information about brain function in adults with PKU who had stopped dietary treatment and to attempt

Phenylketonuria (PKU) is an inborn error of amino acid metabolism. It occurs in approximately 1 in 10,000 of the United Kingdom population and follows an autosomal recessive pattern of inheritance. The disease results from a deficiency or defect of the enzyme phenylalanine hydroxylase which converts phenylalanine (phe) to tyrosine (tyr). In PKU there is an accumulation of phenylalanine that is toxic to the developing brain and causes mental retardation, spasticity and seizures. The treatment of PKU is the adherence to a special phe-restricted diet with amino acid, vitamin and mineral supplements. There are guidelines for the duration of dietary therapy in the United Kingdom produced by the Medical Research Council (MRC) Steering Committee on Phenylketonuria. These guidelines have been reviewed recently and lifelong diet is now recommended. This study began prior to the publication of these recommendations at a time when many centres discontinued diet in early adolescence. The rationale for stopping diet in adolescence is that the majority of brain development is complete by the end of childhood. The risks to the brain of the subsequent rise in phe levels in adolescence and adulthood after diet cessation remain unclear. The impetus to this study was the emergence of reports of adults with PKU (who had discontinued diet after childhood) developing new neurological signs such as spasticity of the limbs. Magnetic resonance imaging (MRI) of the brain in these patients showed an abnormal signal in the cerebral white matter and it was initially suggested that the MRI changes depicted the structural abnormalities causing the loss of function in these individuals. It was postulated by these authors that elevated phe levels in later life had a toxic effect on myelin and that adults with PKU were at risk of later onset neurological damage. This study was designed to obtain more information about brain function in adults with PKU who had stopped dietary treatment and to attempt

Phenylketonuria (PKU) is an inborn error of amino acid metabolism. It occurs in approximately 1 in 10,000 of the United Kingdom population and follows an autosomal recessive pattern of inheritance. The disease results from a deficiency or defect of the enzyme phenylalanine hydroxylase which converts phenylalanine (phe) to tyrosine (tyr). In PKU there is an accumulation of phenylalanine that is toxic to the developing brain and causes mental retardation, spasticity and seizures. The treatment of PKU is the adherence to a special phe-restricted diet with amino acid, vitamin and mineral supplements. There are guidelines for the duration of dietary therapy in the United Kingdom produced by the Medical Research Council (MRC) Steering Committee on Phenylketonuria. These guidelines have been reviewed recently and lifelong diet is now recommended. This study began prior to the publication of these recommendations at a time when many centres discontinued diet in early adolescence. The rationale for stopping diet in adolescence is that the majority of brain development is complete by the end of childhood. The risks to the brain of the subsequent rise in phe levels in adolescence and adulthood after diet cessation remain unclear. The impetus to this study was the emergence of reports of adults with PKU (who had discontinued diet after childhood) developing new neurological signs such as spasticity of the limbs. Magnetic resonance imaging (MRI) of the brain in these patients showed an abnormal signal in the cerebral white matter and it was initially suggested that the MRI changes depicted the structural abnormalities causing the loss of function in these individuals. It was postulated by these authors that elevated phe levels in later life had a toxic effect on myelin and that adults with PKU were at risk of later onset neurological damage. This study was designed to obtain more information about brain function in adults with PKU who had stopped dietary treatment and to attempt

Phenylketonuria (PKU) is an inborn error of amino acid metabolism. It occurs in approximately 1 in 10,000 of the United Kingdom population and follows an autosomal recessive pattern of inheritance. The disease results from a deficiency or defect of the enzyme phenylalanine hydroxylase which converts phenylalanine (phe) to tyrosine (tyr). In PKU there is an accumulation of phenylalanine that is toxic to the developing brain and causes mental retardation, spasticity and seizures. The treatment of PKU is the adherence to a special phe-restricted diet with amino acid, vitamin and mineral supplements. There are guidelines for the duration of dietary therapy in the United Kingdom produced by the Medical Research Council (MRC) Steering Committee on Phenylketonuria. These guidelines have been reviewed recently and lifelong diet is now recommended. This study began prior to the publication of these recommendations at a time when many centres discontinued diet in early adolescence. The rationale for stopping diet in adolescence is that the majority of brain development is complete by the end of childhood. The risks to the brain of the subsequent rise in phe levels in adolescence and adulthood after diet cessation remain unclear. The impetus to this study was the emergence of reports of adults with PKU (who had discontinued diet after childhood) developing new neurological signs such as spasticity of the limbs. Magnetic resonance imaging (MRI) of the brain in these patients showed an abnormal signal in the cerebral white matter and it was initially suggested that the MRI changes depicted the structural abnormalities causing the loss of function in these individuals. It was postulated by these authors that elevated phe levels in later life had a toxic effect on myelin and that adults with PKU were at risk of later onset neurological damage. This study was designed to obtain more information about brain function in adults with PKU who had stopped dietary treatment and to attempt