Strategy for Generating Blinded Evidence for Single-Arm Trials with External Controls Using Expert Review of Home Video.

Introduction: Neurodegenerative diseases cause developmental delays and loss of milestones in infants and children. However, scalable outcome measures that quantify features meaningful to parents/caregivers (P/CGs) and have regulatory precedence are lacking for assessing the effectiveness of treatments in clinical trials of neurodegenerative disorders. To address this gap, we developed an innovative, blinded strategy for single-arm trials with external controls using expert panel review of home video.

Quantifying medical manifestations in Hurler syndrome with the infant physical symptom score: associations with long-term physical and adaptive outcomes.

Background: A physical symptom score (PSS) for the mucopolysaccharidosis (MPS) disorders has been developed to quantitate the somatic burden of disease across multiple organ systems. Studies have demonstrated the sensitivity and its relationship to age, IQ and adaptive functioning of the PSS in older children. With the onset of newborn screening, there is an increased need to characterize the somatic symptoms in the earliest stages of life, especially for young children under 36 months of age.

Quantitative brain MRI morphology in severe and attenuated forms of mucopolysaccharidosis type I.

Objective: To assess our hypothesis that brain macrostructure is different in individuals with mucopolysaccharidosis type I (MPS I) and healthy controls (HC), we conducted a comprehensive multicenter study using a uniform quantitative magnetic resonance imaging (qMRI) protocol, with analyses that account for the effects of disease phenotype, age, and cognition.

Methods: Brain MRIs in 23 individuals with attenuated (MPS IA) and 38 with severe MPS I (MPS IH), aged 4-25 years, enrolled under the study protocol NCT01870375, were compared to 98 healthy controls.

Results: Cortical and subcortical gray matter, white matter, corpus callosum, ventricular and choroid plexus volumes in MPS I significantly differed from HC.

Issues of COVID-19-related distance learning for children with neuronopathic mucopolysaccharidoses.

The COVID-19 pandemic has impacted the education of children around the world, forcing a large proportion of teaching to be carried out remotely. The implications of this disruption have yet to be fully elucidated, but initial assessments suggest that COVID-19-related school closures and reliance on virtual learning may have a long-term negative impact on educational attainment and future earnings as well as life expectancy of children in the United States. Among children with neurodegenerative disorders, such as neuronopathic mucopolysaccharidoses (MPS disorders), the effects of the pandemic are likely to be even greater.

The juvenile gangliosidoses: A timeline of clinical change.

Background: The gangliosidoses are rare inherited diseases that result in pathologic accumulation of gangliosides in the central nervous system and other tissues, leading to severe and progressive neurological impairment and early death in the childhood forms. No treatments are currently approved for the gangliosidoses, and development of treatments is impaired by limited understanding of the natural history of these diseases.

Objective: The objective of this study is to improve understanding of the juvenile gangliosidoses phenotypes and the late-infantile phenotypic subtype.

Intrathecal enzyme replacement for cognitive decline in mucopolysaccharidosis type I, a randomized, open-label, controlled pilot study.

Central nervous system manifestations of mucopolysaccharidosis type I (MPS I) such as cognitive impairment, hydrocephalus, and spinal cord compression are inadequately treated by intravenously-administered enzyme replacement therapy with laronidase (recombinant human alpha-L-iduronidase). While hematopoietic stem cell transplantation treats neurological symptoms, this therapy is not generally offered to attenuated MPS I patients. This study is a randomized, open-label, controlled pilot study of intrathecal laronidase in eight attenuated MPS I patients with cognitive impairment.

Intrathecal enzyme replacement for Hurler syndrome: biomarker association with neurocognitive outcomes.

Purpose: Abnormalities in cerebrospinal fluid (CSF) have been reported in Hurler syndrome, a fatal neurodegenerative lysosomal disorder. While no biomarker has predicted neurocognitive response to treatment, one of these abnormalities, glycosaminoglycan nonreducing ends (NREs), holds promise to monitor therapeutic efficacy. A trial of intrathecal enzyme replacement therapy (ERT) added to standard treatment enabled tracking of CSF abnormalities, including NREs.

Attention and corpus callosum volumes in individuals with mucopolysaccharidosis type I.

Objective: Previous research suggests attention and white matter (WM) abnormalities in individuals with mucopolysaccharidosis type I (MPS I); this cross-sectional comparison is one of the first to examine the relationship of WM structural abnormalities as measured by corpus callosum (CC) volumes with attention scores to evaluate this relationship in a larger sample of patients with MPS I.

Methods: Volumetric MRI data and performance on a computerized measure of sustained attention were compared for 18 participants with the severe form of MPS I (MPS IH), 18 participants with the attenuated form of MPS I (MPS I), and 60 typically developing age-matched controls.

Results: The MPS I groups showed below-average mean attention scores ( < 0.

Inhibiting Epidermal Growth Factor Receptor Dimerization and Signaling Through Targeted Delivery of a Juxtamembrane Domain Peptide Mimic.

Overexpression and deregulation of the epidermal growth factor receptor (EGFR) are implicated in multiple human cancers and therefore are a focus for the development of therapeutics. Current strategies aimed at inhibiting EGFR activity include monoclonal antibodies and tyrosine kinase inhibitors. However, activating mutations severely limit the efficacy of these therapeutics.

Post-transplant adaptive function in childhood cerebral adrenoleukodystrophy.

Objective: Hematopoietic stem cell transplantation (HSCT) is the only treatment known to slow or halt inflammatory demyelination among boys with the cerebral form of X-linked adrenoleukodystrophy (cALD), a devastating childhood condition affecting the central nervous system. HSCT can lead to a range of adverse outcomes including fatality. Previous studies have examined the potential predictors of post-HSCT survival and neurologic functioning.

Comparison of lipid-dependent bilayer insertion of pHLIP and its P20G variant.

The ability of the pH-Low Insertion Peptide (pHLIP) to insert into lipid membranes in a transbilayer conformation makes it an important tool for targeting acidic diseased tissues. pHLIP can also serve as a model template for thermodynamic studies of membrane insertion. We use intrinsic fluorescence and circular dichroism spectroscopy to examine the effect of replacing pHLIP's central proline on the pH-triggered lipid-dependent conformational switching of the peptide.

Language experience differentiates prefrontal and subcortical activation of the cognitive control network in novel word learning.

The purpose of this study was to examine the cognitive control mechanisms in adult English speaking monolinguals compared to early sequential Spanish-English bilinguals during the initial stages of novel word learning. Functional magnetic resonance imaging during a lexico-semantic task after only 2h of exposure to novel German vocabulary flashcards showed that monolinguals activated a broader set of cortical control regions associated with higher-level cognitive processes, including the supplementary motor area (SMA), anterior cingulate (ACC), and dorsolateral prefrontal cortex (DLPFC), as well as the caudate, implicated in cognitive control of language. However, bilinguals recruited a more localized subcortical network that included the putamen, associated more with motor control of language.