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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. 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. Cortical and subcortical gray matter, white matter, corpus callosum, ventricular and choroid plexus volumes in MPS I significantly differed from HC. Thicker cortex, lower white matter and corpus callosum volumes were already present at the youngest MPS I participants aged 4–5 years. Age-related differences were observed in both MPS I groups, but most markedly in MPS IH, particularly in cortical gray matter metrics. IQ scores were inversely associated with ventricular volume in both MPS I groups and were positively associated with cortical thickness only in MPS IA. Quantitatively-derived MRI measures distinguished MPS I participants from HC as well as severe from attenuated forms. Age-related neurodevelopmental trajectories in both MPS I forms differed from HC. The extent to which brain structure is altered by disease, potentially spared by treatment, and how it relates to neurocognitive dysfunction needs further exploration. • Quantitively measured brain macrostructure distinguished MPS I and healthy subjects. • Brain MRI volumes differed in participants with severe and attenuated MPS I forms. • In addition to white matter, other brain regions showed morphometric changes. • Cortical and subcortical gray matter, ventricles, and choroid plexus were altered. • IQ-related associations to ventricular volume and cortical thickness were present. [ABSTRACT FROM AUTHOR]

Background: Treatments for mucopolysaccharidoses (MPSs) have increased longevity, but coronary artery disease (CAD) and cardiovascular complications cause mortality in a high percentage of patients. Non-invasive measures of sub-clinical atherosclerosis, such as carotid intima–media thickness (cIMT) and arterial stiffness, may be useful for prediction of CAD outcomes in MPS patients. Objectives: The aim of the study was to determine if cIMT and arterial stiffness are abnormal in MPS I and II patients compared to healthy controls. Methods: MPS patients underwent carotid artery ultrasonography, and electronic wall-tracking software was used to measure cIMT, carotid artery cross-sectional compliance (cCSC), cross-sectional distensibility (cCSD), and incremental elastic modulus (cIEM). Control data from healthy subjects were obtained from a different study that utilized identical testing within the same laboratory. Results: A total of 406 healthy controls and 25 MPS patients (16 MPS I, 9 MPS II) were studied. All MPS patients had or were receiving treatment: 15 patients (6 MPS I, 9 MPS II) were receiving enzyme replacement therapy (ERT), 9 patients (all MPS I) had received hematopoietic stem cell transplant (HSCT), and 1 patient with MPS I had received HSCT and was receiving enzyme replacement therapy (ERT). MPS patients had significantly higher mean (±SD) cIMT (0.56±0.05mm) compared to controls (0.44±0.04mm; adjusted p<0.001). MPS patients also had increased stiffness compared to controls, showing significantly lower cCSC (0.14±0.09mm2/mmHg versus 0.16±0.05mm2/mmHg; adjusted p=0.019), and higher cIEM (1362±877mmHg versus 942±396mmHg; adjusted p<0.001). cCSD in MPS patients was lower than that of controls (29.7±16.4% versus 32.0±8.2%) but was not statistically significant; p=0.12. Among MPS patients, cCSD showed a significant association with cIMT (p=0.047), while the association between cIEM and cIMT approached significance (p=0.077). No significant differences were observed in cIMT, cCSD, cCSC, and cIEM between MPS I and MPS II patients. Conclusions: Despite treatment, MPS patients had higher cIMT compared to healthy controls, indicating this marker of sub-clinical atherosclerosis may be a useful predictor of CAD outcomes. The association of arterial stiffness measures with cIMT suggests that mechanical and structural changes may occur in concert among MPS patients. Although yet to be confirmed, increased cIMT and arterial stiffness in MPS I and II patients may be a consequence of inflammatory signaling pathways triggered by heparan or dermatan sulfate-derived oligosaccharides. Prospective, longitudinal studies will need to be performed in order to evaluate the usefulness of these carotid measurements as predictors of adverse CAD outcomes in MPS patients. [ABSTRACT FROM AUTHOR]

Abstract: Sapropterin dihydrochloride, a synthetic tetrahydrobiopterin (BH4), works as a chaperone of phenylalanine hydroxylase (PAH) in phenylketonuria (PKU) to facilitate and stabilize folding of PAH into its most active conformation. No standard pharmacogenetic tests exist to identify responsive genotypes. Previous studies have failed to identify genotypes that consistently predict response; they are weakened by varied: 1) doses; 2) response definitions; 3) duration; 4) phenylalanine (PHE) test times during different protein catabolic states; 5) control of dietary PHE. START (sapropterin therapy actual response test) protocol is a double blind, placebo-controlled, 4-week clinical test that obviates the confounders aforementioned. START results were evaluated for response-genotype correlates and trends in molecular characteristics. Results: Seventy-four patients completed START. Thirty-six patients (48.6%) responded, 55 patients'' genotypes are known, 38 unique genotypes are present. Alleles consistently associated with response include Y414C (8/8 patients, 6 genotypes) and I65T (9/9 patients, 6 genotypes). The p.R408W mutation, in which substitution of straight chain arginine with bulky aromatic amine, tryptophan, at the crux of a strategic hinge site activating folding of PAH, amino acid sequence 408, was strongly associated with non-response (21/29 patients non-responsive, 12/17 genotypes non-responsive). Genotypes containing at least one allele with ≥25% residual activity compared to wild type, were strongly associated with response. Conclusions: The START protocol provides a rigorous pharmacogenetic test to identify sapropterin responsiveness and genotypes associated with responsiveness and non-responsiveness. Some genotypes were found to be predictive of responsiveness or non-responsiveness, and responsiveness was associated with specific alleles. The START protocol provides a reliable test for sapropterin responsiveness and will continue to improve understanding of how PKU mutations impact PAH protein-folding dynamics and enhance understanding of PKU disease and its management. [Copyright &y& Elsevier]