Biochemical and clinical response after umbilical cord blood transplant in a boy with early childhood-onset beta-mannosidosis.

BACKGROUND: Deficiency in the enzyme β-mannosidase was described over three decades ago. Although rare in occurrence, the presentation of childhood-onset β-mannosidase deficiency consists of hypotonia in the newborn period followed by global development delay, behavior problems, and intellectual disability. No effective pharmacologic treatments have been available. METHODS: We report 2-year outcomes following the first umbilical cord blood transplant in a 4-year-old boy with early childhood-onset disease. RESULTS: We show restoration of leukocyte β-mannosidase activity which remained normal at 2 years posttransplant, and a simultaneous increase in plasma β-mannosidase activity and dramatic decrease in urine-free oligosaccharides were also observed. MRI of the brain remained stable. Neurocognitive evaluation revealed test point gains, although the magnitude of improvement was less than expected for age, causing lower IQ scores that represent a wider developmental gap between the patient and unaffected peers. CONCLUSION: Our findings suggest that hematopoietic cell transplant can correct the biochemical defect in β-mannosidosis, although preservation of the neurocognitive trajectory may be a challenge

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

PurposeAbnormalities 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. We evaluated safety, biomarker response, and neurocognitive correlates of change.MethodsIn addition to intravenous ERT and hematopoietic cell transplantation, patients (N = 24) received intrathecal ERT at four peritransplant time points; CSF was evaluated at each point. Neurocognitive functioning was quantified at baseline, 1 year, and 2 years posttransplant. Changes in CSF biomarkers and neurocognitive function were evaluated for an association.ResultsOver treatment, there were significant decreases in CSF opening pressure, biomarkers of disease activity, and markers of inflammation. Percent decrease in NRE from pretreatment to final intrathecal dose posttransplant was positively associated with percent change in neurocognitive score from pretreatment to 2 years posttransplant.ConclusionIntrathecal ERT was safe and, in combination with standard treatment, was associated with reductions in CSF abnormalities. Critically, we report evidence of a link between a biomarker treatment response and neurocognitive outcome in Hurler syndrome

Clinical trial of laronidase in Hurler syndrome after hematopoietic cell transplantation.

BackgroundMucopolysaccharidosis I (MPS IH) is a lysosomal storage disease treated with hematopoietic cell transplantation (HCT) because it stabilizes cognitive deterioration, but is insufficient to alleviate all somatic manifestations. Intravenous laronidase improves somatic burden in attenuated MPS I. It is unknown whether laronidase can improve somatic disease following HCT in MPS IH. The objective of this study was to evaluate the effects of laronidase on somatic outcomes of patients with MPS IH previously treated with HCT.MethodsThis 2-year open-label pilot study of laronidase included ten patients (age 5-13 years) who were at least 2 years post-HCT and donor engrafted. Outcomes were assessed semi-annually and compared to historic controls.ResultsThe two youngest participants had a statistically significant improvement in growth compared to controls. Development of persistent high-titer anti-drug antibodies (ADA) was associated with poorer 6-min walk test (6MWT) performance; when patients with high ADA titers were excluded, there was a significant improvement in the 6MWT in the remaining seven patients.ConclusionsLaronidase seemed to improve growth in participants <8 years old, and 6MWT performance in participants without ADA. Given the small number of patients treated in this pilot study, additional study is needed before definitive conclusions can be made

Social functioning and behaviour in Mucopolysaccharidosis IH [Hurlers Syndrome]

Background: Mucopolysaccharidosis type IH (MPS-IH) [Hurlers Syndrome] is a developmental genetic disorder characterised by severe physical symptoms and cognitive decline. This study aimed to investigate the behavioural phenotype of MPS-IH treated by haematopoietic cell transplantation, focusing on social functioning and sleep. Parental stress was also measured. Methods: Participants were 22 children with MPS-IH (mean age 9 years 1 month), of whom 10 were male (45%). Parents completed the Social Responsiveness Scale (SRS), Child Behaviour Checklist (CBCL), Children’s Sleep Habit Questionnaire and Parent Stress Index, Short Form (PSI-SF). Results: Twenty-three per cent of children with MPS-IH scored in the severe range of the SRS, suggesting significant difficulties in social functioning. Children with MPS-IH were more than 30 times more likely to receive scores in the severe range than typically developing children. Thirty-six per cent scored in the mild-to-moderate range, suggesting milder, but marked, difficulties in social interaction. Although children with MPS-IH did not show significantly higher rates of internalising, externalising or total behaviour problems than the normative sample, they received scores that were significantly higher on social, thought and attention problems and rule-breaking behaviour, and all the competence areas of the CBCL. Parents of children with MPS-IH did not score significantly higher on parental stress than parents in a normative sample. Conclusions: Parents of children with MPS-IH rate their children as having problems with social functioning and various areas of competence more frequently than previously thought, with implications for clinical support

Procyanidin B3 Prevents Articular Cartilage Degeneration and Heterotopic Cartilage Formation in a Mouse Surgical Osteoarthritis Model

Osteoarthritis (OA) is a common disease in the elderly due to an imbalance in cartilage degradation and synthesis. Heterotopic ossification (HO) occurs when ectopic masses of endochondral bone form within the soft tissues around the joints and is triggered by inflammation of the soft tissues. Procyanidin B3 (B3) is a procyanidin dimer that is widely studied due to its high abundance in the human diet and antioxidant activity. Here, we evaluated the role of B3 isolated from grape seeds in the maintenance of chondrocytes in vitro and in vivo. We observed that B3 inhibited H2O2-induced apoptosis in primary chondrocytes, suppressed H2O2- or IL-1ß−induced nitric oxide synthase (iNOS) production, and prevented IL-1ß−induced suppression of chondrocyte differentiation marker gene expression in primary chondrocytes. Moreover, B3 treatment enhanced the early differentiation of ATDC5 cells. To examine whether B3 prevents cartilage destruction in vivo, OA was surgically induced in C57BL/6J mice followed by oral administration of B3 or vehicle control. Daily oral B3 administration protected articular cartilage from OA and prevented chondrocyte apoptosis in surgically-induced OA joints. Furthermore, B3 administration prevented heterotopic cartilage formation near the surgical region. iNOS protein expression was enhanced in the synovial tissues and the pseudocapsule around the surgical region in OA mice fed a control diet, but was reduced in mice that received B3. Together, these data indicated that in the OA model, B3 prevented OA progression and heterotopic cartilage formation, at least in a part through the suppression of iNOS. These results support the potential therapeutic benefits of B3 for treatment of human OA and heterotopic ossification

Neurocognition across the spectrum of mucopolysaccharidosis type I: Age, severity, and treatment

OBJECTIVES: Precise characterization of cognitive outcomes and factors that contribute to cognitive variability will enable better understanding of disease progression and treatment effects in mucopolysaccharidosis type I (MPS I). We examined the effects on cognition of phenotype, genotype, age at evaluation and first treatment, and somatic disease burden. METHODS: Sixty patients with severe MPS IH (Hurler syndrome treated with hematopoietic cell transplant and 29 with attenuated MPS I treated with enzyme replacement therapy), were studied with IQ measures, medical history, genotypes. Sixty-seven patients had volumetric MRI. Subjects were grouped by age and phenotype and MRI and compared to 96 normal controls. RESULTS: Prior to hematopoietic cell transplant, MPS IH patients were all cognitively average, but post-transplant, 59% were below average, but stable. Genotype and age at HCT were associated with cognitive ability. In attenuated MPS I, 40% were below average with genotype and somatic disease burden predicting their cognitive ability. White matter volumes were associated with IQ for controls, but not for MPS I. Gray matter volumes were positively associated with IQ in controls and attenuated MPS I patients, but negatively associated in MPS IH. CONCLUSIONS: Cognitive impairment, a major difficulty for many MPS I patients, is associated with genotype, age at treatment and somatic disease burden. IQ association with white matter differed from controls. Many attenuated MPS patients have significant physical and/or cognitive problems and receive insufficient support services. Results provide direction for future clinical trials and better disease management

Computer-aided identification of prostatic adenocarcinoma: Segmentation of glandular structures

Background: Identification of individual prostatic glandular structures is an important prerequisite to quantitative histological analysis of prostate cancer with the aid of a computer. We have developed a computer method to segment individual glandular units and to extract quantitative image features, for computer identification of prostatic adenocarcinoma. Methods: Two sets of digital histology images were used: database I (n = 57) for developing and testing the computer technique, and database II (n = 116) for independent validation. The segmentation technique was based on a k-means clustering and a region-growing method. Computer segmentation results were evaluated subjectively and also compared quantitatively against manual gland outlines, using the Jaccard similarity measure. Quantitative features that were extracted from the computer segmentation results include average gland size, spatial gland density, and average gland circularity. Linear discriminant analysis (LDA) was used to combine quantitative image features. Classification performance was evaluated with receiver operating characteristic (ROC) analysis and the area under the ROC curve (AUC). Results: Jaccard similarity coefficients between computer segmentation and manual outlines of individual glands were between 0.63 and 0.72 for non-cancer and between 0.48 and 0.54 for malignant glands, respectively, similar to an interobserver agreement of 0.79 for non-cancer and 0.75 for malignant glands, respectively. The AUC value for the features of average gland size and gland density combined via LDA was 0.91 for database I and 0.96 for database II. Conclusions: Using a computer, we are able to delineate individual prostatic glands automatically and identify prostatic adenocarcinoma accurately, based on the quantitative image features extracted from computer-segmented glandular structures

Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology

Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive inherited disease, caused by deficiency of the enzyme α-L-iduronidase, resulting in accumulation of the glycosaminoglycans (GAGs) dermatan and heparan sulfate in organs and tissues. If untreated, patients with the severe phenotype die within the first decade of life. Early diagnosis is crucial to prevent the development of fatal disease manifestations, prominently cardiac and respiratory disease, as well as cognitive impairment. However, the initial symptoms are nonspecific and impede early diagnosis. This review discusses common phenotypic manifestations in the order in which they develop. Similarities and differences in the three animal models for MPS I are highlighted. Earliest symptoms, which present during the first 6 months of life, include hernias, coarse facial features, recurrent rhinitis and/or upper airway obstructions in the absence of infection, and thoracolumbar kyphosis. During the next 6 months, loss of hearing, corneal clouding, and further musculoskeletal dysplasias develop. Finally, late manifestations including lower airway obstructions and cognitive decline emerge. Cardiac symptoms are common in MPS I and can develop in infancy. The underlying pathogenesis is in the intra- and extracellular accumulation of partially degraded GAGs and infiltration of cells with enlarged lysosomes causing tissue expansion and bone deformities. These interfere with the proper arrangement of collagen fibrils, disrupt nerve fibers, and cause devastating secondary pathophysiological cascades including inflammation, oxidative stress, and other disruptions to intracellular and extracellular homeostasis. A greater understanding of the natural history of MPS I will allow early diagnosis and timely management of the disease facilitating better treatment outcomes