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John J. Hopwood - One of the best experts on this subject based on the ideXlab platform.
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Axonal dystrophy in the brain of mice with Sanfilippo Syndrome.
Experimental neurology, 2017Co-Authors: Helen Beard, John J. Hopwood, Sofia Hassiotis, Wei Ping Gai, Emma J. Parkinson-lawrence, Kim M HemsleyAbstract:Abstract Axonal dystrophy has been described as an early pathological feature of neurodegenerative disorders including Alzheimer's disease and amyotrophic lateral sclerosis. Axonal inclusions have also been reported to occur in several neurodegenerative lysosomal storage disorders including Mucopolysaccharidosis type IIIA (MPS IIIA; Sanfilippo Syndrome). This disorder results from a mutation in the gene encoding the lysosomal sulphatase sulphamidase, and as a consequence heparan sulphate accumulates, accompanied by secondarily-stored gangliosides. The precise basis of symptom generation in MPS IIIA has not been elucidated, however axonal dystrophy may conceivably lead to impaired vesicular trafficking, neuronal dysfunction and/or death. We have utilised a faithful murine model of MPS IIIA to determine the spatio-temporal profile of neuronal inclusion formation and determine the effect of restoring normal lysosomal function. Dopaminergic (tyrosine hydroxylase-positive), cholinergic (choline acetyltransferase-positive) and GABAergic (glutamic acid decarboxylase65/67-positive) neurons were found to exhibit axonal dystrophy in MPS IIIA mouse brain. Axonal lesions present by ~ seven weeks of age were Rab5-positive but lysosomal integral membrane protein-2 negative, suggesting early endosomal involvement. By 9–12-weeks of age, immunoreactivity for the autophagosome-related proteins LC3 and p62 and the proteasomal subunit 19S was noted in the spheroidal structures, together with wildtype α-synuclein, phosphorylated Thr-181 Tau and amyloid precursor protein, indicative of impaired axonal trafficking. Sulphamidase replacement reduced but did not abrogate the axonal lesions. Therefore, if axonal dystrophy impairs neuronal activity and ultimately, neuronal function, its incomplete resolution warrants further investigation.
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Combined Hurler and Sanfilippo Syndrome in a sibling pair
Molecular genetics and metabolism, 2011Co-Authors: Angela Sun, Jerry N. Thompson, John J. Hopwood, Stephen D. CederbaumAbstract:The mucopolysaccharidoses (MPS) are lysosomal storage disorders caused by defects in the enzymes involved in the degradation of glycosaminoglycans. Hurler Syndrome (MPS I) and Sanfilippo Syndrome (MPS III) are among the more common diseases in the group, each occurring with an incidence of approximately 1 in 100,000. We present a case of siblings, born of a consanguineous union, affected with both MPS I and MPS IIIa. The diagnoses were confirmed with fibroblast enzyme assays and sequence analysis of the genes, which identified homozygous mutations in IDUA and SGSH. We discuss their clinical features and course and examine the psychosocial aspects of their case, specifically, the decision-making process that the medical team and family faced regarding treatment with enzyme replacement therapy.
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Sanfilippo Syndrome: Clinical Genetic Diagnosis and Therapies
Lysosomal Storage Disorders, 2007Co-Authors: John J. HopwoodAbstract:This chapter aims to briefly review the natural history, pathophysiology, clinical features, and molecular genetics of Sanfilippo Syndrome, together with current and emerging advances and future perspectives, particularly to achieve early diagnosis and effective therapy. Sanfilippo Syndrome has a systematic name of mucopolysaccharidosis type III (MPS III). It is an autosomal-recessive lysosomal storage disorder (LSD) that affects about 1 in 70,000 live births (Meikle et al., 1999; Poorthuis et al., 1999). Sanfilippo Syndrome is the most common MPS, and represents four biochemically distinct disorders, each of which results from a deficiency of one of four enzymes required for the lysosomal degradation of the glycosaminoglycan (GAG) heparan sulfate (HS): sulfamidase (MPS IIIA); α-Nacetylglucosaminidase (MPS IIIB); acetyl Co:A glucosamine N-acetyl transferase (MPS IIIC); and glucosamine-6-sulfatase (MPS IIID). Fragments of partially degraded HS accumulate in lysosomes and are elevated in the urine of all Sanfilippo patients. Genes for all but one (type C) of the four MPS III types have been characterized and used to identify mutations that lead to a deficiency of the enzyme product, storage of HS fragments, and the Sanfilippo phenotype. No currently available therapies are yet able alter the natural history of Sanfilippo Syndrome. The grouping and in-depth study of the genes and enzyme systems involved in this Syndrome have provided extensive insight and appreciation of cellular processes involved in the systematic turnover of HS. This insight is slowly but surely identifying options for the development of potential therapies.
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Prenatal diagnosis of Sanfilippo Syndrome.
Prenatal diagnosis, 2005Co-Authors: John J. HopwoodAbstract:The focus of this communication is to comment on the relative importance of enzymatic and molecular genetics, potential false results and future options for prenatal diagnosis of Sanfilippo Syndrome (mucopolysaccharidosis (MPS) types IIIA, IIIB, IIIC and IIID). During the provision of an international service over the past 25 years, our department has identified 7 affected out of 49 MPS III prenatal assessments. During this period, the technology used by us and others (Thompson et al., 1993; Kleijer et al., 1996) in these diagnoses has undergone considerable development in evolution. Our policy to maintain a close relationship between the provision of a diagnostic service and research to achieve an overall goal of early diagnosis and effective therapy have progressed both activities. Copyright © 2005 John Wiley & Sons, Ltd.
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Sanfilippo Syndrome in Turkey: Identification of novel mutations in subtypes A and B
Human mutation, 2002Co-Authors: Serap Emre, Mugen Terzioglu, Aysegul Tokatli, Turgay Coşkun, Imran Özalp, Birgit Weber, John J. HopwoodAbstract:Sanfilippo Syndrome (mucopolysaccharidosis type III, MPS III) is a progressive disorder in which patients are characterized by severe central nervous system degeneration together with mild somatic disease. MPS III results from a deficiency in one of the four enzymes involved in the degradation of heparan sulfate, with sulfamidase (SGSH) being deficient in MPS IIIA and a-N-acetylglucosaminidase (NAGLU) deficient in MPS IIIB. Mutation screening using SSCP/heteroduplex analysis on genomic DNA fragments was performed in five Turkish MPS IIIA and eight Turkish MPS IIIB patients. In this study two mutations of SGSH were identified in MPS IIIA patients: R74C and the novel mutation P288S, and one polymorphism (IVS1+23 C>G). Five different mutations of NAGLU were identified in MPS IIIB patients: L682R, H248R, E153K, g.17703 A>G (novel), and T437I (novel). The clinical data of all patients are reported in detail. A high degree of genetic heterogeneity was observed in the Turkish MPS IIIA and MPS IIIB patients.
Martin B. Delatycki - One of the best experts on this subject based on the ideXlab platform.
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Sleep disturbance in Sanfilippo Syndrome: a parental questionnaire study
Archives of disease in childhood, 2005Co-Authors: J Fraser, Aa Gason, Je Wraith, Martin B. DelatyckiAbstract:Aims: To determine the incidence, manifestations, and best management of sleep disturbance in Sanfilippo Syndrome (mucopolysaccharidosis (MPS) type III). Methods: Families were ascertained through the MPS societies of Australasia, the UK, and the USA. Questionnaires were sent by mail and were answered anonymously. Identical questions regarding sleep disturbance were asked about unaffected siblings to provide control data. Sleep disturbance was quantified by a total sleep disturbance score. Results: A total of 141 responses were received; 91.5% of children with Sanfilippo Syndrome had sleep disturbance and this was significantly higher than for their unaffected sibs; 77.5% of parents had used medication for this problem, with melatonin and antihistamines being most commonly used. Melatonin and benzodiazepines were reported as the most efficacious. Many different environmental modifications had been employed for this problem and some parents reported success with behavioural therapies. Conclusions: Sleep disturbance is common, severe, and difficult to manage in Sanfilippo Syndrome. Based on the parental responses and its safety profile, melatonin is the first line drug that should be tried. Behavioural therapy should be tried in all with Sanfilippo Syndrome and sleep disturbance.
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Sleep disturbance in mucopolysaccharidosis type III (Sanfilippo Syndrome): a survey of managing clinicians.
Clinical genetics, 2002Co-Authors: J Fraser, Je Wraith, Martin B. DelatyckiAbstract:Sanfilippo Syndrome (mucopolysaccharidosis type III) is the commonest mucoploysaccharidosis. It causes neurodegeneration with often profound sleep and behavioral disturbance. Management of the sleep disturbance is difficult and inconsistent. In this study, we surveyed clinicians with particular expertise in the management of individuals with mucopolysaccharidoses. We found that sleep problems are almost universal in this patient population and that no one treatment is consistently viewed as beneficial. Among the clinicians surveyed, melatonin is reported as the medication most likely to be of benefit. Benzodiazepines, chloral hydrate, antihistamines and antipsychotic agents are overall reported as less efficacious. The major side-effect of the medications as a group was reported to be daytime somnolence. Based on this study, recommendations are given regarding the approach to sleep disturbance in Sanfilippo Syndrome.
J Fraser - One of the best experts on this subject based on the ideXlab platform.
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Sleep disturbance in Sanfilippo Syndrome: a parental questionnaire study
Archives of disease in childhood, 2005Co-Authors: J Fraser, Aa Gason, Je Wraith, Martin B. DelatyckiAbstract:Aims: To determine the incidence, manifestations, and best management of sleep disturbance in Sanfilippo Syndrome (mucopolysaccharidosis (MPS) type III). Methods: Families were ascertained through the MPS societies of Australasia, the UK, and the USA. Questionnaires were sent by mail and were answered anonymously. Identical questions regarding sleep disturbance were asked about unaffected siblings to provide control data. Sleep disturbance was quantified by a total sleep disturbance score. Results: A total of 141 responses were received; 91.5% of children with Sanfilippo Syndrome had sleep disturbance and this was significantly higher than for their unaffected sibs; 77.5% of parents had used medication for this problem, with melatonin and antihistamines being most commonly used. Melatonin and benzodiazepines were reported as the most efficacious. Many different environmental modifications had been employed for this problem and some parents reported success with behavioural therapies. Conclusions: Sleep disturbance is common, severe, and difficult to manage in Sanfilippo Syndrome. Based on the parental responses and its safety profile, melatonin is the first line drug that should be tried. Behavioural therapy should be tried in all with Sanfilippo Syndrome and sleep disturbance.
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Sleep disturbance in mucopolysaccharidosis type III (Sanfilippo Syndrome): a survey of managing clinicians.
Clinical genetics, 2002Co-Authors: J Fraser, Je Wraith, Martin B. DelatyckiAbstract:Sanfilippo Syndrome (mucopolysaccharidosis type III) is the commonest mucoploysaccharidosis. It causes neurodegeneration with often profound sleep and behavioral disturbance. Management of the sleep disturbance is difficult and inconsistent. In this study, we surveyed clinicians with particular expertise in the management of individuals with mucopolysaccharidoses. We found that sleep problems are almost universal in this patient population and that no one treatment is consistently viewed as beneficial. Among the clinicians surveyed, melatonin is reported as the medication most likely to be of benefit. Benzodiazepines, chloral hydrate, antihistamines and antipsychotic agents are overall reported as less efficacious. The major side-effect of the medications as a group was reported to be daytime somnolence. Based on this study, recommendations are given regarding the approach to sleep disturbance in Sanfilippo Syndrome.
Csaba Siffel - One of the best experts on this subject based on the ideXlab platform.
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Epidemiology of Sanfilippo Syndrome: results of a systematic literature review.
Orphanet journal of rare diseases, 2018Co-Authors: T. Zelei, Kata Csetneki, Zoltán Vokó, Csaba SiffelAbstract:Sanfilippo Syndrome (mucopolysaccharidosis [MPS] III subtypes A, B, C, and D) is a rare autosomal recessive inherited metabolic disorder that causes progressive neurocognitive degeneration. This systematic literature review was undertaken to compile and assess published epidemiological data, including various frequency measures and geographical variation on Sanfilippo Syndrome. The following databases were systematically searched for terms related to Sanfilippo Syndrome epidemiology: Medline, Embase, Cochrane Database of Systematic Reviews, Academic Search Complete, Cumulative Index to Nursing and Allied Health Literature, and the Centre for Reviews and Dissemination. Qualitative synthesis of research findings was performed. Of 2794 publications found in the initial search, 116 were deemed eligible after title and abstract screening. Following full-text review, 46 papers were included in the qualitative synthesis. Results of this systematic literature review indicate that lifetime risk at birth ranges from 0.17–2.35 per 100,000 live births for all 4 subtypes of MPS III together, and from 0.00–1.62 per 100,000 live births for the most frequent subtype, MPS IIIA. All 4 subtypes of MPS III are exceptionally rare, but they each have devastating effects on children. Higher-quality epidemiological data are needed to appropriately target resources for disease research and management.
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Epidemiology of Sanfilippo Syndrome: results of a systematic literature review
BMC, 2018Co-Authors: T. Zelei, Kata Csetneki, Zoltán Vokó, Csaba SiffelAbstract:Abstract Background Sanfilippo Syndrome (mucopolysaccharidosis [MPS] III subtypes A, B, C, and D) is a rare autosomal recessive inherited metabolic disorder that causes progressive neurocognitive degeneration. This systematic literature review was undertaken to compile and assess published epidemiological data, including various frequency measures and geographical variation on Sanfilippo Syndrome. Methods The following databases were systematically searched for terms related to Sanfilippo Syndrome epidemiology: Medline, Embase, Cochrane Database of Systematic Reviews, Academic Search Complete, Cumulative Index to Nursing and Allied Health Literature, and the Centre for Reviews and Dissemination. Qualitative synthesis of research findings was performed. Results Of 2794 publications found in the initial search, 116 were deemed eligible after title and abstract screening. Following full-text review, 46 papers were included in the qualitative synthesis. Results of this systematic literature review indicate that lifetime risk at birth ranges from 0.17–2.35 per 100,000 live births for all 4 subtypes of MPS III together, and from 0.00–1.62 per 100,000 live births for the most frequent subtype, MPS IIIA. Conclusion All 4 subtypes of MPS III are exceptionally rare, but they each have devastating effects on children. Higher-quality epidemiological data are needed to appropriately target resources for disease research and management
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Additional file 3: of Epidemiology of Sanfilippo Syndrome: results of a systematic literature review
2018Co-Authors: T. Zelei, Kata Csetneki, Zoltรกn Vokรณ, Csaba SiffelAbstract:Table S2. Reported lifetime risk at birth estimates of Sanfilippo Syndrome subtype A. File format: .docx. (DOCX 42ย�kb
Holly L. Peay - One of the best experts on this subject based on the ideXlab platform.
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Parent Experiences of Sanfilippo Syndrome Impact and Unmet Treatment Needs: A Qualitative Assessment
Neurology and Therapy, 2020Co-Authors: Katherine Ackerman Porter, Maria L. Escolar, Cara O’neill, Elise Drake, Samantha Parker, Stacey Montgomery, William Moon, Carolyn Worrall, Holly L. PeayAbstract:Introduction Sanfilippo Syndrome (MPS III) is a rare, degenerative condition characterized by symptoms impacting cognitive ability, mobility, behavior, and quality of life. Currently there are no approved therapies for this severe life-limiting disease. Integrating patient and caregiver experience data into drug development and regulatory decision-making has become a priority of the Food and Drug Administration and rare disease patient communities. Methods This study assesses parents’ perceptions of their child’s Sanfilippo Syndrome disease-related symptoms using a research approach that is consistent with the Center for Drug Evaluation and Research (CDER) guidance. This study was initiated by the Cure Sanfilippo Foundation, and all steps in the research process were informed by a multidisciplinary advisory committee, with an objective of informing biopharmaceutical companies and regulatory agencies. We explored caregiver burden, symptoms with greatest impact, and meaningful but unmet treatment needs. Data were collected from 25 parents through three focus groups and a questionnaire. Transcripts were coded and analyzed using inductive thematic analysis, and descriptive analysis of quantitative data was conducted. Results Participating parents’ children ranged in age from 4 to 36 years. Participants endorsed high caregiving burden across all stages of the disease. Analysis revealed multiple domains of unmet need that impact child and family quality of life, including cognitive-behavioral challenges in communication, relationships, behavior, anxiety, and child safety; and physical health symptoms including sleep, pain, and mobility. Participants reported placing high value on incremental benefits targeting those symptoms, and on a treatment that would slow or stop symptom progression. Conclusion Even modest treatment benefits for Sanfilippo Syndrome were shown to be highly valued. Despite high caregiver burden, most parents expressed a willingness to “try anything,” including treatments with potentially high risk profiles, to maintain their child’s current state.
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Parent Experiences of Sanfilippo Syndrome Impact and Unmet Treatment Needs: A Qualitative Assessment.
Neurology and therapy, 2020Co-Authors: Katherine Ackerman Porter, Maria L. Escolar, Elise Drake, Samantha Parker, Stacey Montgomery, William Moon, Carolyn Worrall, Cara O'neill, Holly L. PeayAbstract:Sanfilippo Syndrome (MPS III) is a rare, degenerative condition characterized by symptoms impacting cognitive ability, mobility, behavior, and quality of life. Currently there are no approved therapies for this severe life-limiting disease. Integrating patient and caregiver experience data into drug development and regulatory decision-making has become a priority of the Food and Drug Administration and rare disease patient communities. This study assesses parents' perceptions of their child's Sanfilippo Syndrome disease-related symptoms using a research approach that is consistent with the Center for Drug Evaluation and Research (CDER) guidance. This study was initiated by the Cure Sanfilippo Foundation, and all steps in the research process were informed by a multidisciplinary advisory committee, with an objective of informing biopharmaceutical companies and regulatory agencies. We explored caregiver burden, symptoms with greatest impact, and meaningful but unmet treatment needs. Data were collected from 25 parents through three focus groups and a questionnaire. Transcripts were coded and analyzed using inductive thematic analysis, and descriptive analysis of quantitative data was conducted. Participating parents' children ranged in age from 4 to 36 years. Participants endorsed high caregiving burden across all stages of the disease. Analysis revealed multiple domains of unmet need that impact child and family quality of life, including cognitive-behavioral challenges in communication, relationships, behavior, anxiety, and child safety; and physical health symptoms including sleep, pain, and mobility. Participants reported placing high value on incremental benefits targeting those symptoms, and on a treatment that would slow or stop symptom progression. Even modest treatment benefits for Sanfilippo Syndrome were shown to be highly valued. Despite high caregiver burden, most parents expressed a willingness to "try anything," including treatments with potentially high risk profiles, to maintain their child's current state.
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Meaningful treatment outcomes for Sanfilippo Syndrome: A study of caregiver preferences and prioritization
Molecular Genetics and Metabolism, 2019Co-Authors: Cara O'neill, Elise Drake, Katherine Porter, Holly L. PeayAbstract:Sanfilippo Syndrome (MPS III) is a rare, degenerative disorder with no approved therapies. This study explored caregiver perceptions of the burden of Sanfilippo Syndrome on the child and family, and meaningful benefits that are desired from a non-curative therapy. We used an innovative mixed-method approach with 25 caregivers (biological and step-parents) of children ages 4-36 years old from 17 U.S. states. We conducted three focus groups comprising three activities: (1) formative validity testing of a symptom/staging survey (not described here), (2) moderated exploration of burden and meaningful treatment benefit, and (3) best-worst scaling (BWS) activities to quantify the relative importance of twelve treatment benefits, which arose during activity 2 and thus varied across focus groups. Thematic analysis revealed common themes and the quantitative analysis used ‘best-worst’ scoring to prioritize meaningful benefits from most to least important. Caregivers’ experiences reflect uncertainty and distress related to progression and increased family burden with progressing symptoms. Participants expressed willingness to “try anything” to slow or stop progression. Meaningful benefits to the family included reducing risky and perceived aggressive/impulsive behaviors and improving ability to communicate needs and preferences. For their children, focus group 1 prioritized addressing communication (relative importance score=.50), pain (score=.35), and child unhappiness (score=.33) group 2 prioritized communication (score=.58), frustration (score=.33), and aggressive behavior (score=.31) and group 3 prioritized communication (score=.50), pain (score=.48), and sleep (score=.23). Caregivers reflected on the relevance of communication challenges across disease progression. Consistent with prior reports, most caregivers identified considerable burden. Modest treatment benefits to communication limitations and problematic behaviors would be highly valued, as would reduced pain-especially given caregiver uncertainty regarding the child’s pain experience. Our next steps include using these data to develop a larger BWS survey to prioritize meaningful treatment benefits across stages of MPS III progression. Funding: Cure Sanfilippo Foundation, BioMarin, Lysogene, Sobi, Orchard Therapeutics.
