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D'Aco K.,Childrens Hospital of Philadelphia | Underhill L.,Genzyme | Rangachari L.,Genzyme | Arn P.,Nemours Childrens Clinic | And 5 more authors.
European Journal of Pediatrics | Year: 2012

Our objective was to assess how the diagnosis and treatment of mucopolysaccharidosis I (MPS I) have changed over time. We used data from 891 patients in the MPS I Registry, an international observational database, to analyze ages at symptom onset, diagnosis, treatment initiation, and treatment allocation (hematopoietic stem cell transplantation, enzyme replacement therapy with laronidase, both, or neither) over time for all disease phenotypes (Hurler, Hurler-Scheie, and Scheie syndromes). The interval between diagnosis and treatment has become shorter since laronidase became available in 2003 (gap during 2006-2009: Hurler-0.2 year, Hurler-Scheie-0.5 year, Scheie-1.4 years). However, the age at diagnosis has not decreased for any MPS I phenotype over time, and the interval between symptom onset and treatment initiation remains substantial for both Hurler-Scheie and Scheie patients (gap during 2006-2009, 2.42 and 6.71 years, respectively). Among transplanted patients, an increasing proportion received hematopoietic stem cells from cord blood (34 out of 64 patients by 2009) and was also treated with laronidase (42 out of 45 patients by 2009). Conclusions: Despite the availability of laronidase since 2003, the diagnosis of MPS I is still substantially delayed for patients with Hurler- Scheie and Scheie phenotypes, which can lead to a suboptimal treatment outcome. Increased awareness of MPS I signs and symptoms by primary care providers and pediatric subspecialists is crucial to initiate early treatment and to improve the quality of life of MPS I patients. © The Author(s) 2012. Source


Kosuga M.,Center for Lysosomal storage diseases | Kosuga M.,National Center for Child Health and Development | Mashima R.,National Center for Child Health and Development | Hirakiyama A.,National Center for Child Health and Development | And 9 more authors.
Molecular Genetics and Metabolism | Year: 2016

Mucopolysaccharidosis type II (MPS II: also called as Hunter syndrome) is an X-linked recessive lysosomal storage disorder characterized by the accumulation of extracellular glycosaminoglycans due to the deficiency of the enzyme iduronate-2-sulfatase (IDS). Previous observations suggested that MPS II can be classified into two distinct disease subtypes: (1) severe type of MPS II involves a decline in the cognitive ability of a patient and (2) attenuated type of MPS II exhibits no such intellectual phenotype. To determine whether such disease subtypes of MPS II could be explained by genetic diagnosis, we analyzed mutations in the IDS gene of 65 patients suffering from MPS II among the Japanese population who were diagnosed with both the accumulation of urinary glycosaminoglycans and a decrease in their IDS enzyme activity between 2004 and 2014. Among the specimens examined, we identified the following mutations: 33 missense, 8 nonsense, 7 frameshift, 4 intronic changes affecting splicing, 8 recombinations involving IDS-IDS2, and 7 other mutations including 4 large deletions. Consistent with the previous data, the results of our study showed that most of the attenuated phenotype was derived from the missense mutations of the IDS gene, whereas mutations associated with a large structural alteration including recombination, splicing, frameshift, and nonsense mutations were linked to the severe phenotype of MPS II. Furthermore, we conducted a homology modeling study of IDS P120R and N534I mutant as representatives of the causative mutation of the severe and attenuated type of MPS II, respectively. We found that the substitution of P120R of the IDS enzyme was predicted to deform the α-helix generated by I119-F123, leading to the major structural alteration of the wild-type IDS enzyme. In sharp contrast, the effect of the structural alteration of N534I was marginal; thus, this mutation was pathogenically predicted to be associated with the attenuated type of MPS II. These results suggest that a combination of the genomic diagnosis of the IDS gene and the structural prediction of the IDS enzyme could enable the prediction of a phenotype more effectively. © 2016 Elsevier Inc. Source


Hwu W.-L.,National Taiwan University Hospital | Okuyama T.,Center for Lysosomal storage diseases | But W.M.,Queen Elizabeth Hospital | Estrada S.,University of the Philippines | And 12 more authors.
Molecular Genetics and Metabolism | Year: 2012

Introduction: Mucopolysaccharidosis (MPS) type VI (Maroteaux-Lamy syndrome) is a clinically heterogeneous lysosomal storage disorder. It presents significant diagnostic and treatment challenges due to the rarity of the disease and complexity of the phenotype. As information about MPS VI in Asia-Pacific countries is limited, a survey was conducted to assess current practices for diagnosis and management of MPS VI in this region. The participants were selected based on their experience in diagnosing and managing MPS patients. Methods: The survey comprised 29 structured quantitative or qualitative questions. Follow-up consultations were undertaken to discuss the data further. Results: Thirteen physicians from eight countries or regions (Australia, China, Hong Kong, Japan, Malaysia, Philippines, Taiwan and Thailand) were surveyed. At the time of the survey twenty-two patients with MPS VI were directly treated by the respondents and most (~80%) had rapidly progressing disease. A wide range of medical specialists are involved in managing patients with MPS VI, the most common being orthopedic surgeons, pediatricians and geneticists. The availability/accessibility of diagnostic tools, therapies and national insurance coverage vary greatly across the countries/regions and, in some cases, between different regions within the same country. Currently, there are national MPS management groups in Australia and Japan. Australia, Taiwan and Hong Kong have local guidelines for managing MPS and local MPS registries are available in Australia, Taiwan, and Japan. Conclusions: This survey highlights differences in the diagnosis and management of MPS VI between Asia-Pacific countries/regions. Important barriers to advancing the identification, understanding and treatment of MPS VI include the paucity of epidemiological information, limited access to laboratory diagnostics and therapies, low disease awareness, and a lack of monitoring and treatment guidelines. There is a clear need to facilitate communications between physicians and establish regional or national disease registries, a multidisciplinary referral network, and a centralized diagnostic and management framework. © 2012 Elsevier Inc. Source


Morimoto N.,National Center for Child Health and Development | Kitamura M.,National Center for Child Health and Development | Kosuga M.,Center for Lysosomal storage diseases | Okuyama T.,Center for Lysosomal storage diseases
Molecular Genetics and Metabolism | Year: 2014

Background: Mucopolysaccharidoses (MPSs) are lysosomal storage disorders caused by lysosomal enzyme deficiencies that result in systemic accumulation of glycosaminoglycans (GAGs). Accumulation of GAGs in the upper airway can lead to respiratory failure. The aim of this study was to investigate changes of the airway by flexible endoscopy and CT. Methods: Thirty-five patients aging from 2 to 16. years (mean: 9.2. ±. 4.4. years) participated in this study. The majority had MPS I (n. = 5) or MPS II (n. = 25). The shape of the trachea and the cross-sectional trachea surface area (TSA) was determined at the Th1 and Th2 levels. Airway obstruction was evaluated from endoscopic findings and classified into 3 grades (Grades 0, 1, and 2). Forty-five patients in the control group who underwent tracheal CT for other conditions were retrospectively selected from the database. Results: Tracheal morphology was abnormal in 50-60%, which showed a transversely collapsing narrow trachea. Tracheal deformity was severe in MPS II and MPS IV. The mean TSA of the MPS patients was 55.5±29.0mm2 at Th1 and 61.4±29.0mm2 at Th2, while that of the control group was 90.1±41.9mm2 and 87.9±39.3mm2, respectively. Respiratory distress was noted in 15 of the 35 patients, among whom 7 patients showed tracheal deformity and 7 patients had laryngeal redundancy. Three patients had no abnormalities of the larynx or trachea, so other factors such as pharyngeal stenosis or lower airway stenosis might have contributed to their respiratory distress. Conclusion: CT and flexible endoscopy allow quantitative and morphological evaluation of airway narrowing, which is beneficial for airway management in MPS children. © 2014 Elsevier Inc. Source


Furujo M.,National Okayama Medical Center | Kubo T.,National Okayama Medical Center | Kosuga M.,Center for Lysosomal storage diseases | Okuyama T.,Center for Lysosomal storage diseases
Molecular Genetics and Metabolism | Year: 2011

Mucopolysaccharidosis type VI (MPS VI) is a progressive, multisystem autosomal recessive lysosomal disorder resulting from deficient N-acetylgalactosamine-4-sulphatase (ASB) and the consequent accumulation of glycosaminoglycan (GAG). Preclinical and clinical studies had demonstrated clinical benefits of early initiation of systemic therapies in patients with MPS. In this case report, two siblings with MPS VI started enzyme replacement therapy (ERT) with weekly infusions of recombinant human ASB (Galsulfase) at 1. mg/kg. Sibling 1 started ERT 5.6. years of age and Sibling 2 was 6. weeks old. The disease status in these two siblings prior to and for no less than 36. months of ERT was followed up and compared. The treatment was well tolerated by both siblings. During 36. months of ERT, symptoms typical of MPS VI including short stature, progressive dysmorphic facial features, hepatosplenomegaly, hearing impairment, corneal clouding, and dysostosis multiplex were largely absent in the younger sibling. Her cardiac functions and joint mobility were well preserved. On the other hand, her affected brother had typical MPS VI phenotypic features described above before commencing ERT at the equivalent age, of 3. years. There was significant improvement in the shoulder range of motion and hearing loss after 36. months of treatment and cardiac function was largely preserved. His skeletal deformity and short stature remained unchanged. The results showed that early ERT initiated at newborn is safe and effective in preventing or slowing down disease progression of MPS VI including bone deformities. These observations indicate that early diagnosis and treatment of MPS VI before development of an irreversible disease is critical for optimal clinical outcome. © 2011 Elsevier Inc. Source

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