Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0037315 (sleep apnea)
 8,000 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mucopolysaccharidosis I (MPS I, McKusick 25280) is caused by the deficiency or absence of the lysosomal enzyme, alpha-L-iduronidase (EC 3.2.1.76). This inherited disease causes progressive cellular, tissue and organ damage across the entire phenotypic spectrum. Disabling, multi-organ disease is the rule, and generally results in death between the first and fourth decades of life. Recently, laronidase (Aldurazyme) [Genzyme], a specific recombinant human alpha-L-iduronidase) became commercially available as long-term enzyme replacement therapy. Results from the Phase I/II and III extended clinical studies have shown that laronidase safely and effectively alleviates many systemic signs and symptoms of this progressive multisystemic disease. Clinically meaningful and sustained improvements in pulmonary function and functional capacity have been observed in Phase III study patients. Significant and sustained reductions in urinary glysosaminoglycan (GAG) excretion and hepatomegaly have also been observed. Improvements in sleep apnoea and joint range of motion occurred in patients with the most severe symptoms at baseline. Improvements in Disability Index scores as measured using the CHAQ and HAQ questionnaires were modest, which may have been related to the fact that these disability measuring tools are not disease-specific. Anecdotal reports of improvements in the performance of daily activities further add to the therapeutic benefits, as do case histories pointing at stabilisation or improvement of symptomatology in various organs, such as the eyes, heart, and muscles. With the availability of specific treatment, the importance of early recognition of the disease and appropriate therapeutic intervention has increased. The variability in clinical symptomatology is reviewed in detail and may allow for a better understanding of the diagnostic and therapeutic challenges. Results of the clinical trials and their initial extension periods, as well as the anecdotal experiences of physicians with laronidase in non-study settings, are discussed.
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PMID:The first 5 years of clinical experience with laronidase enzyme replacement therapy for mucopolysaccharidosis I. 1579 39

Recombinant human alpha-L-iduronidase (Aldurazyme, laronidase) was approved as an enzyme replacement therapy for patients with the lysosomal storage disorder, mucopolysaccharidosis I (MPS I). In order to assess the long-term safety and efficacy of laronidase therapy, 5 of 10 patients in the original laronidase Phase 1/2 clinical trial were re-evaluated after 6 years of treatment. Lysosomal storage was further improved at 6 years (urinary glycosaminoglycans (GAG) excretion decreased 76%; mean liver size at 1.84% of body weight). Shoulder maximum range of motion was maintained or further increased and reached a mean 33.2 (R) and 25.0 (L) degrees gained in flexion and 34.0 (R) and 27.3 (L) degrees gained in extension. Sleep apnea was decreased in four of five patients and the airway size index improved. Cardiac disease evaluations showed no progression to heart failure or cor pulmonale but pre-existing significant valve disease did progress in some patients. Substantial growth was observed for the pre-pubertal patients, with a gain of 33 cm (27%) in height and a gain of 31 kg in weight (105%). In general, the evaluated patients reported an improved ability to perform normal activities of daily living. Overall these data represent the first evidence that laronidase can stabilize or reverse many aspects of MPS I disease during long-term therapy and that early treatment prior to the development of substantial cardiac and skeletal disease may lead to better outcomes.
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PMID:A follow-up study of MPS I patients treated with laronidase enzyme replacement therapy for 6 years. 1701 Dec 23

Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease with progressive multisystem involvement, associated with a deficiency of arylsulfatase B leading to the accumulation of dermatan sulfate. Birth prevalence is between 1 in 43,261 and 1 in 1,505,160 live births. The disorder shows a wide spectrum of symptoms from slowly to rapidly progressing forms. The characteristic skeletal dysplasia includes short stature, dysostosis multiplex and degenerative joint disease. Rapidly progressing forms may have onset from birth, elevated urinary glycosaminoglycans (generally >100 microg/mg creatinine), severe dysostosis multiplex, short stature, and death before the 2nd or 3rd decades. A more slowly progressing form has been described as having later onset, mildly elevated glycosaminoglycans (generally <100 microg/mg creatinine), mild dysostosis multiplex, with death in the 4th or 5th decades. Other clinical findings may include cardiac valve disease, reduced pulmonary function, hepatosplenomegaly, sinusitis, otitis media, hearing loss, sleep apnea, corneal clouding, carpal tunnel disease, and inguinal or umbilical hernia. Although intellectual deficit is generally absent in MPS VI, central nervous system findings may include cervical cord compression caused by cervical spinal instability, meningeal thickening and/or bony stenosis, communicating hydrocephalus, optic nerve atrophy and blindness. The disorder is transmitted in an autosomal recessive manner and is caused by mutations in the ARSB gene, located in chromosome 5 (5q13-5q14). Over 130 ARSB mutations have been reported, causing absent or reduced arylsulfatase B (N-acetylgalactosamine 4-sulfatase) activity and interrupted dermatan sulfate and chondroitin sulfate degradation. Diagnosis generally requires evidence of clinical phenotype, arylsulfatase B enzyme activity <10% of the lower limit of normal in cultured fibroblasts or isolated leukocytes, and demonstration of a normal activity of a different sulfatase enzyme (to exclude multiple sulfatase deficiency). The finding of elevated urinary dermatan sulfate with the absence of heparan sulfate is supportive. In addition to multiple sulfatase deficiency, the differential diagnosis should also include other forms of MPS (MPS I, II IVA, VII), sialidosis and mucolipidosis. Before enzyme replacement therapy (ERT) with galsulfase (Naglazyme), clinical management was limited to supportive care and hematopoietic stem cell transplantation. Galsulfase is now widely available and is a specific therapy providing improved endurance with an acceptable safety profile. Prognosis is variable depending on the age of onset, rate of disease progression, age at initiation of ERT and on the quality of the medical care provided.
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PMID:Mucopolysaccharidosis VI. 2038 7

Mucopolysaccharidosis type I (MPS I) is caused by a deficiency of the lysosomal hydrolase a-L-Iduronidase leading to accumulation of the GAGs, dermatan sulfate, and heparan sulphate, The disease spectrum includes a disorder with severe involvement and CNS disease Hurler disease (HPS I H) a chronic disease without CNS disease Scheie disease (HPS I S5) and the intermediate Hurler/Scheie disease(HPS I HIS).The urine GAGs pattern. confirmed by Iduronidase enzyme assay is diagnostic. Over 200 mutations exist. Genotype / phenotype correlation is poor but two nonsense mutations results in Hurler disease.The skeletal disease dysostosis multiplex (DM) is seen in severe variants of MPS I. The hypoplastic odontoid putting these patients at high risk of cervical cord damage. MPS IH (Hurler Disease) affected infants develop a spinal 'gibbus' deformity, persistent nasal discharge, middle ear effusions and frequent upper respiratory infection. They have "coarse", facial features, and an enlarged tongue. . Progressive upper airway disease leads to obstructive sleep apnoea. Corneal clouding and cognitive impairment appears, growth ceases. Joint stiffness and contractures limit mobility. Cardiac disease is universal. Death occurs before 10 years. SCHEIE patients are diagnosed as teenagers with hepatomegaly, joint contractures, cardiac valve abnormalities and corneal clouding . Prolonged survival with considerable disability without cognitive impairment is usual. MPS IH/S Hurler/Scheie. is diagnosed by 6.5 years, with variable skeletal and visceral manifestations without cognitive involvement. Joint stiffness, corneal clouding, , umbilical hernia, abnormal facies, hepatomegaly, joint contractures, and cervical myelopathy occur. Patients die in their 20s .Haematopoietic stem cell transplantation (HSCT) the standard treatment of MPS IH for 30 years is unpredictable .When performed before 2 years it can stabilize cognitive impairment. Hepatosplenomegaly, urine GAGs excretion, upper airways obstruction and cardiomyopathy improve . The coarse hair and facial features soften and corneas partly clear,but dysostosis multiplex and cervical instability are not improved. Enzyme replacement therapy (ERT) in patients with MPS IH is associated with improved GAG excretion, left ventricular hypertrophy,sleep studies and liver size. The standard treatment of MPS IHIS and MIPS IS is ERT a-L-Iduronidase, laronidase, a life-long therapy. GAG excretion is reduced, respiratory function and physical endurance improve. Joint mobility improves but not dural thickening, cardiac valve lesions or eye changes. MPS I mice have been successfully treated with IDUA-expressing mesenchymaf stem cells . Gene therapy may be developed for MPS I, via an ex vivo approach demonstrated to improve even skeletal outcomes in animal models.
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PMID:Mucopolysaccharidosis type I. 2534 91