Mucopolysaccharidosis VI

Abstract

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 μg/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 μg/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.

Combined Enzyme Replacement Therapy and Hematopoietic Stem Cell Transplantation in Mucopolysacharidosis Type VI

“…Central nervous system manifestations include slowly progressive cervical cord compression caused by, accumulation of T2 negative on MRI fibrogelatinous material, circumferential meningeal thickening and/or bony stenosis, rarely cervical spine instability, communicating hydrocephalus, optic nerve atrophy, and blindness. Most MPS VI patients have relatively normal intellectual development (Valayannopoulos et al 2010). Until recently, supportive care and bone marrow transplantation were the only therapies available for MPS VI patients.…”

Molecular Analysis of Turkish Maroteaux-Lamy Patients and Identification of One Novel Mutation in the Arylsulfatase B (ARSB) Gene

“…Informed consent for genetic analysis was obtained for all patients and their relatives included in the study. For a better comprehension, patients phenotype was classified in the two principal forms of rapidly progressing, or severe, and slowly progressing, or mild, according to a previously published description (Valayannopoulos et al 2010).…”

“…Unlike some other storage disorders, mental development is usually normal. Death generally occurs before or during the second decade of life in patients with rapidly progressive forms, often due to cardiopulmonary complications (Valayannopoulos et al 2010). The birth prevalence ranges between 1 in 43,261 births in the German Turkish immigrants (Baehner et al 2005) and 1 in 1,505,160 births in Sweden (Malm et al 2008).…”

Clinical Evolution After Enzyme Replacement Therapy in Twins with the Severe Form of Maroteaux–Lamy Syndrome

“…Estimates of MPS VI incidence range from 1 in 238,095 to 1 in 1,300,000 in the Netherlands (Poorthuis et al 1999); even higher rates have been reported in Portugal and Brazil (Valayannopoulos et al 2010). This lysosomal disorder, caused by a deficiency in the enzyme N-acetylgalactosamine-4-sulfatase (arylsulfatase B, ASB; EC 3.1.6.12), is a result of mutations in the arylsulfatase B gene (ASB) located on chromosome 5 (5q13-5q14) (Litjens et al 1989).…”

“…They also suffer from skeletal dysplasia, myelopathy, compromised cardiovascular function, corneal clouding, upper airway obstruction, and recurrent ear infections. Death usually occurs in the early teenage years due to respiratory and cardiac problems (Neufeld and Muenzer 2001;Valayannopoulos et al 2010). Symptoms may appear later; in such cases, mortality is expected in the third to fifth decade of life (Th€ umler et al 2012).…”