Fifteen years of enzyme replacement therapy for mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome): a case report.

BACKGROUND: Mucopolysaccharidosis VI, or Maroteaux-Lamy disease, is an autosomal recessive disease characterized by deficiency of the enzyme arylsulfatase B in the lysosomal catabolism of glycosaminoglycans. Due to reduced (or even null) enzyme activity, glycosaminoglycans (mainly dermatan sulfate) accumulates, leading to a multisystemic disease. Mucopolysaccharidosis VI induces reduced growth, coarse face, audiovisual deficits, osteoarticular deformities, and cardiorespiratory issues, hampering the quality of life of the patient. Enzyme replacement therapy with galsulfase (Naglazyme, BioMarin Pharmaceuticals Inc., USA) is the specific treatment for this condition. Although studies have shown that enzyme replacement therapy slows the progression of the disease, the effects of long-term enzyme replacement therapy remain poorly understood. CASE PRESENTATION: A 29-year-old, Caucasian, male patient diagnosed with mucopolysaccharidosis VI was treated with enzyme replacement therapy for over 15 years. Enzyme replacement therapy was initiated when patient was 13 years old. The patient evolved multiplex dysostosis, carpal tunnel syndrome, thickened mitral valve, and hearing and visual loss. CONCLUSIONS: Although enzyme replacement therapy did not prevent the main signs of mucopolysaccharidosis VI, it slowed their progression. Additionally, enzyme replacement therapy was associated with a longer survival compared with the untreated affected sibling. Taken together, the results indicate that enzyme replacement therapy positively modified the course of the disease.

Disease burden, management patterns and multidisciplinary clinical approaches for patients with MPS IVA and VI in selected Latin American Countries.

BACKGROUND: There is a paucity of real-world epidemiological data on patients with mucopolysaccharidoses (MPS) in Latin America. This real-world study assessed the disease burden, management patterns and multidisciplinary clinical approaches for MPS-IVA and MPS-VI patients in Latin America (Colombia, Ecuador, Mexico, Peru). METHODS: Data were collected from physicians/specialists experienced in treating MPS patients between April-June 2020, via an online patient-diary survey. RESULTS: Overall, 29 physicians/specialists participated in this study. Data from 98 patients were analyzed (MPS-IVA, 71 patients and MPS-VI, 27 patients). Mean age for MPS-IVA patients was 17.5 years and for MPS-VI patients was 11.6 years, and the majority were females (52% and 78%, respectively). MPS-IVA and VI patients presented a high absenteeism from school (55% and 37%, respectively; <18 years age) and workplace (78% and 100%, respectively; >18 years age), indicating an impact of the disease on some aspects of the patients' quality of life. The onset of the first symptom occurred at the age of 3.1 years for MPS-IVA patients and at 1 year for MPS-VI, with delay in diagnosis (3.5-3.9 years from symptom onset) and enzyme replacement therapy (ERT) initiation (1.1-3.6 years from diagnosis). ERT interruptions were observed for MPS-IVA (48%) and MPS-VI patients (44%), with non-availability of medication recorded as the main reason for non-adherence (46% and 60% patients, respectively). ERT showed noticeable treatment benefits in MPS-IVA/VI patients, with stabilization/reduction in complications or the number of surgeries. A multidisciplinary clinical team approach was used for patient management. CONCLUSION: The disease burden for MPS-IVA/VI was high in Latin America, with consistent management, treatment and socio-demographic trends throughout the region.

Long-term impact of early initiation of enzyme replacement therapy in 34 MPS VI patients: A resurvey study.

Patients with mucopolysaccharidosis type VI (MPS VI) present with a wide range of disease severity and clinical manifestations, with significant functional impairment and shortened lifespan. Enzyme replacement therapy (ERT) with galsulfase has been shown to improve clinical and biochemical parameters including patient survival, quality of life and growth. The present study is a resurvey of 34 Brazilian MPS VI patients with rapidly progressive disease (classical phenotype) who initiated ERT with galsulfase under five years of age and had been on ERT until data collection in 2019, with few exceptions (n = 4 patients who died before 2019). Anthropometric measures, urinary glycosaminoglycans, and data regarding cardiac, orthopedic, neurologic, sleep apnea, hearing and ophthalmologic outcomes were filled in by specialists. Pubertal development, clinical complications, hospitalizations, and surgeries were also assessed. In this resurvey study, treatment with galsulfase has shown to be safe and well tolerated in MPS VI patients who initiated ERT under the age of 5 years and who have been undergoing ERT for approximately 10 years. Mortality rate suggests that early initiation of ERT may have a positive impact on patients' survival, improving but not preventing disease progression and death. MPS VI patients on ERT also showed improved growth velocity and the pubertal development was normal in all surviving patients. Follow-up data on pneumonia and hospitalization suggest that early ERT may have a protective effect against major respiratory complications. Cardiac valve disease progressed since their prior evaluation and spinal cord compression was observed in a large number of patients, suggesting that these disease complications were not modified by ERT.

Perthes-Like Disease Masquerading Non-Classical MPS

Abstract Mucopolysaccharidoses (MPS) are inborn errors of metabolism caused by deficient lysosomal enzymes, leading to organomegaly, hip osteonecrosis, coarse facial features, bone deformities, joint stiffness, cardiac and pulmonary symptoms (MPS VI) or hypermobility (MPS IVA). Some patients may present with non-classical forms of the disease in which osteoarticular abnormalities are the initial symptoms of non-classical forms. As orthopedists and surgeons are the specialists most frequently consulted before the diagnosis, it is critical that MPS may be considered as a differential diagnosis for patients with bone dysplasia. Experts in Latin America reviewed medical records focusing on disease onset, first symptoms and the follow-up clinical and surgical outcomes of non-classical MPS VI and IVA patients. All patients displayed orthopedic issues, which worsened over time, followed by cardiac and ophthalmological abnormalities. Our findings enlighten the necessity of including non-classical MPS as possible diagnosis for patients who report osteoarticular abnormalities in absence of inflammation.

Evaluation of oral manifestations of patients with mucopolysaccharidosis IV and VI: clinical and imaging study.

OBJECTIVE: The aim of this study is to assess oral manifestations in patients with mucopolysaccharidosis IV (MPS IVA) and mucopolysaccharidosis VI (MPS VI). MATERIALS AND METHODS: Seventeen patients were assessed, nine with MPS IVA and eight with MPS VI, treated at the Medical Genetics Outpatient Clinic of Hospital Universitário Alcides Carneiro (HUAC) in Campina Grande, Paraíba State, Brazil. Assessments included clinical and intraoral examinations, analysis of occlusal function, and panoramic X-rays. RESULTS: Among all, 64.7% of the patients had unerupted teeth and 52.9% of them had enamel hypoplasia. Regarding the temporomandibular joint, 88.2% of the patients showed flattening of the mandibular condyle, 52.9% showed condylar hypoplasia, and all of them showed decreased mobility. Enamel hypoplasia was observed only in patients with MPS IVA (p < 0.05). On the other hand, only MPS VI patients presented with anterior open bite, restricted mouth opening (p < 0.05), and a higher rate of unerupted teeth, hyperplastic tooth follicle, and condylar defects (p < 0.05). CONCLUSIONS: Enamel hypoplasia was observed only in patients with MPS IVA, whereas anterior open bite was observed only in patients with MPS VI. Abnormal findings in the maxillomandibular complex were more frequent in patients with MPS VI. CLINICAL RELEVANCE: The relevant frequency of MPS VI and IVA in the sample allows us to compare the changes occurring in both groups of patients, therefore enabling us to further comprehend the oral manifestations in specific types of MPS.

Long-Term Galsulfase Treatment Associated With Improved Survival of Patients With Mucopolysaccharidosis VI (Maroteaux-Lamy Syndrome): 15-Year Follow-Up From the Survey Study

Abstract Mucopolysaccharidosis VI (MPS VI) is a progressive lysosomal storage disorder with multiorgan and multisystemic pathology. Currently, galsulfase enzyme replacement therapy (ERT) is the only approved treatment for MPS VI. A crosssectional survey study of 121 patients with MPS VI conducted in 2001 to 2002 and a 10-year follow-up study of the same patients (resurvey study; ClinicalTrials.gov NCT01387854) found that those receiving galsulfase at any time showed physical improvements and a lower mortality rate (16.5%) versus treatment-naive patients (50%). After *15 years, galsulfasetreated patients (n » 104) continue to have a survival advantage over treatment-naive patients (n » 14), as demonstrated by a 24% versus 57% mortality rate. This survival advantage is further supported by data from the commercial use of galsulfase (2005-2016), which show a 5-year mortality rate for galsulfase-treated patients of 12.5%. Together, these findings suggest that galsulfase ERT can increase life expectancies for patients with MPS VI over a period of at least 15 years.

Impact of Enzyme Replacement Therapy in a Patient Younger Than 2 Years Diagnosed With Maroteaux-Lamy Syndrome (MPS VI)

Abstract Introduction: Mucopolysaccharidosis type VI, also known as Maroteaux-Lamy syndrome (#OMIM 253200), is a rare autosomal recessive genetic disorder due to deficient activity of the enzyme N-acetylgalactosamine 4-sulfatase (arylsulfatase B) required for the breakdown of dermatan sulfate and chondroitin sulfate. Patient: Report of a female patient started on enzyme replacement therapy at 17 months of age. At the time of diagnosis (14 months), the patient presented mild corneal opacity and significant thoracolumbar kyphosis, but no visceral involvement or growth arrest. At 73 months of treatment, weight was normal, although the patient was in a low height percentile. The patient showed adequate neural development, with improvement in lumbar spine and joint involvement. Corneal compromise or valvular disease progression was not evident. Conclusion: Early and timely diagnosis and treatment with enzyme replacement therapy are essential, as the means to change the natural history of the disease, avoiding comorbidities and improving final prognosis.

Molecular findings of Colombian patients with type VI mucopolysaccharidosis (Maroteaux-Lamy syndrome).

INTRODUCTION: Maroteaux-Lamy syndrome, or mucopolysaccharidosis (MPS) type VI, is an autosomal recessive lysosomal storage disease caused by a deficient activity of the enzyme arylsulfatase B (ARSB), required to degrade dermatan sulfate. The onset and progression of the disease vary, producing a spectrum of clinical presentation. So far, 133 mutations have been reported. The aim of this study is to determine the mutations in the ARSB gene that are responsible for this disease in Colombian patients. RESULTS: Fourteen patients with clinical manifestations and biochemical diagnosis of MPS VI were studied, including two siblings. The 8 exons of the gene were directly sequenced from patients' DNA, and 14 mutations were found. 57% of these mutations had not been previously reported (p.H111P, p.C121R, p.G446S, p.*534W, p.S334I, p.H147P, c.900T > G, and c.1531_1553del) and 43% had been previously reported (p.G144R, p.W322*, p.G302R, p.C447F, p.L128del, and c.1143-1G > C). Of the previously reported mutations, 80% have been associated with severe phenotypes and 20% with intermediate-severe phenotypes. Bioinformatic predictions indicate that the new mutations reported in this paper are also highly deleterious. CONCLUSIONS: Most of the Colombian patients in this study had private mutations.

Diagnostic and treatment strategies in mucopolysaccharidosis VI.

Mucopolysaccharidosis VI (MPS VI) is a very rare autosomal recessive disorder caused by mutations in the ARSB gene, which lead to deficient activity of the lysosomal enzyme ASB. This enzyme is important for the breakdown of the glycosaminoglycans (GAGs) dermatan sulfate and chondroitin sulfate, which accumulate in body tissues and organs of MPS VI patients. The storage of GAGs (especially dermatan sulfate) causes bone dysplasia, joint restriction, organomegaly, heart disease, and corneal clouding, among several other problems, and reduced life span. Despite the fact that most cases are severe, there is a spectrum of severity and some cases are so attenuated that diagnosis is made late in life. Although the analysis of urinary GAGs and/or the measurement of enzyme activity in dried blood spots are useful screening methods, the diagnosis is based in the demonstration of the enzyme deficiency in leucocytes or fibroblasts, and/or in the identification of pathogenic mutations in the ARSB gene. Specific treatment with enzyme replacement has been available since 2005. It is safe and effective, bringing measurable benefits and increased survival to patients. As several evidences indicate that early initiation of therapy may lead to a better outcome, newborn screening is being considered for this condition, and it is already in place in selected areas where the incidence of MPS VI is increased. However, as enzyme replacement therapy is not curative, associated therapies should be considered, and research on innovative therapies continues. The management of affected patients by a multidisciplinary team with experience in MPS diseases is highly recommended.

Mucopolysaccharidosis type VI on enzyme replacement therapy since infancy: Six years follow-up of four children.

Clinical and biochemical improvements are reported on Mucopolysaccharidosis type VI (MPS VI) patients on Enzyme Replacement Therapy (ERT) with rhASB (galsulfase, Naglazyme®), and preclinical and clinical studies have shown clinical benefits of early initiation. We report four unrelated MPS VI children who began ERT as infants (ages 5 days­10 months). The three older patients showed the first clinical signs of MPS VI at baseline, also presenting different degrees of dysostosis multiplex, and two had mild heart disease. The two oldest also had mild facial coarseness, one had hearing conduction deficit and sleep disorder and the other corneal clouding at baseline. After six years on ERT, all four patients have normal urinary GAG values. Although they all showed normal motor and mental development, brain and cervical spine MRI images available from two of the older patients showed abnormalities, while the youngest child continues having normal images. The four patients presented slower progression of bone and joint disease when compared to their affected older siblings. It should be noticed that only two patients in this sample are currently below the 3rd percentile for height: the youngest who has a constitutional factor associated and the eldest who already presented frank dysostosis at 10 months of age. These findings confirm previous studies that report that skeletal features of the disease cannot be completely prevented despite early ERT. Heart disease already present in two of the four infants at baseline got worse over time and appeared in another patient, but the youngest child on ERT introduction still has a normal echocardiogram at six years of age; he also is the only one without corneal clouding after six years follow-up. Our results also suggest that early ERT prevented storage in spleen and liver and may also have improved or prevented progression of facial dysmorphic features, corroborating similar findings seen in previous studies. No safety concerns were identified and none of the patients experienced a serious adverse event. The baseline severity of the disorder of these four infants seems related to age and it is tempting to say that severity on the first year of life is progressive and ERT effectiveness is indirectly related to it. Despite being known that MPS VI progresses differently among patients, the fact that these infants had a slower progression than their older siblings speaks in favor of a very early start of ERT. In conclusion, this report confirms the early manifestations of the disease and provides additional evidence on safety and of the beneficial effects of ERT in patients less than 1 year of age.

Natural history and galsulfase treatment in mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome)--10-year follow-up of patients who previously participated in an MPS VI Survey Study.

Mucopolysaccharidosis VI (MPS VI) is a clinically heterogeneous and progressive disorder with multiorgan manifestations caused by deficient N-acetylgalactosamine-4-sulfatase activity. A cross-sectional Survey Study in individuals (n = 121) affected with MPS VI was conducted between 2001 and 2002 to establish demographics, urinary glycosaminoglycan (GAG) levels, and clinical progression of disease. We conducted a Resurvey Study (ClinicalTrials.gov: NCT01387854) to obtain 10-year follow-up data, including medical histories and clinical assessments (n = 59), and survival status over 12 years (n = 117). Patients received a mean (SD) of 6.8 (2.2) years of galsulfase ERT between baseline (Survey Study) and follow-up. ERT patients increased in height by 20.4 cm in the 4-7-year-old baseline age group and by 16.8 cm in the 8-12-year-old baseline age group. ERT patients <13 years-old demonstrated improvement in forced vital capacity (FVC) by 68% and forced expiratory volume in 1 sec (FEV1) by 55%, and those ≥13 years-old increased FVC by 12.8% and maintained FEV1. Patients with >200 µg/mg baseline uGAG levels increased FVC by 48% in the <13-year-old baseline age group and by 15% in the ≥13-year-old baseline age group. ERT patients who completed the 6-min walk test demonstrated a mean (SD) increase of 65.7 (100.6) m. Cardiac outcomes did not significantly improve or worsen. Observed mortality rate among naïve patients was 50% (7/14) and 16.5% (17/103) in the ERT group (unadjusted hazard ratio, 0.24; 95% CI, 0.10-0.59). Long-term galsulfase ERT was associated with improvements in pulmonary function and endurance, stabilized cardiac function and increased survival.

Aspectos clínicos da mucopolissacaridose tipo VI / Clinical aspects of mucopolysaccharidosis type VI

JUSTIFICATIVA E OBJETIVOS: Este estudo visou destacar os principais sinais clínicos para a suspeita diagnóstica da mucopolissacaridose do tipo VI (MPS VI). Desta feita, espera-se que os profissionais de saúde aprofundem seus conhecimentos relacionados ao tema e identifiquem precocemente os pacientes portadores desta síndrome, possibilitando um tratamento adequado e, consequentemente, minimizando sequelas. CONTEÚDO: Realizou-se uma pesquisa ao banco de dados do MedLine/PubMed e do Pediatrics (Journal of the American Academy of Pediatrics) com a palavra-chave "Maroteaux-Lamy" selecionando-se apenas os estudos de livre acesso. Foram encontrados 19 estudos nas bases de dados consultadas, no período de setembro de 2009 a fevereiro de 2010. CONCLUSÃO: A MPS VI é uma doença autossômica recessiva cuja etiologia relaciona-se à atividade deficiente da hidrolase lisossômica N-acetilgalactosamina 4-sulfatase, ou arilsulfatase B. A maioria dos pacientes apresenta os primeiros sinais da doença na infância (hepatoesplenomegalia, face infiltrada e alterações na coluna). Com a sua evolução, os pacientes passam a apresentar alterações em vários órgãos e tecidos, que podem incluir: retardo de crescimento; contraturas flexionais de dedos, joelhos ou ombros; alterações cardiovasculares (estenose de valvas, regurgitação e cardiomegalia); alterações oculares (opacificação de córnea, glaucoma e papiledema com atrofia ótica); alterações neurológicas (hidrocefalia e compressão medular) e síndrome da apneia obstrutiva do sono. As complicações cardiorrespiratórias são progressivas e podem levar o paciente ao óbito, sendo imprescindível a identificação precoce da doença e instituição de terapêutica adequada.

BACKGROUND AND OBJECTIVES: This study aims to highlight the main clinical criteria for suspected diagnosis of mucopolysaccharidosis type VI (MPS VI). Consequently, we hope that the health professionals learn a little more about MPS VI and can identify patients with the syndrome in time to make appropriate treatment and thus minimize sequels. CONTENTS: We searched the database of MedLine/PubMed and Pediatrics (Journal of the American Academy of Pediatrics) with the keyword "Maroteaux-Lamy" by selecting only the open access studys. We found 19 studys in the databases consulted in the period of September 2009 to February 2010. CONCLUSION: MPS VI is an autosomal recessive disease whose etiology is related to deficiency of lysosomal hydrolase N-acetylgalactosamine 4-sulfatase, or arylsulfatase B. Most patients show early signs of disease in childhood (hepatosplenomegaly, facial infiltration and changes in column). With the evolution of the disease the patients started to show abnormalities in many organs and tissues, which may include: growth retardation; inflectional contractures of the fingers, knees or shoulders; cardiovascular disorders (stenosis, valve regurgitation and cardiomegaly); eyes (opacification cornea, glaucoma, and papilledema with optic atrophy); neurological disorders (hydrocephalus and spinal cord compression) and syndrome of obstructive sleep apnea. Cardiorespiratory complications are progressive and can lead the patient to death; due to this fact is essential early identification of disease and institution of therapy.

Mucopolysaccharidosis I, II, and VI: Brief review and guidelines for treatment.

Mucopolysaccharidoses (MPS) are rare genetic diseases caused by the deficiency of one of the lysosomal enzymes involved in the glycosaminoglycan (GAG) breakdown pathway. This metabolic block leads to the accumulation of GAG in various organs and tissues of the affected patients, resulting in a multisystemic clinical picture, sometimes including cognitive impairment. Until the beginning of the XXI century, treatment was mainly supportive. Bone marrow transplantation improved the natural course of the disease in some types of MPS, but the morbidity and mortality restricted its use to selected cases. The identification of the genes involved, the new molecular biology tools and the availability of animal models made it possible to develop specific enzyme replacement therapies (ERT) for these diseases. At present, a great number of Brazilian medical centers from all regions of the country have experience with ERT for MPS I, II, and VI, acquired not only through patient treatment but also in clinical trials. Taking the three types of MPS together, over 200 patients have been treated with ERT in our country. This document summarizes the experience of the professionals involved, along with the data available in the international literature, bringing together and harmonizing the information available on the management of these severe and progressive diseases, thus disclosing new prospects for Brazilian patients affected by these conditions.

Mucopolysaccharidosis I, II, and VI: brief review and guidelines for treatment

Mucopolysaccharidoses (MPS) are rare genetic diseases caused by the deficiency of one of the lysosomal enzymes involved in the glycosaminoglycan (GAG) breakdown pathway. This metabolic block leads to the accumulation of GAG in various organs and tissues of the affected patients, resulting in a multisystemic clinical picture, sometimes including cognitive impairment. Until the beginning of the XXI century, treatment was mainly supportive. Bone marrow transplantation improved the natural course of the disease in some types of MPS, but the morbidity and mortality restricted its use to selected cases. The identification of the genes involved, the new molecular biology tools and the availability of animal models made it possible to develop specific enzyme replacement therapies (ERT) for these diseases. At present, a great number of Brazilian medical centers from all regions of the country have experience with ERT for MPS I, II, and VI, acquired not only through patient treatment but also in clinical trials. Taking the three types of MPS together, over 200 patients have been treated with ERT in our country. This document summarizes the experience of the professionals involved, along with the data available in the international literature, bringing together and harmonizing the information available on the management of these severe and progressive diseases, thus disclosing new prospects for Brazilian patients affected by these conditions.