The clinical and genotypic-phenotypic findings of mucopolysaccharidosis VI patients: an Iraqi single-study descriptive study.

Background: Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI; MPS VI) is a chronic illness that causes progressive enlargement, inflammation, or scarring of several tissues and organs until their collapse. In most cases, an infant with MPS VI shows no symptoms. The early signs and symptoms of MPS VI in children often develop in the first few months of life. MPS VI affects various systems in the body, including the skeletal, cardiac, and respiratory systems. The authors aim in our study to describe the clinical and genotypic-phenotypic findings of MPS VI patients in 'children Welfare Teaching Hospital, Medical City Complex.' Methods: The single-center study was conducted at the 'children Welfare Teaching Hospital, Medical City Complex' from November 2016 to May 2022. The research recruited 72 MPS VI patients from Iraq, all under 20. The authors investigated the sociodemographic characteristics, hematological lab results, gene-phenotype findings, and clinical features and evaluated the severity and progression of the MPS 6 disease. Results: Seventy-two Iraqi MPS VI patients were involved in the study, and the average age of the study sample was 6.38±3.4 (0.3-19). The consanguinity rate was 94.4%. In the research, females comprised 56.9% of the patients, and the Z-scores for body mass index and occipital-frontal head circumference were -2.66 and 1.2. The fascial features at diagnosis, 'coarse facies' (90.3%), dysostosis multiplex (93%), short stature (94.4%), and recurrent respiratory infections (91.6%), were the most common clinical features among the enrolled patients. The most frequent mutation was (complementary DNA: c.753C>G, protein effect: p.(Tyr2*) or p.(Tyr251Term), and the codon cross-tabulation: premature stop codon, or homozygous stop nonsense mutation/exon N.3) (33/69 (47.82%)). Furthermore, a statistically significant correlation existed between lower weight and height readings and the progressed and severe stages of the MPS VI illness. Conclusion: As the first research in Iraq with a sufficient sample size of MPS VI patients, the investigation presented important clinical and gene-phenotype findings and revealed the necessity for enhancing the diagnosis of MPS VI, including the updated molecular analysis and monitoring the multisystem parameters, aberrant comorbidities, and the progression and severity.

Successful combined umbilical cord blood and bone marrow transplantation from an HLA-matched sibling for MPS VI: a case report.

Mucopolysaccharidosis type VI (MPS VI), also known as Maroteaux-Lamy syndrome, polydystrophic dwarfism, and arysulfatase B (ASB) deficiency, is a lysosomal storage disorder with autosomal recessive inheritance characterized by progressive multisystem involved that causes many tissues and organs to enlarge and become inflamed. Skeletal deformities are common that progress and worsen in varying degrees thus affecting quality of life and life expectancy. Many studies have shown that allogeneic hematopoietic stem cell transplantation can reduce morbidity and enhance the survival and quality of life in such patients. We present a case of a 6-year-old girl diagnosed with MPS VI at the age of 3 years. Thereafter the patient developed various complications of the disease causing morbidity. She was then treated with combined umbilical cord blood (UCB) and bone marrow (BM) transplantation from complete human leukocyte antigen-matched (6/6) donor which was her younger sibling. The transplant was successful without any serious adverse effects. No additional treatments such as enzyme replacement therapy (ERT) were required. The transplantation of UCB along with BM can be considered as an effective treatment approach for this rare disease. Plain language summary: Case of MPS VI treated with stem cell transplantation: This article reports a case of a 6-year-old girl who was diagnosed with mucopolysaccharidosis type VI also known as MPS VI, an autosomal recessive disorder that caused her arysulfatase B (ASB) deficiency. This disorder affects growth velocity, gives coarse facial features, gives rise to skeletal deformities, frequent upper-airway infections, enlarged liver and spleen, hearing loss, and joint stiffness. However, very few studies have reported definitive ways to treat or cure MPS VI. To help her combat this disorder, combined umbilical cord blood and bone marrow transplantation was done. This transplant alleviated her symptoms, and the patient did not need any further treatment. Follow-up, 4 years after transplantation, shows normal enzyme level, no complications, and improved quality of life.

Surgical treatment of pycnodysostosis associated with pathological tibial fracture : Case report and review of the literature.

BACKGROUND: Pycnodysostosis is a rare autosomal recessive lysosomal disorder of bone characterized by diffuse skeletal condensation with thickening of the cortex and narrowing of the medullary canal. CASE PRESENTATION: We present the case of a 4-year-old girl diagnosed with pycnodysostosis and associated pathological tibial fracture. The tibia had an absence of medullary canal. Surgery included reduction and reaming of the canal with placement of a 5 mm diameter telescopic growing nail. CONCLUSION: The presentation of pycnodysostosis as tibial fracture is rare and there is limited literature on its management. We showed its approach focusing mainly on the management of the absent medullary canal.

Comparison of growth dynamics in different types of MPS: an attempt to explain the causes.

BACKGROUND: Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by deficient activity of enzymes responsible for the catabolism of glycosaminoglycans (GAGs), resulting in progressive damage to various tissues and organs. Affected individuals present with skeletal deformities, bone growth impairment, joint stiffness and frequently mental retardation. RESULTS: The objective of the study was to summarise over 30 years of observations of the growth dynamics in patients with different types of MPS, performed at the Children's Memorial Health Institute (CMHI, Warsaw, Poland). A retrospective analysis of anthropometric data collected from 1989 to 2020 was performed for 195 patients with MPS I, MPS II, MPS III, MPS IVA and MPS VI. Mean values for birth body length were statistically significantly greater than in the general population. The mean z-scores for other MPS groups showed that until the 24th month of life, the growth pattern for all patients was similar, and the average z-scores for body height were greater than in reference charts. Afterwards, growth patterns began to differentiate for MPS groups. CONCLUSIONS: The long-term follow up showed that the growth pattern in patients with all types of mucopolysaccharidoses significantly deviates from the general population. Patients with MPS IVA had the most severe growth impairments compared to other patients in the study group. Neuropathic MPS I and II demonstrated severe growth impairments compared to other patients in this study. Patients with MPS III showed the mildest growth impairments compared to other MPS patients and reached the 3rd percentile last.

Novel chorioretinal findings in two siblings with mucopolysaccharidosis type VI.

PURPOSE: To describe and compare the systemic and ocular findings in two siblings with mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome), one treated with recombinant galsulfase, and one who was untreated. METHOD: One female patient aged 33 years (case 1) who had received galsulfase enzyme replacement therapy for 11 years, and her younger male sibling by 3 years (case 2), who had declined systemic treatment, underwent clinical ophthalmic examination and retinal ocular coherence tomography. The female sibling underwent electrophysiology testing of visual function. RESULTS: Case 1 had best corrected visual acuity right 6/4.8 and left 6/6. Case 2 had best corrected visual acuity of 6/6 in each eye. Case 1 had bilateral mild corneal haze and a clinically unremarkable posterior segment examination. Case 2 had bilateral very mild corneal haze and retinal striae on examination. Ocular coherence tomography showed choroidal folds at the maculae in both patients, more pronounced in Case 2, who also had retinal folds and epiretinal membrane. Electroretinography showed very mild involvement of the rods only in Case 1. CONCLUSION: These two siblings with mucopolysaccharidosis type VI, one treated and one untreated, displayed variable levels of systemic, corneal, and chorioretinal involvement in their disease Further studies of choroidal changes in MPS VI may prove useful as a biomarker of ocular response to treatment outside the blood-retina barrier. Both patients have provided written consent to publish case details.

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.

Mucopolysaccharidosis Type VI, an Updated Overview of the Disease.

Mucopolysaccharidosis type VI, or Maroteaux-Lamy syndrome, is a rare, autosomal recessive genetic disease, mainly affecting the pediatric age group. The disease is due to pathogenic variants of the ARSB gene, coding for the lysosomal hydrolase N-acetylgalactosamine 4-sulfatase (arylsulfatase B, ASB). The enzyme deficit causes a pathological accumulation of the undegraded glycosaminoglycans dermatan-sulphate and chondroitin-sulphate, natural substrates of ASB activity. Intracellular and extracellular deposits progressively take to a pathological scenario, often severe, involving most organ-systems and generally starting from the osteoarticular apparatus. Neurocognitive and behavioral abilities, commonly described as maintained, have been actually investigated by few studies. The disease, first described in 1963, has a reported prevalence between 0.36 and 1.3 per 100,000 live births across the continents. With this paper, we wish to contribute an updated overview of the disease from the clinical, diagnostic, and therapeutic sides. The numerous in vitro and in vivo preclinical studies conducted in the last 10-15 years to dissect the disease pathogenesis, the efficacy of the available therapeutic treatment (enzyme replacement therapy), as well as new therapies under study are here described. This review also highlights the need to identify new disease biomarkers, potentially speeding up the diagnostic process and the monitoring of therapeutic efficacy.

Deep intronic variant in the ARSB gene as the genetic cause for Maroteaux-Lamy syndrome (MPS VI).

Maroteaux-Lamy syndrome (MPS-VI) is a rare autosomal-recessive disorder with a wide spectrum of clinical manifestations, ranging from an attenuated to a rapidly progressive disease. It is caused by variants in ARSB, which encodes the lysosomal arylsulfatase B (ARSB) enzyme, part of the degradation process of glycosaminoglycans in lysosomes. Over 220 variants have been reported so far, with a majority of missense variants. We hereby report two siblings of Bedouin origin with a diagnosis of MPS-VI. Western blots in patient fibroblasts revealed total absence of ARSB protein production. Complete sequencing of the coding region of ARSB did not identify a candidate disease-associated variant. However, deep sequencing of the noncoding region of ARSB by whole genome sequencing (WGS) revealed a c.1142+581A to G variant. The variant is located within intron 5 and fully segregated with the disease in the family. Determination of the genetic cause for these patients enabled targeted treatment by enzyme replacement therapy, along with appropriate genetic counseling and prenatal diagnosis for the family. These results highlight the advantage of WGS as a powerful tool, for improving the diagnostic rate of rare disease-causing variants, and emphasize the importance of studying deep intronic sequence variation as a cause of monogenic disorders.

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.

Double valve replacement in a patient with Maroteaux - Lamy syndrome as an ultimate team challenge.

BACKGROUND: The Maroteaux-Lamy syndrome (Mucopolysaccharidosis type VI) is a rare, inherited metabolic disease that results in progressive tissue accumulation of dermatan-sulfated glycosaminoglycans and inflammatory consequences that almost always affects the heart valves. From the anesthesia point of view, managing the airway and ventilation might be a serious challenge due to specific features of the syndrome. Additionally, it is more than probable that the surgical team will perform a non-straightforward procedure. CASE PRESENTATION: A 42-year-old male with Maroteaux-Lamy syndrome was referred to our department with shortness of breath, due to severe aortic stenosis, and at least moderate mitral valve regurgitation. The patient was initially scheduled for aortic valve replacement. After multiple attempts with video assisted laryngoscopy, the endotracheal intubation was achieved with the aid of fiberoptic bronchoscopy, while the ventilation succeeded only with laryngeal mask. The somatic features of the syndrome that made the anesthesia induction extremely difficult, also affected the surgical procedure. Suboptimal exposure of the mitral valve, patch enlargement of the aortic root to host the bigger possible prosthesis, and the hard decision to replace the mitral valve even with a marginal indication were the intraoperative challenges for the surgical team. Finally, the patient underwent a successful double valve replacement with aortic root enlargement and 18 months postoperatively remains improved. CONCLUSION: Patients with Maroteaux-Lamy syndrome represent a challenge for both anesthesiologists and cardiac surgeons. The whole team should be well prepared to deal with difficulties in airway management, ventilation and surgical valve exposure. The cardiac surgeon should be ready to offer additional procedures and even replace "prematurely" a moderately diseased valve in order to avoid a dangerous reoperation. The limited knowledge on the natural history of the Maroteaux-Lamy syndrome valvulopathy and the difficulties in anesthesia induction support this approach.

Atlantoaxial instability in a case of Maroteaux-Lamy syndrome.

A relatively rare report of an 8-year-old girl with Maroteaux-Lamy syndrome that is Type VI mucopolysaccharidosis who presented with symptoms of spastic quadriparesis related to atlantoaxial instability is presented. Atlantoaxial stabilization resulted in rapid and sustained neurological recovery.

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.

Long-term outcomes of patients with mucopolysaccharidosis VI treated with galsulfase enzyme replacement therapy since infancy.

OBJECTIVE: Long-term outcomes of patients with mucopolysaccharidosis (MPS) VI treated with galsulfase enzyme replacement therapy (ERT) since infancy were evaluated. METHODS: The study was a multicenter, prospective evaluation using data from infants with MPS VI generated during a phase 4 study (ASB-008; Clinicaltrials.govNCT00299000) and clinical data collected ≥5 years after completion of the study. RESULTS: Parents of three subjects from ASB-008 (subjects 1, 2, and 4) provided written informed consent to participate in the follow-up study. One subject was excluded as consent was not provided. Subjects 1, 2, and 4 were aged 0.7, 0.3, and 1.1 years, respectively, at initiation of galsulfase and 10.5, 7.9, and 10.5 years, respectively, at follow-up. All subjects had classical MPS VI based on pre-treatment urinary glycosaminoglycans and the early onset of clinical manifestations. At follow-up, subject 4 had normal stature for age; subjects 1 and 2 had short stature, but height remained around the 90th percentile of growth curves for untreated classical MPS VI. Six-minute walk distance was normal for age/height in subjects 1 (550 m) and 4 (506 m), and reduced for subject 2 (340 m). Subject 2 preserved normal respiratory function, while percent predicted forced vital capacity and forced expiratory volume in 1 s decreased over time in the other subjects. Skeletal dysplasia was already apparent in all subjects at baseline and continued to progress. Cardiac valve disease showed mild progression in subject 1, mild improvement in subject 4, and remained trivial in subject 2. All subjects had considerably reduced pinch and grip strength at follow-up, but functional dexterity was relatively normal for age and there was limited impact on activities of daily living. Bruininks-Oseretsky Test of Motor Proficiency (BOT-2) results showed that subjects 2 and 4 had numerous fine and gross motor competencies. Corneal clouding progressed in all subjects, while progression of hearing impairment was variable. Liver size normalized from baseline in subjects 1 and 4, and remained normal in subject 2. CONCLUSION: Very early and continuous ERT appears to slow down the clinical course of MPS VI, as shown by preservation of endurance, functional dexterity, and several fine and gross motor competencies after 7.7-9.8 years of treatment, and less growth impairment or progression of cardiac disease than could be expected based on the patients' classical phenotype. ERT does not seem to prevent progression of skeletal or eye disease in the long term.

Epidemiology and Genetics of Mucopolysaccharidosis Type VI in Russia.

Mucopolysaccharidosis VI (MPS VI) is an autosomal recessive lysosomal storage disease caused by mutations in the arylsulfatase B gene (ARSB) and consequent deficient activity of ARSB, a lysosomal enzyme involved in the glycosaminoglycan (s) (GAGs) metabolism. Here, we present the results of the study of ARSB DNA analysis in MPS VI patients in the Russian Federation (RF) and other republics of the Former Soviet Union. In a cohort of 68 patients (57 families) with MPS VI, a total of 28 different pathogenic alleles were found. The most prevalent nucleotide changes included NM_000046.5:c.194C>T and NM_000046.5:c.454C>T. Five pathogenic alleles were novel, not previously reported (NM_000046.5:c.304C>G, NM_000046.5:c.533A>G, NM_000046.5:c.941T>C, NM_000046.5:c.447_456del10, and NM_000046.5:c.990_10003del14). The nucleotide variant NM_000045.6:c.454C>T was the prevalent allele among Slavic Russian patients. The nucleotide variant NM_000045.6:c.194C>T was found only in MPS VI families from the Republic of Dagestan. Based on the analysis of dry blood spots (DBSs) collected from newborns in this RF region, we showed the frequency of this mutant allele in the Republic of Dagestan to be 0.01 corresponding to the MPS VI frequency of nearly 1:10,000, which is one of the highest worldwide. This may eventually make the selective asymptomatic carrier test and newborn screening highly feasible in this region of the country.

A case study of three patients with mucopolysaccharidoses in Hue Central Hospital.

Mucopolysaccharidosis is a group of rare metabolic disorders characterized by a deficiency of enzymes in the degradation of glycosaminoglycans. The incomplete degradation process leads to the accumulation of glycosaminoglycans in lysosomes of various tissues, which interferes with cell function. We report three cases that were classified as Hurler-Mucopolysaccharidosis I, Morquio-Mucopolysaccharidosis IV A, and Maroteaux-Lamy-Mucopolysaccharidosis VI. Clinical presentations of these cases vary, depending on each type of enzyme defect. All the patients appeared healthy at birth, and symptoms appear at around 1 or 2 years. Clinical features, radiological findings, and especially enzyme assays have allowed us to establish a definitive diagnosis in these cases. These cases highlight that abnormal clinical symptoms, such as growth failure, coarse facial features, and joint problems, are key points for further investigation relating to mucopolysaccharidosis disease. However, in low- and middle-income countries, it is difficult to have a definitive diagnosis of one of the mucopolysaccharidoses due to lacking enzyme assays.

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.

Enzyme replacement therapy initiated in adulthood: Findings from the mucopolysaccharidosis VI Clinical Surveillance Program.

OBJECTIVE: To evaluate the impact of galsulfase enzyme replacement therapy (ERT) when initiated in adulthood for patients with mucopolysaccharidosis (MPS) VI. METHODS: In 2005, the multi-national, MPS VI Clinical Surveillance Program (CSP) was established to collect long-term observational data from routine clinical and laboratory assessments. A sub-analysis was performed in patients who started ERT at ≥16 years of age and had received galsulfase for ≥6 months. Urinary glycosaminoglycans (uGAG), 6-min walk test (6MWT), 3-min stair climb test (3MSCT), pulmonary function measures, cardiac function, ophthalmology measures, liver and spleen sizes, and safety were evaluated. RESULTS: Of 223 patients enrolled in the CSP, 51 were included in the sub-analysis. Patients were between 16 and 63 years of age at first infusion. From pre-treatment baseline, uGAG level decreased by a mean (±standard deviation [SD]) of 66 (±45)% (N = 29) after a median follow-up of 7.2 years. 6MWT distance decreased slightly by a mean of 17 (±107) meters (N = 23) after 6.6 years. Stairs/min in the 3MSCT increased by a mean of 26 (±33) (N = 14) after 2.8 years. Pulmonary function measures, forced expiratory volume in 1 second and forced vital capacity, increased by a mean of 0.06 (±0.21) L after 7.3 years and 0.05 (±0.28) L after 7.2 years, respectively (N = 19 for both measures). Overall, galsulfase was well tolerated, with most adverse events reported being MPS-related clinical manifestations and not related to galsulfase. CONCLUSIONS: Results of this sub-analysis of the CSP suggest that initiation of galsulfase in adulthood is well tolerated and can possibly stabilize MPS VI in the long term.

Recommendations for the management of MPS VI: systematic evidence- and consensus-based guidance.

INTRODUCTION: Mucopolysaccharidosis (MPS) VI or Maroteaux-Lamy syndrome (253200) is an autosomal recessive lysosomal storage disorder caused by deficiency in N-acetylgalactosamine-4-sulfatase (arylsulfatase B). The heterogeneity and progressive nature of MPS VI necessitates a multidisciplinary team approach and there is a need for robust guidance to achieve optimal management. This programme was convened to develop evidence-based, expert-agreed recommendations for the general principles of management, routine monitoring requirements and the use of medical and surgical interventions in patients with MPS VI. METHODS: 26 international healthcare professionals from various disciplines, all with expertise in managing MPS VI, and three patient advocates formed the Steering Committee group (SC) and contributed to the development of this guidance. Members from six Patient Advocacy Groups (PAGs) acted as advisors and attended interviews to ensure representation of the patient perspective. A modified-Delphi methodology was used to demonstrate consensus among a wider group of healthcare professionals with expertise and experience managing patients with MPS VI and the manuscript has been evaluated against the validated Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument by three independent reviewers. RESULTS: A total of 93 guidance statements were developed covering five domains: (1) general management principles; (2) recommended routine monitoring and assessments; (3) enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT); (4) interventions to support respiratory and sleep disorders; (5) anaesthetics and surgical interventions. Consensus was reached on all statements after two rounds of voting. The greatest challenges faced by patients as relayed by consultation with PAGs were deficits in endurance, dexterity, hearing, vision and respiratory function. The overall guideline AGREE II assessment score obtained for the development of the guidance was 5.3/7 (where 1 represents the lowest quality and 7 represents the highest quality of guidance). CONCLUSION: This manuscript provides evidence- and consensus-based recommendations for the management of patients with MPS VI and is for use by healthcare professionals that manage the holistic care of patients with the intention to improve clinical- and patient-reported outcomes and enhance patient quality of life. It is recognised that the guidance provided represents a point in time and further research is required to address current knowledge and evidence gaps.

Identification of arylsulfatase B gene mutations and clinical presentations of Iranian patients with Mucopolysaccharidosis VI.

BACKGROUND: Mucopolysaccharidosis (MPS) type VI, also known as Maroteaux-Lamy syndrome, is an autosomal recessive lysosomal storage disorder caused by a deficiency in arylsulfatase B (ARSB) enzyme. Our objectives were to investigate clinical phenotypes and performed molecular studies in Iranian patients with MPS VI, for the first time, in the southwestern Iran. METHODS: We studied 14 cases from 10 unrelated kindreds with MPS VI that were enrolled during 8 years. The mutational analysis of coding and flanking regions of ARSB gene was performed for the patients and their families using genomic DNA from whole blood by direct sequencing. RESULTS: All cases had parental consanguinity. Except one who had Fars ethnicity and presented with a very mild degree of coarse face, but normal otherwise, even near normal height, all were from Arab ethnicity with characteristic phenotypes including severe facial changes, cardiac involvement and dysostosis multiplex. Sequencing analysis of ARSB gene revealed four pathogenic homozygote mutations, including a novel nonsense mutation c.281C>A (p.Ser94X) in 9 patients, as well as, a known nonsense mutation c.753C>G (p.Try251X) in 3 cases, and two missense mutations c.904G>A (p.Gly302Arg) and c.454C>T (p.Arg152Trp) in two cases. The type of mutations affected the severity patient's phenotypes. CONCLUSIONS: These findings increased the genetic databases of Iranian patients with MPS VI and would be so much helpful for the high-risk families to speed the detection of carriers with accuracy and perform the prenatal test of disorder with cost-effective in this population.