Increased ocular wall thickness and decreased globe volume in children with mucopolysaccharidosis type VI.

PURPOSE lthough clinical ophthalmologic findings have been reported, no study documented magnetic resonance imaging (MRI) findings in mucopolysaccharidosis (MPS) type VI. The aim of this study was to determine the ophthalmologic imaging findings of MPS type VI in the pediatric age group retrospectively. METHODS Brain MRIs of 10 patients with MPS type VI and 49 healthy children were evaluated independently by two pediatric radiologists for the following characteristics: globe volume, ocular wall thickness, and optic nerve sheath diameter for each orbit. The means of the measurement of each group were compared by using an independent t-test. Agreement and bias between reviewers were assessed by intra-class correlation coefficients (ICC). RESULTS A total of 59 children [32 girls (54.23%), 27 boys (45.77%); age range, 4-16 years; mean age, 10.37 ± 3.73 years] were included in the study. Statistical analysis revealed smaller eyeballs and thicker ocular walls of patients with MPS type VI (P < .001 and P < .001, respectively). However, there was no statistically significant difference in terms of optic nerve sheath diameter between the two groups (P=.648). CONCLUSION Patients with MPS type VI displayed reduced globe volumes and increased ocular wall thicknesses compared to the healthy children. Therefore, we recommend that ophthalmologic imaging findings might prove to be an auxiliary tool in the diagnosis of MPS patients.

A novel approach in diagnosing multiple dentigerous cysts using CBCT illustration indicative of Mucopolysaccharidosis VI - a case report.

Mucopolysaccharidosis VI is a genetic disorder affecting multiple organs with sundry clinical presentations. The main etiological factor reflects the disturbances in mucopolysaccharide metabolism leading to deposition of acid mucopolysaccharide in various tissues. The pathognomonic features of the disease include a large head, short neck, corneal opacity, open mouth associated with an enlarged tongue, enlargement of the skull, and long anteroposterior dimension with unerupted dentition, dentigerous cyst-like follicles, condylar defects, and gingival hyperplasia. An 18-year-old boy with Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI) is described in this article, emphasizing the oral manifestations and radiographic illustration of lesions in the jaws. It also emphasizes the essential role of cone-beam computed tomography to identify and analyze multicentric pathologies in the jaws.

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.

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.

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.

Retrospective chart review of urinary glycosaminoglycan excretion and long-term clinical outcomes of enzyme replacement therapy in patients with mucopolysaccharidoses.

BACKGROUND: Mucopolysaccharidoses (MPS) are a group of rare, inherited metabolic diseases that result from a deficiency in one of several lysosomal enzymes essential for stepwise glycosaminoglycan (GAG) degradation, leading to GAG accumulation and widespread cellular pathology and clinical disease. Although disease presentation is heterogeneous, the clinical hallmarks are largely comparable across several MPS subtypes. Extensive data have shown that the level of urinary GAG (uGAG) excretion above normal is strongly correlated with disease severity and clinical outcomes in MPS diseases. Thus, change in uGAG excretion may have significant value as a potential primary endpoint in clinical trials of MPS diseases that are too rare to study using traditional clinical endpoints. METHODS: A retrospective medical chart review was undertaken of patients with MPS I, II, and VI who had been treated long term with enzyme replacement therapy (ERT). The relationship between uGAG reduction and clinical outcomes relevant to the major clinical manifestations of these MPS diseases was evaluated. A multi-domain responder index (MDRI) score was calculated, measuring the following 4 domains: 6-min walk test, pulmonary function, growth rate, and Clinician Global Impression of Change. For each domain, a minimal important difference (MID) was defined based on published information of these outcome measures in MPS and other diseases. RESULTS: Of the 50 patients evaluated, 18 (36%) had MPS I, 23 (46%) had MPS II, and 9 (18%) had MPS VI. Forty-two were clinical practice patients and 8 had participated in clinical trials. Across all MPS subtypes, the mean (± SD) uGAG level at baseline was 66.0 ± 51.5 mg/mmol creatinine (n = 48) and there was a mean reduction of 54.6% following ERT. Analysis of the MDRI score based on the MID defined for each domain showed a greater magnitude of improvement in patients with increased uGAG reduction when compared with those patients with lower uGAG reduction for all assessed uGAG thresholds, and a trend toward a higher likelihood of positive mean MDRI score in patients with a uGAG reduction ≥40%. CONCLUSIONS: In this retrospective study, uGAG reduction was associated with long-term clinical outcomes as assessed by a number of approaches, supporting the use of uGAG reduction as a biomarker primary endpoint.

Glycosaminoglycans analysis in blood and urine of patients with mucopolysaccharidosis.

To explore the correlation between glycosaminoglycan (GAG) levels and mucopolysaccharidosis (MPS) type, we have evaluated the GAG levels in blood of MPS II, III, IVA, and IVB and urine of MPS IVA, IVB, and VI by tandem mass spectrometry. Dermatan sulfate (DS), heparan sulfate (HS), keratan sulfate (KS; mono-sulfated KS, di-sulfated KS), and the ratio of di-sulfated KS in total KS were measured. Patients with untreated MPS II had higher levels of DS and HS in blood while untreated MPS III had higher levels of HS in blood than age-matched controls. Untreated MPS IVA had higher levels of KS in blood and urine than age-matched controls. The ratio of blood di-sulfated KS/total KS in untreated MPS IVA was constant and higher than that in controls for children up to 10 years of age. The ratio of urine di-sulfated KS/total KS in untreated MPS IVA was also higher than that in age-matched controls, but the ratio in untreated MPS IVB was lower than controls. ERT reduced blood DS and HS in MPS II, and urine KS in MPS IVA patients, although GAGs levels remained higher than the observed in age-matched controls. ERT did not change blood KS levels in MPS IVA. MPS VI under ERT still had an elevation of urine DS level compared to age-matched controls. There was a positive correlation between blood and urine KS in untreated MPS IVA patients but not in MPS IVA patients treated with ERT. Blood and urine KS levels were secondarily elevated in MPS II and VI, respectively. Overall, measurement of GAG levels in blood and urine is useful for diagnosis of MPS, while urine KS is not a useful biomarker for monitoring therapeutic efficacy in MPS IVA.

Mucopolysaccharidosis Type VI in a Great Dane Caused by a Nonsense Mutation in the ARSB Gene.

Mucopolysaccharidoses are inherited metabolic disorders that result from a deficiency of lysosomal enzymes required for the catabolism of glycosaminoglycans. Lysosomal glycosaminoglycan accumulation results in cell and organ dysfunction. This study characterized the phenotype and genotype of mucopolysaccharidosis VI in a Great Dane puppy with clinical signs of stunted growth, facial dysmorphia, skeletal deformities, corneal opacities, and increased respiratory sounds. Clinical and pathologic evaluations, urine glycosaminoglycan analyses, lysosomal enzyme assays, and ARSB sequencing were performed. The urine mucopolysaccharide spot test was strongly positive predominantly due to the accumulation of dermatan sulfate. Enzyme assays in leukocytes and tissues indicated a deficiency of arylsulfatase B (ARSB) activity. Histologic examination revealed cytoplasmic vacuoles in many tissues. Analysis of the exonic ARSB DNA sequences from the affected puppy compared to the published canine genome sequence revealed a homozygous nonsense mutation (c.295C>T) in exon 1, replacing glutamine with a premature stop codon (p.Gln99*), predicting no enzyme synthesis. A polymerase chain reaction-based restriction fragment length polymorphism test was established to assist with the clinical diagnosis and breeding of Great Danes. This genotyping test revealed that the clinically healthy parents and some other relatives of the puppy were heterozygous for the mutant allele, but all 200 clinically healthy dogs screened including 15 Great Danes were homozygous for the normal allele. This ARSB mutation is the fourth identified genetic variant causing canine mucopolysaccharidosis VI. Mucopolysaccharidosis VI is the first lysosomal storage disorder described in Great Danes but does not appear to be widespread in this breed.

Genotypic-phenotypic features and enzyme replacement therapy outcome in patients with mucopolysaccharidosis VI from Turkey.

Mucopolysaccharidosis type VI (MPS VI) is a lysosomal storage disorder (LSD) characterized by a chronic, progressive course with multiorgan involvement. In our study, clinical, biochemical, molecular findings, and response to enzyme replacement therapy (ERT) for at least 6 months were evaluated in 20 patients with MPS VI. Treatment effects on clinical findings such as liver and spleen sizes, cardiac and respiratory parameters, visual and auditory changes, joints' range of motions, endurance tests and changes in urinary glycosaminoglycan excretions, before and after ERT were analyzed. ERT caused increased physical endurance and decreased urinary dermatan sulfate/chondroitin sulfate ratios. Changes in growth parameters, cardiac, respiratory, visual, auditory findings, and joint mobility were not significant. All patients and parents reported out an increased quality of life, which were not correlated with clinical results. The most prevalent mutation was p.L321P, accounting for 58.8% of the mutant alleles and two novel mutations (p.G79E and p.E390 K) were found. ERT was a safe but expensive treatment for MPS VI, with mild benefits in severely affected patients. Early treatment with ERT is mandatory before many organs and systems are involved.

Functional characterization of arylsulfatase B mutations in Indian patients with Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI).

MPS VI is an autosomal recessive disorder which occurs due to the deficiency of N-acetyl galactosamine-4-sulfatase (Arylsulfatase B - ARSB) involved in catabolism of dermatan sulfate resulting from disease-causing variations in the ARSB gene. Human Gene Mutation Database (HGMD) search revealed 200 different mutations in ARSB worldwide. In the present study we carried out molecular and functional analyses to characterize the mutations reported by us in Indian population. Mutation analysis of 19 MPS VI patients revealed presence of a total of 15 different mutations of which twelve were novel [p.Asp53Asn (c.157G>A; p.D53N), p.Leu98Arg (c.293T>G; p.L98R), p.Tyr103Serfs*9 (c.306_312delCTACCAG+146del; p.Y103Sfs*9), p.Phe166Leufs*18 (c.496delT; p.F166Lfs*18), p.Ile220Serfs*5 (c.659_660delTA; p.I220Sfs*5), p.Ile350Phe (c.1048A>T; p.I350F), p.Trp353* (c.1059G>A; p.W353*), p.His393Arg (c.1178A>G; p.H393R), p.Ser403Tyrfs* (c.1208delC; p.S403Yfs*), p.Pro445Leu (c.1334C>T; p.P445L), p.Trp450Leu (c.1349G>T; p.W450L) and p.Trp450Cys (c.1350G>C; p.W450C)] and three were known mutations [p.Asp54Asn (c.160G>A; p.D54N), p.Ala237Asp (c.710C>A; p.A237D) and p.Ser320Arg (c.960C>G; p.S320R)]. Functional characterization using site-directed mutagenesis followed by cell transfection assays, immunoblot, reverse transcriptase PCR and immunofluorescence studies for the putative pathogenic variants detected in our MPS VI patient cohort helped us to confirm the pathogenic potential of the variants in ARSB.

Aortic Root Dilatation in Mucopolysaccharidosis I-VII.

The prevalence of aortic root dilatation (ARD) in mucopolysaccharidosis (MPS) is not well documented. We investigated aortic root measurements in 34 MPS patients at the Children's Hospital of Orange County (CHOC). The diagnosis, treatment status, age, gender, height, weight and aortic root parameters (aortic valve annulus (AVA), sinuses of Valsalva (SoV), and sinotubular junction (STJ)) were extracted by retrospective chart review and echocardiographic measurements. Descriptive statistics, ANOVA, and paired post-hoc t-tests were used to summarize the aortic dimensions. Exact binomial 95% confidence intervals (CIs) were constructed for ARD, defined as a z-score greater than 2 at the SoV. The patient age ranged from 3.4-25.9 years (mean 13.3 ± 6.1), the height from 0.87-1.62 meters (mean 1.24 ± 0.21), and the weight from 14.1-84.5 kg (mean 34.4 ± 18.0). The prevalence of dilation at the AVA was 41% (14/34; 95% CI: 25%-59%); at the SoV was 35% (12/34; 95% CI: 20%-54%); and at the STJ was 30% (9/30; 95% CI: 15%-49%). The highest prevalence of ARD was in MPS IVa (87.5%). There was no significant difference between mean z-scores of MPS patients who received treatment with hematopoietic stem cell transplantation (HSCT) or enzyme replacement therapy (ERT) vs. untreated MPS patients at the AVA (z = 1.9 ± 2.5 vs. z = 1.5 ± 2.4; p = 0.62), SoV (z = 1.2 ± 1.6 vs. z = 1.3 ± 2.2; p = 0.79), or STJ (z = 1.0 ± 1.8 vs. z = 1.2 ± 1.6; p = 0.83). The prevalence of ARD was 35% in our cohort of MPS I-VII patients. Thus, we recommend screening for ARD on a routine basis in this patient population.

The constellation of skeletal deformities in a family with mixed types of mucopolysaccharidoses: Case report.

INTRODUCTION: A 13-year-old child was clinically diagnosed with mucopolysaccharidosis type VI-Maroteaux-Lamy syndrome (MPS VI) at the age of 5 years, and the diagnosis was confirmed biochemically and genetically (homozygous mutation in ARSB gene). At that time, his older brother manifested with increasing severe mental retardation. His urinary glycosaminoglycan excretion in urine was elevated, but there was only 1 mutation in the ARSB gene defining him as a healthy carrier of MPS VI. The 15-year-old boy was born with dysmorphic facial features, cleft lip and palate, and multiple contractures associated with profound skeletal deformities manifested, severe mental retardation, and seizures, leading to the diagnosis of cerebral palsy from birth on.Clinical and radiographic phenotypic characterization was the baseline tool to document the older sibling, parents, and relatives, all of them examined at the Orthopaedic Hospital of Speising, Vienna, Austria. The family history (from maternal and paternal sides) showed >10 subjects with variable clinical histories of hyperactivity and attention deficit disorder, depression, and a diversity of skeletal abnormalities, such as dysplastic spondylolisthesis, discovertebral degeneration, osteopenia, osteophytosis, and progressive degeneration of the weight bearing zones (mostly developed at middle age). METHODS: Eleven patients in a family with interrelated marriages (two male siblings of 15 and 13-year-old), parents and relatives over three generations were enrolled. One of the siblings was diagnosed with Maroteaux-Lamy syndrome at the age of five-years and mutation of the ARBS gene has been encountered. The older sibling manifested at birth craniofacial abnormalities associated with multiple contracture and seizures. Cerebral palsy was the suggested diagnosis. Clinical and radiographic phenotypes were the baseline tool to document the older sibling, parents and relatives at the orthopaedic Hospital of Speising, Vienna, Austria. These were followed by whole Exome sequencing in three family subjects. RESULTS: A series of genetic studies in the older sibling showed homozygous mutation in GNS gene compatible with MPS IIID. Both parents are first related and were found to be heterozygous for N-acetylglucosamine-6-sulfatase GNS gene. Family history showed more than 10 subjects with variable clinical presentations such as dysplastic spondylolisthesis, disco-vertebral degeneration, osteopenia, osteophytosis, and progressive degeneration of the weight bearing zones (mostly developed at middle age). CONCLUSION: Owing to the multiple systemic involvements, a genetic cause was suspected and a molecular genetic investigation by using whole-exome-sequencing method in 3 family subjects (trios) was performed: the 15-year-old boy and his parents. A homozygous splice-site-mutation in the GNS gene could be found, compatible with mucopolysaccharidosis-Sanfillipo syndrome (type IIID). Both parents are first related and were now found also to be heterozygous for the GNS gene mutation found in their older son. Therefore, both parents are heterozygous carriers for the ARSB gene mutation but also the GNS gene mutation. In the son with MPS VI, no mutation in the GNS gene was found, but the brother with MPS IIID was heterozygous for the ARSB gene mutation.We presume that the intrafamilial variability of clinical signs in different family members could be the result of various mutations in the ARSB/GNS genes in the carriers or potential modulating effects of other genes or differences in genetic backgrounds.

Novel mutations of the arylsulphatase B (ARSB) gene in Indian patients with mucopolysaccharidosis type VI.

BACKGROUND & OBJECTIVES: Mucopolysaccharidosis type VI (MPS VI) is a rare, autosomal recessive lysosomal storage disorder caused by deficient enzymatic activity of N-acetyl galactosamine-4-sulphatase resulting from mutations in the arylsulphatase B (ARSB) gene. The ARSB gene is located on chromosome 5q11-q13 and is composed of eight exons. More than hundred ARSB mutations have been reported so far, but the mutation spectrum of MPS VI in India is still unknown. Hence, the aim of the present study was to identify the mutational spectrum in patients with MPS VI in India and to study the genotype-phenotype association and functional outcomes of these mutations. METHODS: Molecular characterization of the ARSB gene by Sanger sequencing was done for 15 patients (aged 15 months to 11 yr) who were enzymatically confirmed to have MPS VI. Age of onset, clinical progression and enzyme activity levels in each patient were studied to look for genotype-phenotype association. Haplotype analysis performed for unrelated patients with the recurring mutation W450C, was suggestive of a founder effect. Sequence and structural analyses of the ARSB protein using standard software were carried out to determine the impact of detected mutations on the function of the ARSB protein. RESULTS: A total of 12 mutations were identified, of which nine were novel mutations namely, p.D53N, p.L98R, p.Y103SfsX9, p.W353X, p.H393R, p.F166fsX18, p.I220fsX5, p.W450L, and p.W450C, and three were known mutations (p.D54N, p.A237D and p.S320R). The nine novel sequence variants were confirmed not to be polymorphic variants by performing sequencing in 50 unaffected individuals from the same ethnic population. INTERPRETATION & CONCLUSIONS: Nine novel mutations were identified in MPS VI cases from India in the present study. The study also provides some insights into the genotype-phenotype association in MPS VI.

Avaliação da força de preensão e amplitude de movimentos dos membros superiores em pacientes com mucopolissacaridose VI / Evaluation of grip strength and range of motion of the upper limbs in patients with mucopolysaccharidosis VI

Objetivo: O presente estudo tem como objetivo avaliar a força de preensão manual e amplitude de movimento dos membros superiores de pacientes com Mucopolissacaridose VI afim de observar o quanto tais fatores podem vir a afetar e se correlacionar com as atividade de vida diária. Método: A amostra foi composta por 13 pacientes, sendo 8 homens e 5 mulheres com média de idade de 17,76 anos e médias de peso e altura de 31,30Kg e 1,17cm respectivamente que aceitaram participar do estudo e que atendessem aos critérios de inclusão pedidos. O estudo foi realizado no estado de Pernambuco no Centro de Tratamento de Erros Inatos do Metabolismo, localizado no Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), coletou-se medidas de amplitude de movimentos (ADM) dos membros superiores, força de preensão manual além de perguntas através de um questionário estruturado. Resultados: No presente estudo a flexão da articulação do ombro que apresenta maior comprometimento em sua maioria, não seguiu tal padrão visto que a média de ADM da articulação foi 90,38 para membro esquerdo e 93,38 em membro direito. A ADM mais abaixo da média predita encontrada no estudo foi da extensão de punho tanto em membro esquerdo como direito. Na avaliação de dinamometria apenas 1 indivíduo apresentou média acima da predita, 9 (69,21%) mostraram grau de força entre 0 e 2 libras (lb) em mão direita e 8 (61,52%) em mão esquerda. Conclusão: Esperamos que o estudo sirva como forma de acompanhamento e evolução da MPS VI, e que possa subsidiar novos estudos e protocolos de avaliação e reabilitação motora

Objective: The present study aims to evaluate the grip strength and range of motion of the upper limbs of patients with Mucopolysaccharidosis VI in order to observe how these factors can affect and correlate with the activities of daily living. Methods: The sample consisted of 13 patients: 8 males and 5 females, with a mean age of 17.76 years, mean weight of 31.30Kg, and a mean height of 1.17m, who agreed to participate and who met the inclusion criteria. The study was conducted in the state of Pernambuco at the Inborn Errors of Metabolism Treatment Center (Centro de Tratamento de Erros Inatos do Metabolismo), located at the Integrative Medicine Institute (Instituto de Medicina Integral) Prof. Fernando Figueira (IMIP). Range of motion (ROM) measurements of their upper limbs and manual grip strength were collected, and the subjects answered a structured questionnaire. Results: In this study the flexion of the shoulder joint that had the greater impairment mostly did not follow this pattern, since the average ROM for the left arm was 90.38 and 93.38 for the right. The ROM found to be the farthest below the predicted average in the study was for wrist extension in both the left and right limbs. In grip strength assessment, only one individual measured above the predicted average, 9 (69.21%) showed a degree of strength between 0 and 2 pounds (lb) in the right hand and 8 (61.52%) in the left. Conclusion: This study hopes to serve as a means of monitoring the evolution of MPS VI, which can support new studies, evaluation protocols, and motor rehabilitation

Mucopolysaccharidosis type VI in a juvenile miniature schnauzer dog with concurrent hypertriglyceridemia, necrotizing pancreatitis, and diabetic ketoacidosis.

A 7-month-old, neutered male miniature schnauzer dog with a history of cryptorchidism and umbilical hernia was referred for diabetic ketoacidosis. Clinical evaluation revealed stunted growth, skeletal abnormalities, hypertriglyceridemia, diabetic ketoacidosis, and acute necrotizing pancreatitis. Further testing was diagnostic for mucopolysaccharidosis type VI causing the stunted growth and skeletal deformities, but no connection between mucopolysaccharidosis type VI, hypertriglyceridemia, and pancreatic diseases was found.

Mucopolysaccharidose de type VI chez un jeune chien Schnauzer miniature atteint d'hypertriglycéridémie, de pancréatite nécrosante et d'acidocétose diabétique concomitantes. Un chien Schnauzer miniature castré âgé de 7 mois avec une anamnèse de cryptorchidie et d'hernie ombilicale a été référé pour une acidocétose diabétique. L'évaluation clinique a révélé une croissance arrêtée, des anomalies squelettiques, l'hypertriglycéridemie, l'acidocétose diabétique et une pancréatite nécrosante aiguë. Des tests supplémentaires ont permis de diagnostiquer une mucopolysaccharidose de type VI causant une croissance arrêtée et des difformités squelettiques, mais aucun lien avec la mucopolysaccharidose de type VI, l'hypertriglycéridémie et les maladies pancréatiques n'a été trouvé.(Traduit par Isabelle Vallières).

Dose responsive effects of subcutaneous pentosan polysulfate injection in mucopolysaccharidosis type VI rats and comparison to oral treatment.

BACKGROUND: We previously demonstrated the benefits of daily, oral pentosan polysulfate (PPS) treatment in a rat model of mucopolysaccharidosis (MPS) type VI. Herein we compare these effects to once weekly, subcutaneous (s.c.) injection. The bioavailability of injected PPS is greater than oral, suggesting better delivery to difficult tissues such as bone and cartilage. Injected PPS also effectively treats osteoarthritis in animals, and has shown success in osteoarthritis patients. METHODOLOGY/PRINCIPAL FINDINGS: One-month-old MPS VI rats were given once weekly s.c. injections of PPS (1, 2 and 4 mg/kg, human equivalent dose (HED)), or daily oral PPS (4 mg/kg HED) for 6 months. Serum inflammatory markers and total glycosaminoglycans (GAGs) were measured, as were several histological, morphological and functional endpoints. Overall, weekly s.c. PPS injections led to similar or greater therapeutic effects as daily oral administration. Common findings between the two treatment approaches included reduced serum inflammatory markers, improved dentition and skull lengths, reduced tracheal deformities, and improved mobility. Enhanced effects of s.c. treatment included GAG reduction in urine and tissues, greater endurance on a rotarod, and better improvements in articular cartilage and bone in some dose groups. Optimal therapeutic effects were observed at 2 mg/kg, s.c.. No drug-related increases in liver enzymes, coagulation factor abnormalities or other adverse effects were identified following 6 months of s.c. PPS administration. CONCLUSIONS: Once weekly s.c. administration of PPS in MPS VI rats led to equal or better therapeutic effects than daily oral administration, including a surprising reduction in urine and tissue GAGs. No adverse effects from s.c. PPS administration were observed over the 6-month study period.

Clinical manifestations of 17 patients affected with mucopolysaccharidosis type VI and eight novel ARSB mutations.

Mucopolysaccharidosis (MPS) type VI or Maroteaux-Lamy syndrome is a very rare autosomal recessive lysosomal storage disease, caused by a deficiency of the enzyme N-acetylgalactosamine-4-sulfatase (Arylsulfatase B, ARSB). Clinical examination, biochemical studies, and molecular genetic analyses have been performed in 17 patients affected with MPS VI from 15 unrelated families from Thailand, India, and Turkey. Large ear lobule appears to be a newly recognized finding of this syndrome. Mutation analysis of the ARSB gene revealed seven missense and three frameshift mutations of which eight were novel. Novel missense mutations were p.Asp53Asn, p.Val376Glu, p.Glu390Lys, p.Pro445Leu, and p.Trp450Cys, while an Indian patient was homozygous for two novel missense mutations (p.Pro445Leu and p.Trp450Cys). Three novel frameshift mutations were p.Pro70fsX123, p.Ser403fs, and p.Thr526fs. Two previously reported mutations, p.Arg160Gln and p.Leu321Pro, were also observed in our cohort. The amino acid Arg160 appears to be the mutational hot spot for the ARSB gene. Five patients homozygous for p.Leu321Pro mutation had early onset of the disease, and haplotype analysis showed that the mutation is a founder mutation in Turkish population.

Oral manifestations of 17 patients affected with mucopolysaccharidosis type VI.

OBJECTIVE: To assess oral manifestations of 17 patients with mucopolysaccharidosis type VI (MPS VI) or Maroteaux-Lamy syndrome. METHODS: We performed comprehensive oral examinations in 17 patients with MPS VI. Panoramic radiographs was performed only in 14 patients. All patients were of Thai, Turkish, and Indian origins. Ten of 17 patients had enzyme replacement therapy (ERT) (Naglazyme). Most Turkish patients (10/11) were on ERT. The Thai and Indian patients have never had ERT. RESULTS: Oral and radiographic examinations showed that hypoplastic mandibular condyles (93.3 %), malposition of unerupted teeth (92.9 %), large dental follicles (92.3 %), anterior open bite (86.7 %), maxillary constriction (56.3 %), and taurodontism (53.8 %) were common among patients with MPS VI. Newly recognized oral findings found in our study included taurodontism, long tooth roots, abnormal frenum, missing teeth, supernumerary teeth, and microdontia. Two patients who started ERT prior to 3 years old did not develope anterior open bite and one of them had mildly affected mandibular condyles. CONCLUSION: Our study provides the most comprehensive study of oral manifestations in patients with MPS VI. Receiving ERT at very young ages may lessen craniofacial malformations including hypoplasic mandibular condyles and anterior open bite. Oral manifestations can be used as diagnostic features for MPS VI prior to assessing leukocyte ARSB activity or urinary excretion of dermatan sulfate.

New insights in mucopolysaccharidosis type VI: neurological perspective.

OBJECTIVE: Mucopolysaccharidosis type VI is a rare autosomal recessive storage disorder, caused by deficiency of arylsulfatase B. Data on neurological involvement in mucopolysaccharidosis type VI patients under enzyme-replacement therapy are limited. This study explores the neurological and magnetic resonance imaging findings in a sample of mucopolysaccharidosis type VI patients receiving enzyme-replacement therapy. METHODS: We performed a cross-sectional study including six patients with biochemical confirmation of mucopolysaccharidosis type VI and at least 105 consecutive weeks (two years) receiving intravenous enzyme-replacement therapy. The protocol included a comprehensive clinical examination, brain and spinal cord magnetic resonance imaging for all subjects. RESULTS: Overall, cognition was spared, while we found presence of hearing impairment, increasing in deep tendon reflexes and deep sensation reduction in three patients. In addition to the classical abnormalities related to other types of mucopolysaccharidosis, imaging studies demonstrated morphological changes in anatomy of middle cranial fossa and sella shape. Even in asymptomatic or mild compromised patients, spinal cord compression was found. In four patients we noticed atlantoaxial joint subluxation and three had cervical spinal stenosis. Degenerative processes involving vertebral column, including discal protrusion and axis abnormalities, were present in all patients. CONCLUSIONS: Neuroaxis involvement was a universal finding and neurological examination might not predict the severity of the disease in course. Image studies should not be performed according exclusively clinical parameters for these patients, once we have demonstrated that neurological involvement may be silent in these patients.