Tandem mass spectrometric assay of N-acetylglucosamine-6-sulfatase for multiplex analysis of mucopolysaccharidosis-IIID in dried blood spots.

Previously we developed a multiplex liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay using dried blood spots for all subtypes of mucopolysaccharidoses (MPS) except MPS-IIID. Here we show that the MPS-IIID enzyme N-acetylglucosamine-6-sulfatase (GNS) is inhibited in dried blood spot (DBS) extracts, but activity can be recovered if the extract is diluted to reduce the concentrations of endogenous inhibitors. The new GNS assay displays acceptable characteristics including linearity in product formation with incubation time and amount of enzyme, low variability, and ability to distinguish MPS-IIID-affected from healthy patients using DBS. The assay can be added to the LC-MS/MS multiplex panel for all MPS subtypes requiring ∼2 min per newborn for the LC-MS/MS run.

Glycosaminoglycan-induced proinflammatory cytokine levels as disease marker in mucopolysaccharidosis.

Recently, it has been shown disturbances in oxidant/antioxidant system and increases in some inflammatory markers in animal studies and in some Mucopolysaccharidoses (MPSs) patients. In this study, we aimed to determine the oxidative stress/antioxidant parameters and pro-inflammatory cytokine levels in the serum of MPS patients, in order to evaluate the possible role of inflammation in these patient groups regarding to accumulated metabolites. MPS I (n = 3), MPS II (n = 8), MPS III (n = 4), MPS IVA (n = 3), MPS VI (n = 3), and VII (n = 1) patients and 20 age-matched healthy subjects were included into the study. There was no statistically significant change in activities of SOD, Catalase, GSH-Px and lipid peroxidation levels in erythrocytes between the MPS patients and healthy controls. While IL-1alpha (p = 0.054), IL-6 (p = 0.008) levels, and chitotriosidase activity (p = 0.003) elevated in MPS3 patients, IL1α (p = 0.006), IL-1ß (p = 0.006), IL-6 (p = 0.006), IFNγ (p = 0.006), and NFκB (p = 0.006) levels increased in MPS-6 patients. Elevated levels of IL-6, IL1α and chitotriosidase activity demonstrated macrophage activation in MPSIII untreated with enzyme replacement. Our study showed for the first time that high levels of IL1α, IL-6, IL1ß and NFκB were present in MPSVI patients, demonstrating the induction of inflammation by dermatan sulphate. The low level of paraoxonase in MPSVI patients may be a good marker for cardiac involvement. Overall, this study provides important insights into the relationship between lysosomal storage of glycosaminoglycan and inflammation in MPS patients. It highlights possible pathways for the increased release of inflammatory molecules and suggests new targets for the development of treatments.

Generation of induced pluripotent stem cell line (RCMGi012-A) from fibroblasts of patient with mucopolysaccharidosis type VI.

Skin fibroblasts obtained from a 5-year-old girl with genetically proven (two heterozygous mutations in ARSB gene) and clinically manifested mucopolysaccharidosis type VI were successfully transformed into induced pluripotent stem cells by using Sendai virus-based reprogramming vectors including the four Yamanaka factors namely SOX2, OCT3/4, KLF4, and c-MYC. These iPSCs expressed pluripotency markers, had a normal karyotype and the potential to differentiate into three germ layers in spontaneous differentiation assay. The line may be used for cell differentiation and pharmacological investigations, and also may provide a model for development of a personalized treatment including drug screening and genome editing.

Safety outcomes and patients' preferences for home-based intravenous enzyme replacement therapy (ERT) in pompe disease and mucopolysaccharidosis type I (MPS I) disorder: COVID-19 and beyond.

BACKGROUND: The Italian Medicines Agency (AIFA) demands precise information on benefit/risk profile of home-based enzyme replacement therapy (ERT) for the treatment of patients with Pompe disease and Mucopolysaccharidosis type I (MPS I). This passage is necessary to obtain the authorization for ERT home therapy, even after the coronavirus disease-19 (COVID-19) pandemic period. This research intends to evaluate the safety, treatment satisfaction, and compliance of MPS I patients treated with laronidase (Aldurazyme®) and Pompe Disease patients treated with alglucosidase alfa (Myozyme®) in a homecare setting. RESULTS: We report herein an early interim analysis of the HomERT (Home infusions of ERT) study, a multicenter, non-interventional, double-cohort study that retrospectively analyzed 38 patients from 14 sites in Italy: cohort A (Pompe disease - 32 patients) and cohort B (MPS I - 6 patients). Among the selected patients who started home therapy before enrollment, the average number of missed home-based infusions was 0.7 (1.3) in cohort A and 3.8 (6.4) in cohort B with no return to the hospital setting. Irrespective of the treatment location, 3 prior ADRs per cohort were reported. The majority of patients preferred home-based infusions (cohort A: 96.9%; cohort B: 100%): the main reason was attributed to treatment convenience (cohort A: 81.3%; cohort B: 83.3%). Despite the underlying conditions, most patients self-evaluated their health as "good" (cohort A: 50%; cohort B: 83.3%). CONCLUSIONS: Evidence of favorable safety profile, improved treatment compliance and personal satisfaction validates the use of ERT with laronidase and alglucosidase alfa as a strong candidate for home therapy.

Skeletal phenotype amelioration in mucopolysaccharidosis VI requires intervention at the earliest stages of postnatal development.

Mucopolysaccharidosis VI (MPS VI) is a rare lysosomal disease arising from impaired function of the enzyme arylsulfatase B (ARSB). This impairment causes aberrant accumulation of dermatan sulfate, a glycosaminoglycan (GAG) abundant in cartilage. While clinical severity varies along with age at first symptom manifestation, MPS VI usually presents early and strongly affects the skeleton. Current enzyme replacement therapy (ERT) does not provide effective treatment for the skeletal manifestations of MPS VI. This lack of efficacy may be due to an inability of ERT to reach affected cells or to the irreversibility of the disease. To address the question of reversibility of skeletal phenotypes, we generated a conditional by inversion (COIN) mouse model of MPS VI, ArsbCOIN/COIN, wherein Arsb is initially null and can be restored to WT using Cre. We restored Arsb at different times during postnatal development, using a tamoxifen-dependent global Cre driver. By restoring Arsb at P7, P21, and P56-P70, we determined that skeletal phenotypes can be fully rescued if Arsb restoration occurs at P7, while only achieving partial rescue at P21 and no significant rescue at P56-P70. This work has highlighted the importance of early intervention in patients with MPS VI to maximize therapeutic impact.

Defect-free graphene enhances enzyme delivery to fibroblasts derived from patients with lysosomal storage disorders.

Enzyme replacement therapy shows remarkable clinical improvement in treating lysosomal storage disorders. However, this therapeutic approach is hampered by limitations in the delivery of the enzyme to cells and tissues. Therefore, there is an urgent, unmet clinical need to develop new strategies to enhance the enzyme delivery to diseased cells. Graphene-based materials, due to their dimensionality and favourable pattern of interaction with cells, represent a promising platform for the loading and delivery of therapeutic cargo. Herein, the potential use of graphene-based materials, including defect-free graphene with positive or negative surface charge and graphene oxide with different lateral dimensions, was investigated for the delivery of lysosomal enzymes in fibroblasts derived from patients with Mucopolysaccharidosis VI and Pompe disease. We report excellent biocompatibility of all graphene-based materials up to a concentration of 100 µg mL-1 in the cell lines studied. In addition, a noticeable difference in the uptake profile of the materials was observed. Neither type of graphene oxide was taken up by the cells to a significant extent. In contrast, the two types of graphene were efficiently taken up, localizing in the lysosomes. Furthermore, we demonstrate that cationic graphene flakes can be used as carriers for arylsulfatase B enzyme, for the delivery of the lacking enzyme to the lysosomes of Mucopolysaccharidosis VI fibroblasts. Arylsulfatase B complexed with cationic graphene flakes not only retained the enzymatic activity, but also exerted biological effects almost twice as high as arylsulfatase B alone in the clearance of the substrate in Mucopolysaccharidosis VI fibroblasts. This study lays the groundwork for the potential use of graphene-based materials as carriers for enzyme replacement therapy in lysosomal storage disorders.

Persistent bone and joint disease despite current treatments for mucopolysaccharidosis types I, II, and VI: Data from a 10-year prospective study.

The mucopolysaccharidosis (MPS) disorders have many potential new therapies on the horizon. Thus, historic control data on disease progression and variability are urgently needed. We conducted a 10-year prospective observational study of 55 children with MPS IH (N = 23), MPS IA (N = 10), non-neuronopathic MPS II (N = 13), and MPS VI (N = 9) to systematically evaluate bone and joint disease. Annual measurements included height, weight, and goniometry. Mixed effects modeling was used to evaluate changes over time. All participants had been treated with hematopoietic cell transplantation and/or enzyme replacement therapy. Height z-score decreased over time in MPS IH, MPS II, and MPS VI, but not MPS IA. Adult heights were 136 ± 10 cm in MPS IH, 161 ± 11 cm in MPS IA, 161 ± 14 cm in MPS II, and 128 ± 15 cm in MPS VI. Adult average BMI percentiles were high: 75 ± 30%ile in MPS IH, 71 ± 37%ile in MPS IA, 71 ± 25%ile in MPS II, and 60 ± 42%ile in MPS VI. Every participant had joint contractures of the shoulders, elbows, hips, and/or knees. Joint contractures remained stable over time. In conclusion, despite current treatments for MPS I, II, and VI, short stature and joint contractures persist. The elevation in average BMI may be related, in part, to physical inactivity due to the ongoing bone and joint disease. Data from this longitudinal historical control study may be used to expedite testing of experimental bone and joint directed therapies and to highlight the need for weight management as part of routine clinical care for patients with MPS.

The articular and the craniocervical abnormalities are of confusing age of onset in patients with Maroteaux-Lamy disease (MPS VI).

BACKGROUND: Maroteaux-Lamy disease (MPS Type VI) is an autosomal recessive lysosomal storage disorder. Skeletal abnormalities are vast. Early recognition may facilitate timely diagnosis and intervention, leading to improved patient outcomes. The most challenging is when patients manifest a constellation of craniocervical and articular deformities with variable age of onset. METHODS: We collected 15 patients with MPS VI (aged from 6 years-58 years). From within our practice in Pediatric Orthopedics, we present patients with MPS type VI who were found to manifest a diverse and confusing clinical presentation of hip deformities and cervical cord compression. Stem cell transplants were proposed as treatment tool and enzyme replacement therapy has been instituted in some patients. RESULTS: The spectrum of the clinical involvement in our group of patients was supported firstly via the clinical phenotype followed by assessment of the biochemical defect, which has been detected through the deficiency of N-acetylgalactosamine-4-sulfatase (arylsulphatase B) leading to increased excretion of dermatan sulphate. Secondly, through the molecular genetic results, which showed homozygous or compound heterozygous mutation in the ARSB gene on chromosome 5q14. Hip replacements and decompression operations have been performed to restore function and to alleviate pain in the former and life saving procedure in the latter. CONCLUSIONS: The efforts in searching for the etiological diagnosis in patients with skeletal dysplasia/MPSs has not been rewarding as many had anticipated. This emerged from several facts such as improper clinical documentation, missing diagnostic pointers in radiographic interpretations, limited knowledge in skeletal dysplasia and its variants, and the reliance on underpowered studies. Physicians and radiologists are required to appreciate and assess the diverse phenotypic and the radiographic variability of MPS VI. The importance of considering MPS in the differential diagnosis of other forms skeletal dysplasia is mandatory. Finally, we stress that the value of early diagnosis is to overcome dreadful complications.

Mucopolisacaridosis tipo VI: a propósito de un caso / Mucopolysaccharidosis type VI. Case report

La mucopolisacaridosis tipo VI o síndrome de Maroteaux-Lamy se produce por la deficiencia de la enzima arilsulfatasa B que ocasiona la acumulación intracelular de dermatán sulfato. El riesgo de compresión medular es particularmente elevado y muy frecuente en la unión occipito-cervical. La terapia de reemplazo enzimático ha sido esencial para los pacientes con esta enfermedad; sin embargo, no tiene efecto sobre las alteraciones esqueléticas, y su impacto sobre la estabilidad espinal está aún en estudio. Se sugiere un examen anual (evaluación neurológica, radiografías, resonancia magnética y potenciales provocados somatosensitivos) y, en caso de anomalías, cada 6 meses. Pese al alto riesgo anestésico, la mielopatía y los síntomas progresivos indican la necesidad de una descompresión quirúrgica. Presentamos a una niña de 12 años con mucopolisacaridosis tipo VI tratada con terapia de reemplazo enzimático desde los 7 años, que acude a la consulta con síntomas compatibles con mielopatía cervical alta progresiva. Fue sometida a una descompresión y artrodesis occipito-cervical con ampliación del foramen magno. Esta enfermedad es infrecuente; por lo tanto, es imperativo el seguimiento multidisciplinario del paciente, así como conocer el riesgo de compresión medular y su oportuno tratamiento quirúrgico a cargo de cirujanos espinales. Nivel de Evidencia: IV

Mucopolysaccharidosis type VI, also known as Maroteaux-Lamy syndrome, is caused by a deficiency of the arylsulfatase B enzyme, which causes intracellular accumulation of dermatan sulfate. The risk of spinal cord compression is particularly high and frequent at the occipitocervical junction. Enzyme replacement therapy has been essential for patients with this disease; however, it has no effect on skeletal abnormalities, and its impact on spinal stability is still under study. An annual examination (neurological evaluation, radiography, magnetic resonance imaging, and somatosensory evoked potentials) is recommended. In case of anomalies, it should be repeated every 6 months. Despite the high anesthetic risk, myelopathy and progressive symptoms indicate the need for surgical decompression. We present the case of a 12-year-old girl with mucopolysaccharidosis type VI treated with enzyme replacement therapy since the age of 7, who came to the consultation with symptoms compatible with progressive high cervical myelopathy. She underwent occipitocervical decompression and fusion with enlargement of the foramen magnum. This disease is rare; therefore, multidisciplinary patient follow-up is imperative, as well as knowing the risk of spinal cord compression and its timely surgical treatment by spinal surgeons. Level of Evidence: IV

Surgical treatment of craniovertebral stenosis in two siblings with type vi mucopolysaccharidosis / Tratamento cirúrgico de estenose craneo-vertebral em dois irmãos com mucopolisacaredose tipo vi / Tratamiento quirúrgico de estenosis craneo-vertebral en dos hermanos con mucopolisacaridosis tipo vi

ABSTRACT We describe two cases of surgical treatment of craniovertebral stenosis in preschool-aged brothers with Maroteaux-Lamy (MPS type VI) syndrome. The older brother was diagnosed with MPS during her second pregnancy. Literature describing familial cases of the disease and the treatment strategy in young children with MPS type VI and spinal canal stenosis is scarce. Based on the presented observations, indications, surgical treatment approaches, and perioperative management of patients with mucopolysac-charidosis are suggested. MPS type VI may have familial forms of the disease and the course of craniovertebral stenosis is similar in siblings. Surgical treatment of craniovertebral stenosis in these patients should be performed timely. We adhere to the point of view of early treatment of craniovertebral stenosis in patients with MPS before irreversible spinal cord dysfunction develops. Level of Evidence IV; Prognostic Studies - Investigating the Effect of a Patient Characteristic on the Outcome of Disease and Case series.

Resumo: Descreve-se dois casos de tratamento cirúrgico de estenose craniovertebral entre irmãos em idade pré-escolar com síndrome de Maroteaux-Lamy (MPS tipo VI). O irmão mais velho foi diagnosticado com MPS durante a segunda gravidez. A literatura que descreve casos familiares da doença e a estratégia de tratamento em crianças pequenas com MPS tipo VI e estenose do canal raquidiano é escassa. Com base nas observações apresentadas, foram sugeridas indicações, abordagens de tratamento cirúrgico e manejo perioperatório de pacientes com mucopolissacaridose. A MPS tipo VI pode apresentar formas familiares da doença e o curso da estenose craniovertebral é semelhante entre irmãos. O tratamento cirúrgico da estenose craniovertebral nesses pacientes deve ser realizado em tempo hábil. Adere-se ao conceito de tratamento precoce da estenose craniovertebral em pacientes com MPS antes que se desenvolva uma disfunção irreversível da medula espinhal. Nível de Evidência IV; Estudos Prognósticos - Investigando o Efeito de uma Característica de Paciente sobre o Resultado de uma Doença e de uma Série de Casos.

Resumen: Se describen dos casos de tratamiento quirúrgico de estenosis craneovertebral en hermanos de edad preescolar con síndrome de Maroteaux-Lamy (MPS tipo VI). Al hermano mayor se le diagnosticó MPS durante el segundo embarazo. La bibliografía que expone casos familiares de la enfermedad y la estrategia de tratamiento en niños pequeños con MPS tipo VI y estenosis del tubo vertebral es escasa. Sobre el fundamento de las observaciones presentadas, se sugieren indicaciones, enfoques de tratamiento quirúrgico y manejo perioperatorio de pacientes con mucopolisacaridosis. La MPS tipo VI puede presentar formas familiares de la enfermedad y el curso de la estenosis craneovertebral es semejante en los hermanos. El tratamiento quirúrgico de la estenosis craneovertebral en estos pacientes debe realizarse tempranamente. Se adhiere al planteamiento del tratamiento precoz de la estenosis craneovertebral en pacientes con MPS anticipándose al desarrollo de una disfunción irreversible de la médula espinal. Nivel de Evidencia IV; Estudios Pronósticos - Investigando el Efecto de una Característica del Paciente en el Resultado de la Enfermedad y Series de Casos.

Clinical, Endocrine and Genetic spectrums of Mucopolysaccharidoses type VI in Duhok city, Kurdistan Region, Iraq.

Mucopolysaccharidoses type VI is a rare disorder and establishing the diagnosis requires assays that are unavailable in a routine care setting. There is an increased risk of considerable diagnostic delay and missing patients due to incorrect diagnosis. The present study was conducted to determine the socio-demographic characteristics, clinical manifestations, and anthropometric parameters of patients with MPS type VI. Patients' enzyme levels and genetic profiles were also examined. The present study included a total of 16 patients who had been diagnosed as MPS type VI and were referred to Hivi Pediatric Hospital in Duhok, Kurdistan Region, Iraq, till the time period of March 2022. Diagnoses were made in all the patients by analyzing the enzyme level. Moreover, a genetic study was performed to confirm the diagnosis. From each of the patients, a blood sample was taken to determine the hematological parameters. Among the study participants, 9 were males and 7 were females. The mean age of the patients was 6.81±4.99 years and the age at diagnosis was 21.13±15.19 months. All of them presented with a course facial features, 75% had short stature, 87.5% had corneal clouding, 12.5%  had glaucoma, 68.75% had poor vision, 18.75% of them had optic nerve disease, 56.25% had otitis media, 56.25% had poor hearing, 68.75% had a history of recurrent sinusitis, 50% had an enlarged tongue, and 75% had abnormal teeth. Approximately 56.25% of the patients presented with sleep apnea, 37.5% had obstructive and restrictive airway disease, none of the patients had cardiac arrhythmia, 37.5% had cardiomyopathy, 31.25% had abdominal hepatosplenomegaly, 81.25% had skeletal abnormalities, all of the patients had normal intelligence, 9 (56.25%) had a past medical history of other systemic illness and 7 (43.75%) had a past history of surgery. Out of the total number of patients, 13 patients had c.962T>C (p.(Leu321Pro)) mutation, one patient had c.585T>A (p.(ASP195Glu)) mutation, one patient had c.[585T>A];[753C>G] (Asp195 Glu];[Tyr251 Ter]), and one patient had c.{288C>A];[962T>C]   (p.[Ser96Arg];[Leu321Pro]) mutations. Due to the rarity in prevalence, early detection of the said disorder is critical; early treatment may result in improved outcomes, which may have potential significance for newborn screening.

Profound Impact of Decline in N-Acetylgalactosamine-4-Sulfatase (Arylsulfatase B) on Molecular Pathophysiology and Human Diseases.

The enzyme N-acetylgalactosamine-4-sulfatase (Arylsulfatase B; ARSB) was originally identified as a lysosomal enzyme which was deficient in Mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy Syndrome). The newly directed attention to the impact of ARSB in human pathobiology indicates a broader, more pervasive effect, encompassing roles as a tumor suppressor, transcriptional mediator, redox switch, and regulator of intracellular and extracellular-cell signaling. By controlling the degradation of chondroitin 4-sulfate and dermatan sulfate by removal or failure to remove the 4-sulfate residue at the non-reducing end of the sulfated glycosaminoglycan chain, ARSB modifies the binding or release of critical molecules into the cell milieu. These molecules, such as galectin-3 and SHP-2, in turn, influence crucial cellular processes and events which determine cell fate. Identification of ARSB at the cell membrane and in the nucleus expands perception of the potential impact of decline in ARSB activity. The regulation of availability of sulfate from chondroitin 4-sulfate and dermatan sulfate may also affect sulfate assimilation and production of vital molecules, including glutathione and cysteine. Increased attention to ARSB in mammalian cells may help to integrate and deepen our understanding of diverse biological phenomenon and to approach human diseases with new insights.

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.

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.

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.

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.

Cardiac involvement in MPS patients: incidence and response to therapy in an Italian multicentre study.

BACKGROUND: Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders caused by the deficit of lysosomal hydrolases involved in the degradation of glycosaminoglycans (GAGs). The course is chronic and progressive, with multisystemic involvement that often leads to cardiovascular disease. We describe the overall incidence and type of cardiac damage in a cohort of Italian MPS patients, and their progression over time, also with reference to treatment efficacy in patients under Enzyme Replacement Therapy (ERT). Moreover, we report a possible association between genetic variants and cardiac phenotype in homozygous and hemizygous patients to understand whether a more aggressive clinical phenotype would predict a greater cardiac damage. RESULTS: Our findings confirm that cardiac involvement is very common, already at diagnosis, in MPS VI (85.7% of our cohort), and in MPS II (68% of our cohort) followed by MPS I subjects (55% of our cohort). The most frequent heart defect observed in each MPS and at any time-point of evaluation was mitral insufficiency; 37% of our patients had mitral insufficiency already at diagnosis, and 60% at post-ERT follow-up. After at least six years of treatment, we observed in some cases (including 6 MPS II, 2 MPS IV and 2 MPS VI) a total regression or improvement of some signs of the cardiac pathology, including some valve defects, though excluding aortic insufficiency, the only valvulopathy for which no regression was found despite ERT. The general clinical phenotype proved not to be strictly correlated with the cardiac one, in fact in some cases patients with an attenuated phenotype developed more severe heart damage than patients with severe phenotype. CONCLUSIONS: In conclusion, our analysis confirms the wide presence of cardiopathies, at different extent, in the MPS population. Since cardiac pathology is the main cause of death in many MPS subtypes, it is necessary to raise awareness among cardiologists about early cardiac morpho-structural abnormalities. The encouraging data regarding the long-term effects of ERT, also on heart damage, underlines the importance of an early diagnosis and timely start of ERT.

Addressing the need for patient-friendly medical communications: adaptation of the 2019 recommendations for the management of MPS VI and MPS IVA.

BACKGROUND: Patients are the most important stakeholders in the care of any disease and have an educational need to learn about their condition and the treatment they should receive. Considering this need for patient-focused materials, we present a directed approach for mucopolysaccharidosis (MPS) VI and MPS IVA, a pair of rare, inherited diseases that affects multiple organs and parts of the body. Independent guidelines on the treatment of these diseases were recently published, providing evidence- and expertise-driven recommendations to optimize patient management. However, while healthcare providers may have the training and knowledge to understand these guidelines, patients and their caregivers can find the technical content challenging. Hence, we aimed to develop plain language summaries (PLS) of the MPS VI and MPS IVA guidelines with patients as the primary audience. RESULTS: A review of the guidelines by an expert team identified six domains of information relevant to patients: The multidisciplinary team, regular tests and check-ups, disease-modifying and supportive treatments, general anesthetics, ear-nose-throat/respiratory care, and surgeries. This information was adapted into a series of infographics specific to either MPS VI or MPS IVA, designed to appeal to patients and clearly present information in a concise manner. CONCLUSIONS: The use of patient-friendly materials, like the infographics we have developed, has the potential to better inform patients and engage them in their care. We issue a "call to arms" to the medical community for the development of similar PLS materials in rare diseases intended to inform and empower patients.