Spinal cord compression in patients with mucopolysaccharidosis.

PURPOSE: Spinal abnormalities frequently occur in patients with mucopolysaccharidosis (MPS) types I, II, IV, and VI. The symptoms are manifold, which sometimes prolongs the diagnostic process and delays therapy. Spinal stenosis (SS) with spinal cord compression due to bone malformations and an accumulation of storage material in soft tissue are serious complications of MPS disease. Data on optimal perioperative therapeutic care of SS is limited. METHODS: A retrospective chart analysis of patients with MPS and SS for the time period 01/1998 to 03/2021 was performed. Demographics, clinical data, neurological status, diagnostic evaluations (radiography, MRI, electrophysiology), and treatment modalities were documented. The extent of the SS and spinal canal diameter were analyzed. A Cox regression analysis was performed to identify prognostic factors for neurological outcomes. RESULTS: Out of 209 MPS patients, 15 were included in this study. The most dominant type of MPS was I (-H) (n = 7; 46.7%). Preoperative neurological deterioration was the most frequent indication for further diagnostics (n = 12; 80%). The surgical procedure of choice was dorsal instrumentation with microsurgical decompression (n = 14; 93.3%). A univariate Cox regression analysis showed MPS type I (-H) to be associated with favorable neurological outcomes. CONCLUSION: Early detection of spinal stenosis is highly relevant in patients with MPS. Detailed neurological assessment during follow-up is crucial for timeous detection of patients at risk. The surgical intervention of choice is dorsal instrumentation with microsurgical decompression and resection of thickened intraspinal tissue. Patients with MPS type I (-H) demonstrated the best neurological course.

Delayed Onset Post-Operative Neurologic Deficit in a Patient With Mucopolysaccharidosis type VI: A Case Report.

Background: Mucopolysaccharidoses (MPS) are lysosomal storage disorders characterized by abnormal deposition of glycosaminoglycans (GAGs) in tissues. In type VI MPS, otherwise known as Maroteaux-Lamy syndrome, the defect is in the enzyme N-acetylgalactosamine-4-sulfatase. Thoracolumbar kyphosis results from GAG deposition, leading to incompetence of posterior ligamentous structures as well as poor trunk control. Though neurologic symptoms from canal compression due to deformity and hypertrophy of tissues have been described, occasionally requiring surgical decompression, there has not been a prior report of late onset of symptoms in a previously neurologically intact patient following surgery to correct spine deformity. Methods: The case reviewed is a 14 year old girl with mucopolysaccharidosis type VI underwent anterior release and posterior instrumentation for correction of severe progressive lumbar kyphosis. Postoperatively she developed delayed onset of profound lower extremity weakness and underwent urgent wide laminectomies and resection of thickened ligamentum flavum. At 1 year follow-up, she had near complete neurologic recovery. Conclusion: Patients with mucopolysacchari-doses are at significant risk for neurologic compromise both as part of the natural history of the disease, and as a risk of deformity correction. The surgeon must consider the pathologic thickening of tissues surrounding the spinal cord when planning surgery. Level of Evidence: IV.

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.

Liver transplantation: New treatment for mucopolysaccharidosis type VI in rats.

BACKGROUND: Mucopolysaccharidosis (MPS) VI is a rare, autosomal recessive congenital metabolic disorder caused by deficient activity of the lysosomal metabolic enzyme, N-acetylgalactosamine 4-sulfatase. Enzyme replacement therapy (ERT) is the current treatment for MPS VI, although it involves limited compliance to the therapy and high cost. The aim of this study was to develop a new method of treatment by conducting an orthotopic liver transplantation (LTx) using an animal model of human MPS VI, and to evaluate and examine its effectiveness for treating MPS VI. METHODS: LTx was carried out from normal unaffected to affected MPS VI rats (MPR), which were then killed after LTx, and tissues from the heart, spleen, and knee joint, as well as serum, collected for biological and morphologic evaluation. RESULTS: Liver-transplanted (LTx) MPR had the same level of N-acetylgalactosamine 4-sulfatase activity in the liver and lungs as normal unaffected MPR, and the urinary secretion of mucopolysaccharides/glycosaminoglycan (GAG) in LTx MPR was significantly decreased. Furthermore, on histopathology, the spleens of LTx MPR showed elimination of vacuole cells. In the knee joints, growth plates became thinner, and on radiography the facial and cranial bones of LTx MPR were morphologically normal. CONCLUSIONS: LTx from normal to affected MPR was effective for symptoms of MPS and accumulation of GAG, suggesting that LTx could be a promising alternative approach for MPS VI.

Atypical Presentation of Acute Angle-Closure Glaucoma in Maroteaux-Lamy Mucopolysaccharidosis with Patent Prophylactic Laser Peripheral Iridotomy: A Case Report.

INTRODUCTION: Maroteaux-Lamy syndrome (MLS) is a rare progressive condition characterized by inflammation and scarring of multiple organs. Ocular complications caused by anterior segment abnormalities commonly cause visual impairment in MLS. Angle-closure glaucoma is one such complication, but there are limited data on presentation, workup, and management of this condition. CASE PRESENTATION: This case report describes an atypical presentation of acute angle-closure glaucoma in a patient with MLS despite a prior prophylactic laser peripheral iridotomy-which would typically prevent an acute angle-closure attack-that was patent and intact at the time of angle closure. DISCUSSION: Because of severe congenital anterior segment crowding, high axial hyperopia, and constant accommodative demand in patients with MLS, we recommend performing two prophylactic laser peripheral iridotomies simultaneously in the same eye instead of one. The mechanism for this indication differs from that in patients at risk of acute angle-closure glaucoma because of lens zonulopathy alone. We hope that this case report may help prevent vision loss and optimize quality of life in patients with MLS who may be wheelchair-bound but are typically high functioning with normal intelligence.

Tracheobronchial stents in mucopolysaccharidosis.

INTRODUCTION: The mucopolysaccharidoses are a group of hereditary disorders pathologically characterized by tissue accumulation of glycosaminoglycans due to deficient lysosomal metabolism which often leads to progressive airway stenosis and respiratory insufficiency. Relentless and treatment-refractory narrowing of the lower airways with ensuing severe limitation of quality of life is a challenging problem in mucopolysaccharidoses. CASE REPORTS: We report 2 cases of MPS (Hunter's and Maroteaux-Lamy's syndrome resp.) in whom tracheal stents were placed to relieve severe tracheal obstruction. The first patient could be weaned from mechanical ventilation after stent placement but showed significant long-term stent-related morbidity. The second patient suffered a severe procedure-related complication due to positioning problems typical for MPS. CONCLUSIONS: Very good short-term success can be achieved with airway stent placement in patients with MPS and severe lower airway stenosis but a high risk of severe complications and important long-term morbidity have to be weighed against potential individual benefit.

Therapy for mucopolysaccharidosis VI: (Maroteaux-Lamy syndrome) present status and prospects.

Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disorder caused by deficient activity of Arylsulphatase B (ARSB). The disease is progressive and multisystemic, usually leading to death in the first decades of life. In addition to supportive management, specific treatments for MPS VI are the hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT). Both are effective for some aspects of the disease, but fail in correcting important clinical features, such as bone deformities and heart valve thickening. Based on that, new treatments are currently being tested to be used alone or in combination with the current therapies. Here we summarize some of these new approaches and the preliminary results obtained, reporting their limitations and indicating possible future trends in MPS VI treatment. We discuss intrathecal ERT, gene therapy and therapies based on anti-inflammatory molecules, among other approaches. Finally, we highlight the importance of early treatment and diagnosis for a better outcome in these patients.

Macrophage involvement in mitral valve pathology in mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome).

Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI) is a rare lysosomal storage disorder in which the pathologic storage of glycosaminoglycans in various tissues can lead to severe symptoms, including cardiomyopathy. We report on a child with Maroteaux-Lamy syndrome whose cardiac condition deteriorated and eventually led to cardiac failure at the age of 7 years due to severe mitral regurgitation. She received a mitral valve replacement and tricuspid repair with successful outcome. Histologic examination of the mitral valve showed abundant "clear" cells in both the leaflets and chordae tendineae. In Hurler disease (MPS I), similar cells have been identified as activated valvular interstitial cells (VICs, a myofibroblast like cell type). Here we report that the "clear" cells are CD68 positive, a frequently used marker of macrophage lineage. The "clear" cells remained unstained with the more specific macrophage marker CD14 while persistent staining of other cells demonstrated macrophage infiltration. From these observations, we infer that macrophages are involved in mitral valve pathology in MPS VI.

Craniocervical decompression in patients with mucopolysaccharidosis VI: development of a scoring system to determine indication and outcome of surgery.

OBJECTIVE: To analyse diagnostic value of somato-sensory evoked potentials (SEP), magnetic resonance imaging (MRI), and clinical neurological examination in the decision for decompression surgery in mucopolysaccharidosis (MPS) VI patients with craniocervical cord compression (CCJ). METHODS: We retrospectively analysed neurological examination, SEP of the median nerve and MRI outcomes from 31 MPS VI patients. Individual scores for each test (based on severity of findings) and a sum of scores of all three procedures (CCJ score) were evaluated for their potential to measure the need for and improvement after surgery. Differences between rapidly and slowly progressive patients were also evaluated. RESULTS: Fourteen patients (45 %) aged 4-34 years underwent decompression surgery. Median age at first operation was lower in rapidly than in slowly progressive patients (12 vs. 24 years; P = 0.008). Neurological and SEP findings but not MRI results differed significantly between non-operated and operated patients (P < 0.001, P = 0.003 and P = 0.08, respectively). A significant relationship was found between MRI and clinical neurological examination (P < 0.001) and between SEP and clinical neurological examination (P = 0.01) but not between MRI and SEP (P = 0.06). The CCJ score discriminated between operated and non-operated patients (4-9 points vs. 0-3 points; P < 0.001) and decreased in 61.5 % of patients after surgery. CONCLUSIONS: CCJ is common in rapidly and slowly progressive MPS VI patients. The CCJ score is an objective and transparent tool for assessing pathology of the CCJ, the need for surgery, and improvement after surgery.

Anesthesia in a patient with mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome).

We report a case of anesthesia during surgery to enlarge the foramen magnum in a pediatric patient with an extremely rare form of mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome). Airway control was unexpectedly easy, and intraoperative anesthetic management with total intravenous anesthesia went smoothly. However, the disease is progressive, with no guarantee that future anesthetic management of this patient will remain easy. If repeated surgery is required, thorough testing should be conducted over time to assess both airway and systemic complications. Nevertheless, we found that safe anesthetic management of affected patients is possible with anesthetics currently used in a clinical setting.

Deep anterior lamellar keratoplasty for Maroteaux-Lamy syndrome.

PURPOSE: To present a case of Maroteaux-Lamy syndrome (MLS), which underwent deep anterior lamellar keratoplasty (DALK) for visual rehabilitation. METHODS: A 15-year-old girl with MLS was admitted with severe corneal opacity. We performed DALK on her left eye for visual rehabilitation. Big-bubble technique was used to perform lamellar separation. RESULTS: Corneal graft was clear 24 months after surgery. Best spectacle-corrected visual acuity of left eye was 20/25 with the correction of +0.75/-0.50 diopters × 170. At the last follow-up, in vivo confocal microscopy revealed mild haze in the posterior stroma at the graft interface level. Endothelial cell count was 2473.4 cells per square millimeter using a noncontact specular microscope. CONCLUSIONS: Given systemic problems in patients with MLS and less postoperative complications of DALK in comparison with penetrating keratoplasty, it seems DALK is the better choice for these patients.

Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI): a single dose of galsulfase further reduces urine glycosaminoglycans after hematopoietic stem cell transplantation.

BACKGROUND: Maroteaux-Lamy syndrome, or mucopolysaccharidosis (MPS) type VI, is the autosomal recessive lysosomal disorder resulting from deficient N-acetylgalactosamine 4-sulfatase (ARSB) and the consequent accumulation of glycosaminoglycan (GAG). Patients fully engrafted after hematopoietic stem cell transplantation (HSCT) demonstrate several indicators of metabolic correction such as reduction in liver size, absence of hepatic ultrastructural pathology, and patients do not develop cervical cord compression. Engrafted patients demonstrate reduction in urine GAG achieving near-normal levels. HYPOTHESIS: We presumed that HSCT engraftment from a normal individual would provide sufficient systemic enzyme to accomplish maximal metabolic correction, and that no additional benefit would accrue from additional therapy such as with intravenous recombinant human ARSB protein, galsulfase. MATERIALS AND METHODS: A 22-year-old male had received an allogeneic bone marrow transplant from an HLA-identical sibling donor, and remained fully engrafted after 20 years. In response to his request regarding the potential benefit of enzyme replacement therapy, we administered a single, standard dose of galsulfase while monitoring urine GAG daily, before and after the treatment. RESULTS: Urine GAG declined from slightly high pre-treatment levels (7.63 mg GAG/mmol creatinine; range 7.0-8.5, N=3) progressively declining below the age-specific normal range (<6.5) over 10 days to the lowest level of 4.4, with a mean post-treatment level of 5.60 (N=10). CONCLUSIONS: Somewhat surprisingly, the biomarker urine GAG was significantly reduced after a single treatment of intravenous galsulfase thus suggesting that supplemental enzyme replacement therapy might improve the clinical outcome for donor-engrafted patients with MPS VI.

Long-term follow-up of a girl with Maroteaux-Lamy syndrome after bone marrow transplantation.

BACKGROUND: Mucopolysaccharidosis type VI (MPS VI or Maroteaux-Lamy syndrome) is a rare autosomal recessive genetic disorder. We treated a 10-year-old girl with Maroteaux-Lamy syndrome successfully with bone marrow transplantation (BMT). METHODS: The patient had reconstitution with bone marrow from her HLA-matched brother. One month after BMT, arylsulfatase activity of the recipient's leukocytes became normal. No graft-versus-host disease (GVHD) was observed. Arylsulfatase B activity was maintained and the urinary excretion of glycosaminoglycans (GAGs) became normal. RESULTS: The clinical response of the patient was slow but persistent during 12 years after BMT. Improved motor function included walking alone for a long distance without aid, riding a bicycle, taking a bath by herself, etc. Besides, few infections occurred. Exertional dyspnea, severe snoring, and vertigo were much improved. CONCLUSIONS: Early intervention is recommended for BMT. Allogeneic BMT may provide a better life quality as illustrated in the present case.

Neurosurgical interventions in children with Maroteaux-Lamy syndrome. Case report and review of the literature.

This paper reports the case of a 14-year-old child with Maroteaux-Lamy syndrome (mucopolysaccharidosis type 6) who was treated consecutively for compressive damage of the optic nerves, hydrocephalus communicans and progressive spastic tetraparesis within 2 years. The clinical course of the patient is presented and the pathophysiologic mechanisms of disease progression in patients with Maroteaux-Lamy syndrome are discussed and reviewed.

Craniovertebral abnormalities in Type VI mucopolysaccharidosis (Maroteaux-Lamy syndrome).

INTRODUCTION: The craniovertebral abnormalities found in patients with Type VI mucopolysaccharidosis (Maroteaux-Lamy syndrome) are described, and the indications for and outcomes of surgery in this group are assessed. METHODS: The clinical histories and radiological findings in all patients with Type VI mucopolysaccharidosis treated at Royal Manchester Children's Hospital during the past 10 years were reviewed. RESULTS: The typical findings in patients with this disease are of canal stenosis at the level of the foramen magnum and upper cervical spine with or without cord compression. The stenosis is secondary to thickening of the posterior longitudinal ligament. Atlantoaxial instability is rare. Of nine patients under regular clinical review, four underwent decompressive surgery for cervical cord compression. Three of the four showed improvement in their neurological symptoms and signs postoperatively. Of the children reviewed, six had radiological evidence of cord compression, although only those with neurological signs or symptoms were treated surgically. DISCUSSION: Despite the often formidable anesthetic challenge, surgery is indicated in those patients who present with progressive neurological deficit due to cervical myelopathy. Surgery can be undertaken safely if the associated medical problems in these children are recognized and managed appropriately.

Mild form of Maroteaux-Lamy syndrome: corneal histopathology and ultrastructure.

PURPOSE: Maroteaux-Lamy syndrome is one of the mucopolysaccharidoses (MPSs) that is caused by the incomplete degradation and storage of dermatan sulfate. METHODS: We describe a 49-year-old female patient with the mild form of the disease (MPS VI-B) who developed bilateral increasing corneal opacification and increased intraocular pressure after cervical-fusion surgery. After treatment of the increased intraocular pressure, she underwent a penetrating keratoplasty of her right eye. RESULTS: The histopathologic and ultrastructural features of the corneal button were the accumulation of membrane-bound vacuoles containing fibrillogranular and lamellated material in keratocytes and endothelial cells and thinning of Descemet's membrane with excrescences. CONCLUSION: Our review of the literature reveals only two prior histologic studies of corneas affected by MPS VI B.

Ocular abnormalities in the mucopolysaccharidoses after bone marrow transplantation. Longer follow-up.

OBJECTIVE: The purpose of the study was to provide longer follow-up of ocular findings in patients with mucopolysaccharidoses (MPS) after bone marrow transplantation (BMT). DESIGN: The study design was a retrospective 6-year cohort evaluation. PARTICIPANTS: Twenty-three patients with MPS (19 with MPS type I-H, 3 with MPS type III, 1 with MPS type VI) were studied. INTERVENTION: Bone marrow transplantation was performed. MAIN OUTCOME MEASURES: The following outcome measures were considered: vision, slit-lamp biomicroscopic and funduscopic examinations, intraocular pressure, electroretinography (ERG), and retinoscopy. RESULTS: Thirteen (81%) of 16 patients showed ERG improvement in the first year. However, all patients showed slowly progressive decline of the ERG over longer follow-up. Other ocular findings included optic atrophy (n = 7 patients), disc edema (n = 6 patients), strabismus (n = 6 patients), nystagmus (n = 6 patients), cataract (n = 3 eyes), keratoconjunctivitis sicca (n = 4 eyes), ocular hypertension (n = 2 eyes), and glaucoma (n = 2 eyes). CONCLUSIONS: The MPS are rare and heterogeneous disorders characterized by progressive retinal degeneration and blindness. Ocular abnormalities can occur as a result of the disease or as a consequence of BMT. Successful BMT has been shown to improve systemic health, but this may not reflect continuing ocular status and retinal function. Despite early improvement in ERG function, longer follow-up suggests progressive retinal decline.