Maroteaux-Lamy Research Articles

Mucopolysaccharidosis VI: cardiac involvement and the impact of enzyme replacement therapy

To describe cardiac abnormalities in patients with mucopolysaccharidosis (MPS) VI and to evaluate the impact of enzyme replacement therapy (ERT) on cardiac structure and function. Data from electrocardiographic and echocardiographic evaluations were retrospectively collected from patients with MPS VI who are followed up at the Children's Hospital of Mainz. The study included 44 (16 male and 28 female) patients. At baseline, valvular regurgitation (mainly aortic and mitral) and left ventricular (LV) volume overload were present in over half of patients. Other common cardiac manifestations were sinus tachycardia, LV hypertrophy, concentric LV remodelling, and pulmonary hypertension. One patient had left atrial dilation and one had congestive heart failure. Interventricular septal wall thickness and LV posterior wall thickness were above normal in most patients. Twenty five patients had a pre-ERT and at least one follow-up visit after ERT start. Mean follow-up after ERT start was 5.6 (SD 2.3) years. Despite the late onset (mean age 14.6years) of treatment, ERT appeared to improve or arrest the progression of LV remodelling and LV hypertrophy and suspend the progression of cardiac valve disease. MPS VI is associated with an array of cardiac manifestations. ERT appears to have some impact on cardiac structure and function when started late in life, but may have better long-term results when started during early infancy.

Haploidentical stem cell transplantation in two children with mucopolysaccharidosis VI: clinical and biochemical outcome

BackgroundMucopolysaccharidosis VI (MPS VI) is an autosomal recessive progressive multiorgan disorder due to mutation in the gene encoding the enzyme Arylsulfatase B (ARSB). Dysfunctional ARSB causes lysosomal accumulation of glycosaminoglycans (GAG). Currently, enzyme replacement therapy (ERT) is preferred to hematopoietic stem cell transplantation (SCT) due to the treatment-related risks of the latter. However, ERT constitutes an expensive life-long treatment. Increased experience and safety of SCT-procedures in recent years suggest that SCT should be further explored as a treatment option.This is the first report on haploidentical SCT in patients with MPS VI. The primary objective was to assess the treatment safety and clinical and biochemical outcome.Patients and methodsTwo siblings diagnosed with MPS VI at 10 months of age and at birth with genotype p.C192R, reported as mild to intermediate phenotype, underwent unrelated umbilical cord blood transplantation pre-symptomatic. Due to graft failure, both patients were urgently re-transplantated with haploidentical SCT with the father as donor. Continuous clinical and biochemical status was monitored and concluded 3.8 and 4.6 years after the haploidentical SCT.ResultsHaploidentical SCT resulted in prompt and sustained engraftment. Complete donor chimerism was achieved in both patients, apart from mixed B cells chimerism in patient 2. ARSB activity in leukocytes post transplant increased from 0.0 to 19.0 μkat/kg protein (patient 1) and from 3.6 to 17.9 μkat/kg protein (patient 2) (ref. 17–40). Total urinary GAG normalized in both patients, although patient 2’s values slightly exceed normal range since 6 months. However, dermatan sulfaturia was substantially normalized since 16 months and 12 months post-SCT, respectively. Height was -1.85 SD and -1.27 SD at follow-up. Patient 1 had impaired visual acuity and discrete hepatomegaly. Patient 2 had elevated intraocular pressure and X-ray revealed steep acetabular angles and slightly flattened lumbar vertebrae.ConclusionThis study demonstrates that young children with MPS VI tolerate haploidentical SCT. Normalization of enzyme production and dermatan sulfaturia indicates correction of the inborn error of metabolism and coincide with no obvious symptoms of progressive MPS VI up to 4.6 years post-SCT.

Oral manifestations of 17 patients affected with mucopolysaccharidosis type VI

To assess oral manifestations of 17 patients with mucopolysaccharidosis type VI (MPS VI) or Maroteaux-Lamy syndrome. 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. 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 3years old did not develope anterior open bite and one of them had mildly affected mandibular condyles. 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.

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.

Dentomaxillofacial manifestations of mucopolysaccharidosis VI: clinical and imaging findings from two cases, with an emphasis on the temporomandibular joint

Using a clinical survey, panoramic, cone-beam computed tomography (CBCT), and magnetic resonance (MR) imaging, this study was conducted to ascertain primary maxillofacial abnormalities in patients with mucopolysaccharidosis VI (MPS VI). Two patients previously diagnosed with MPS VI underwent clinical and imaging surveys (panoramic radiographs, CBCT, and MR imaging). Jaw involvement was present in all patients. The most prevalent findings were enlarged marrow spaces, osteopenia, dentigerous cyst-like follicles, effacement of the jaw structures, and osteosclerosis. This is the first study to describe temporomandibular joint (TMJ) involvement for MPS VI. CBCT and MR imaging were needed to observe features that were not clear in conventional radiographs. Both patients reported symptoms in the TMJ and demonstrated involvement during their examinations. A multicenter study is necessary to better document maxillofacial involvement in MPS VI.

Plasmatic dermatan sulfate and chondroitin sulfate determination in mucopolysaccharidoses

The evaluation of plasmatic galactosaminoglycans, dermatan sulfate (DS) and chondroitin sulfate (CS) can be helpful in the early identification of MPS patients, also considering that primary storage of one type of GAG can lead to secondary accumulation of other lysosomal substrates. We explore the possibility to determine plasmatic DS and CS in numerous healthy pediatric (and sometimes adult) subjects depending on age and in patients affected by various forms of MPS. A highly sensitive HPLC separation and fluorescence detection was applied for plasma/serum DS and CS determination after a specific enzymatic treatment able to release their constituent disaccharides. DS and CS content decrease significantly with age in controls having high values in the first year (∼8μg/mL). A highly significant decrease was observed for 1–5-year-old (∼−33%) and 5–10-year-old (∼−65%) healthy subgroups. No further decrease was determined showing a stabilization after 5 years of age. MPS I Scheie and Hurler patients showed rather similar DS and CS content significantly higher than controls matched for age. Similarly, MPS II, III and IV subjects all presented significantly higher plasmatic DS and CS content compared to healthy subjects matched for age. The same trend was determined for the only patient affected by MPS VI. Plasmatic DS and CS analyzed by the present procedure may be a useful diagnostic and screening marker for various forms of MPS.

Illness Perception and Clinical Treatment Experiences in Patients with M. Maroteaux-Lamy (Mucopolysaccharidosis Type VI) and a Turkish Migration Background in Germany

IntroductionMucopolysaccharidosis VI (MPS VI) is an inherited lysosomal storage disease caused by a mutation of the gene for arylsulfatase B (ASB). Of the thirty-one patients registered in Germany, almost fifty percent have a Turkish migration background. MPS VI is treated by enzyme replacement therapy (ERT), which is time-consuming and expensive.MethodsThis interdisciplinary study explored the illness perceptions and clinical treatment experiences among ten MPS VI patients with a Turkish migration background in two centers for metabolic diseases (Berlin and Mainz, Germany). The clinical treatment situation was observed and semi-structured interviews were conducted with patients and health care personnel, in addition to participatory observation in four patients' everyday environments in Berlin. The data from the interviews, patient records, and personal field notes were encoded, cross-related, and analyzed.ResultsPatients' acknowledgement of the disease and coping strategies are influenced predominantly by the perception of their individual health status and the handling of the disease within their family. Patients' willingness to cooperate with treatment strategies is further modified by their knowledge of the disease and the relationships with their health care providers. In this analysis, cultural factors turned out to be marginally relevant.ConclusionAs with other chronic and debilitating diseases, effective treatment strategies have to reach beyond delivering medication. Health care providers need to strengthen the support for patients with a migration background. In this regard, they should respect the patients' cultural and social background and their personal perception of the disease and the therapy. Yet structural and social aspects (clinical setting, family and educational background) may be more crucial here than “cultural barriers.”

Hornhaut-Schlüsselbefunde im Kindesalter als Hinweis für therapierbare systemische Stoffwechselerkrankungen

Many systemic lysosomal storage disorders show basic corneal opacities already in childhood. The lysosome is a cell organelle, produced by Golgi's apparatus, that is surrounded by a membrane and contains hydrolytic enzymes that break down food molecules, especially proteins and other complex molecules. The ophthalmologist's precise diagnosis of corneal clouding at the slit-lamp may reveal the correct interpretation of the specific lysosomal storage disorder. It is very important to diagnose such diseases as soon as possible because today the development of systemic enzymatic therapies has broadened the therapeutic armamentarium for the current standard of care. The following corneal landmarks of systemic storage diseases and of the modern systemic therapy are presented: cornea verticillata in Fabry's disease, periodic infusion of alpha-galactosidase a; Kayser-Fleischer's ring in Wilson's disease, zinc, trienetin, low copper diet; multiple, punctiform crystals in cystinosis, cysteamine, Raptor RP 103(DR cysteamine) that reduces the cytotoxity in form of continous dissolving of cystine from lysosome, renal transplantation, haematopoietic stem cell transplantation; peripheral ring, but not true lipid arc, and moderate stromal haze in LCAT-deficiency, injection of recombinant enzyme or of encapsulated LCAT-secreting cells; diffuse stromal haze in mucopolysaccharidoses (MPS). Enzyme replacement therapy is currently indicated for MPS I, MPS II, and MPS VI, haematopoietic stem cell transplantation; painful, bilateral pseudo-dendritic opacities in tyrosinemia type II (eponym: Richner-Hanhart syndrome), low phenylalanine and tyrosine diet result in complete disappearance of corneal alterations with a consecutive painfree period. Strict diet during the whole life is necessary to prevent corneal recurrences and the occurrence of palmo-plantar keratoses. Such therapies can enable the patient to lead an otherwise normal life for decades.

Home sleep study characteristics in patients with mucopolysaccharidosis

Mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders caused by the deficiency of hydrolases involved in the degradative pathway of glycosaminoglycans. In MPS, upper airway obstruction may result from multiple causative factors which may impact severely upon morbidity and mortality. We evaluated upper airway obstructive disease and related clinical findings through home sleep study in 19 patients (11 with MPS VI, 4 with MPS I, 4 with MPS II) with MPS followed at Gazi University Pediatric Metabolic Unit. Patients underwent home-based sleep measurements, and sleep respiratory problems were asked in a detailed clinical history. Measurements of apnea, apnea-hypopnea index (AHI), hypopnea index, oxygen desaturation index, and minimal oxygen saturation were obtained through home sleep study. For 19 children, the disorder was normal in 1, mild (AHI=1.5-5/h) in 5, moderate (AHI=5-10/h) in 2, and severe (AHI>10/h) in 11. The prevalence of OSA was 94.7 % (18/19) in patients with MPS. Snoring, witnessed apnea, pectus carinatum, and macroglossia were the main clinical findings. Echocardiograms showed evidence of pulmonary hypertension in 13 patients. Home sleep study is a quick and accessible screening test to determine the abnormalities of breathing during sleep and enables clinicians to take necessary action for patients with severe manifestations.

359. In Vitro and In Vivo Characterization of an Engineered Arylsulfatase B for Therapy of Mucopolysaccharidosis VI

359. In Vitro and In Vivo Characterization of an Engineered Arylsulfatase B for Therapy of Mucopolysaccharidosis VI

360. Gene Therapy for MPS VI Is Effective in Cats without Pre-Existing Immunity to AAV8

360. Gene Therapy for MPS VI Is Effective in Cats without Pre-Existing Immunity to AAV8

Mucopolysaccharidosis type VI: A predominantly cardiac phenotype associated with homozygosity for p.R152W mutation in the ARSB gene

Mucopolysaccharidosis type VI (MPS VI) is a rare lysosomal, autosomal recessive storage disorder caused by deficient activity of N-acetylgalactosamine-4-sulfatase (ARSB). Approximately, 140 ARSB gene mutations have been identified; however, most are private mutations making genotype-phenotype correlation for most MPS VI patients difficult. The aim of this study was to describe the natural clinical course in patients homozygous for the p.R152W mutation from eight unrelated families. From our database of 70 patients with MPS VI, we selected 10 patients homozygous for the p.R152W mutant allele (median age 27.5 years, range 18-38 years). We performed a cross-sectional observational study characterizing the onset and prevalence of clinical manifestations. First signs of the disease, such as cardiac valve disease, slightly decreased joint range of motion and mild growth retardation, were observed in mid-adolescent years (median 15 years). Within the disease course, the most common clinical feature in all the patients was progressive heart disease of predominantly valve origin leading to symptoms of heart failure. Other typical MPS VI features were subtle and not present in all the patients. Delays up to 23 years (median 8.5 years) intervened between symptom onset and disease diagnosis. Patients homozygous for the p.R152W mutation present a cardiac variant of MPS VI characterized by progressive cardiac valve disease leading to serious cardiac complications including abrupt death due to cardiac failure.

Mucopolysaccharidosis type VI phenotypes-genotypes and antibody response to galsulfase

BackgroundMucopolysaccharidosis type VI (Maroteaux-Lamy syndrome; MPS VI) is an autosomal recessive lysosomal storage disorder in which deficiency of N-acetylgalactosamine 4-sulfatase (arylsulfatase B; ARSB) leads to the storage of glycosaminoglycans (GAGs) in connective tissue. The genotype-phenotype correlation has been addressed in several publications but the picture is not complete. Since 2007, enzyme-replacement therapy (ERT) has been available for patients with MPS VI in the Netherlands. The purpose of our study was to learn more about the genotype-phenotype correlations in MPS VI and the antibody response to ERT with galsulfase (recombinant human arylsulfatase B).MethodsWe identified ARSB mutations in 12 patients and used site-directed mutagenesis to study their effect. Antibody levels to galsulfase were measured using ELISA and a semi-quantitative immunoprecipitation method. We assessed the in vitro inhibitory effect of antibodies on galsulfase uptake and their effect on clinical outcome.ResultsFive patients had a rapidly progressive phenotype and seven a slowly progressive phenotype. In total 9 pathogenic mutations were identified including 4 novel mutations (N301K, V332G, A237D, and c.1142 + 2 T > C) together composing 8 pathogenic genotypes. Most mutations appeared not to affect the synthesis of ARSB (66 kD precursor), but to hamper its maturation (43 kD ARSB). Disease severity was correlated with urinary GAG excretion. All patients developed antibodies to galsulfase within 26 weeks of treatment. It was demonstrated that these antibodies can inhibit the uptake of galsulfase in vitro.ConclusionsThe clinical phenotypes and the observed defects in the biosynthesis of ARSB show that some of the mutations that we identified are clearly more severe than others. Patients receiving galsulfase as enzyme-replacement therapy can develop antibodies towards the therapeutic protein. Though most titers are modest, they can exceed a level at which they potentially affect the clinical outcome of enzyme-replacement therapy.

Enzyme replacement therapy with galsulfase in 34 children younger than five years of age with MPS VI

BackgroundMucopolysaccharidosis type VI (MPS VI) is a progressive, chronic and multisystem lysosomal storage disease with a wide disease spectrum. Clinical and biochemical improvements have been reported for MPS VI patients on enzyme replacement therapy (ERT) with rhASB (recombinant human arylsulfatase B; galsulfase, Naglazyme®, BioMarin Pharmaceutical Inc.), making early diagnosis and intervention imperative for optimal patient outcomes. Few studies have included children younger than five years of age. This report describes 34 MPS VI patients that started treatment with galsulfase before five years of age. MethodsData from patients who initiated treatment at <5years of age were collected from patients' medical records. Baseline and follow-up assessments of common symptoms that led to diagnosis and that were used to evaluate disease progression and treatment efficacy were evaluated. ResultsA significant negative correlation was seen with treatment with ERT and urinary GAG levels. Of those with baseline and follow-up growth data, 47% remained on their pre-treatment growth curve or moved to a higher percentile after treatment. Of the 9 patients with baseline and follow-up sleep studies, 5 remained unaffected and 1 patient initially with mild sleep apnea showed improvement. Data regarding cardiac, ophthalmic, central nervous system, hearing, surgical interventions and development are also reported. No patient discontinued treatment due to an adverse event and all that were treatment-emergent resolved. ConclusionsThe prescribed dosage of 1mg/kg IV weekly with galsulfase ERT is shown to be safe and effective in slowing and/or improving certain aspects of the disease, although patients should be closely monitored for complications associated with the natural history of the disease, especially cardiac valve involvement and spinal cord compression. A long-term follow-up investigation of this group of children will provide further information on the benefits of early treatment as well as disease progression and treatment efficacy and safety in this young patient population.

Up to five years experience with 11 mucopolysaccharidosis type VI patients

Maroteaux–Lamy syndrome (mucopolysaccharidosis type VI, MPS VI) is a rare progressive metabolic disorder characterized by coarse facial features, hepatosplenomegaly, restrictive pulmonary function, cardiac abnormalities and stiff joints. The disease is caused by a deficiency of the lysosomal enzyme N-acetyl galactosamine 4-sulfatase which leads to glycosaminoglycan (GAG) storage in various tissues. It presents as a clinical spectrum with varying disease progressions and severities. While the phases I/II/III studies proved the effectiveness of enzyme-replacement therapy (ERT) with recombinant human arylsulfatase B, long-term data are still scarce.Over treatment periods ranging from 1.3 to 5.4years, this prospective open-label follow-up study in 11 Dutch mucopolysaccharidosis type VI patients (age 2–18years) showed that ERT had significant positive effects on cardiac-wall diameters (IVSd and LVMI), left and right shoulder flexions (p<0.001), liver size and spleen size (p<0.001), urinary GAG excretion (p<0.001), and the scales of quality of life (motor functioning and body functioning). ERT did not affect cardiac valve regurgitation or hearing function; HRQoL decreased slightly in two domains (‘anxiety’ and ‘negative emotions’), and patients with the rapid and slow progressive forms of the disease differed with regard to baseline GAG excretion and GAG decrease during treatment.In conclusion, ERT had an effect on several clinical parameters. This effect was established in an open cohort of young mucopolysaccharidosis type VI patients.

Mucopolysaccharidoses (MPS)

This special edition of the Journal of Inherited Metabolic Disease brings together several publications focused on the mucopolysaccharidoses (MPS). The development of enzyme replacement therapy (ERT) for many of these disorders has led to a burgeoning interest in this field, as reflected in this group of articles. The general theme of phenotypic presentation is highlighted in the report by Hendriksz and colleagues (10.1007/s10545-011-9410-9), who present the natural history and treatment outcomes from a clinical surveillance program for MPS 6 (Maroteaux-Lamy disease). The focus then shifts to organ systems in the MPS disorders, centered primarily cardiovascular manifestations. Three reports firstly by van der Ploeg and co-workers (10.1007/s10545-011-9444-z) summarize the cardiac features of MPS I (Hurler syndrome), MPS II (Hunter syndrome) and MPS VI, and the associated outcomes with ERT. The report by Harmatz and co-workers (10.1007/s10545-012-9481-2) summarizes the long term cardiac outcomes in a cohort of MPS VI patients, while the report of Wynn and colleagues (10.1007/s10545-012-9500-3) highlights cardiac outcomes in a subgroup of MPS I patients who manifest cardiomyopathy. The latter report provides management guidelines and represents an important adjuvant for clinicians dealing with MPS patients. The critical association between the timeline of ERT prior to BMT, and its relationship to ablation therapy geared to optimize outcomes, is highlighted in this paper. Rounding out the discussion of cardiac findings is the report by Braunlin and co-workers (10.1007/s10545-011-9438-x) who overview the endothelial dysfunction of cardiac tissue in MPS patients, which may help to explain the increased risk for cardiovascular complications in these disorders. The overall theme of systems and organ involvement is continued with reports on the respiratory and central nervous system (CNS) in MPS patients. The respiratory system, poorly understood in most MPS disorders, is closely linked to airway patency in many of these disorders. Berger and colleagues (10.1007/s10545-012-9555-1) examines this topic in conjunction with a supporting article on anaesthesia management by Walker and colleagues (10.1007/s10545-012-9563-1). The latter should become a pivotal “must read” for anaesthetists involved in the management of MPS patients. Moving to the theme of CNS disorders, Cross and co-workers (10.1007/s10545-012-9572-0) evaluate the behavioural phenotypes of several MPS disorders, followed by reports from the Hendriksz (10.1007/s10545-011-9430-5 and 10.1007/s10545-012-9459-0) and Guigliani (10.1007/s10545-012-9559-x) groups that begin to describe the CNS involvement in MPS IVa and MPS VI, which is at variance with the classical concept that these disorders have no impact on the brain. For both disorders, the pathology of the cervical spine has been very topical, and Solanki and colleagues (10.1007/s10545-013-9585-3) address this issue via morphometric evaluation of the spine in MPSV IA patients followed by an overview of management guidelines for spinal manifestations (10.1007/s10545-013-9586-2). The latter paper overviews anatomy, neuroimaging, and the approach to follow-up, and may well become an important future treatment reference for MPS disorders. Moving from phenotype to genotype, Pollard and co-workers (10.1007/s10545-012-9533-7) present 104 novel mutations in a cohort of 355 MPS patients, representing a significant contribution to the molecular diagnostic armamentarium. Progressing to a discussion of diagnosis, Wood and colleagues (10.1007/s10545-013-9587-1) present an excellent overview on the diagnostic approach to MPS IVA (Morquio A syndrome) that further highlights the diagnostic pitfalls and conundrums with this disorder. Wijburg and colleagues continue the theme of diagnosis with two papers evaluating the effects of therapy on urinary glycosaminoglycans and frequently employed biomarkers for disease severity in the MPS disorders (10.1007/s10545-012-9535-5 and 10.1007/s10545-012-9538-2). Readers who seek a “taste” of basic science and animal models are not forgotten in this issue. Tomatso and colleagues (10.1007/s10545-012-9522-x) report on the micro CT evaluation of the bone dysplasia in different MPS mouse models, while Fildes and co-workers (10.1007/s10545-012-9508-8) characterize the immune system of the murine model of MPS1, with a focus on both T and dendritic cells. Auricchio and co workers (10.1007/s10545-012-9521-y) explore the potential of some MPSVI mutations as potential targets for read through therapies. The effects of disease on the family are not forgotten as well, and Hare and colleagues (10.1007/s10545-012-9558-y) assess the coping strategies of parents of Sanfilippo syndrome in comparison to parental strategies for handling other intellectual disabilities. The authors and Editorial Board are confident that this special edition will evolve into an invaluable resource for clinicians and laboratory personnel dealing with MPS patients. None.

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

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). 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. 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. 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.

The Morquio A Clinical Assessment Program: Baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects

ObjectivesThe objectives of this study are to quantify endurance and respiratory function and better characterize spectrum of symptoms and biochemical abnormalities in mucopolysaccharidosis IVA subjects. MethodsMorCAP was a multicenter, multinational, cross sectional study amended to be longitudinal in 2011. Each study visit required collection of medical history, clinical assessments, and keratan sulfate (KS) levels. ResultsData from the first visit of 325 subjects (53% female) were available. Mean age was 14.5years. Mean±SD height z-scores were −5.6±3.1 as determined by the CDC growth charts. Mean±SD from the 6-minute-walk-test was 212.6±152.2m, revealing limitations in functional endurance testing, and 30.0±24.0stairs/min for the 3-minute-stair-climb test. Respiratory function showed limitations comparable to MPS VI patients; mean±SD was 1.2±0.9l based on forced vital capacity and 34.8±25.5l/min based on maximum voluntary ventilation. Mean urinary keratan sulfate (uKS) was elevated for all ages, and negatively correlated with age. Higher uKS correlated with greater clinical impairment based on height z-scores, endurance and respiratory function tests. The MPS Health Assessment Questionnaire reveals impairments in mobility and activities of daily living in comparison to an age-matched control population. ConclusionsMPS IVA is a multisystem disorder with a continuum of clinical presentation. All affected individuals experience significant functional limitations and reduced quality of life. Older patients have more severe exercise and respiratory capacity limitations, and more frequent cardiac pathology illustrating the progressive nature of disease.

Characterization of pulmonary function impairments in patients with mucopolysaccharidoses—changes with age and treatment

The mucopolysaccharidoses (MPS) comprise a group of inherited lysosomal storage disorders characterized by deficiencies in enzymes catalyzing the degradation of glycosaminoglycans. Impairment of pulmonary function is an important health problem for patients with MPS. However, there are few published reports on the prevalence and severity of pulmonary dysfunction in relation to age and treatment in this disorder. To evaluate pulmonary function in patients with MPS, we performed spirometry in 35 patients (22 males and 13 females; 1 with MPS I, 12 with MPS II, 16 with MPS IVA, and 6 with MPS VI; mean age, 14.6 ± 5.9 years; age range, 6.4 years to 33 years). Forced vital capacity (FVC), forced expired volume in 1 sec (FEV1), FEV1 to FVC ratio (FEV1/FVC), peak expiratory flow (PEF), and mean forced expiratory flow during the middle half of FVC (FEF25-75% ) were measured. Mean FVC, FEV1 , PEF, and FEF25-75% were 74.2%, 73.9%, 64.7%, and 37.1% of the predicted values, respectively. By spirometric classification, 32 patients (91%) had small airway disease (FEF25-75% < 65%), 17 (48%) had restrictive lung disease, and 3 (9%) had obstructive lung disease. Percent predicted FVC, FEV1 , and PEF, as well as FEV1 /FVC, were all negatively correlated with age (P < 0.01), such that pubertal and post-pubertal patients had significantly lower values than younger patients. Of eight attenuated MPS II and VI patients who underwent follow-up pulmonary function testing after receiving enzyme replacement therapy (ERT) for 1.5-7.4 years, six showed improvements in % predicted FVC and five improved in % predicted FEV1 . Our additional characterization of the types and prevalence of pulmonary function abnormalities seen in MPS patients should be useful for clinical care.

Gene Therapy for Mucopolysaccharidosis Type VI Is Effective in Cats Without Pre-Existing Immunity to AAV8

Liver gene transfer with adeno-associated viral (AAV) 2/8 vectors is being considered for therapy of systemic diseases like mucopolysaccharidosis type VI (MPS VI), a lysosomal storage disease due to deficiency of arylsulfatase B (ARSB). We have previously reported that liver gene transfer with AAV2/8 results in sustained yet variable expression of ARSB. We hypothesized that the variability we observed could be due to pre-existing immunity to wild-type AAV8. To test this, we compared the levels of AAV2/8-mediated transduction in MPS VI cats with and without pre-existing immunity to AAV8. In addition, since levels of lysosomal enzymes as low as 5% of normal are expected to be therapeutic, we evaluated the impact of pre-existing immunity on MPS VI phenotypic rescue. AAV2/8 administration to MPS VI cats without pre-existing neutralizing antibodies to AAV8 resulted in consistent and dose-dependent expression of ARSB, urinary glycosaminoglycan (GAG) reduction, and femur length amelioration. Conversely, animals with pre-existing immunity to AAV8 showed low levels of ARSB expression and limited phenotypic improvement. Our data support the use of AAV2/8-mediated gene transfer for MPS VI and other systemic diseases, and highlight that pre-existing immunity to AAV8 should be considered in determining subject eligibility for therapy.