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pected. on readmission to the obstetric ward, her treatment included risperidone (2 mg/day), alprazolam (1.5 mg/day), the phenothiazine antipsychotic cyamemazine (62.5 mg/day), and the anticholinergic tropatepine (10 mg/day). Antibiotic treatment was started to treat a possible infection. Unlike in her previous postpartum episodes, Mrs. G’s mental status responded only partially to antipsychotic treatment. A liaison psychiatry consultation was requested. the liaison psychiatrist found a mildly agitated and disoriented young woman who had wet herself and was circling around her bed. the patient was logorrheic, and her speech, which was mostly incoherent, revealed memory impairment. Strikingly, this mild state of confusion fluctuated during the interview, confirming midwives’ reports of hourly changes in the patient’s behavior. Mrs. G anxiously expressed feelings of guilt toward her newborn and the belief that her diagnosis of postpartum psychosis made her less able to take care of her children. She displayed no anger toward her children and no ideas of persecution, infanticide, or suicide. She also expressed the belief that “God talks to humankind through premonitory dreams or providential meetings,” a claim that had previously been interpreted as a mystic delusion. However, it appeared that this view was part of her cultural and religious background, as was later confirmed by her husband, who reported that she had held this belief for a long time and that it was shared by her relatives. overall, Mrs. G was more confused and less delusional than one would have expected in a typical postpartum psychosis. Puzzled by this clinical picture, the psychiatrist reconsidered the diagnosis of postpartum psychosis and extended his examination to assess the differential diagnosis. He found that Mrs. G had chronic headaches and a habitual reluctance to consume meat. His clinical examination revealed little; the patient had a well-tolerated fever, stable blood pressure and pulse, and no signs of severe sepsis. A neurological examination was unremarkable. the psychiatrist ordered immediate blood tests, including ammonia levels. Within an hour, hyperammonemia was confirmed (224 μmol/liter, controls

Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a rare, inherited disorder caused by deficiency of the lysosomal enzyme iduronate-2-sulfatase. As a result of this deficiency, glycosaminoglycans accumulate in lysosomes in many tissues, leading to progressive multisystemic disease. The cardiopulmonary and neurological problems associated with MPS II have received considerable attention. Orthopedic manifestations are common but not as well characterized. This study aimed to characterize the prevalence and severity of orthopedic manifestations of MPS II and to determine the relationship of these signs and symptoms with cardiovascular, pulmonary and central nervous system involvement. Orthopedic manifestations of MPS II were studied using cross-sectional data from the Hunter Outcome Survey (HOS). The HOS is a global, physician-led, multicenter observational database that collects information on the natural history of MPS II and the long-term safety and effectiveness of enzyme replacement therapy. As of January 2009, the HOS contained baseline data on joint range of motion in 124 males with MPS II. In total, 79% of patients had skeletal manifestations (median onset, 3.5 years) and 25% had abnormal gait (median onset, 5.4 years). Joint range of motion was restricted for all joints assessed (elbow, shoulder, hip, knee and ankle). Extension was the most severely affected movement: the exception to this was the shoulder. Surgery for orthopedic problems was rare. The presence of orthopedic manifestations was associated with the presence of central nervous system and pulmonary involvement, but not so clearly with cardiovascular involvement. Orthopedic interventions should be considered on an individual-patient basis. Although some orthopedic manifestations associated with MPS II may be managed routinely, a good knowledge of other concurrent organ system involvement is essential. A multidisciplinary approach is required.

Pulmonary function is impaired in untreated mucopolysaccharidosis type VI (MPS VI). Pulmonary function was studied in patients during long-term enzyme replacement therapy (ERT) with recombinant human arylsulfatase B (rhASB; rhN-acetylgalactosamine 4-sulfatase). Pulmonary function tests prior to and for up to 240 weeks of weekly infusions of rhASB at 1 mg/kg were completed in 56 patients during Phase 1/2, Phase 2, Phase 3 and Phase 3 Extension trials of rhASB and the Survey Study. Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and, in a subset of patients, maximum voluntary ventilation (MVV), were analyzed as absolute volume in liters. FEV1 and FVC showed little change from baseline during the first 24 weeks of ERT, but after 96 weeks, these parameters increased over baseline by 11% and 17%, respectively. This positive trend compared with baseline continued beyond 96 weeks of treatment. Improvements from baseline in pulmonary function occurred along with gains in height in the younger group (5.5% change) and in the older patient group (2.4% change) at 96 weeks. Changes in MVV occurred earlier within 24 weeks of treatment to approximately 15% over baseline. Model results based on data from all trials showed significant improvements in the rate of change in pulmonary function during 96 weeks on ERT, whereas little or no improvement was observed for the same time period prior to ERT. Thus, analysis of mean percent change data and longitudinal modeling both indicate that long-term ERT resulted in improvement in pulmonary function in MPS VI patients.

Hunter syndrome is a rare, X-linked disorder caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase. In the absence of sufficient enzyme activity, glycosaminoglycans accumulate in the lysosomes of many tissues and organs and contribute to the multisystem, progressive pathologies seen in Hunter syndrome. The nervous, cardiovascular, respiratory, and musculoskeletal systems can be involved in individuals with Hunter syndrome. Although the management of some clinical problems associated with the disease may seem routine, the management is typically complex and requires the physician to be aware of the special issues surrounding the patient with Hunter syndrome, and a multidisciplinary approach should be taken. Subspecialties such as otorhinolaryngology, neurosurgery, orthopedics, cardiology, anesthesiology, pulmonology, and neurodevelopment will all have a role in management, as will specialty areas such as physiotherapy, audiology, and others. The important management topics are discussed in this review, and the use of enzyme-replacement therapy with recombinant human iduronate-2-sulfatase as a specific treatment for Hunter syndrome is presented.

Niemann-Pick disease type C (NP-C) is a devastating genetic disorder characterised by progressive neurological deterioration. However, data on the progression of neurological manifestations, particularly across different patient age-of-disease onsets, are limited. This is an observational retrospective cohort study designed to assess the progression of neurological disease in patients with NP-C. Physicians were asked to retrospectively complete a web-based questionnaire for each patient, at diagnosis and at up to three follow-up visits. An NP-C-specific disability scale was used to measure disease progression. The scale comprised four key parameters of neurological disease progression; ambulation, manipulation, language and swallowing. Disease progression was evaluated based on the annual rate of change in each parameter and the composite score using a linear mixed model analysis, and by classifying patients according to the number of worsened parameters during the observation period. Data were collected from 57 patients. The rate of deterioration was similar across the four individual parameters of the disability scale. The mean (95% CI) annual disease progression was +0.12 (0.09, 0.15) units. Among patients with a time interval of at least 1 year between diagnosis and last visit (n=49), 42 (86%) patients had progressed disease and 7 (14%) patients had stable disease. Disease progression was consistently more rapid in patients diagnosed in early childhood, compared with those diagnosed in late childhood, or with juvenile or adult presentation. In conclusion, our findings showed a progression in all four parameters of the disability scale, representing a continuous, unbroken progression of neurological manifestations.

International audience; Niemann-Pick C (NPC) is a fatal progressive neurolipidosis. Miglustat, an inhibitor of glycosphingolipid synthesis, has been proposed to treat patients but questions remain regarding its efficacy. A major problem has been the lack of suitable objective efficacy endpoints. Three adults with NPC were treated with miglustat for 24 months. Efficacy of treatment was assessed clinically and using brain magnetic resonance spectroscopy. All patients reported mild clinical improvement or stabilization. Furthermore, a sustained decrease in the choline/creatine ratio was observed in all three patients over time. Although these preliminary results require confirmation on a larger cohort of patients, they suggest that miglustat has some beneficial effect on brain dysfunction in NPC and that MRS could be used routinely as a non invasive surrogate marker of treatment efficacy.

Contains fulltext : 80534.pdf (Publisher’s version ) (Closed access) Objectives Isolated methylmalonic acidurias (MMAurias) are caused by deficiency of methylmalonyl-CoA mutase or by defects in the synthesis of its cofactor 5'-deoxyadenosylcobalamin. The aim of this study was to evaluate which parameters best predicted the long-term outcome. Methods Standardized questionnaires were sent to 20 European metabolic centres asking for age at diagnosis, birth decade, diagnostic work-up, cobalamin responsiveness, enzymatic subgroup (mut(0), mut(-), cblA, cblB) and different aspects of long-term outcome. Results 273 patients were included. Neonatal onset of the disease was associated with increased mortality rate, high frequency of developmental delay, and severe handicap. Cobalamin non-responsive patients with neonatal onset born in the 1970s and 1980s had a particularly poor outcome. A more favourable outcome was found in patients with late onset of symptoms, especially when cobalamin responsive or classified as mut(-). Prevention of neonatal crises in pre-symptomatically diagnosed newborns was identified as a protective factor concerning handicap. Chronic renal failure manifested earlier in mut(0) patients than in other enzymatic subgroups. Conclusion Outcome in MMAurias is best predicted by the enzymatic subgroup, cobalamin responsiveness, age at onset and birth decade. The prognosis is still unfavourable in patients with neonatal metabolic crises and non-responsiveness to cobalamin, in particular mut(0) patients.

Background Hyperammonemia in patients with methylmalonic aciduria (MMA) and propionic aciduria (PA) is caused by accumulation of propionyl-CoA which decreases the synthesis of N-acetyl-glutamate, the natural activator of carbamyl phosphate synthetase 1. A treatment approach with carglumic acid, the structural analogue of N-acetyl-glutamate, has been proposed to decrease high ammonia levels encountered in MMA and PA crises. Case presentation We described two patients (one with MMA and one with PA) with hyperammonemia at diagnosis. Carglumic acid, when associated with standard treatment of organic acidurias, may be helpful in normalizing the ammonia level. Conclusion Even though the usual treatment which decreases toxic metabolites remains the standard, carglumic acid could be helpful in lowering plasma ammonia levels over 400 micromol/L more rapidly.

Mucopolysaccharidosis are rare, multisystemic and progressive diseases with an extremely various clinical spectrum. For the type I, II and VI mucopolysaccharidosis, enzyme replacement therapy is available. In these three diseases, enzyme replacement therapy induces a reduction in urinary glycosaminoglycanes excretion and on improvement in functional tests, 6 minutes walk test, pulmonary function test and range of motion.

This study describes the experience of one to five years of follow-up of 43 patients (35 men, 8 women, 40% have less than 18 years to the moment of the diagnostic) after treatment of Fabry's disease by Fabrazyme. A simple self-report questionnaire was developed in order to measure the effectiveness of the treatment on pain (present in the vast majority of patients since many years), activity, heat tolerance, sudation, well-being sensation before and after treatment. Pain and quality of life scores increased. Mean ventricular wall thickness and left ventricular hypertrophy measured by echography decreased. Patients with subnormal renal function (GFR60 ml/min) remain a stable renal function during the follow-up. The standard dosage was of 1 mg per KgBW every 2 weeks. Related adverse events were described and were usually mild.

A global, observational disease registry has been established to characterize the course of disease and track clinical outcomes in patients with Mucopolysaccharidosis Type I (MPS I), a rare and treatable lysosomal storage disorder. This report outlines procedures for data collection and presents the recommended minimum schedule of assessments that comprise the disease-specific clinical and laboratory parameters that are tracked in the database. Aggregate data are summarized for the first 302 patients enrolled, representing entries from 24 countries. The median current age of the patients is 9.0 years (range: 0.4-64.8). Syndrome diagnoses include 47% Hurler (severe form), 25% Hurler-Scheie (attenuated form with an intermediate phenotype), 13% Scheie (most attenuated form), and 15% unknown. Younger ages at symptom onset and disease diagnosis are associated with the severe Hurler syndrome, but there is overlap among syndromes. Diagnosis was delayed by years to decades in several patients with Hurler-Scheie and Scheie syndromes. Patients with symptom onset before age 5 are more likely to have a gibbus, cognitive impairment, and pneumonia, whereas patients with symptom onset above age 5 are more likely to have carpal tunnel syndrome, myelopathy, and glaucoma. Cardiac valve abnormalities, joint contractures, corneal clouding, and hernia are reported by over 70% of patients regardless of the age of symptom onset. Approximately 80% of the patients have received enzyme replacement therapy, hematopoietic stem cell transplantation, or both. Overall, the MPS I Registry database contains a broad sample of the global patient population, providing a potentially useful tool for expanding knowledge of MPS I and facilitating evidence-based decisions about the optimal means of monitoring and treating affected individuals.

Fabry disease, an inherited deficiency of the lysosomal enzyme alpha-galactosidase A, causes progressive intralysosomal accumulation of globotriaosylceramide (GL-3) and premature death from renal, cardiac, and cerebrovascular manifestations. To determine the long-term safety and efficacy of recombinant human alpha-galactosidase A, an open-label, phase III extension study was conducted, involving 58 patients who had classic Fabry disease and completed a 20-wk, double-blind, randomized, placebo-controlled, phase III study of agalsidase beta and were transitioned to an extension trial to receive biweekly 1 mg/kg agalsidase beta for up to an additional 54 mo. GL-3 accumulation was evaluated in the capillary endothelia of the skin, kidney, and heart. Renal function was assessed. By month 54, all patients with optional kidney biopsies (n = 8) maintained complete GL-3 clearance in renal capillary endothelial cells and multiple cell types. Continued, complete clearance of skin (31 of 36) and heart (six of eight) capillary endothelium was demonstrated. Mean plasma GL-3 levels remained decreased in the normal range. Median serum creatinine and estimated GFR remained stable (normal) in patients with renal data at month 54 (n = 41). Six patients had renal disease progression; most (four of six) were older than 40 yr and had significant proteinuria at baseline and evidence of sclerotic glomeruli pretreatment. Adverse events were generally mild and unrelated to treatment. The most common treatment-related adverse events were infusion-associated reactions, which decreased over time. Long-term agalsidase beta therapy stabilizes renal function in patients without renal involvement at baseline, maintains reduction of plasma GL-3, and sustains GL-3 clearance in capillary endothelial cells and multiple renal cell types.

Objectives To describe a nationwide system for pre-marketing follow-up (cohort ATU protocol, i.e. “therapeutic utilization”) of a new taste-masked formulation of sodium phenylbutyrate (NaPB) granules (Pheburane®) in France and to analyse safety and efficacy in this group of patients with urea cycle disease (UCD). Methods In October 2012 a cohort ATU was established in France to monitor the use of Pheburane® on a named-patient basis. All UCD treated patients were included in a follow-up protocol developed by the Laboratory (Lucane Pharma) and the French Medicines Agency (ANSM) which recorded demographics, dosing characteristics of NaPB, concomitant medications, adverse events and clinical outcome. Following the granting of the EU Marketing Authorization, the cohort ATU was terminated, approximately one year after its initiation, as the product was launched on the French market. Results Ease of administration and acceptability were much better with the new taste-masked formulation than with the previous treatment. No episode of metabolic decompensation was observed during 3 to 11 months of Pheburane® treatment and the range of ammonia and glutamine levels improved and remained within the normal range. No adverse events were reported with Pheburane®. Conclusions The recently developed taste-masked formulation of NaPB granules improved the quality of life for UCD patients. This may translate into improved compliance, efficacy and safety, which may be demonstrated either in further studies or in the post marketing use of the product.

Pyruvate carboxylase (PC) is a key enzyme for gluconeogenesis and anaplerotic pathways in brain. PC deficiency is a rare autosomal recessive neurometabolic disorder with three described characteristic presentations. We report a patient with atypical clinical and neuroradiological aspects. He survived from neonatal lactic acidemia and is alive at 9 years of age with a mild developmental delay. A brain MRI performed by the age of 18 months disclosed an unusual subcortical leucodystrophic process.

A cross-sectional survey in individuals affected with the lysosomal storage disease Mucopolysaccharidosis VI (MPS VI) was conducted to establish demographics, urinary glycosaminoglycan (GAG) levels, and clinical progression of the disease. The survey evaluated 121 bona fide MPS VI-affected individuals over the age of 4 years from 15 countries across the Americas, Europe, and Australasia representing greater than 10% of the estimated world prevalence of the disease. A medical history, complete physical exam, urinary GAG determination, and assessment of several clinical measures related to physical endurance, pulmonary function, joint range of motion, strength, and quality of life were completed for each participant. Although a wide variation in clinical presentation was observed, several general findings were obtained reflecting progression of the disease. Impaired physical endurance, as measured by the distance achieved in a 6-min walk, could be demonstrated across all age groups of MPS VI-affected individuals. High urinary GAG values (200 mug/mg creatinine) were associated with an accelerated clinical course comprised of age-adjusted short stature and low body weight, impaired endurance, compromised pulmonary function, and reduced joint range of motion. An unexpected result was the predominance of urinary GAG values100 mug/mg creatinine for those participants over the age of 20 years. Pending the collection of longitudinal data, these results suggest that urinary GAG levels predict clinical morbidity, and longer-term survival is associated with urinary GAG levels below a threshold of 100 mug/mg creatinine.

Fabry's disease is due to alpha-galactosidase deficiency. This rare lysosomal storage disease is transmitted by recessive X-linked heredity. Sphingolipids (galactosyl-glucosyl-ceramide) accumulate in many organs.A 19-year-old man with known hypoparathyroidism presented with telangiectasia and angiokeratomas on the buttocks, the hips, the hands and around the navel. For many years, he suffered from paroxysmal pain in the hands and feet. From childhood, he had complained of diffuse abdominal pain, associated with diarrhea. Ophthalmological slit lamp fundus examination showed corneal telangiectasia and cornea verticella. There was no kidney or heart involvement. The diagnosis of Fabry's disease was confirmed by very low levels of alpha-galactosidase.We did not find any other association of hypoparathyroidism and Fabry's disease in the literature. Hypoparathyroidism is not a manifestation of Fabry's disease. Idiopathic hypoparathyroidism is very rare and a genetic origin is known. This disease can be recessive X-linked. A co-transmission of idiopathic hypoparathyroidism and Fabry's disease is probable in our patient.

UNLABELLED Establishing correlations between a patient's genotype and clinical phenotype is based on the assumption that the same clinical consequences will be observed in individuals with the same residual function of a specific metabolic step. In mucopolysaccharidosis type II (MPS II; Hunter disease), patients present with a wide clinical spectrum. Furthermore, current methods for measuring the activity of the deficient enzyme in MPS II--iduronate-2-sulphatase (IDS)--are insufficiently sensitive to differentiate between complete absence of activity and the presence of residual activity. Attempts have therefore been made to establish genotype-phenotype correlations in order to explain the large degree of heterogeneity and to serve as a better guide to prognosis on which to base genetic counselling and treatment options. Using MPS II as an example, this paper illustrates the difficulties and potential advantages of determining genotype-phenotype correlations in lysosomal storage diseases. The response of patients with MPS II to allogenic bone marrow transplantation provides some insight into the likely influence of certain genotypes on therapeutic efficacy. CONCLUSIONS Evaluation of residual activity of IDS in MPS II using gene analysis, expression studies and transcript analysis does not always allow prediction of a patient's phenotype. The variable response to bone marrow transplantation, however, illustrates the potential importance of determining the genotype for selecting the most appropriate therapy for individual patients.

During the last 20 years, an increasing number of inborn errors of metabolism have been treated by organ (or marrow) transplantation for either end-stage organ failure (target organs) or organ replacement (protein source). More recently, enzymatic and biochemical assistance has been proposed in selected metabolic diseases in order to delay, and sometimes to avoid, end-stage organ failure and subsequent transplantation.

Prenatal diagnosis was offered to a family at risk of mevalonic aciduria. A chorionic villus sample was obtained and both mevalonate kinase activity and mutation analysis were done. An affected fetus was diagnosed.

Congenital disorders of glycosylation (CDG) are a group of genetic diseases characterized by defective protein glycosylation. N-glycosylation defects are divided into two groups (I and II). CDG group II (types IIa to IIe) refers to defects in the Golgi processing of protein-bound glycans. We report a patient with CDG IIx and an unusual phenotype.

Objective To evaluate the efficacy and safety of oral miglustat treatment in patients with mucopolysaccharidosis type III. The primary outcome was efficacy with improvement or stabilization in at least two domains of Vineland Adaptative Behavior Scales at 6 months. The secondary outcome measured the evolution of other cognitive tests at 12 months. The safety and tolerability were assessed throughout the study. Study design This was a randomized, double-blind, placebo-controlled, monocenter, institutional, phase IIb to III study. In case of efficacy at 6 months, the study would go on for another 6 months on an open design with all patients receiving miglustat. In the absence of efficacy at 6 months, the trial had to be continued for 6 more months with the initial design. Results After 6 months, efficacy was not superior in patients with miglustat. The independent review board confirmed continuing the study until 12 months. Conclusion Miglustat treatment was not associated with any improvement/stabilization in behavior problems in patients with mucopolysaccharidosis type III. Miglustat has an acceptable safety profile. However, the study has confirmed that miglustat is able to pass through the blood-brain barrier without significantly decreasing ganglioside levels.

La maladie de Gaucher est une maladie genetique a transmission autosomique recessive due a un deficit de l'enzyme D-glucosidase acide (ou glucocerebrosidase). Trois principaux phenotypes sont classiquement distingues selon l'absence (type 1) ou la presence (type 2 ou 3) de manifestations neurologiques. Les caracteristiques de la maladie de Gaucher chez les enfants sont decrites.

Abstract 4441 Introduction Gaucher Disease (GD) management is well defined but little is known about the management of patients in routine practice. To describe it, this multicentre retrospective survey was proposed to all French Hospital Departments in whom Gaucher patients are monitored. Demographic and clinical data were collected, and therapeutic regimens were detailed. Results In 2008, 118 patients were enrolled in 54 centres, including 111 type 1 (GD1) and 7 type 3 (GD3). 90% of patients were adults at inclusion. At time of diagnosis 40% of GPS patients were less than 16 years. Glucocerebrosidase activity assay and bone marrow aspiration were part of the diagnosis in 80% and 51% of patients, respectively. A family survey has been performed in all children and overall in 85 % of patients, with positive results in 44% of cases. 54% of patients are managed by the physician who diagnosed the GD and the mean annual number of visits at hospital is 10 and 4 for children and adults, respectively. In patients diagnosed after the age of 16 years, 20.7% were splenectomised at time of inclusion. On average, hemogram and chitotriosidase are assessed twice a year, as bone mineral density and skeletal MRI are performed every 2 years. Ninety-six patients are treated with imiglucerase, 3 patients with miglustat and 2 patients with a combination of both. Adult patients were treated on average for 87.6 months versus 53 months for children. The mean Imiglucerase dose is 54 U/kg by infusion for GD1 with no significant difference regarding infusions frequencies, and 96 U/kg for GD3 and The treatment is infused every two weeks in 74% of the patients, and every 3 weeks in 18% of them, using a gravity infusion in 57 % of the cases. Only 7.8% of the GPS population is infused using a central venous access with similar rates in adults and children. Infusions are administered at hospital in 60% of cases and at patient's home in 40% of cases. A central venous access is used in 11% of patients who are treated at home. Infusion time is less than 2 hours in 55% of patients and is slightly longer at home compared to hospital. Observance is good or excellent in more than 95% of cases. Conclusion This is the first large national survey about Care Practices in GD patients. The clinical and biological follow-up is globally in line with French Guidelines. Treatment with imiglucerase is administered on average at the recommended dose and frequency, but with an infusion time often longer than that recommended. Patients should be more frequently treated at home, and thus quality of life studies and encouragement of home infusions organisation should be performed in France. Disclosures: Off Label Use: Cerezyme (imiglucerase) : enzymatic replacement therapy for Gaucher disease patients. The aim of imiglucerase is to replace glucocerebrosidase deficiency; The dose of treatment initiation is 60u/kg/2 weeks.. Bruno:Genzyme: Employment.

Objective To evaluate the safety and explore the efficacy of enzyme replacement therapy with agalsidase beta (recombinant human α-galactosidase A; Fabrazyme [Genzyme Corporation, Cambridge, MA]) in pediatric patients with Fabry disease, a genetic disorder in which deficient endogenous enzyme causes pathogenic tissue accumulation of globotriaosylceramide (GL-3). Study design Fourteen male and 2 female patients, 8 to 16 years old, were treated in this open-label study. A 12-week observation period to collect baseline data preceded the 48-week treatment period when agalsidase beta (1 mg/kg) was infused intravenously every 2 weeks. No primary efficacy end point was specified. Results Before treatment, results of skin biopsies from 12 male patients showed moderate or severe GL-3 accumulation in superficial dermal capillary endothelial cells; with treatment, these cells were completely cleared of GL-3 in week-24 biopsies from all 12 male patients and in all available week-48 biopsies. With treatment, reports of gastrointestinal symptoms declined steadily. Patient diaries documented significant reductions in school absences due to sickness. Agalsidase beta was generally well tolerated; most treatment-related adverse events were mild or moderate infusion-associated reactions involving rigors, fever, or rhinitis. Conclusions Agalsidase beta safely and effectively reduced the GL-3 accumulation in dermal endothelium already evident in children with Fabry disease. Early intervention may prevent irreversible end-organ damage from chronic GL-3 deposition.

The objective of this Phase 3 study was to confirm the efficacy and safety of recombinant human arylsulfatase B (rhASB) treatment of mucopolysaccharidosis type VI (MPS VI; Maroteaux-Lamy syndrome), a rare, fatal lysosomal storage disease with no effective treatment.Thirty-nine patients with MPS VI were evaluated in a randomized, double-blind, placebo-controlled, multicenter, multinational study for 24 weeks. The primary efficacy variable was the distance walked in a 12-minute walk test (12MWT), whereas the secondary efficacy variables were the number of stairs climbed in a 3-minute stair climb (3MSC) and the level of urinary glycosaminoglycan (GAG) excretion. All patients received drug in an open-label extension period for an additional 24 weeks.After 24 weeks, patients receiving rhASB walked on average 92 meters (m) more in the 12MWT (p=.025) and 5.7 stairs per minute more 3MSC (p=.053) than patients receiving placebo. Continued improvement was observed during the extension study. Urinary GAG declined by -227+/-18 microg/mg more with rhASB than placebo (p.001). Infusions were generally safe and well tolerated. Patients exposed to drug experienced positive clinical benefit despite the presence of antibody to the protein.rhASB significantly improves endurance, reduces GAG, and has an acceptable safety profile.

169 Update on Enzyme Replacement Therapy (ERT) with Recombinant Human Arylsulfatase B (RHASB) for MPS VI (Maroteaux-Lamy)

International audience; Background: Mucopolysaccharidosis II (MPS II) is associated with a broad spectrum of chronic and progressive, life-limiting symptoms. Idursulfase is approved for MPS II enzyme replacement therapy (ERT) in over 50 countries. This retrospective study evaluated the MPS II burden, organization of clinical care, and effects of idursulfase treatment on the disease in France. Methods: MPS II patients who had received idursulfase ERT in the French healthcare system were enrolled. In addition to clinician and patient questionnaires, the Clinical Global Impression-Improvement (CGI-I); Patient Global Impression-Improvement (PGI-I); KIDSCREEN-27, and EuroQoL-5D for adult patients scales were used to assess quality of life (QoL) and efficacy. Results: Fifty-two patients were enrolled from 5 sites in France. The majority of patients (69.2%) presented a severe MPS II phenotype with progressive neurocognitive impairment. Major impacts on QoL were apparent, with at least 1 member of the family having to reorganize working hours (45.5%) or to stop working (22.7%). KIDSCREEN-27 and EuroQoL-5D scale scores were well below those for referent (control) populations. Most families (70.0%) experienced a diagnostic delay of at least 3 years after the initial observation of symptoms. The MPS II diagnosis was often delivered without adequate sensitivity, psychological support, or comprehensive information about the disease. The study population had received a mean of 3.8 +/- 1.3 years ERT. Forty-four percent of patients with the attenuated phenotype (without progressive neurocognitive impairment) showed symptom improvement during both the first year (Period 1) and from the end of the first year of treatment to "the present" (Period 2), as measured by CGI-I/PGI-I. 30.3% and 9.1% of severe patients experienced symptom improvement during Periods 1 and 2, respectively, while 63.6% and 51.5% displayed no change. The most common adverse reactions reported were skin rash and other infusion-associated reactions. Conclusions: MPS II adversely affects multiple domains of QoL for patients and families, requiring multiple healthcare services and social aid programs. The majority of patients with either phenotype experienced either improvement or stability in their symptoms during the first year of ERT, but this was clearly less so for patients with the severe phenotype after the first year of treatment.