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Background : Gaucher disease (GD) is a rare lysosomal storage disorder classically subdivided into type 1 (non-neuronopathic) GD, and types 2 and 3 (neuronopathic) GD. It is typically characterized by clinical manifestations including anemia, thrombocytopenia, hepatosplenomegaly, bone lesions, and (in more severe forms) neurological impairment. However, less-commonly reported and often under-recognized manifestations exist, which potentially have a significant impact on patient outcomes. Greater efforts are needed to understand, recognize, and manage these manifestations. Objectives : This review provides a synthesis of published information about three under-recognized GD manifestations (pulmonary involvement, lymphadenopathy, and Gaucheroma) and recommends diagnostic, management, and treatment strategies based on the available literature and author experience. The authors aim to raise awareness about these serious, progressive, and sometimes life-threatening conditions, which are often diagnosed late in life. Conclusions : Little is known about the incidence, pathophysiology, prognostic factors, and optimal management of pulmonary involvement, lymphadenopathy, and Gaucheroma in patients with GD. Enzyme replacement therapy (ERT) has shown limited efficacy for the prevention and treatment of these manifestations. More research is needed to evaluate the potential effect of substrate reduction therapy (SRT) with glucosylceramide synthase (GCS) inhibitors, and to develop additional approaches to treat these GD manifestations. Improvements in data collection registries and international data-sharing are required to better understand the impact of these manifestations on GD patients, help develop effective management strategies, and, ultimately, improve patient outcomes. [ABSTRACT FROM AUTHOR]

Background Niemann-Pick disease Type C (NP-C) is a genetic lipid storage disorder characterised by progressive neurovisceral symptomatology. Typically, disease progression is more pronounced in patients with early onset of neurological symptoms. Heterogeneous clinical presentation may hinder disease recognition and lead to delays in diagnosis. Here we describe the prevalence of signs and symptoms observed in patients with NP-C and analyse the relationship between these symptoms in different age groups. Methods The combined patient cohort used in the analyses comprised NP-C cases (n = 164) and controls (n = 135) aged 0 to 60 years from two previously published cohorts; a cohort of all ages from which patients ≤ 4 years of age were excluded and a cohort with early-onset NP-C and age-matched controls. The analysis of relationships between different signs and symptoms was performed for both NP-C cases and controls in two sub-groups, ≤ 4 and > 4 years of age, using cluster analyses. The threshold of 4 years of age was selected to reflect the minimum age cut-off for satisfactory discriminatory power of the original NP-C SI. To assess the prevalence of individual signs and symptoms at age of diagnosis, patients were categorised by age into 5-year sub-groups, and prevalence values estimated for each sign and symptom of NP-C. Results Two main clusters of symptoms were clearly defined for NP-C cases in each age sub-group, whereas clusters were not as clearly defined for controls. For NP-C cases ≤ 4 years of age, one cluster comprised exclusively visceral symptoms; the second cluster combined all other signs and symptoms in this age group. For NP-C cases > 4 years of age, each cluster contained a mixture of visceral, neurological and psychiatric items. Prevalence estimations showed that visceral symptoms ( e.g. isolated unexplained splenomegaly) were most common in NP-C cases ≤ 4 years of age. Neurological symptoms were generally more common in NP-C cases > 4 years of age than in younger patients, with the exception of hypotonia and delayed developmental milestones. Conclusions These analyses provide a comprehensive overview of symptomatology observed in a large combined cohort of patients with NP-C and controls across a wide range of ages. The results largely reflect observations from clinical practice and support the importance of multi-disciplinary approaches for identification of patients with NP-C, taking into account age-specific manifestations and their possible correlations. [ABSTRACT FROM AUTHOR]

The differential diagnoses for metabolic liver diseases may be challenging in clinical settings, which represents a critical issue for disorders such as lysosomal acid lipase deficiency (LAL-D). LAL-D is caused by deficient activity of the LAL enzyme, resulting in the accumulation of cholesteryl esters and triglycerides throughout the body, predominately in the liver, spleen, gastrointestinal tract, and blood vessel walls. LAL-D is a progressive, multi-organ disease with early mortality and significant morbidity characterized by a combination of hepatic dysfunction and dyslipidemia. Evidence suggests LAL-D may be substantially underdiagnosed or misdiagnosed, which is critical given that disease progression can be unpredictable, with liver failure and/or accelerated atherosclerosis potentially contributing to early mortality. However, given the development of a simple diagnostic test and recently approved treatment, LAL-D should be incorporated into the differential diagnosis in relevant clinical settings. LAL-D can be diagnosed using an LAL enzyme-based biochemical test, thereby allowing for active monitoring of patients to detect potential disease complications and consider treatment options including diet, lipid-lowering medication, and treatment with sebelipase alfa, a recombinant enzyme replacement therapy shown to provide clinical benefit and improve disease-relevant markers in clinical trials. To illustrate the complexity of diagnosing LAL-D, this manuscript will describe the path to diagnosing LAL-D in a series of patient cases in which LAL-D was diagnosed as well as in patients where other diseases, such as Gaucher disease and Niemann-Pick disease, were initially suspected. [ABSTRACT FROM AUTHOR]

Abstract: Background: The principal manifestations of type 1 Gaucher disease (GD) (increased risk of bleeding, anaemia, splenomegaly, hepatomegaly and bone disease) are likely to affect females during reproductive events such as menarche and menstruation; fertility, pregnancy, parity, delivery and lactation; and menopause. In order to determine the optimal management of female Gaucher patients based on available data, we examine reproductive events and GD in untreated and alglucerase and/or imiglucerase-treated females. Methods: A panel of international clinicians experienced in the management of GD reviewed and presented evidence from peer-reviewed literature, a pharmacovigilance database on imiglucerase, and their own clinical experience to support discussions and recommendations. Nine panel members completed a 130-item-questionnaire on the outcomes of the management of female patients in their clinical practice. Results, covering menarche (137 females), menstruation (261 reports), fertility (295 females), pregnancy (416 pregnancies in 247 women) and menopause (45 women) were analysed. Data from a recent Canadian survey on 50 patients with 39 pregnancies, the imiglucerase pharmacovigilance database (100 pregnancies), and relevant literature (56 items covering 398 pregnancies in 205 women) were also reviewed. Key results: Menarche: May be delayed in girls with GD. Menorrhagia: Appears to be more common in GD than in the non-Gaucher population and may be ameliorated by alglucerase and/or imiglucerase treatment (menorrhagia in 67/133 (50.4%) untreated females compared with 37/128 (28.9%) treated; Mann–Whitney U test: p =0.001). Fertility: There is no evidence of decreased fertility in GD. Pregnancy: Pregnancy in GD may be complicated by haematological disease, organomegaly and bone involvement. GD diagnosis occurs frequently during pregnancy. Questionnaire results demonstrate: a reduced risk of spontaneous abortion in women treated with alglucerase and/or imiglucerase (untreated: 26/189 (13.8%); treated 1/58 (1.7%) χ 2 p =0.010); reduced risk of Gaucher-related complications during delivery (untreated 43/109 (39.4%); treated 3/46 (6.5%) χ 2 p <0.0005): and a reduced risk of Gaucher-related complications during the post partum period (untreated 15/71 (21.1%); treated 3/43 (7%) χ 2 p =0.014). There is no evidence to date of any untoward effect of alglucerase and/or imiglucerase on the fetus, or on infants breast fed by mothers receiving alglucerase and/or imiglucerase. Menopause: The impact of GD on menopause requires further study especially in relation to bone pathology. Conclusions: On the basis of this review, GD may have an impact on reproductive events in affected women. Enzyme therapy may have benefits in reducing menorrhagia, spontaneous abortions and complications associated with delivery and the postpartum period. [Copyright &y& Elsevier]

Interpretation of genetic variants detected by sequencing of genomic DNA, which may cause splicing defects, regularly requires mRNA analysis. Usually, only bioinformatic testing is provided, because simple and non-invasive assay protocols are lacking. Furthermore, the detection of mis-splicing is often hampered by nonsense mediated mRNA decay (NMD). Starting from a case of Pompe disease with two potential splicing variants an assay for the analysis of splice defects in general was developed. We analyzed the transcripts from the gene of interest by standard methods after short-term culture of the patient's lymphocytes in the presence and absence of a NMD inhibitor. Variant and wild type transcript expression were quantified by allele specific PCR in the patient and both parents and the expression ratio with/without NMD inhibition was calculated for each transcript. NMD detection in lymphocytes was optimized and evaluated by analyzing a naturally occurring NMD transcript. Several compounds inhibited NMD successfully, including potential therapeutic agents. Sample storage for up to 4 days at room temperature prior to lymphocyte isolation did not affect results. In a proof of concept we identified two candidate variants as severe splicing variants in a patient with Pompe disease, but the strategy can also be used to screen for any mis-spliced transcripts prone to NMD. We developed a simple, non-invasive assay for the detection and characterization of potential splicing variants. This is essential, because early and near-term diagnosis and disease classification is required to facilitate therapy in many genetic diseases. • A simple and non-invasive assay for detection and characterization of potential splicing variants. • The assay is adapted to the requirements of a diagnostic laboratory. • With this assay two pathogenic variants in a patient with Pompe disease are characterized. [ABSTRACT FROM AUTHOR]

Abstract Background Acid sphingomyelinase deficiency (ASMD), a rare lysosomal storage disease, results from mutations in SMPD1 , the gene encoding acid sphingomyelinase (ASM). As a result, sphingomyelin accumulates in multiple organs including spleen, liver, lung, bone marrow, lymph nodes, and in the most severe form, in the CNS and peripheral nerves. Clinical manifestations range from rapidly progressive and fatal infantile neurovisceral disease, to less rapidly progressing chronic neurovisceral and visceral forms that are associated with significant morbidity and shorter life span due to respiratory or liver disease. Objectives To provide a contemporary guide of clinical assessments for disease monitoring and symptom management across the spectrum of ASMD phenotypes. Methods An international group of ASMD experts in various research and clinical fields used an evidence-informed consensus process to identify optimal assessments, interventions, and lifestyle modifications. Results Clinical assessment strategies for major organ system involvement, including liver, spleen, cardiovascular, pulmonary, and neurological/developmental are described, as well as symptomatic treatments, interventions, and/or life style modifications that may lessen disease impact. Conclusions There is currently no disease-specific treatment for ASMD, although enzyme replacement therapy with a recombinant human ASM (olipudase alfa) is in clinical development. Current monitoring addresses symptoms and multisystem involvement. Recommended interventions and lifestyle modifications are designed to address morbidity and disease complications and improve patient quality of life. While infantile neurovisceral ASMD is uniformly fatal in early childhood, patients with chronic visceral and chronic neurovisceral ASMD require appropriate management throughout childhood and adulthood by an interdisciplinary clinical team. [ABSTRACT FROM AUTHOR]

Gaucher disease (GD) is a rare hereditary disorder caused by a deficiency of the lysosomal enzyme β-glucocerebrosidase. Diagnosis is challenging owing to a wide variability in clinical manifestations and severity of symptoms. Many patients may experience marked delays in obtaining a definitive diagnosis. The two surveys reported herein aimed to explore the patient journey to diagnosis of GD from the perspectives of Gaucher expert physicians and patients. Findings from the surveys revealed that many patients experienced diagnostic delays and misdiagnoses, with nearly 1 in 6 patients stating that they were not diagnosed with GD for 7 years or more after first consulting a doctor. Physicians and patients both reported multiple referrals to different specialties before a diagnosis of GD was obtained, with primary care, haematology/haematology-oncology and paediatrics the main specialties to which patients first presented. Splenomegaly, thrombocytopenia, anaemia and bone pain were reported as the most common medical problems at first presentation in both surveys. These findings support a clear need for straightforward and easy-to-follow guidance designed to assist non-specialists to identify earlier patients who are at risk of GD. [ABSTRACT FROM AUTHOR]

Objective To report and discuss the multi-domain impact of elosulfase alfa, with focus on tertiary and composite endpoints, in the 24-week, randomized, double-blind, placebo-controlled phase 3 trial in patients with Morquio A syndrome (mucopolysaccharidosis IVA). Methods Patients with Morquio A syndrome aged ≥ 5 years were randomized 1:1:1 to elosulfase alfa 2.0 mg/kg/week (qw; N = 58), elosulfase alfa 2.0 mg/kg/every other week (qow; N = 59), or placebo (N = 59) for 24 weeks. Primary and secondary efficacy measures were 6-minute walk test (6MWT; primary), 3-minute stair climb test (3-MSCT) and urinary keratan sulfate (KS). Safety was also evaluated. Tertiary efficacy measures included respiratory function measures, activities of daily living (MPS Health Assessment Questionnaire [MPS-HAQ]), anthropometric, echocardiographic and radiographic measures, hearing and corneal clouding assessment. In order to fully characterize treatment impact in this heterogeneous disorder, the effect of elosulfase alfa on composite efficacy measures was evaluated as well. Results The study was not designed to have sufficient power for any of the tertiary outcomes. For most tertiary endpoints, subjects treated with the weekly dose of elosulfase alfa improved more than those receiving placebo. The largest treatment effects were seen in maximal voluntary ventilation (MVV), MPS-HAQ, height, and growth rate. The qow group appeared similar to placebo. The analysis of a pre-specified composite endpoint (combining changes from baseline in 6MWT, 3MSCT and MVV z-scores equally weighted) showed a modest positive impact of elosulfase alfa qw versus placebo group ( P = 0.053). As a pre-specified supportive analysis, the O'Brien Rank Sum composite endpoint (changes from baseline in 6MWT, 3MSC, and MVV), analysis also showed that the qw group performed better than the placebo group ( P = 0.011). In post-hoc analyses, combinations of other endpoints were also explored using the O'Brien Rank Sum test and showed statistically significant differences between elosulfase alfa qw and placebo favoring elosulfase alfa qw. Differences between elosulfase alfa qow and placebo were not statistically significant. Positive changes were observed in most tertiary variables, demonstrating the efficacy of weekly treatment with elosulfase alfa. Conclusions Treatment with weekly elosulfase alfa led to improvements across most efficacy measures, resulting in clinically meaningful benefits in a heterogeneous study population. [ABSTRACT FROM AUTHOR]

Taliglucerase alfa is a β-glucosidase enzyme replacement therapy (ERT) approved in the US and other countries for the treatment of Gaucher disease (GD) in adults and is approved in pediatric and adult patients in Australia and Canada. It is the first approved plant cell-expressed recombinant human protein. A Phase 3, multicenter, open-label, 9-month study assessed safety and efficacy of switching to taliglucerase alfa in adult and pediatric patients with GD treated with imiglucerase for at least the previous 2 years. Patients with stable disease were offered taliglucerase alfa treatment using the same dose (9–60 U/kg body weight) and regimen of administration (every 2 weeks) as imiglucerase. This report summarizes results from 26 adult and 5 pediatric patients who participated in the trial. Disease parameters (spleen and liver volumes, hemoglobin concentration, platelet count, and biomarker levels) remained stable through 9 months of treatment in adults and children following the switch from imiglucerase. All treatment-related adverse events were mild or moderate in severity and transient in nature. Exploratory parameters of linear growth and development showed positive outcomes in pediatric patients. These findings provide evidence of the efficacy and safety profile of taliglucerase alfa as an ERT for GD in patients previously treated with imiglucerase. This trial was registered at www.clinicaltrials.gov as # NCT00712348 . [ABSTRACT FROM AUTHOR]

Abstract: Background: The obstetric risk in patients with Pompe disease (glycogen storage disease type II), a mainly skeletal muscle disorder, is unknown. Methods: The clinical course and the outcome of pregnancy, and the effect of pregnancy on disease manifestations or clinical signs and symptoms in Pompe disease were analyzed retrospectively using a questionnaire. Participating women with Pompe disease were recruited by the German and the UK sections of the International Pompe Association, and by centers associated within the German Pompe Group. The data was compared with information from the German statistical almanac, perinatal registry, and perinatal quality survey. Results: 66 of 136 women responded to the questionnaire (median age: 47years, range: 18–74). In 10 of 52 women who had been pregnant, the symptoms of Pompe disease were present during pregnancy (n=7 1st, n=1 2nd, n=1 3rd pregnancy). Muscle weakness worsened in 3 women, and first presented in 3 others during the first pregnancy (4.5% each). Respiratory problems deteriorated in 2/10 women during pregnancy. These 10 symptomatic women had 17 pregnancies (15 deliveries, 2 miscarriages, no abortions). The 42 asymptomatic women (63.6%) had 109 pregnancies (72.4% deliveries, 19.3% miscarriages, 7.3% abortions). There were no significant differences between the mean duration of pregnancies or the mean birth weight in symptomatic and asymptomatic women, or compared to the data from the general population. The same was true of pregnancy and delivery complications (including Cesarean section). Conclusions: Our data show that women with Pompe disease do not appear to have an increased risk of pregnancy or delivery complications. However, muscle weakness and respiratory complications might manifest or worsen during pregnancy in some women. [Copyright &y& Elsevier]

Abstract: Fabry disease is a lysosomal storage disorder with onset of adverse signs and symptoms usually during childhood and progressive life-threatening decline in organ functions. A validated and feasible Fabry disease severity scoring system (DS3) is needed to reliably quantify the disease burden, monitor disease progression and treatment response, and compare disease status among patient cohorts in clinical studies. We developed a new Fabry DS3 and tested its reliability and validity using a combination of expert consensus formation and statistical techniques. Relevant Fabry disease domains and items were identified, inclusion of items was refined and scaling of scores for individual assessments was optimized to maximize the correlation between the instrument’s total score and the assigned clinical global impression of severity (CGI-S scores). Furthermore, the minimum clinically important difference in each of the instrument’s domains was estimated and the DS3’s quantitative content validity was judged. The current Fabry DS3 working model has 5 domains; 4 clinical domains (Peripheral Nervous System, Renal, and Cardiac, each with 3 items, Central Nervous System with 2 items) and a patient-reported domain (Patient-Reported domain with one item). The domain score is obtained by averaging the scores for all domain items. The Content Validity Index and Feasibility Index were shown to be good; 0.96 and 0.97, respectively. There was no significant inter-rater difference and the level of concordance was high. Correlation with the CGI-S was R 2 =0.89 indicating excellent criterion and construct (convergent) validity. In summary, initial estimations of validity, reliability and feasibility for the new Fabry DS3 instrument suggest that it is a feasible and reliable means of assessing disease severity and progression over time and comparing inter-patient severity of Fabry disease. Our results demonstrate that the Fabry DS3 correlates highly with the clinical assessment by Fabry disease experts. [Copyright &y& Elsevier]

Abstract: Gaucher disease is the first lysosomal disorder for which clinically effective enzyme replacement therapy has been introduced. Lifelong treatment with imiglucerase, the recombinant glucocerebrosidase manufactured by the Genzyme Corporation (MA, USA), is administered intravenously — usually at biweekly intervals. An acute shortage of imiglucerase (to 20% of prior global supply) has occurred as a result of viral contamination of the production facility; production was halted, and a full supply of imiglucerase is not anticipated until January 2010. An urgent meeting of physicians, researchers, and patients was convened through the agency of the European Working Group for Gaucher Disease; this was instigated by patients internationally represented by the European Gaucher Alliance. Here we present a position statement based on the findings of the group, with key recommendations about identification and monitoring of at-risk patients threatened by the abrupt withdrawal of treatment, the equitable distribution of residual imiglucerase — and access to alternative treatments including those that have completed phase III clinical trials but have not yet been licensed. [Copyright &y& Elsevier]

Abstract: Niemann-Pick disease type C (NP-C) is a lysosomal storage disease in which impaired intracellular lipid trafficking leads to excess storage of cholesterol and glycosphingolipids in the brain and other tissues. It is characterized clinically by a variety of progressive, disabling neurological symptoms including clumsiness, limb and gait ataxia, dysarthria, dysphagia and cognitive deterioration (dementia). Until recently, there has been no disease-modifying therapy available for NP-C, with treatment limited to supportive measures. In most countries, NP-C is managed through specialist centers, with non-specialist support provided locally. However, effective patient support is hampered by the absence of national or international clinical management guidelines. In this paper, we seek to address this important gap in the current literature. An expert panel was convened in Paris, France in January 2009 to discuss best care practices for NP-C. This commentary reviews current literature on key aspects of the clinical management of NP-C in children, juveniles and adults, and provides recommendations based on consensus between the experts at the meeting. [Copyright &y& Elsevier]

Abstract: Enzyme replacement therapy has been in clinical practice for the non-neuronopathic form of Gaucher disease for 15 years. However, the wide phenotypic variability in this disorder poses challenges to clinicians to assess patient severity and disease progression in order to effectively manage patients. Once therapy is initiated, methods to monitor the complex biochemical changes associated with the disease, and the response of these changes to therapy, are required in order to tailor therapy regimens to individual patients. We have evaluated the suitability of plasma sphingolipids and phospholipids as biochemical markers of disease burden and the efficacy of therapy to reduce that burden. Over 60 lipid species were measured using electrospray ionization-tandem mass spectrometry in plasma from controls and Gaucher patients, pre- and post-therapy. Glucosylceramide, molecular species of phosphatidylglycerol and GM3 ganglioside were elevated in Gaucher disease, whereas species of ceramide, dihexosylceramide and sphingomyelin were decreased. Multivariate analysis enabled us to calculate the combined response of these lipids to therapy in Gaucher patients and correlate them with patient severity. Plasma lipids are proposed to be useful biomarkers for Gaucher disease. [Copyright &y& Elsevier]