Taliglucerase alfa leads to favorable bone marrow responses in patients with type I Gaucher disease.

Taliglucerase alfa (Protalix Biotherapeutics, Israel) is a carrot-cell-expressed recombinant human beta-glucocerebrosidase recently approved in the United States for the treatment of type 1 Gaucher disease (GD). As bone disease is one of the most debilitating features of GD, quantification of bone marrow involvement is important for monitoring the response to treatment. Therefore, bone marrow fat fraction (Ff) measured by quantitative chemical shift imaging (QCSI) was included as exploratory parameter to evaluate bone marrow response in treatment naïve GD patients participating in a double-blind, randomized phase III study. Eight GD patients with intact spleens were treated with 30 or 60U/kg biweekly. Ff results were compared to outcomes in 15 untreated Dutch GD patients with a follow-up interval of 1year. Five taliglucerase alfa treated patients had a Ff below the threshold that relates to complication risk (<0.23) at baseline (median (n=8) 0.19, range 0.11-0.35). Ff significantly increased compared to baseline (p=0.012) and compared to untreated patients (p=0.005), already after 1year of follow-up with further improvement up to 36months. In four patients with the lowest Ff, the higher dose resulted in increases above 0.23 within 1year. All patients had sustained improvements in all other parameters. There was no influence of antibodies on response parameters. Treatment with taliglucerase alfa results in significant increases in lumbar spine fat fractions, which indicates clearance of Gaucher cells from the bone marrow.

Mandibular and dental manifestations of Gaucher disease.

Gaucher disease is a systemic lysosomal storage disorder with a high prevalence among Ashkenazi Jews. It is caused by an inherited deficiency of the lysosomal enzyme glucocerebrosidase. Common signs and symptoms include hepatosplenomegaly, anemia, thrombocytopenia, and skeletal involvement. Oral and dental manifestations are less commonly seen. These manifestations are often asymptomatic, although they may be detected by routine dental x-rays. There are several case reports and a few larger series published describing patients with Gaucher disease who have mandibulo-maxillofacial involvement. This review aims to examine the oral manifestations observed in Gaucher disease and to suggest practical guidelines for dealing with these often worrisome signs. Among the critical issues are the benign nature of Gaucher cell infiltration of the mandible and the critical importance of being prepared for postprocedure bleeding and/or infections. Therefore, it is essential that dental practitioners be aware of the possible oral and dental complications of Gaucher disease, as well as the available treatment modalities.

Thrombocytopenia and bleeding in dental procedures of patients with Gaucher disease.

The risk of bleeding during dental procedures may be increased in patients with Gaucher disease. We aimed to evaluate potential coagulation and platelet function abnormalities and targeted therapy accordingly. Patients with type 1 Gaucher disease who were treated at the Oral and Maxilo-Facial surgery clinic at Sheba Medical Center between 2003 and 2010 comprised the study cohort. Data collected included disease history, enzyme treatment, platelet counts, dental therapy and outcome. Bleeding was defined as excessive bleeding during or immediately following procedure. Coagulation studies and platelet function tests including aggregometry were performed on all patients. Dental procedures (n = 14, including eight teeth extractions, two crown lengthening procedures, one cyst enucleation and three deep dental scaling) of seven patients were studied. Mean platelet count prior to procedure was 73 K ± 14.8 mm(3). Patients bleeding risk score was calculated according to previous history of bleeding tendency, degree of thrombocytopenia, presence of comorbid coagulopathy and the type of dental procedure. Two patients with highest risk score received prophylactic platelet transfusions, three patients (medium-risk) received DDAVP preprocedure and all received systemic tranexamic acid, which was the only systemic therapy for low-risk patients. Meticulous surgical local haemostasis was applied. No excessive intra-operative or postoperative bleeding occurred. Patients with Gaucher disease who have thrombocytopenia and abnormal platelet function tests may be safely treated if meticulous haemostasis is applied along with systemic therapy as required. Platelet transfusions are not mandatory and should be applied considering the procedure-related risk and the patient's calculated haematological risk for bleeding.

Severe heart disease complicating pregnancy does not preclude a favourable pregnancy outcome: 15 years' experience in a single centre.

Heart disease (HD) in pregnancy remains a major cause of non-obstetric maternal and neonatal mortality and morbidity. This study describes the outcome in 164 pregnant women with HD (158 deliveries in women in New York Heart Association (NYHA) Classes 1 and 2; 17 in NYHA Classes 3 and 4) who received good antenatal care and benefitted from a specific protocol and experience of a dedicated staff. There were no maternal or neonatal deaths; 46 women were diagnosed peripartum. Based on a sub-division into NYHA categories, and when sub-divided by HD, there were no statistically significant differences between groups with regard to maternal age, gestational age at admission or at delivery, birth weight, 5 min Apgar scores, mode of delivery (caesarean delivery), senior obstetric/anaesthesiology staff in attendance or delivery during day/working hours. There was a higher incidence of pre-term deliveries in women with rheumatic heart disease and Marfan syndrome (p = 0.06) relative to others. Babies of women with coronary heart disease had prolonged postpartum course in the NICU (p = 0.0001) and longer total hospital stays for the mother. In conclusion, well-managed, motivated mothers with HD who benefit from comprehensive antenatal care, and are managed primarily by their obstetric and anaesthesia teams, can aspire to a good outcome for themselves and their babies.

Early achievement and maintenance of the therapeutic goals using velaglucerase alfa in type 1 Gaucher disease.

INTRODUCTION: Therapeutic goals have been described to monitor achievement, maintenance and continuity of therapeutic response in patients with type 1 Gaucher disease receiving enzyme replacement therapy. AIM: To benchmark the impact of velaglucerase alfa treatment against therapeutic goals for 5 key clinical parameters of type 1 Gaucher disease (anemia, thrombocytopenia, hepatomegaly, splenomegaly and skeletal pathology). METHODS: In an open-label Phase I/II study, twelve adults with symptomatic type 1 Gaucher disease and intact spleens received velaglucerase alfa for 9 months (60 U/kg infusion every other week [EOW]). Eleven patients completed the study and 10 enrolled in a long-term extension. After 1 year, patients who achieved ≥ 2 hematological or organ goals began step-wise dose reduction from 60 to 45 then 30 U/kg EOW. Data for anemia, thrombocytopenia, hepatomegaly, splenomegaly and skeletal pathology at baseline and 4 years are available for 8 patients (3 male, 5 female). The proportion of patients at goal for anemia, thrombocytopenia, hepatomegaly and splenomegaly at baseline was compared with the proportion achieving each goal at 4 years. The proportion achieving the skeletal pathology goal was determined on the basis of Z-score improvement from baseline to 4 years. The proportion of patients who achieved all 5 goals at 4 years was compared with the proportion at goal for all 5 parameters at baseline. RESULTS: At baseline, no patient was at goal for all clinical parameters. After 1 year of treatment, all patients maintained goals present at baseline, and all achieved ≥ 2 goals. All 8 patients began step-wise dose reduction from 60 to 30 U/kg EOW between 15 and 18 months. By year 4 of treatment, all patients met goals for all 5 clinical parameters; therefore 100% achievement was seen for each of the 5 long-term, therapeutic goals. DISCUSSION: In this velaglucerase alfa Phase I/II and extension study, clinically meaningful achievement of each long-term, therapeutic goal was observed for each patient, despite dose reduction after 1 year. This is the first report of a cohort where all patients receiving ERT for type 1 Gaucher disease achieved all 5 of these long-term, therapeutic goals within 4 years of starting treatment and after ≥ 2years dose reduction.

Congenital diaphragmatic hernia: review of the literature in reflection of unresolved dilemmas.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a rare but clinically and scientifically challenging condition. The introduction of ultrasound has enabled early prenatal detection and consequently, hope of early therapeutic intervention. AIM: We undertook the task to review the recent developments in understanding the pathology of CDH as well as the history and current management strategies to aid perinatologists in consultations with parents of CDH-affected foetuses. STUDY DESIGN: A Medline search was undertaken of all reports and reviews published between 1980 and 2008 using MeSH search terms 'diaphragmatic hernia', 'congenital' and 'newborn'. RESULTS: The true incidence of CDH is still difficult to estimate because of the high incidence of hidden mortality of CDH. Complete case ascertainment also poses difficulties in assessment of the impact of new therapeutic modalities on overall survival. Recent improvements in prenatal detection are a milestone in affording time for re-assessments and parental counselling. The true benefit of antenatal therapy is circumscribed and should be offered only in selected cases of isolated severe CDH as defined by existing guidelines. Postnatal intensive respiratory supportive therapy and innovative surgical techniques within specialized tertiary centres has had a major impact on survival of babies with CDH. CONCLUSION: The high survival of 'selected cases' that are live births and benefit from optimal care will be difficult to improve by antenatal interventions. The multidisciplinary approach to basic research and randomized clinical trials will further define the best approach to the foetus and neonate with CDH.

Prevalence of low serum cobalamin in infertile couples.

A high prevalence of low levels of cobalamin had been found in a survey of multi-ethnic normal individuals in Israel. The purpose of this study was to investigate the incidence of cobalamin deficiency among Israeli couples suffering from infertility. All couples seen at the in vitro fertilization clinic at an urban hospital (Shaare Zedek Medical Center) in Jerusalem for a 6-month period were invited. Mean cobalamin levels were 259.2 pg ml(-1) in males and 275.1 pg ml(-1) in females (normal >200 pg ml(-1)), 35.5% of 172 men and 23.3% of 223 females had cobalamin deficiency (P = 0.01). There were 171 couples with complete demographic questionnaires and cobalamin values for each partner. In 74 couples (43.3%), one partner was cobalamin deficient, with no significant difference between those with unexplained infertility versus those with explained infertility; and in 13 couples, both partners were cobalamin deficient. Thirty-nine per cent of all men with an abnormal semen analysis had cobalamin deficiency, a finding that requires further investigation. This study questions whether higher rates of male infertility in Israel are partially ascribable to cobalamin deficiency. Recommendation for supplementation in both males and females to achieve high-normal levels of cobalamin would be prudent.

Increased red blood cell aggregation in patients with Gaucher disease is non-inflammatory.

Red blood cell (RBC) aggregation is enhanced in the presence of ongoing inflammation, because of plasma protein effects, especially fibrinogen. Large RBC aggregates, in addition to being a marker of systemic inflammation, may hinder tissue perfusion and oxygenation. Gaucher disease, the most common lysosomal storage disorder, evinces many of the hallmarks of chronic inflammation. Manifestations of Gaucher disease which may be related to microvascular occlusion include avascular necrosis (AVN), bone crisis, and pulmonary hypertension. This study aims to determine whether increased RBC aggregation in non-splenectomized patients with Gaucher disease is due to Gaucher-related inflammation. The Cell Flow Properties Analyzer (CFA) monitors blood under conditions of different shear stress by creating varying pressure gradients. Blood from non-splenectomized patients with Gaucher disease showed only a slight correlation between aggregation parameters and fibrinogen levels, whereas blood from non-splenectomized patients treated with enzyme replacement therapy (ERT) showed marked correlation between aggregation parameters and fibrinogen, as in the control group. These results underscore the hypothesis that RBC aggregation in Gaucher disease is increased by (at least) two mechanisms: a fibrinogen-mediated inflammatory process and another non-inflammatory process that may be induced by elevated glucocerebroside levels in the RBC and/or inhibited by elevated plasma cerebroside levels.

Neurocognitive testing in late-onset Tay-Sachs disease: a pilot study.

OBJECTIVES: To test neurocognitive function in patients with late-onset Tay-Sachs disease (LOTS) using a computerized system to assess whether cognition is a clinically relevant outcome measure of possible therapeutic intervention in LOTS. METHODS: Ten adults with Tay-Sachs disease were administered at least one battery of the Mindstreams Neurotrax system for evaluation of cognitive function. Six sub-scores and a Global Cognitive Score (GCS) were tabulated. A disease specific severity score was also devised with six domains. RESULTS: Despite identical genotypes, all patients but the two oldest had > or = 3/6 sub-scores one standard deviation below normal mean (100); verbal and executive functions were most affected. The severity score measured other functions. CONCLUSIONS: Because of provocative findings on re-testing in patients exposed to miglustat, and despite the very small cohort, cognitive function may be an appropriate and clinically relevant outcome measure for future therapeutic interventions in LOTS.

Correlation between interleukin-6 promoter and C-reactive protein (CRP) polymorphisms and CRP levels with the Mainz Severity Score Index for Fabry disease.

OBJECTIVES: Fabry disease is a multisystem disorder with phenotypic heterogeneity only partially explained by genotype. Elevated interleukin-6 (IL-6) plasma levels and C-reactive protein (CRP) serum levels are associated with increased risk and worse outcome of ischaemic events, a serious prognostic sign in Fabry disease. METHODS: 56 patients (34 hemizygous males, 22 females; 5 children) were studied. A promoter polymorphism -174G > C of the IL-6 gene associated with serum IL-6 levels was compared with the Mainz Severity Score Index (MSSI) in patients with Fabry disease. CRP levels and polymorphism 1059 G > C were evaluated as markers of inflammation to ascertain the possibility of an inflammatory mechanism of IL-6. Nonparametric ANOVA, Fisher's exact, Bonferroni, and Hardy-Weinberg (HW) statistics were used. RESULTS: Mean age of adults = 42 (range 26-58) years; 29 patients received enzyme therapy (ERT). Mean total MSSI = 26.7 (range 14.2-39.2) points, i.e. moderate disease, but females were lower (total 23.4 +/- 12.6 vs 32.2 +/- 13.6). Controls but not patients were in HW equilibrium. Significant correlation existed between all sub-scores of the MSSI and IL-6 genotypes in females but only with three MSSI sub-scores for males. The IL-6 C/C genotype was significantly correlated with the neurological, general and total MSSI sub-scores, generally twofold higher. There were no statistically significant correlations with CRP levels/polymorphisms and MSSI sub-scores nor with IL-6 polymorphisms. CRP levels decreased after ERT in patients with IL-6 G/G or G/C genotypes but increased in patients with C/C (p = 0.003). CONCLUSIONS: The prevalence of the IL-6 C allele significantly influences MSSI, i.e. clinical severity, especially in females. This is unrelated to IL-6 as a pro-inflammatory marker as demonstrated by lack of correlations with CRP levels and genotypes. IL-6 -174 polymorphic C allele may be a prognostic marker in Fabry disease, especially in females.

The effect of hormone replacement therapy on cognitive function in post-menopausal women.

BACKGROUND: Despite interest in causes of dementia in older persons, particularly in post-menopausal women, it is unclear whether hormone replacement therapy (HRT) is a risk factor. AIM: To assess cognitive function in post-menopausal women with high educational status receiving HRT, compared to non-users. DESIGN: Cognitive functioning was assessed with in women aged 55-60 years with at least university-level education, using the Mindstreams system, a computerized cognitive battery with multiple domains. RESULTS: Of 165 women meeting the inclusion/exclusion criteria, 82 women (49.7%) declined participation. Of the remaining 83, 40 (48.2%) had never received HRT; the remainder was divided into women receiving 5-9 years HRT (n = 29)versus those with >or=10 years HRT (n = 11). There were no statistically significant differences between HRT users and non-users in global scores or sub-domains of cognitive functioning, and no difference between those women receiving HRT for 5-9 years vs. >or=10 years. DISCUSSIONS: Long-term HRT does not appear to impair cognitive functioning in highly-educated women. Recommendations regarding post-menopausal HRT should be made on an individual basis.

PAPP-A levels as an early marker of idiopathic preterm birth: a pilot study.

OBJECTIVE: To evaluate late PAPP-A levels as predictive of preterm birth in symptomatic women. STUDY DESIGN: Prospective cohort study of singleton gestations, 23 to 34 weeks, and symptoms of preterm labor. PAPP-A, IGF-I and IGF-III analysis were performed. Primary end point was delivery < or =7 days. Accuracy and optimally predictive PAPP-A values were based on receiver operator characteristic (ROC) curves. RESULT: In all, 26 women (51%) delivered < or =7 days post-admission (Group 1); 25 women (49%) >7 days (Group 2). Group 1 mean PAPP-A=38 000 vs 55 333 for Group 2 (P<0.04). Group 1 mean gestational age at delivery=29 weeks vs 37 weeks for Group 2 (P<0.00014). PAPP-A level < or =30,000 mU l(-1) had highest specificity (88%), sensitivity (50%), and positive predictive (81%) and negative predictive (62%) values for delivery < or =7 days. ROC area under curve=0.703. CONCLUSION: PAPP-A levels < or =30,000 mU l(-1) at admission was associated with increased risk for preterm birth < or =7 days, supporting active management and therapeutic approach in these women.

Temporizing treatment for the respiratory-compromised gravida: an observational study of maternal and neonatal outcome.

Acute lung disease may originate in pregnancy because of the pregnancy itself or because of an intercurrent etiology. The purpose of this study was to describe the effect of prolonged antepartum mechanical ventilatory support on the mother and the neonate when the strategy was to prolong the pregnancy rather than deliver preterm. Among 72 312 parturients over eight years, three gravidae required mechanical ventilation 12-48 h after admission for different conditions, 45-91 days before delivery. Gestational age at intubation was 21-28 weeks. Appropriate analgesia, broad-spectrum antibiotics, vasopressors and betamethsone for fetal lung maturity were used in all cases. None received tocolysis. Despite uterine distension, respiratory support provided adequate oxygenation and FiO2 could be maintained below critical levels, obviating the need for early delivery. All women survived, were weaned from ventilatory support, discharged, and delivered healthy neonates at term. Mode of delivery was dictated by obstetrical indicators only. All five infants (two sets of twins) are healthy at 12-36 months with appropriate developmental milestones. We conclude that when the maternal condition is amenable to therapy, and given the risks of labor induction and of prematurity, there is only limited benefit of delivery while on mechanical ventilation.

Are symptoms of peripheral neuropathy more prevalent in patients with Gaucher disease?

BACKGROUND: A previous epidemiological survey from an American referral clinic noted a high incidence of neurological symptoms among patients with type I (non-neuronopathic) Gaucher disease all of whom were treated with specific enzyme replacement. OBJECTIVES: The current study replicates the above in a larger cohort of Ashkenazi Jewish patients with at least one N370S mutation which has been assumed to be protective of neurological involvement. About half the patients had mild disease and were untreated. Methods - Self-reporting questionnaires were sent to patients and their significant others as socio-economically matched controls. RESULTS: There was no significant difference between groups in incidence of concomitant diseases and medications, except patients who reported a significantly higher incidence of vitamin B(12) deficiency and gammopathies. Patients reported significantly higher incidence of virtually all symptoms and signs of peripheral neuropathy and a significantly higher number of symptoms than controls (mean 4.4 vs 2.4). CONCLUSIONS: The conclusion of this study, as of the seminal study, is that the high incidence of neurological complaints in patients with the non-neuronopathic form of Gaucher disease should be viewed in the context of concomitant illnesses, specifically, vitamin B(12) deficiency and gammopathies, regardless of the need for enzyme replacement therapy.

Fibromyalgia and Gaucher's disease.

BACKGROUND: Patients with symptomatic Gaucher's disease sometimes have non-specific symptoms (such as general malaise with widespread musculoskeletal pains) that respond poorly to enzyme replacement treatment. These may indicate fibromyalgia syndrome; if so, other therapeutic options might be more appropriate. AIM: To identify patients with Gaucher's disease for whom fibromyalgia-specific therapy may be therapeutic. DESIGN: Questionnaire-based survey. METHODS: Adult patients (n = 109) with non-neuronopathic Gaucher's disease and adult healthy controls (n = 108) completed health-related questionnaires including the Fibromyalgia Impact Questionnaire, and underwent testing with a dolorimeter to ascertain sensitivity at 22 tender points. RESULTS: Six patients, but no controls, met the criteria for fibromyalgia. Patients with fibromyalgia had a significantly greater incidence of co-morbidities (p = 0.014) relative to other patients with Gaucher's disease; four suffered from bone involvement and were receiving enzyme therapy, but two were untreated. DISCUSSION: The presence of fibromyalgia-specific trigger points may result from multiple aetiologies, or may be an independently-sorting predisposition. Our findings cannot distinguish between these possibilities, but if fibromyalgia were the cause, enzyme replacement therapy would be expensive and inappropriate.

Sustained therapeutic effects of oral miglustat (Zavesca, N-butyldeoxynojirimycin, OGT 918) in type I Gaucher disease.

It has been shown that treatment with miglustat (Zavesca, N-butyldeoxynojirimycin, OGT 918) improves key clinical features of type I Gaucher disease after 1 year of treatment. This study reports longer-term efficacy and safety data. Patients who had completed 12 months of treatment with open-label miglustat (100-300 mg three times daily) were enrolled to continue with therapy in an extension study. Data are presented up to month 36. Liver and spleen volumes measured by CT or MRI were scheduled every 6 months. Biochemical and haematological parameters, including chitotriosidase activity (a sensitive marker of Gaucher disease activity) were monitored every 3 months. Safety data were also collected every 3 months. Eighteen of 22 eligible patients at four centres entered the extension phase and 14 of these completed 36 months of treatment with miglustat. After 36 months, there were statistically significant improvements in all major efficacy endpoints. Liver and spleen organ volumes were reduced by 18% and 30%, respectively. In patients whose haemoglobin value had been below 11.5 g/dl at baseline, mean haemoglobin increased progressively from baseline by 0.55 g/dl at month 12 (NS), 1.28 g/dl at month 24 (p =0.007), and 1.30 g/dl at month 36 (p =0.013). The mean platelet count at month 36 increased from baseline by 22 x 10(9)/L. No new cases of peripheral neuropathy occurred since previously reported. Diarrhoea and weight loss, which were frequently reported during the initial 12-month study, decreased in magnitude and prevalence during the second and third years. Patients treated with miglustat for 3 years show significant improvements in organ volumes and haematological parameters. In conclusion, miglustat was increasingly effective over time and showed acceptable tolerability in patients who continued with treatment for 3 years.

Anesthesia for obstetric patients with Gaucher disease: survey and review.

Pregnancy and delivery in patients with non-neuronopathic Gaucher disease, whether treated with enzyme replacement or untreated, are usually uncomplicated. Various factors may influence mode of delivery, vaginal or cesarean section, as well as type of anesthesia, general or regional, used during delivery. This retrospective review was intended to highlight some of the practical issues relating to obstetric anesthetic management, based on a review of the literature and experiences from a large referral clinic for Gaucher disease. In the past decade, there were 16 deliveries in 11 women in our institution. There were five normal vaginal deliveries, two vacuum extractions, one placental extraction, and eight cesarean sections. Platelet counts were 27-215 x 10(9)/L. Two spontaneous deliveries and one vacuum extraction were performed under epidural anesthesia; two other women having vaginal deliveries and one vacuum extraction were given i.v. analgesia; the fifth was given i.v. patient-controlled analgesia. The placental extraction was performed under general anesthesia. Seven of the women having cesarean deliveries received spinal anesthesia; the breech presentation required general anesthesia. There were no anesthesia-related side effects or complications, although there were some instances of post-partum bleeding irrespective of enzyme therapy. Gaucher disease affects multiple organs and can be a challenge to the anesthesiologist. Based on this survey we suggest that anesthetic management requires particular attention to hematological parameters before delivery. A multidisciplinary approach and extensive communication among obstetrician, hematologist and anesthesiologist is required to anticipate the possibility of post-partum hemorrhage, and preclude skeletal damage.

The role of the iminosugar N-butyldeoxynojirimycin (miglustat) in the management of type I (non-neuronopathic) Gaucher disease: a position statement.

N-Butyldeoxynojirimycin (NB-DNJ, miglustat 'Zavesca') is an orally active iminosugar which inhibits the biosynthesis of macromolecular substrates that accumulate pathologically in glycosphingolipidoses. Clinical trials of NB-DNJ in patients with Gaucher's disease demonstrate the therapeutic potential of such substrate inhibitors in the glycolipid storage disorders. However, macrophage-targetted enzyme replacement using intravenous mannose-terminated human glucocerebrosidase (imiglucerase, Cerezyme) is highly effective in ameliorating many of the manifestations of Gaucher's disease and is a treatment in widespread use. Given that imiglucerase and miglustat are now both licensed for the treatment of Gaucher's disease, there is a need to review their therapeutic status. Here the treatment of type 1 (non-neuronopathic) Gaucher disease is evaluated with particular reference to the emerging role of oral N-butyldeoxynojirimycin (miglustat) as a substrate-reducing agent. This position statement represents the consensus viewpoint of an independent international advisory council to the European Working Group on Gaucher Disease.