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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Anomalous mobilities of Na,K-ATPase alpha subunit isoforms in SDS-PAGE: identification by N-terminal sequencing.

Three isoforms of the alpha subunit of Na,K-ATPase, alpha 1, alpha 2, and alpha 3 have been characterized at the DNA, mRNA and protein levels. In admixtures, isoforms migrate as doublets (i.e. alpha 1 and another band originally designated alpha +, comprising alpha 2 + alpha 3) when analyzed by SDS-PAGE. As deduced from cDNA sequences their masses range from 111.7 to 112.6 kDa. With conventional protein standards, however, SDS-PAGE yields nominal masses of 85-105 kDa. In this system, the presence of a doublet that reacted with a polyclonal anti-Na,K-ATPase antibody in the kidney was interpreted as indicating two molecular or conformational species of the kidney alpha sub-unit (Siegel, G.J. and Desmond, T.J. (1989) J. Biol. Chem. 264, 4751-4754). We report that Na,K-ATPase purified from dog, guinea pig and rat kidney medulla or from rat brain, can yield two distinct bands when analyzed by SDS-PAGE or STS-PAGE, migrating between 85 and 105 kDa. An additional band migrating at 117 and 120 kDa appears often in enzyme purified from rat and guinea pig kidney medulla. The apparent molecular weights and relative intensities of these bands vary with temperature and duration of incubation during sample preparation. N-terminal sequencing and monospecific antibody probes revealed that the two distinct bands obtained from the kidney enzyme consist only of the alpha 1 isoform. The band appearing at 117-120 kDa also contains only the alpha 1 N-terminal sequence. In contrast, as reported earlier (Sweadner, K.J. (1979) J. Biol. Chem. 254, 6060-6067), the doublet seen in brain preparations consists of alpha 1 and alpha 2 or (alpha 2 + alpha 3). We conclude that monospecific antibody probes or N-terminal sequencing must be used to identify Na,K-ATPase isoforms by SDS- or STS-PAGE. In addition, gel conditions that may affect the mobilities of the isoforms are discussed.

Low-dose enzyme replacement therapy for Gaucher's disease: effects of age, sex, genotype, and clinical features on response to treatment.

Although alglucerase therapy has become the treatment of choice for symptomatic patients with Gaucher's disease, the low-dose/high-frequency regimen introduced as a means to reduce the high cost of treatment has raised major controversy. We evaluated the efficacy and safety of low-dose alglucerase in 29 patients with Gaucher's disease who completed 6 to 28 months of therapy. All received intravenous alglucerase at a monthly dose of 30 units/kg, given usually in equal doses 3 times a week. All patients responded well to treatment. The hematological improvement and the reduction in organomegaly were satisfactory. No correlation was found between age, sex, genotype, previous splenectomy, or severity score index and the response to treatment. Patients with a greater degree of hepatomegaly tended to have a more pronounced decrease in liver size, although this reduction did not reach statistical significance. We confirmed that a low-dose/high-frequency regimen of alglucerase was as effective as a high-dose/low-frequency protocol in the treatment of Gaucher's disease, even in the severely ill. Whenever cost is an issue, we recommend using this low-dose regimen.

Incidence of thrombophilia in patients with Gaucher disease.

An inherited risk for thrombosis, including mutant thermolabile variant of methylenetetrahydrofolate reductase (MTHFR), factor V Leiden, or prothrombin may be the co-factor(s) for avascular necrosis (AVN) in patients with sickle cell disease. Similarly, heterozygosity for factor V Leiden is sufficient to explain the increased blood viscosity observed in children with Legg-Calve-Perthes disease who develop AVN. Because there are no laboratory tests or clinical markers that are helpful in predicting which patients with Gaucher disease may develop AVN, the current study was undertaken to ascertain if there exists an inherited predilection to hypercoagulability in patients with Gaucher disease and AVN. Analysis was performed on genomic DNA extracted from 56 adult patients with type I Gaucher disease. In this cohort of Ashkenazi Jewish patients, the frequency of mutations in the MTHFR, prothrombin, and factor V Leiden genes was found to be low, as was the presence of anticardiolipin antibodies; and none was correlated with increased incidence of AVN. Splenectomy, that may be a predisposing factor to AVN in patients with Gaucher disease, was factored out. Hence the presence of any of the above thrombophilic factors, and which by extension may be risk factors for AVN in other diseases, are not more common in patients with Gaucher disease who develop AVN. Studies in larger cohorts and possibly inclusion of additional factors may be needed to ascertain whether a correlation exists.

High prevalence of complement C7 deficiency among healthy blood donors of Moroccan Jewish ancestry.

The incidence of the specific component deficiencies in various ethnic groups is not known, although there appears to be an ethnic predilection for C6 and C8alpha-gamma deficiencies in blacks, whereas C7 and C8beta deficiencies are predominantly noted in Caucasians. Infectious diseases, particularly recurrent meningococcal infections, are observed more commonly with late component deficiencies. In the current study, we have simplified the PCR technique by using site-directed mutagenesis and designer primers in a cohort of Israeli Moroccan Jewish blood donors to ascertain allele frequency in this ethnic group, which, based on earlier studies, was considered to be at risk for C7 deficiency. The total mutant allele frequency in this ethnic cohort was 1.1% of a total of 365 healthy Israeli Moroccan Jews, including one homozygote. The identification of mutant alleles was efficient and inexpensive, and hence a large cohort was studied. The finding of complement deficiency identifies individuals at risk for Neisserial infections, which are known to be potentially life-threatening. Conversely, when a patient of Moroccan ancestry is diagnosed with a Neisserial infection, it is important to determine the complement status.

Decreased salivary output in patients with Gaucher disease.

BACKGROUND: Gaucher disease, the most common sphingolipid storage disease, results in accumulation of glucocerebroside in macrophages or "Gaucher cells". In a preliminary screening of 109 patients with type I disease, when asked specifically about dry mouth, approximately one quarter claimed to suffer from this symptom. AIM: To ascertain whether decreased salivary output is a feature of Gaucher disease. DESIGN: Prospective case-control study. METHODS: Salivary output was measured in 65 adult patients and 65 healthy controls using the Saxon test with Hochberg's modification. RESULTS: Mean salivary output was 1.91+/-1.19 g/min in the patient group vs. 2.74+/-1.17 g/min in the control group (p<0.001). This difference was greater among males. These results were not improved in the patients receiving enzyme replacement therapy, which is effective in ameliorating most Gaucher-related signs and symptoms. DISCUSSION: Recent studies have implicated an association between sicca syndrome and viral hepatitis C infection, which may imply an immunological trigger for these findings, but in this specific cohort, only three patients were reactive for hepatitis C. Follow-up of patients, both untreated and receiving enzyme therapy, is needed to delineate the association with salivary hypofunction, and ascertain whether enzyme therapy may induce sicca symptoms.

Low-dose low-frequency imiglucerase as a starting regimen of enzyme replacement therapy for patients with type I Gaucher disease.

The issue of the interplay of optimal dosage and frequency regimens for enzyme replacement therapy in type I Gaucher disease has been a source of controversy during the 7 years since the introduction of the placenta-derived enzymatic preparation in 1991. We present the results of treatment with the human recombinant form of the enzyme in 28 type I Gaucher patients, who have been treated for 6 to 24 months. As long as cost is an important factor in the management of patients with Gaucher disease, low-dose low-frequency imiglucerase promises satisfactory clinical improvement without compromising quality of life.