Impact of obesity on taste receptor expression in extra-oral tissues: emphasis on hypothalamus and brainstem.

Sweet perception promotes food intake, whereas that of bitterness is inhibitory. Surprisingly, the expression of sweet G protein-coupled taste receptor (GPCTR) subunits (T1R2 and T1R3) and bitter GPCTRs (T2R116, T2R118, T2R138 and T2R104), as well as the α-subunits of the associated signalling complex (αGustducin, Gα14 and αTransducin), in oral and extra-oral tissues from lean and obese mice, remains poorly characterized. We focused on the impact of obesity on taste receptor expression in brain areas involved in energy homeostasis, namely the hypothalamus and brainstem. We demonstrate that many of the GPCTRs and α-subunits are co-expressed in these tissues and that obesity decreases expression of T1R3, T2R116, Gα14, αTrans and TRPM5. In vitro high levels of glucose caused a prominent down-regulation of T1R2 and Gα14 expression in cultured hypothalamic neuronal cells, leptin caused a transient down-regulation of T1R2 and T1R3 expression. Intriguingly, expression differences were also observed in other extra-oral tissues of lean and obese mice, most strikingly in the duodenum where obesity reduced the expression of most bitter and sweet receptors. In conclusion, obesity influences components of sweet and bitter taste sensing in the duodenum as well as regions of the mouse brain involved in energy homeostasis, including hypothalamus and brainstem.

Potential of UCHL1 as biomarker for destruction of pancreatic beta cells.

There is a clinical need for plasma tests for real-time detection of beta cell destruction, as surrogate endpoint in islet transplantation and immunoprevention trials in type 1 diabetes. This study reports on the use of label-free LC-MS/MS proteomics for bottom-up selection of candidate biomarkers. Ubiquitin COOH-terminal hydrolase 1 (UCHL1) was identified as abundant protein in rat and human beta cells, showing promising beta cell-selectivity, and was selected for further validation in standardized toxicity models. In vitro, H2O2-induced necrosis of INS-1 cells and human islets resulted in intracellular UCHL1 depletion and its extracellular discharge. In vivo, streptozotocin progressively depleted UCHL1 from islet cores and in 50% of animals, an associated plasma UCHL1 surge was detected preceding the GAD65 peak. UCHL1 was cleared with a half-life of 20min. Whole-body dynamic planar imaging of (99m)-Technetium-labeled UCHL1 indicated a rapid UCHL1 uptake in the liver and spleen, followed by urinary excretion of mainly proteolytic UCHL1 fragments. We conclude that LC-MS/MS proteomics is a useful tool to prioritize biomarkers for beta cell injury with promising molar abundance. Despite its consistent UCHL1 discharge by damaged beta cells in vitro, its in vivo use might be restrained by its rapid elimination from plasma. BIOLOGICAL SIGNIFICANCE: Our bottom-up LC-MS/MS proteomics represents a pragmatic approach to identify protein-type biomarkers of pancreatic beta cell injury. UCHL1 successfully passed sequential validation steps of beta cell-selectivity, antigenicity and toxic discharge in vitro. Whole-body dynamic planar imaging of radiolabeled recombinant UCHL1 indicated rapid clearance through the liver, spleen and urinary excretion of proteolytic fragments, likely explaining non-consistent detection in vivo. Integration of kinetic biomarker clearance studies in the a priori selection criteria is recommended before engaging in resource-intensive custom development of sensitive immunoassays for clinical translation.

Increased glucocerebrosidase expression and activity in preeclamptic placenta.

INTRODUCTION: Lysosomal glucosidase beta acid (GBA) deficiency is inherent to Gaucher disease, Parkinsonism and Lewy-body dementia. Increased GBA expression has never been associated with human disease. We describe increased GBA expression and activity in placenta from preeclamptic pregnancies. METHODS: 112 placenta biopsies were available for qPCR, analysis of GBA gene expression and activity. Microanalysis was performed on 20 placenta samples. Alternatively spliced placental GBA transcripts were cloned, expressed in HEK293 cells and analyzed by Western blot and activity assay. RESULTS: GBA is expressed in the syncytiotrophoblast layer of human placenta already at 5 weeks of gestation. We identified five novel GBA transcripts in placenta that enzymatically inactive when expressed in HEK293 cells. Both GBA RNA expression and enzymatic activity are upregulated in preeclamptic placenta. Microarray analysis of 20 placenta tissues identified 158 genes co-regulating with GBA expression and gene enrichment analysis highlights lysosomal function. In our micro-array data GBA expression does not correlate with FLT1 expression, currently the most powerful marker for preeclampsia. There are 89 transcripts that are negatively correlated with GBA expression of which BMP4 and TFEB are interesting as they are essential to early placenta function. DISCUSSION: Although very speculative, we hypothesize that increased GBA expression might relate to placentation through decreased BMP4 signaling or vascularization through downregulation of TFEB. Ceramide, the product of hydrolysis of glucosylceramide by GBA and involved in the regulation of cell differentiation, survival and apoptosis, is another putative candidate linking increased GBA activity to preeclampsia. Both pathways merit further investigation.

Value of plasma chitotriosidase to assess non-neuronopathic Gaucher disease severity and progression in the era of enzyme replacement therapy.

Gaucher disease (GD) is caused by deficiency of the enzyme glucocerebrosidase catalysing the regular lysosomal degradation of glucosylceramide. In the common non-neuropathic variant of GD, glucosylceramide-laden macrophages (Gaucher cells) accumulate in various tissues. Gaucher cells secrete chitotriosidase, an active chitinase, resulting in increased plasma chitotriosidase levels, which can be sensitively monitored by an enzyme activity assay. Plasma chitotriosidase is a rough estimate of body burden of Gaucher cells. Non-neuronopathic GD is presently treated by enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). We addressed the question whether plasma chitotriosidase acts as (predictive) marker of clinical manifestations in non-neuronopathic GD patients receiving treatment. Reductions in plasma chitotriosidase during therapy correlated with corrections in liver and spleen volumes and showed positive trends with improvements in haemoglobin and platelet count and bone marrow composition. The occurrence of long-term complications and associated conditions such as multiple myeloma, bone complications, Parkinson's disease, hepatocellular carcinoma and pulmonary hypertension positively correlated with the plasma chitotriosidase level pre-therapy, the average plasma chitotriosidase during 3 years of ERT and the residual plasma chitotriosidase after 2 years of ERT. In summary, plasma chitotriosidase is a valuable marker in the assessment and follow-up of GD patients.

B cell lymphoma and myeloma in murine Gaucher's disease.

Multiple myeloma and B cell lymphoma are leading causes of death in Gaucher's disease but the nature of the stimulus driving the often noted clonal expansion of immunoglobulin-secreting B cells and cognate lymphoid malignancy is unknown. We investigated the long-term development of B cell malignancies in an authentic model of non-neuronopathic Gaucher's disease in mice: selective deficiency of ß-glucocerebrosidase in haematopoietic cells [Gba(tm1Karl/tm1Karl)Tg(Mx1-cre)1Cgn/0, with excision of exons 9-11 of the murine GBA1 gene, is induced by poly[I:C]. Mice with Gaucher's disease showed visceral storage of ß-glucosylceramide and greatly elevated plasma ß-glucosylsphingosine [median 57.9 (range 19.8-159) nm; n = 39] compared with control mice from the same strain [median 0.56 (range 0.04-1.38) nm; n = 29] (p < 0.0001). Sporadic fatal B cell lymphomas developed in 11 of 21 GD mice (6-24 months) but only two of eight control animals developed tumours by age 24 months. Unexpectedly, most mice with overt lymphoma had absent or few Gaucher cells but local inflammatory macrophages were present. Eleven of 39 of Gaucher mice developed monoclonal gammopathy, but in the control group only one animal of 25 had clonal immunoglobulin abnormalities. Seven of 10 of the B cell lymphomas were found to secrete a monoclonal paraprotein and the lymphomas stained intensely for pan-B cell markers; reactive T lymphocytes were also present in tumour tissue. In the Gaucher mouse strain, it was notable that, as in patients with this disease, CD138(+) plasma cells frequently surrounded splenic macrophages engorged with glycosphingolipid. Our strain of mice, with inducible deficiency of ß-glucocerebrosidase in haematopoietic cells and a high frequency of sporadic lethal B cell malignancies, faithfully recapitulates human Gaucher's disease: it serves as a tractable model to investigate the putative role of bioactive sphingolipids in the control of B cell proliferation and the pathogenesis of myelomatosis-the most prevalent human cancer associated with this disorder.

No difference in glycosphingolipid metabolism and mitochondrial function in glucocorticoid-induced insulin resistance in healthy men.

OBJECTIVE: Glucocorticoids (GCs) are well known to induce insulin resistance; however, mechanisms that cause the impairement of the insulin signaling pathway have not yet been identified. In this study we measured whether GC-induced insulin resistance in humans is related to changes in muscle ceramide, GM3, and muscle mitochondrial function. METHODS: In a randomized, placebo-controlled, double-blind, dose-response intervention study, 32 healthy males (aged 22 ± 3 years; body mass index 22.4 ± 1.7 kg/m(-2)) were allocated to prednisolone (PRED) 7.5 mg once daily (n = 12), PRED 30 mg once daily (n = 12), or placebo (n = 8) for 2 weeks using block randomization. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp before and after treatment. Muscle biopsies were performed to measure ceramide, monosialodihexosylganglioside (GM3), and mitochondrial function. RESULTS: Peripheral insulin sensitivity was dose dependently decreased after the PRED treatment. Muscle ceramide and GM3 concentration and mitochondrial function were not altered by 2 weeks of PRED treatment. CONCLUSION: Short-term GC treatment dose dependently impaired whole-body insulin sensitivity in healthy males, without concomitant changes in muscle ceramide, GM3, or mitochondrial function. These findings suggest that other mechanisms play a role in GC-related impairment of insulin sensitivity.

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.

Acid sphingomyelinase (Asm) deficiency patients in The Netherlands and Belgium: disease spectrum and natural course in attenuated patients.

Niemann-Pick disease (NPD) is a neurovisceral lysosomal storage disorder caused by acid sphingomyelinase (ASM) deficiency, which can be categorized as either Niemann-Pick disease type A [NPD-A], with progressive neurological disease and death in early childhood, or as Niemann-Pick disease type B [NPD-B], with a more variable spectrum of manifestations. Enzyme replacement therapy (ERT) with recombinant sphingomyelinase is currently studied as potential treatment for NPD-B patients. The objective of this study is to characterize the clinical features of patients with ASM deficiency in the Netherlands and Belgium with focus on the natural disease course of NPD-B patients. Prospective and retrospective data on ASM deficient patients were collected in The Netherlands and part of Belgium. Patients with NPD-B that could be followed prospectively were evaluated every 6-12 months for pulmonary function tests, 6 minute walk test (6 MWT), imaging (bone marrow infiltration measured by QCSI, organ volumes by MRI and CT scan of the lungs) and biochemical markers. Twenty-five patients with ASM deficiency were identified (13 males, 12 females, median age 13years, range 1-59 years). Nine patients had died at the time of the study, including four NPD-A patients at the age of 1,1, 2, 3 and five NPDB patents at the age of 5, 6, 43, 56 and 60 years. There was a high prevalence of homozygosity and compound heterozygosity for the common p.Arg608del mutation in 43% and 19% of NPD-B patients, respectively. In NPD-B patients, thrombocytopenia was present in most, while anemia and leucopenia were less common (33% and 6 % respectively). HDL cholesterol was reduced in most patients. Pulmonary disease was severe in several patients. Follow-up up to 11 years revealed a gradual decrease in platelet count. Detailed investigations in 6 NPD-B patients with follow-up in 4 patients revealed remarkable stable disease parameters up to 6 years, with some decline in pulmonary function and 6 MWT. Bone marrow fat fractions were decreased, indicating the presence of storage macrophages. Lung involvement was not related to the extent of visceromegaly, cytopenia or bone marrow involvement. In conclusion, in NPD-B patients pulmonary disease is the most debilitating feature. Disease manifestations are mostly stable in attenuated patients. Bone marrow infiltration is a less prominent feature of the disease.

Markers of bone turnover in Gaucher disease: modeling the evolution of bone disease.

CONTEXT: Gaucher disease (GD) is a lysosomal storage disorder characterized by abundant presence of macrophages. Bone complications and low bone density are believed to arise from enhanced bone resorption mediated through macrophage-derived factors. OBJECTIVE: The objective of the study was to investigate the relationship between bone turnover and bone complications in GD. DESIGN: This was a retrospective cohort study and review of the literature. PATIENTS: Forty adult type I GD patients were included in the study. OUTCOME MEASURES: Levels of the bone-resorption marker, type 1 collagen C-terminal telopeptide, and two bone-formation markers, N-terminal propeptide of type 1 procollagen and osteocalcin, were investigated in relation to clinical bone disease, measures of overall disease severity, and imaging data representing bone marrow infiltration. RESULTS: Osteocalcin was decreased in 50% of our patients (median 0.35 nmol/liter, normal 0.4-4.0), indicating a decrease of bone formation. Type 1 collagen C-terminal telopeptide and N-terminal propeptide of type 1 procollagen were within the normal range for most patients. Osteocalcin concentration was negatively correlated to measures of overall disease severity and positively correlated with imaging data (correlation coefficient 0.423; P = 0.025), suggesting a relation with disease severity. A review of the literature revealed variable outcomes on bone resorption markers but more consistent abnormalities in bone formation markers. Two of three reports conclude that bone-formation parameters increase in response to enzyme therapy, but none describes an effect on bone-resorption markers. CONCLUSIONS: In contrast to earlier hypotheses, we propose that in GD patients, primarily a decrease in bone formation causes an imbalance in bone remodeling.

A monozygotic twin pair with highly discordant Gaucher phenotypes.

We describe monozygotic twin sisters, born to consanguineous Moroccan parents, who are highly discordant for the manifestations of Gaucher disease. Both carry Gaucher genotype N188S/N188S. One has severe visceral involvement, epilepsy, and a cerebellar syndrome. Her twin does not manifest any symptoms or signs of Gaucher disease but suffers from type 1 diabetes mellitus. The concurrence of a mild Gaucher mutation with a severe phenotype, as well as the occurrence of highly discordant phenotypes in a pair of monozygotic twins, is discussed.

Pharmacological small molecules for the treatment of lysosomal storage disorders.

IMPORTANCE OF THE FIELD: Inherited lysosomal storage diseases often cause severe disability and have a devastating effect on quality of life. Enzyme replacement therapy (ERT) forms a cornerstone in the treatment of lysosomal enzyme deficiencies. Although for some lysosomal disorders ERT is lifesaving, important intrinsic restrictions of the approach are limited access of infused enzyme to less accessible body compartments such as the CNS, the burden of frequent intravenous administration, the emergence of antibodies and the high associated costs. Pharmacological small molecules may overcome these limitations. AREAS COVERED IN THIS REVIEW: Several novel therapeutic approaches using small molecules are emerging: substrate reduction therapy, pharmacological chaperone therapy, premature nonsense mutation suppressors and proteostasis regulators. WHAT THE READER WILL GAIN: Based on an extensive literature search up until June 2010, we here review the various therapeutic approaches with small compounds, including those currently in clinical use and those that have entered clinical trials. Compounds that are still in the preclinical phase are also briefly discussed. TAKE HOME MESSAGE: pharmacological small molecules are a new class of agents that show great promise for the treatment of lysosomal storage disorders.

Plasma globotriaosylsphingosine: diagnostic value and relation to clinical manifestations of Fabry disease.

Fabry disease is an X-linked lysosomal storage disorder due to deficiency of alpha-Galactosidase A, causing accumulation of globotriaosylceramide and elevated plasma globotriaosylsphingosine (lysoGb3). The diagnostic value and clinical relevance of plasma lysoGb3 concentration was investigated. All male and adult female patients with classical Fabry disease could be discerned by an elevated plasma lysoGb3. In young pre-symptomatic Fabry heterozygotes, lysoGb3 levels can be normal. Individuals carrying the R112H and P60L mutations, without classical Fabry symptoms, showed no elevated plasma lysoGb3. Multiple regression analysis showed that there is no correlation of plasma lysoGb3 concentration with total disease severity score in Fabry males. However, plasma lysoGb3 concentration did correlate with white matter lesions (odds ratio: 6.1 per 100 nM lysoGb3 increase (95% CI: 1.4-25.9, p=0.015). In females, plasma lysoGb3 concentration correlated with overall disease severity. Furthermore, plasma lysoGb3 level was related to left ventricular mass (19.5+/-5.5 g increase per 10 nM lysoGb3 increase; p=0.001). In addition, it was assessed whether lifetime exposure to lysoGb3 correlates with disease manifestations. Male Fabry patients with a high lysoGb3 exposure (>10,000 U), were moderately or severely affected, only one mildly. Female patients with a low exposure (<1000 U) were asymptomatic or mildly affected. A large proportion of the females with an exposure >1000 U showed disease complications. Plasma lysoGb3 is useful for the diagnosis of Fabry disease. LysoGb3 is an independent risk factor for development of cerebrovascular white matter lesions in male patients and left ventricular hypertrophy in females. Disease severity correlates with exposure to plasma lysoGb3.

Screening for Fabry disease in high-risk populations: a systematic review.

INTRODUCTION: Fabry disease (FD) may present with left ventricular hypertrophy (LVH), renal insufficiency or stroke. Several studies investigated FD prevalence in populations expressing these symptoms. A systematic review was conducted to calculate the overall prevalence of FD in these cohorts. METHODS: Online databases were searched for studies on screening for FD. Study population selection, screening methods and outcome of screening were recorded. RESULTS: 20 studies were identified, 10 of which included both male and female patients. In all (n=19) studies with male and almost all (n=10) with female patients, alpha-galactosidase A (alpha-Gal A) activity was used as the screening method. In men on dialysis (10 studies), overall FD prevalence was 0.33% (95% CI 0.20% to 0.47%) and in women (6 studies) 0.10% (95% CI 0% to 0.19%). Combined prevalence of FD in patients with renal transplant was 0.38% in men (95% CI 0.07% to 0.69%) and 0% in women. In patients with LVH, selection of study population and differences in the method of screening hampered the calculation of an overall prevalence (ranging from 0.9% to 3.9% in men and 1.1% to 11.8% in women). In premature strokes (n=2 studies), overall FD prevalence was 4.2% (95% CI 2.4% to 6.0%) in men and 2.1% (95% CI 0.5% to 3.7%) in women. DISCUSSION: The prevalence of FD in dialysis patients is 0.33% for men and 0.10% for women. The prevalence of FD in LVH is at least 1% for both genders. In women, most studies were performed with alpha-Gal A activity measurements as the screening tool, although this method fails to detect one third of female patients with FD, underestimating the overall prevalence in women.

Vasculopathy in patients with Fabry disease: current controversies and research directions.

Fabry disease is an X-linked lysosomal storage disorder due to deficiency of the enzyme alpha-galactosidase A. The principal clinical manifestations of Fabry disease consist of cardiovascular complications including cerebrovascular, renal and cardiac disease but the pathophysiology of this specific vasculopathy is unclear. With the development of targeted treatment for Fabry disease, i.e. enzyme replacement therapy, it has become apparent that the removal of stored glycosphingolipid from the endothelial cells does not prevent progression of vascular disease in many patients. The aim of this study is to review the current available literature on vascular function tests, imaging and pathology studies and propose a hypothesis on the evolution of arterial complications in Fabry disease. Clearly, although premature atherosclerosis is suggested to occur, most studies describe absence of characteristic plaque formation. Smooth muscle cell hypertrophy, is probably the earliest feature of a complex vasculopathy, as in females and atypical cardiac variants, who have residual enzyme activity, no endothelial storage of significance is found. Subsequently, processes occur as observed in neo intima formation however with formation of more fibrotic structures. In the presence of a hyperdynamic circulation in combination with a less compliant vascular wall, it is hypothesized that upregulation of local renin angiotensine systems may occur. Angiotensin II is known to increase adhesion molecules, cytokines and chemokines and exerts a pro-inflammatory effect on leucocytes, endothelial cells and vascular smooth muscle cells. This enhances release of pro-thrombotic factors and opposes actions mediated through angiotensin 2 (AT2) receptor, including the release of nitric oxide (NO). A combination of reduced vascular compliance and activation of pro-thrombotic factors can lead to vascular complications in Fabry disease.

Different dose-dependent correction of MIP-1beta and chitotriosidase during initial enzyme replacement therapy.

In tissue lesions of type I Gaucher patients, characteristic lipid-laden macrophages, 'Gaucher cells', are surrounded by inflammatory phagocytes. Gaucher cells secrete the elevated plasma chitotriosidase. The elevated plasma MIP-1beta in Gaucher patients stems from the phagocytes surrounding the Gaucher cells. Plasma chitotriosidase and MIP-1beta decrease upon successful enzyme replacement therapy (ERT) with mannose-terminated recombinant glucocerebrosidase (alglucerase). Previous histochemical analysis of Gaucher spleens revealed that Gaucher cells express little mannose receptor, in contrast to surrounding phagocytes. We therefore investigated the corrective effects of ERT on plasma MIP-1beta and chitotriosidase in more detail. We also compared effects of one year of treatment with a relatively low dose and a relatively high dose of ERT. A more rapid correction in plasma MIP-1beta, compared to chitotriosidase, was observed in most patients on low-dose ERT. Correction of plasma MIP-1beta and chitotriosidase levels was more pronounced in the higher-dosed patient group. Upon prolonged treatment, differences in the effects of enzyme dose were no longer significant. Normalization of plasma MIP-1beta and chitotriosidase levels was attained in the majority of patients. In conclusion, ERT with mannose-terminated gluocerebrosidase results in prominent corrections of plasma chitotriosidase, a marker of Gaucher cells, and in particular of plasma MIP-1beta, a marker of inflammatory phagocytes. The sharper response in plasma MIP-1beta to ERT is in line with the observation that especially phagocytes surrounding Gaucher cells express mannose-receptors.

Low HDL cholesterol levels in type I Gaucher disease do not lead to an increased risk of cardiovascular disease.

OBJECTIVE: A low plasma high-density lipoprotein cholesterol (HDL-c) concentration is an important risk factor for the development of atherosclerotic cardiovascular disease. HDL-c levels are abnormally low in type I Gaucher disease (GD) patients. The aim of this study was to determine whether GD is associated with premature atherosclerosis. METHODS: Lipid profiles, apolipoproteins, and carotid artery intima-media thickness (cIMT) were analyzed in 40 type I GD patients, 34 carriers and 41 control subjects. cIMT is a non-invasive validated biomarker for the status of atherosclerosis and present and future cardiovascular disease risk. RESULTS: Compared to control subjects, patients showed decreased HDL-c (1.1+/-0.3 mmol/L) as well as mildly decreased low-density lipoprotein cholesterol (LDL-c) levels (2.8+/-0.7 mmol/L), with an increased ApoB/ApoA1 ratio. In carriers, HDL-c levels were normal, but LDL-c levels were decreased (2.7+/-0.8 mmol/L). Mean cIMT measurements were not different in the three study groups (patients: 0.63+/-0.1mm versus carriers: 0.64+/-0.1mm versus control subjects: 0.65+/-0.1 mm). CONCLUSION: In Gaucher disease low HDL-c levels do not lead to premature atherosclerosis as assessed by cIMT measurement. This indicates that the inverse relationship between levels of HDL-c and risk of cardiovascular disease in the general population may not be present in all conditions characterised by low HDL-c levels.

Potential efficacy of enzyme replacement and substrate reduction therapy in three siblings with Gaucher disease type III.

We report three siblings with Gaucher disease type III, born between 1992 and 2004. During this period, new developments resulted in different potential therapies, changing clinical practice. The two eldest siblings received enzyme replacement therapy (ERT) from the age of 24 and 5 months respectively, later followed by an increase in dosage. ERT was combined with substrate reduction therapy (SRT) from the ages of 12 and 8 years, respectively. In the youngest sibling the combination of high-dose ERT and SRT was given from the age of 5 months. The two eldest siblings showed significant neurological impairment from the age of 1.5 years, starting with a convergent strabismus and partial oculomotor apraxia, followed by cognitive decline and an abnormal EEG and BAER. In contrast, the neurological development in the youngest sibling is almost completely normal. At the age of 3 years, cognitive development, EEG and BAER are all normal. Disturbed saccadic eye movements, which were already present at the start of therapy, remained stable. In addition to the clinical efficacy, we report on the biochemical response to therapy. Based on our results, the combination of high-dose ERT and SRT should be considered as a possible therapeutic approach for GD III, especially if started at a young age. Further follow-up studies are necessary to explore the long-term therapeutic effects.

Management of non-neuronopathic Gaucher disease with special reference to pregnancy, splenectomy, bisphosphonate therapy, use of biomarkers and bone disease monitoring.

Enzyme replacement was introduced as treatment for non-neuronopathic Gaucher disease more than 15 years ago. To ensure the best use of this costly ultra-orphan agent, a systematic disease management approach has been proposed by an international panel; this includes the development, by consensus, of achievable treatment goals. Here we critically review these goals and monitoring guidelines and incorporate emerging experience of the disease in the therapeutic era, as well as contemporary clinical research. This review makes recommendations related specifically to the management of pregnancy; the appropriate use of splenectomy and bisphosphonate treatment; the relevance of biochemical markers to disease monitoring; and the use of semi-quantitative methods for assessing bone marrow infiltration. In addition, we identify key areas for development, including the requirement for a validated index of disease severity; the need to correlate widely used biomarkers with long-term disease outcomes, and the desirability of establishing agreed standards for monitoring of bone disease particularly in infants and children with Gaucher disease.