Divair Doneda

Effects of imiglucerase on the growth and metabolism of Gaucher disease type I patients: a systematic review.

BackgroundGaucher disease (GD) type I is the most common type of GD. Its main clinical manifestations are hepatosplenomegaly as well as bone and hematological abnormalities. The objective of the present study was to perform a literature review on the growth and metabolism of GD type I patients.MethodsWe searched Pubmed and Scielo.br databases with predetermined study limits: case series (n≥5), clinical trials, systematic reviews, and meta-analyses, and enzyme replacement therapy (ERT) with alglucerase or imiglucerase. The outcomes of interest were the following: growth and development, weight, height, malnutrition, overweight, obesity, basal metabolism, hypermetabolism, insulin resistance, and diabetes. A total of 175 articles were found, of which 28 met the inclusion criteria; these articles were grouped into three central themes: 1) growth of children and adolescents before and after ERT; 2) metabolic changes that remained during ERT; and 3) changes in metabolic status resulting from the treatment.Results and discussionThe articles included in the present literature review are very heterogeneous, which hinders the analysis of data. They indicated that GD patients usually show low weight and height before ERT, which are improved with treatment in children and adolescents. Studies evaluating the energy metabolism by indirect calorimetry have indicated that the disease is associated with hypermetabolism. In adults, some changes in energy metabolism remain on ERT, and alterations, such as insulin resistance, seem to be associated with the treatment. It is not clear which are the required doses of imiglucerase for obtaining an adequate cost-effective relation, as well as the advisable therapeutic measures to avoid possible long-term adverse effects related to ERT.ConclusionsERT tends to normalise the growth of children and adolescents with GD type I, it seems to cause a partial response in relation to some metabolic changes associated with the disease, and it can causes metabolic changes such as weight gain in adult patients. Therefore, additional research is necessary.

Gaucher disease type I: Assessment of basal metabolic rate in patients from southern Brazil

INTRODUCTION Gaucher disease (GD) is characterized by clinical heterogeneity and is associated with metabolic abnormalities such as increased resting energy expenditure. OBJECTIVES To assess the basal metabolic rate (BMR) of patients with GD type I followed at the Gaucher Disease Reference Center of Rio Grande do Sul, Brazil. PATIENTS AND METHODS Fourteen patients (male=6) and 14 healthy controls matched by gender, age and body mass index (BMI) were included in the study. The nutritional status of patients was assessed by BMI. The BMR was measured by indirect calorimetry. In two patients, it was possible to perform BMR in the pre- and the post-treatment periods. RESULTS Mean age and BMI of patients and controls were, respectively, 32.8 ± 17.6 and 32.1 ± 16.6 years and 23.3 ± 3.1 and 22.4 ± 3.1 kg/m(2). Twelve patients were receiving enzyme replacement therapy (ERT) with imiglucerase (mean duration of treatment=5.2 ± 4.3 years; mean dosage of imiglucerase=24.2 ± 7.3 UI/kg/inf). Five patients (36%) were overweight, and nine (64%) were normal weight. Mean BMR of patients on ERT was 27.1% higher than that of controls (p=0.007). There was no difference between the BMR of patients on ERT and not on ERT (n=4) (p=0.92). Comparing the BMR of patients on ERT and their controls with the BMR estimated by the Harris-Benedict equation, the BMR of patients was 6.3% higher than the estimated (p = 0.1), while the BMR of their controls was 17.0% lower than the estimated (p = 0.001). CONCLUSION Most treated GD type I patients were normal weight. The patients including those on ERT showed higher BMR when compared to controls. Imiglucerase is probably unable to normalize the hypermetabolism presented by GD type I patients. Additional studies should be performed to confirm our findings.

Ghrelin, leptin and adiponectin levels in Gaucher disease type I patients on enzyme replacement therapy

BACKGROUND Gaucher disease type I (GD type I) is characterized by clinical heterogeneity and is associated with metabolic abnormalities such as increased basal metabolic rate. OBJECTIVE To evaluate ghrelin, leptin and adiponectin levels in patients with GD type I on enzyme replacement therapy (ERT). SUBJECTS AND METHODS A cross-sectional study of patients with GD type I (n = 15), matched for sex, age and BMI with healthy controls. The levels of glucose, insulin, ghrelin, leptin and adiponectin were assessed in both groups. Insulin resistance was defined by the index HOMA-IR. RESULTS Eight patients had adequate weight, seven were overweight (4 preobese, 3 obese class I). Eight patients presented metabolic syndrome, five of whom with insulin resistance. The median levels of ghrelin, leptin and adiponectin of the patients did not differ from those of the controls. Ghrelin and adiponectin levels were correlated with each other; inversely correlated with BMI, waist circumference and triglyceride levels; and directly correlated with HDL-cholesterol. Leptin levels were inversely correlated with LDL-cholesterol and directly correlated with BMI, waist circumference, enzyme dosage, triglycerides, insulin, and HOMA-IR. CONCLUSIONS Metabolic syndrome and overweight appear to be common in patients with GD type I on ERT. As leptin was strongly associated with insulin and HOMA index, it could become a biomarker to assess early evidence of insulin resistance in patients with GD. Further studies are needed to investigate the associations found.

Enzyme Replacement Therapy in a Patient with Gaucher Disease Type III: A Paradigmatic Case Showing Severe Adverse Reactions Started a Long Time After the Beginning of Treatment.

INTRODUCTION There are three recombinant enzymes available for the treatment of Gaucher disease (GD): imiglucerase, velaglucerase alfa, and taliglucerase alfa. CASE REPORT A male GD type III patient, 14 years old, genotype p.L444P/L444, diagnosed at 2 years old. He had been treated with imiglucerase for 9 years since the diagnosis. In 2008, however, he presented a severe adverse reaction to imiglucerase, characterized by cough, laryngeal stridor, and periorbital edema. The infusions were suspended for 3 months when imiglucerase was restarted with premedication and a slower infusion rate. After 5 months, he presented a new adverse reaction with vomiting, tachypnea, cough, and periorbital edema. Intradermal testing confirmed IgE-mediated reaction but serological tests were negative. After 2 years and 10 months with no specific treatment and a significant worsening of the clinical picture, taliglucerase alfa was prescribed, with premedication and a slower infusion rate. At the first infusion, he presented moderate adverse reaction and the infusions were suspended. After 2 months, velaglucerase alfa was initiated uneventfully. He maintains day-hospital infusions without premedication and shows improvement of clinical and laboratory parameters. CONCLUSION This is the first report of the use of velaglucerase alfa in patients with GD type III. The use of recombinant enzymes is safe for the majority of GD patients, but severe reactions may occur even many years after the beginning of the treatment. Premedication and slower infusion rate reduce the incidence of adverse reactions but may not solve the problem. This case report further demonstrates the different safety profile among all the recombinant enzymes available for the treatment of GD.

The prognostic value of the serum ferritin in a southern Brazilian cohort of patients with Gaucher disease

Abstract The clinical utility of serum ferritin as a biomarker of disease severity and prognosis in Gaucher disease (GD) is still debated. Here, we aimed to evaluate ferritin and its relation to clinicolaboratory parameters of GD patients seen at the Reference Center for Gaucher Disease of Rio Grande do Sul, Brazil, so as to gather evidence on the utility of ferritin as a biomarker of this condition. A retrospective chart review was performed collecting pre-and posttreatment data from GD patients. Eighteen patients with ferritin levels available before and after treatment were included in the study. Nine of these participants were males, and seventeen had type I GD. All patients were given either enzyme replacement (n = 16) or substrate reduction therapy (n = 2), and ferritin was found to decrease from 756 [318-1441] ng/mL at baseline to 521 [227-626] ng/mL (p=0.025) after 28.8 month soft treatment. Serum ferritin levels did not correlate with measures of disease severity, but showed an association with age at onset of treatment (ρ= 0.880; n = 18; p < 0.001). In conclusion, although serum ferritin did not correlate with disease severity, after a median 28.8 months of treatment, clinical outcomes had clearly improved, and ferritin levels had decreased.

Gastrointestinal disorders and miglustat therapy: A case report

CO RR EC TE D P RO OF the juvenile forms by age of onset, rate of disease progression and age of death. There are no approved treatments for gangliosidoses. Biomarkers for evaluating disease phenotype, disease progression, and response to therapies would serve to facilitate the design and development of potential treatment of these diseases, but such biomarkers have not been identified. Increasing evidence from animal models and human cadavers suggests inflammatory mediators in the CNS play a role in disease pathology and progression. Hypothesis: The more rapid disease progression and more severe clinical phenotype of the infantile GM1and GM2-gangliosidosis relative to juvenile forms will coincide with levels of disease specific inflammatory mediators in the CNS. Methods: CSF and serum inflammatory markers were quantified by immunoassay in 8 children with infantile forms of gangliosidoses (including patients with Tay–Sachs disease, Sandhoff disease and GM1 gangliosidosis). Findings were compared to values from 4 patients with more slowly progressing forms of gangliosidoses (i.e., late-infantile, juvenile forms) and to values of 9 children with mucopolysaccharidosis (MPS) diseases. Results: Of 188 analytes assayed, elevated inflammatory markers occurredmore often in the CSF of infantile gangliosidosis patients when compared to the more slowly progressing forms of juvenile gangliosidosis and MPS disease. Five candidate biomarkers were distinguished by persistent elevation in the CSF of patients with the severe infantile phenotype: ENA-78, MCP-1, MIP-1α, MIP-1β, TNFR2. Additional candidates for CNS and serum inflammatory markers for infantile and juvenile phenotypes were found. Conclusion: This study identified candidate biomarkers of CNS inflammatory disease in infantile and juvenile gangliosidoses that are promising as markers for evaluating CNS disease progression, distinguishing infantile and juvenile phenotypes and monitoring response to future therapeutic interventions in the gangliosidoses. (Supported by Lysosomal Disease Network, NIH U54NS065768 and Pharmacotherapy for InheritedMetabolic Diseases Fellowship training program, GenzymeSanofi.)