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Biomedical subjects

N W Barton

Publications and source records attributed to N W Barton.

At least 37 records · Page 2Linked to original sources
PubMed1995

Enzyme therapy in type 1 Gaucher disease: comparative efficacy of mannose-terminated glucocerebrosidase from natural and recombinant sources.

OBJECTIVE: To compare the efficacy of mannose-terminated glucocerbrosidase prepared from natural (alglucerase; Ceredase, Genzyme Corp., Cambridge, Massachusetts) and recombinant (imiglucerase; Cerezyme, Genzyme Corp.) sources in treating type 1 Gaucher disease. DESIGN: Double-blind, randomized, parallel trial. SETTING: University medical center and clinical research hospital. PATIENTS: 15 patients (4 children and 11 adults) randomly assigned to receive Ceredase and 15 patients (3 children and 12 adults) assigned to receive Cerezyme. INTERVENTION: Ceredase and Cerezyme were infused every 2 weeks for 9 months at a dose of 60 U/kg body weight. OUTCOME MEASURES: Hemoglobin levels, platelet counts, and serum acid phosphatase and angiotensin-converting enzyme activities were monitored every 2 weeks during the trial. Hepatic and splenic volumes were assessed at the time of randomization and after 6 and 9 months of enzyme infusion. Formation of IgG antibodies to Ceredase or Cerezyme was monitored every 3 months by radioimmunoprecipitation assay. RESULTS: No significant differences were found in the rate or extent of improvement in hemoglobin levels, platelet counts, serum acid phosphatase or angiotensin-converting enzyme activities, or hepatic or splenic volumes between either treatment group. The incidence of IgG antibody formation was greater in the Ceredase group (40%) than in the Cerezyme group (20%). No major immunologic adverse events occurred in either group. CONCLUSIONS: Our study shows the therapeutic similarity of Ceredase and Cerezyme. Cerezyme has the advantage of being theoretically unlimited in supply and free of potential pathogenic contaminants.

Adolescent↗
PubMed1995

Outcome of partial splenectomy for type I Gaucher disease.

Partial splenectomy was introduced to achieve the benefits of splenectomy and to avoid the risk of overwhelming infection in patients with symptomatic Gaucher disease. We observed regrowth of the splenic remnant, reemergence of preoperative symptoms, and new bone involvement among most of our patients who had undergone partial splenectomy. Enzyme replacement therapy has markedly limited indications for splenectomy, partial or total, for Gaucher disease.

Adolescent↗
PubMed1995

Proton magnetic resonance spectroscopic imaging in childhood ataxia with diffuse central nervous system hypomyelination.

The spatial distribution of metabolite signal intensities can be measured within entire sections of the brain by proton magnetic resonance spectroscopic imaging (1H-MRSI). A group of six patients (4 unrelated girls and 2 brothers from 5 families) with childhood ataxia with diffuse CNS hypomyelination (CACH) underwent long-echo-time, single-slice 1H-MRSI. Relative to controls, there was a decrease in the signal intensity of N-acetylaspartate, choline, and creatine throughout the white matter in all six patients. We identified lactate signals in white matter in three of them with advanced disease. The degree of white matter involvement was not homogeneous over the entire patient group, but did correlate with clinical presentation. Deep and posterior white matter tended to be more involved. There were no 1H-MRSI abnormalities in the gray matter. 1H-MRSI findings suggest that this syndrome is secondary to a metabolic defect causing hypomyelination, axonal degeneration, and, in the most compromised cases, accumulation of lactate. This study shows that CACH is not limited to girls.

Aspartic Acid↗
PubMed1994

Enzyme replacement therapy for Gaucher disease: critical investigations beyond demonstration of clinical efficacy.

Enzyme replacement therapy is highly effective for patients with Type 1 Gaucher disease. In order to estimate the quantity of enzyme that would be necessary for clinical benefit, we conducted a single-infusion, dose-response study in nonsplenectomized patients with Gaucher disease. Biochemical and histologic changes were compared in liver biopsy specimens obtained before and 44 h following the infusion of varying quantities of enzyme. Based on the information obtained from this investigation, patients in our initial clinical efficacy trial were given 60 IU of macrophage-targeted glucocerebrosidase/kg body wt every other week. All patients had significant improvement of their anemia and reduction of splenomegaly after 6 months of treatment. In a subsequent investigation, 10 moderately symptomatic patients with intact spleens were given 10 IU of glucocerebrosidase/kg body wt every other week. After 6 months of treatment, only a portion of these patients had beneficial responses. We concluded that the rate and extent of response to enzyme replacement therapy in patients with Gaucher disease are dependent upon the quantity of enzyme administered. When treatment is initiated in patients with mild to moderately severe disease, a lower dose of enzyme can be selected. Moreover, the maintenance dose of glucocerebrosidase has been shown to be much less than the amount initially required to reduce the accumulated lipid. Some patients require enzyme infusions on only a monthly basis, require enzyme infusions on only a monthly basis, and it is possible that even this frequency may eventually be reduced. These refinements in treatment strategy merit serious consideration for the long-term management of patients with Gaucher disease.

Enzyme Therapy↗
PubMed1994

Modifying exogenous glucocerebrosidase for effective replacement therapy in Gaucher disease.

Important therapeutic principles were established in developing effective enzyme replacement therapy for patients with Gaucher disease. The background and sequence of the investigations that led to effective delivery of exogenous glucocerebrosidase to the lipid-storing macrophages in patients with Gaucher disease are described. The principle of targeting the intravenously injected enzyme to the mannose lectin on the surface of these cells by engineering the glycoform of the enzyme is a useful model of an essential requirement for effective enzyme therapy. Similar strategies are expected to be effective for the treatment of a number of hereditary metabolic disorders of humans.

Adult↗
PubMed1994

Pyridoxine-responsive hyper-beta-alaninemia associated with Cohen's syndrome.

We report intermittent seizures, lethargy, and Cohen's syndrome in a 4-year-old girl with hyper-beta-alaninemia and a partial deficiency of beta-alanyl-alpha-ketoglutarate transaminase (AKT). To examine the role of beta-alanine (beta ALA) in cellular metabolism, we cultured her skin fibroblasts in medium containing increasing amounts of beta ALA. At concentrations of 10 to 25 mM, beta ALA caused more than a 50% reduction in the growth of her cells compared with normal control skin fibroblasts. The addition of 0.1 mM of pyridoxine to the culture medium abolished these toxic effects and increased her skin fibroblast AKT enzyme activity more than twofold. During a 2-year period of clinical observation, there were no further episodes of seizures or somnolence in our patient while she received oral pyridoxine therapy.

4-Aminobutyrate Transaminase↗
PubMed1993

The role of neurogenetics in Gaucher disease.

Gaucher disease is the most prevalent hereditary metabolic storage disorder, and the most common genetic disease in individuals of Ashkenazic Jewish ancestry. Patients with Gaucher disease have been classified into three clinical phenotypes. Patients with type 1 disease exhibit markedly variable hepatosplenomegaly, anemia, thrombocytopenia, skeletal, and, to a lesser extent, pulmonary and kidney involvement. The central nervous system does not appear to be involved. In patients with type 2 Gaucher disease, hepatosplenomegaly and extensive central nervous system damage are apparent in infancy. These patients usually die between 1 and 2 years of age. Patients with type 3 Gaucher disease have been subclassified into types 3a and 3b. Type 3a patients exhibit mild-to-moderate hepatosplenomegaly and slowly progressive neurologic deterioration. Recurrent myoclonic seizures are common. Patients with type 3b Gaucher disease exhibit splenomegaly along with extensive hepatomegaly that is frequently accompanied by esophageal varices. Horizontal supranuclear gaze paresis is the major neurologic sign. Excessive quantities of glucocerebroside accumulate in the organs of patients with Gaucher disease because of a deficiency of the enzyme glucocerebrosidase. In the vast majority of patients, the reduction of glucocerebrosidase activity is caused by mutations in the gene that codes for glucocerebrosidase. In a few instances, glucocerebroside accumulates due to a lack of saposin C, a cohydrolase that is required in addition to glucocerebrosidase for the catabolism of glucocerebroside. Mutations in the glucocerebrosidase gene are discussed in the context of the severity of disease and the presence or absence of nervous system involvement. Enzyme replacement therapy is highly beneficial for patients with type 1 Gaucher disease. Enzyme replacement is also being investigated for patients with type 3b Gaucher disease. Novel procedures must be developed to deliver glucocerebrosidase to the nervous system so that patients with type 2 and type 3a Gaucher disease can be helped. Exploration of gene therapy for Gaucher disease is under way.

Alleles↗
PubMed1993

Radiopharmacology of inhaled 133Xe in skeletal sites containing deposits of Gaucher cells.

Gaucher's disease is a lysosomal storage disease in which cells of the reticuloendothelial system accumulate the lipid glucocerebroside. It is characterized by slowly progressive visceral and osseous involvement. One of the latter manifestations includes lipid infiltration of bone marrow. We monitored the rate of inhaled 133Xe uptake and wash-out over diseased and normal metaphyseal and epiphyseal areas of the knee. Twenty-two patients (15 adults, 7 children) with various degrees of previously diagnosed Gaucher's disease were positioned supine under a gamma-camera interfaced to a computer system. All patients rebreathed 133Xe gas from a closed system for 10 min followed by 14 min of wash-out. Digitized images of the lung, liver, spleen, bony sites and soft tissue were obtained at 1 min intervals during the wash-in and wash-out phases. Counts for each ROI were normalized per 100 pixels and plotted as a function (time). Maximum uptake was also calculated by relating the counts/ROI/100 pixels to the 10 min integrated lung count during equilibrium (the administered "dose"). There was essentially no 133Xe uptake in liver and spleen involved with Gaucher's disease. Monophasic uptake and biphasic wash-out curves were observed in the limited investigative population. Skeletal Gaucher deposits released the 133Xe at a greater rate relative to soft tissue.

Administration, Inhalation↗
PubMed1993

Gaucher's disease: a pilot study of the symptomatic responses to enzyme replacement therapy.

Symptomatic responses to enzyme replacement therapy were studied in 12 patients with an inherited lipid storage disorder (Type 1 Gaucher's disease) in order to determine the impact of treatment on perceptions of well being. Before each intravenous infusion of enzyme, patients were asked to comment on the presence or absence of disease-specific symptoms presented in questionnaire format. Symptoms were grouped into five major categories: bleeding abnormalities, chronic fatigue, gastrointestinal complaints, bone pain and psychosocial function. Each reported symptom was discussed in detail with the clinic nurse coordinator and documented in the medical record. After six months of enzyme replacement therapy, each patient's chart was reviewed and changes in the frequency of disease-specific symptoms over time were evaluated. The major subjective changes included a decrease in the frequency and severity of nosebleeds, reduced bruising, increased vigor and energy level, visible reduction in abdominal girth, increased self-esteem and enhanced self-image. Patients frequently described relief of their symptoms well before changes were confirmed by objective laboratory measurements. These observations may prove useful in the comprehensive management of patients with Gaucher's disease as they recover from a chronic, debilitating illness while receiving enzyme replacement therapy. The extent and ease with which these patients can achieve a state of normal, healthy function is unknown at the present time and will require further study.

Activities of Daily Living↗
PubMed1993

Prevalence of nine mutations among Jewish and non-Jewish Gaucher disease patients.

The frequency of nine different mutated alleles known to occur in the glucocerebrosidase gene was determined in 247 Gaucher patients, of whom 176 were of Jewish extraction, 2 were Jewish with one converted parent, and 69 were of non-Jewish origin. DNA was prepared from peripheral blood, active glucocerebrosidase sequences were amplified by using the PCR technique, and the mutations were identified by using the allele-specific oligonucleotide hybridization method. The N37OS mutation appeared in 69.77% of the mutated alleles in Jewish patients and in 22.86% of the mutated alleles in non-Jews. The 84GG mutation, which has not been found so far among non-Jewish patients, existed in 10.17% of the disease alleles among Jewish patients. The IVS + 1 mutation constituted 2.26% of the disease alleles among Jewish patients and 1.43% among the non-Jewish patients. RecTL, a complex allele containing four single-base-pair changes, occurred in 2.26% of the alleles in Jewish patients and was found in two (1.43%) of the patients of non-Jewish extraction. Another complex allele, designated "RecNciI" and containing three single-point mutations, appeared in 7.8% of alleles of non-Jewish patients and in only two (0.56%) of the Jewish families. The prevalence of the L444P mutation among non-Jewish Gaucher patients was 31.43%, while its prevalence among Jewish patients was only 4.24%. The prevalence of two other point mutations--D409H and R463C--was 5.00% and 3.57%, respectively, among non-Jewish patients and was not found among the Jewish Gaucher patient population. The prevalence of the R496H mutation, found so far only among Jewish patients, was 1.13%. The results presented demonstrate that seven mutations identify 90.40% of the mutations among Jewish patients and that these seven mutations allow diagnosis of only 73.52% of the non-Jewish patients. Identification of additional mutant alleles will enhance the accuracy of carrier detection.

Base Sequence↗
PubMed1992

Fabry's disease presenting with stroke.

An atypical patient with Fabry's disease is presented. This patient developed a left internal capsule lacunar stroke at the age of 25. The etiology of the stroke was unclear. At the age of 29 he was discovered to have corneal lesions suggestive of Fabry's disease but had no other clinical features typical of Fabry's disease. The diagnosis of Fabry's disease was confirmed biochemically. Fabry's disease should be included in the differential diagnosis of stroke of unclear etiology in young male patients.

Adult↗
PubMed1992

Effect of platelet count on the DDAVP-induced shortening of the bleeding time in thrombocytopenic Gaucher's patients.

As part of an investigative protocol requiring serial liver biopsies in patients with Type I Gaucher's disease who were receiving enzyme replacement therapy, we gave 11 patients a total of 15 infusions of DDAVP (0.3 micrograms/kg IV) and measured the Simplate bleeding time pre- and postin-fusion. All patients were thrombocytopenic (one patient 100-150,000; seven 66-99,000; and three 50-65,000/microliters). Nine of 15 infusions resulted in at least a 2-min shortening of the bleeding time; in 6/11 infusions in which the platelet count was greater than 65,000, the bleeding time shortened to less than or equal to 10 min, in 1/11 it shortened greater than or equal to 2 min but not to less than or equal to 10 min. In only 2/4 infusions given to patients with platelet counts less than 65,000 did the bleeding time demonstrate any significant shortening. None of the six liver biopsies performed in the patients whose bleeding time shortened to less than or equal to 10 min resulted in any significant bleeding; blood products were not transfused either pre- or postprocedure. These limited data demonstrate that a high percentage of patients with platelet counts of 65-100,000/microliters can manifest a significant shortening of bleeding time following a standard infusion of DDAVP, and that in approximately half of these patients the bleeding time will shorten enough to safely allow the performance of a liver biopsy without the need for prophylactic transfusion of blood products.

Adolescent↗
PubMed1992

Gaucher disease: abdominal MR imaging findings in 46 patients.

Abdominal magnetic resonance imaging findings were reviewed in 46 patients with Gaucher disease. All patients had hepatosplenomegaly at the time of initial imaging. Splenic nodules were present in 14 patients (30%) and varied in signal intensity. These nodules were isointense on T1-weighted and hypointense on T2-weighted images. Splenic infarcts were seen in 15 patients (33%), and four of these patients (9%) also had subcapsular fluid collections. Both nodules and infarcts were present in the spleen in four patients (9%). Pathologic correlation was performed with specimens from two patients who underwent partial splenectomy. Focal areas of abnormal signal intensity were noted in the liver in nine patients (20%). They were either stellate or segmental, and may represent fibrotic septa with ischemic changes associated with aggregates of Gaucher cells. No changes were noted in the kidneys or abdominal lymph nodes.

Adolescent↗
PubMed1992

Quantitative imaging of Gaucher disease.

Twenty-three patients with type 1 Gaucher disease were evaluated with a battery of quantitative imaging techniques. Plain radiographs were used to measure cortical thickness and Erlenmeyer flask deformity. Xenon-133 uptake was measured in scans of the lower extremities. Dual-energy quantitative computed tomography was used for calculation of trabecular bone and bone marrow fat content in the spine and long bones. Magnetic resonance (MR) imaging was performed to evaluate disease extent and three-dimensional splenic volume. MR images were also used to provide quantitative measurements of each vertebral fat fraction. Each imaging modality was correlated with the others as well as with the clinical history of skeletal complications and the hematocrit and acid phosphatase activity. There was a strong relationship between splenic volume and disease severity as measured clinically and with laboratory testing. The spinal fat fraction also correlated with these measures of disease severity and with the femoral fat fraction and xenon uptake. No measurement allowed discrimination of patients with from those without skeletal complications.

Adolescent↗
PubMed1992

Hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP syndrome).

We describe the clinical and laboratory studies of an 11-year-old girl with prominent orofacial dyskinesia, dystonia, and progressive dementia. Investigations revealed hypoprebetalipoproteinemia, acanthocytosis, atypical retinitis pigmentosa, and evidence of iron deposition in the pallidal nuclei. Electroneuromyography and skin and sural nerve biopsies were normal. The "eye-of-the-tiger" sign, used to describe the pallidal nuclei in Hallervorden-Spatz syndrome, was present on T2-weighted MRIs (GE Signa, 1.5 T). Phase-contrast microscopy of whole blood showed 80 to 90% acanthocytes whose morphology was confirmed by electron microscopy. High-resolution lipoprotein electrophoresis demonstrated an absence of the pre-beta fraction. This case differs phenotypically from the previous reports of Hallervorden-Spatz disease with acanthocytosis by the presence of prominent orofacial dyskinesia and abnormal serum lipoproteins.

Acanthocytes↗