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Biomedical subjects

R Schiffmann

Publications and source records attributed to R Schiffmann.

At least 73 records · Page 4Linked to original sources
PubMed1995

Growth factors and stromal support generate very efficient retroviral transduction of peripheral blood CD34+ cells from Gaucher patients.

We have achieved high-efficiency gene transfer into nonmobilized peripheral blood (PB) CD34+ cells from patients with Gaucher's disease using a clinically acceptable retroviral supernatant transduction protocol. In our studies, bone marrow (BM) and PB CD34+ cells were transduced using a high titer (10(8) particles/mL) retroviral supernatant once a day for 4 consecutive days in the presence of interleukin-3 (IL-3), IL-6, and stem cell factor (SCF), with or without an irradiated allogeneic BM stromal layer. The growth factors alone resulted in 29% +/- 10% gene transfer of PB CD34+ clonogenic cells in contrast with 71% +/- 17% gene transfer efficiency using stroma with the growth factors; a 2.5-fold increase. The increase in gene transfer efficiency was less prominent when BM CD34+ cells were used (40% +/- 16% without and 57% +/- 8% with stroma, a 1.5-fold increase). The overall transduction efficiency of both PB and BM CD34+ cells was lower when the cells were transduced over a stromal cell layer without added growth factors. The combination of IL-3, IL-6, and SCF with stroma transduced 75% of primitive long-term culture initiating cells (PB LTC-ICs) in comparison with 34% of LTC-ICs when IL-3, IL-6, and SCF were used without stromal support. Using this clinically acceptable supernatant/cytokines/stroma transduction protocol, correction of the glucocerebrosidase (GC) deficiency in the progeny cells of PBLTC-ICs from Gaucher's-disease patients has been accomplished. Efficient transduction of the PB CD34+ cells using this transduction protocol may allow repeated delivery of "GC-corrected" hematopoietic stem and progenitor cells to Gaucher's-disease patients.

Antigens, CD↗
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

Childhood ataxia with diffuse central nervous system hypomyelination.

A significant number of patients with progressive leukodystrophy do not have a definitive diagnosis. This report describes the clinical, morphological, and biochemical characteristics of 4 unrelated girls with progressive ataxic diplegia of unknown etiology. These patients had normal development until the ages of 1.5 to 5 years. A diffuse confluent abnormality of the white matter of the central nervous system was present on computed tomography and magnetic resonance scans obtained early in the course of the illness. Dementia was not present and peripheral nerves were normal. All patients were evaluated for known metabolic and degenerative diseases and no abnormalities were observed. Light and electron microscopy of open-brain biopsy specimens from 2 girls showed selective white matter abnormalities including hypomyelination, demyelination, and gliosis. Myelin-specific proteins in the subcortical white matter were examined immunocytochemically and by Western blot analysis. They were of normal molecular size but were markedly reduced in quantity in both patients compared to control subjects. Lipid analysis revealed decreased levels of characteristic myelin lipids. When examined by magnetic resonance spectroscopic imaging, all patients showed a marked decrease of N-acetylaspartic acid, choline, and creatine in white matter only. The magnetic resonance spectroscopic imaging profile is a unique diagnostic feature of this clinicopathological syndrome.

Ataxia↗
PubMed1994

Correction of the enzyme deficiency in hematopoietic cells of Gaucher patients using a clinically acceptable retroviral supernatant transduction protocol.

Gaucher disease is a lysosomal storage disorder caused by a deficiency of the enzyme glucocerebrosidase (GC), and is an excellent candidate for gene replacement therapy. To develop a clinically acceptable protocol for this purpose, we created two amplified (A) high-titer retroviral vector-producer cell lines to efficiently transduce hematopoietic stem and progenitor cells. GP+envAm12/A-LGSN (A-LGSN), contained the GC cDNA driven by the retroviral long terminal repeat (LTR) and the neomycin phosphotransferase gene expressed from the simian virus 40 early promoter. GP+envAm12/A-LG4 (A-LG4) contained only the GC gene driven by the LTR. Both A-LGSN and A-LG4 contained multiple proviral copies and gave approximately 10-fold higher titers on 3T3 cells compared to their unamplified counterparts. These vectors were packaged in GP+envAm12 cells because vectors produced in this cell line transduced hematopoietic cells more efficiently than other packaging cells tested. Bone marrow mononuclear cells and purified CD34+ cells were infected with virus supernatants four times in the presence of interleukin-3 (IL-3), IL-6, and stem cell factor (SCF) over 96 hours in culture. Cells were then plated in semisolid cultures and colony-forming unit-granulocyte/macrophage (CFU-GM) colonies were scored for vector presence by polymerase chain reaction (PCR). Transduction efficiency of CFU-GM colonies derived from CD34+ cells was improved considerably using the amplified vectors in the GP+envAm12 packaging line. For A-LGSN, A-LG4, and unamplified LGSN, transduction efficiencies were 41, 42, and 25%, respectively. Therefore, multiple proviral copies resulting in higher titer improves retroviral transduction of human hematopoietic progenitor cells. Hematopoietic cells from Gaucher patients were transduced and placed into long-term bone marrow culture (LTBMC). Viral supernatant from the amplified producer lines transduced long-term culture initiating cells (LTCIC) efficiently (30 to 50%) using this clinically acceptable protocol. Both sustained mRNA expression and GC enzyme production are achieved in the long-term culture of LTCIC and lead to correction of the GC deficiency in their progeny cells.

Bone Marrow Cells↗
PubMed1993

Posterior fossa abnormalities in children with infantile spasms.

In order to explore possible pathophysiologic involvement of the brain stem in infantile spasms, we retrospectively compared clinical and electroencephalographic (EEG) features of 14 children with infantile spasms who had gross posterior fossa abnormalities on neuroimaging studies with 84 children with infantile spasms who had either normal neuroimaging (n = 19) or supratentorial abnormalities (n = 65). Children with posterior fossa abnormalities how lower mean initial and follow-up developmental quotients compared to those with normal imaging or supratentorial abnormalities alone. Age of onset of infantile spasms, latency to treatment, response to steroids, and follow-up EEG pattern were not significantly different among the three groups. Six children (6%) had Dandy-Walker cysts, an association rarely reported with infantile spasms. We conclude that the presence of posterior fossa abnormalities in patients with infantile spasms portends a relatively poor developmental outcome.

Age of Onset↗
PubMed1993

The effect of cholesterol-lowering agents on hepatic and plasma cholesterol in Niemann-Pick disease type C.

Niemann-Pick disease type C (NP-C) is a neurovisceral lipidosis characterized by defective intracellular trafficking of cholesterol and lysosomal accumulation of unesterified cholesterol, believed to be an offending metabolite. We studied the effect of cholesterol-lowering agents on hepatic and plasma cholesterol levels in NP-C by randomly assigning 25 patients with NP-C to one of five treatment regimens containing different combinations of cholestyramine, lovastatin, nicotinic acid, or dimethyl sulfoxide (DMSO). Unesterified cholesterol content was measured in liver biopsies before and after 4 months' treatment. All drug regimens except DMSO alone reduced hepatic and plasma cholesterol levels. Toxicity was limited and did not prevent any patient from completing the study. The combination of cholestyramine, lovastatin, and nicotinic acid lowered cholesterol levels in liver and blood with minimal side effects. A controlled clinical study will be necessary to determine if this regimen influences the rate of neurologic progression.

Adolescent↗
PubMed1992

[Infantile neuroaxonal dystrophy].

Infantile neuroaxonal dystrophy is a degenerative disease, mostly of nerve endings in the central and peripheral nervous system, with typical pathological findings. We describe a 3-year-old boy who had suffered from nystagmus, progressive muscle weakness and dementia since the age of 10 months. Biochemical work-up, MRI of the brain, and electrophysiological studies were within normal limits. Only skin biopsy, and sural nerve biopsy at a later stage, were diagnostic. We stress the importance of performing tissue biopsy even when intensive investigation is negative.

Biopsy↗
PubMed1992

Severe periodic febrile myalgia in infancy due to carnitine palmitoyltransferase deficiency.

A 7 1/2-yr-old girl suffered, since early infancy, severe recurrent myalgia during periodic attacks of fever, vomiting and pharyngitis. Neither myoglobinuria nor exercise-induced muscle pain was present. She was found to have carnitine palmitoyltransferase deficiency (CPTD) in leukocytes, fibroblasts and muscle. This case exemplifies the importance of looking for an associated metabolic etiology of recurrent febrile myalgia even in the absence of myoglobinuria.

Carnitine O-Palmitoyltransferase↗
PubMed1992

Molecular diagnostics for myelin proteolipid protein gene mutations in Pelizaeus-Merzbacher disease.

Pelizaeus-Merzbacher disease (PMD) is a clinically heterogeneous, slowly progressive leukodystrophy. The recent detection of mutations in the myelin proteolipid protein (PLP) gene in several PMD patients offers the opportunity both to design DNA-based tests that would be useful in diagnosing a proportion of PMD cases and, in particular, to evaluate the diagnostic utility of single-strand conformation polymorphism (SSCP) analysis for this disease. A combination of SSCP analysis and direct sequencing of PCR-amplified DNA was used to screen for PLP mutations in 24 patients affected with leukodystrophies of unknown etiology. Two heretofore undescribed mutations in the PLP gene were identified, Asp202His in exon 4 and Gly73Arg in exon 3. The ease and efficiency of SSCP analysis in detecting new mutations support the utilization of this technique in screening for PLP mutations in patients with unexplained leukodystrophies.

Base Sequence↗
PubMed1992

Nonketotic hyperglycinemia presenting with pin-point pupils and hyperammonemia.

We describe two siblings who presented with lethargy, decreased sucking, respiratory failure and seizures in their first days of life. Pin-point pupils were noted in both siblings. Amino acid analysis revealed elevated concentrations of glycine in plasma and cerebrospinal fluid (CSF), with abnormal CSF/plasma ratios, compatible with hyperglycinemia. Urine organic acid analysis was unremarkable. Hyperammonemia was found in both siblings, but this subsided within 24-72 h. We suggest that pin-point pupils may be an additional presenting sign of nonketotic hyperglycinemia and, if looked for early enough, hyperammonemia may be found in this disorder.

Ammonia↗
PubMed1991

An autosomal recessive form of benign familial neonatal seizures.

We present a consanguineous sibship with benign familial neonatal seizures. The mode of transmission of the disorder in this family seems to be autosomal recessive, which is contrary to the usual autosomal dominant type. Linkage analysis failed to show tight linkage between the disease locus and the autosomal dominant locus assigned to chromosome 20q. We thus conclude that benign familial neonatal seizures is a genetically heterogeneous type of epilepsy.

Chromosomes, Human, Pair 20↗
PubMed1989

Transient neonatal hyperglycinemia.

Two patients with neonatal seizures and subsequent normal neurological development were found to have nonketotic hyperglycinemia. In both patients, hyperglycinemia resolved at 6 weeks of age. After cerebrospinal fluid glycine levels were normalized, the seizures stopped completely in one child and were markedly improved in the other. The possible mechanisms for the hyperglycinemia are discussed.

Amino Acid Metabolism, Inborn Errors↗
PubMed1985

Obstructive hypertrophic adenoids and tonsils as a cause of infantile failure to thrive: reversed by tonsillectomy and adenoidectomy.

Isolated failure to thrive in an infant caused by chronic hypoventilation due to hypertrophic adenoids and tonsils, has not been previously described. A 9 month-old infant presented with weight loss and mild clinical respiratory signs. Hypoxemia and CO2 retention, however, were documented by transcutaneous gas measurement, and ENT examination revealed enlarged tonsils and adenoids. Adenoidectomy and tonsillectomy at 9 1/2 months of age completely reversed the patient's hypoventilation and growth pattern. While the exact mechanism of failure to thrive secondary to upper airway obstruction in infancy is not clear, we conclude that routine ENT evaluation should be a regular part of the workup of infants under one year who suffer from failure to thrive.

Adenoidectomy↗