Biomedical subjects

R Schiffmann

Publications and source records attributed to R Schiffmann.

At least 37 records · Page 2Linked to original sources

PubMed2001

Evidence for neuroaxonal injury in patients with proteolipid protein gene mutations.

The authors used proton MRS to investigate neuropathologic correlates in nine patients with proteolipid protein (PLP) gene mutations who did not show cerebral atrophy on cranial MRI. When compared with 16 age-matched control participants, patients with PLP mutations had significant and widespread decreased brain N-acetyl aspartate, a neuronal marker. The authors conclude that PLP mutations cause neuroaxonal injury, which in turn contributes to the neurologic deficit observed in these patients.

Adolescent↗

PubMed2001

Somatosensory evoked potentials as a marker of disease burden in type 3 Gaucher disease.

The authors compared stretch-evoked somatosensory evoked potentials (SEP) of 18 type 3 Gaucher disease (GD3) patients (two with progressive myoclonus epilepsy [PME]) with 22 age-matched normal controls and six patients with type 1 (nonneuronopathic) Gaucher disease (GD1). The mean P1-N2 SEP amplitude in GD3 patients was significantly larger than the SEP in controls and in GD1 patients, and there was a significant negative correlation between SEP amplitude and the IQ of GD3 patients. The authors conclude that abnormal cortical inhibition is a unifying feature of GD3 patients and correlates with the degree of cognitive deficit.

Adolescent↗

PubMed2001

Enzyme replacement therapy in Fabry disease.

Recent clinical trials have demonstrated that enzyme replacement therapy with alpha-galactosidase A (alpha-Gal A) constitutes a major clinical advance in the treatment of patients with Fabry disease. This new therapeutic approach has been shown to be well tolerated and effective in reducing levels of the storage product globotriaosylceramide and in normalizing many of the debilitating manifestations of the disorder. A double-blind placebo-controlled trial in 26 hemizygous male patients showed that agalsidase alfa (human alpha-Gal A) significantly reduced neuropathic pain (p = 0.02), increased creatinine clearance (p = 0.02), improved glomerular histology, reduced the QRS interval on electrocardiography and increased weight gain. Positron emission tomography also revealed normalization of cerebrovascular flow. After the 6-month controlled period, all patients were given agalsidase alfa for a further 12 months. At the end of this period, all patients had a decrease in neuropathic pain, and there was a significant improvement in their ability to sense heat and cold. In addition, renal function stabilized, even in patients with renal insufficiency at the onset of treatment, and patients reported a normalization of sweating and improvements in their level of energy and sense of well-being. These findings show that enzyme replacement therapy offers promise as an effective management strategy for patients with Fabry disease.

Animals↗

PubMed2001

Natural history of Fabry disease in males: preliminary observations.

A large cohort of patients with Fabry disease is being studied to determine the natural history of the disease and how this relates to the specific mutation involved and the amount of residual alpha-galactosidase A activity. To date, we have investigated the progression of cerebral lesions and stroke, as identified by magnetic resonance imaging, and renal disease. Results have shown that cerebral lesions do not appear until 23 years of age, but are present in all patients by 55 years of age. The peak onset of proteinuria occurred in the fourth decade, and the peak onset of chronic renal insufficiency and end-stage renal disease occurred in the fifth decade of life. Renal outcome was related to the type of mutation and residual enzyme activity. Data from these studies in untreated patients will be important when assessing the long-term efficacy of enzyme replacement therapy.

Brain Diseases↗

PubMed2001

Identification of fifteen novel mutations and genotype-phenotype relationship in Fabry disease.

Fabry disease is an X-linked recessive disorder caused by a deficiency in the lysosomal enzyme alpha-galactosidase A, which results in a progressive multisystem disease. Most families have private mutations and no general correlation between genotype and disease manifestations has been described to date. Forty-nine patients (47 males and 2 females) from 36 affected families were selected for the study. Their evaluation included clinical examination, identification of alpha-galactosidase A gene mutations and residual enzymatic activity. For mutation detection, each exon with flanking intronic sequences was amplified by polymerase chain reaction (PCR) from the patient's genomic DNA and sequenced. Analysis of the resulting sequences was conducted to identify structural defects in the gene. Each of the Fabry patients carried a mutation in the alpha-galactosidase A gene. Fifteen mutations were novel. They included missense mutations (M51K, Y123M, G261D), nonsense point mutations (E251X) and small insertions or deletions creating a premature translational termination signal (P6X, D93X, W162X, K240X, H302X, I303X, L403X, S345X, G375X, F396X). Residual alpha-galactosidase A activity was significantly lower in patients with neuropathic pain (p=0.01) and in patients with mutations leading to a nonconservative amino acid change (p=0.04). Our findings emphasize the wide variety of genetic mechanisms leading to Fabry disease. A significant genotype-phenotype relationship was found.

Codon, Nonsense↗

PubMed2001

Oral and craniofacial findings in Fabry's disease: a report of 13 patients.

OBJECTIVE: Fabry's disease is an X-linked metabolic disease caused by the deficiency of the lysosomal enzyme alpha-galactosidase A. The purpose of this study was to assess oral and craniofacial findings in a cohort of patients with Fabry's disease to facilitate recognition of this condition and early treatment of its manifestations. STUDY DESIGN: This is a case series describing oral and craniofacial findings of 13 male patients diagnosed with Fabry's disease. Data were collected by means of a standardized questionnaire, clinical examination, panoramic and cephalometric radiographs, and magnetic resonance imaging. RESULTS: A variety of abnormalities are described, including an increased prevalence of cysts/pseudocysts of the maxillary sinuses (PCMs) and the presence of maxillary prognathism. CONCLUSION: Given the high prevalence of oral and dental abnormalities, we recommend a thorough stomatologic evaluation of these patients.

Adult↗

PubMed2001

The efficacy of enzyme replacement therapy in patients with chronic neuronopathic Gaucher's disease.

OBJECTIVE: To assess the long-term systemic and neurologic responses to enzyme replacement therapy (ERT) with macrophage-targeted glucocerebrosidase in patients with type 3 Gaucher's disease. STUDY DESIGN: Patients with type 3 Gaucher's disease (n = 21), aged 8 months to 35 years, were enrolled in a prospective study. Enzyme dose was adjusted to control systemic manifestations. Clinical and laboratory evaluations were performed at baseline and every 6 to 12 months thereafter. Patients were followed up for 2 to 8 years. RESULTS: Significant improvement in hemoglobin levels, platelet count, and acid phosphatase values occurred. Liver and spleen volume markedly decreased, and bone structure improved. Nineteen patients had asymptomatic interstitial lung disease unresponsive to ERT. Supranuclear gaze palsy remained stable in 19 patients, worsened in one patient, and improved in one. Cognitive function remained unchanged or improved over time in 13 patients but decreased in 8 patients, 3 of whom developed progressive myoclonic encephalopathy accompanied by cranial magnetic resonance imaging and electroencephalographic deterioration. CONCLUSIONS: At relatively high doses, ERT reverses almost all the systemic manifestations in patients with type 3 Gaucher's disease. Most treated patients do not deteriorate neurologically. Novel therapeutic strategies are required to reverse the pulmonary and neuronopathic aspects of the disease.

Adolescent↗

PubMed2001

An update on the leukodsytrophies.

This review centers on important recent advances in the understanding of the role of glial fibrillary acidic protein in Alexander disease and of proteolipid protein in hypomyelinating disorders such as Pelizaeus-Merzbacher and spastic paraplegia. We also describe seven novel leukodystrophies. These include childhood ataxia with central nervous system hypomyelination, a relatively common leukodystrophy syndrome with linkage to chromosome 3 in some patients, and megalencephalic leukoencephalopathy with subcortical cysts whose gene has recently been cloned. These, along with five other disorders, including leukodystrophy with polyol metabolism abnormality, demonstrate that an increasing number of protein and metabolic abnormalities can cause primary myelin disorders.

Adult↗

PubMed2001

Selective arterial distribution of cerebral hyperperfusion in Fabry disease.

Fabry disease is an X-linked recessive deficiency of lysosomal alpha-galactosidase A associated with an increased risk of early onset cerebrovascular disease. The disorder is reported to affect the posterior circulation predominantly. This hypothesis was investigated directly by the measurement of regional cerebral blood flow with positron emission tomography (PET). Resting regional cerebral blood flow (rCBF) in 26 hemizygous patients with Fabry disease and 10 control participants was examined using H(2)15O and PET. Statistical parametric mapping (SPM(t), SPM99) and PET images of patients and controls were produced. Significantly increased SPM(t) clusters were then color coded and blended with a coregistered T1 magnetic resonance imaging (MRI) template. Cerebral arterial territory maps were digitized and rescaled. Custom OpenGL and ImageVision Library C++ code was written to allow a first-order affine transformation of the blended SPM(t) and MRI template onto the arterial territory map. The affine transformation was constrained by choosing corresponding cerebral landmark "tie points" between the SPM(t) [symbol: see text] MRI template images and the cerebral arterial territory maps. The data demonstrated that the posterior circulation is the predominant arterial territory with a significantly increased rCBF in Fabry disease. No arterial distribution had a decreased rCBF.

Adult↗

PubMed2001

Enhanced endothelium-dependent vasodilation in Fabry disease.

BACKGROUND AND PURPOSE: Fabry disease is an X-linked lysosomal storage disease secondary to deficiency of alpha-galactosidase A with resulting glycolipid accumulation, particularly globotriaosylceramide in arterial smooth muscle and endothelial cells. A systemic vasculopathy, including early-onset stroke, is prevalent without a clear pathogenesis. METHODS: Seventeen normotensive and normocholesterolemic hemizygous Fabry patients (aged 21 to 49 years) and 13 control subjects (aged 21 to 48 years) were investigated by venous plethysmography, allowing assessment of forearm blood flow. Plethysmographic measurements were obtained at baseline and during intra-arterial infusion of acetylcholine and sodium nitroprusside both with and without N(G)-monomethyl-L-arginine (L-NMMA). RESULTS: Forearm blood flow was significantly higher in patients than in control subjects at all 3 acetylcholine doses (P=0.014). Patients had a greater response to acetylcholine even after the addition of L-NMMA (P=0.036). CONCLUSIONS: These results demonstrate an increased endothelium-mediated vascular reactivity in Fabry disease. The increased vessel response to acetylcholine with and without L-NMMA suggests altered functionality of non-NO endothelium-dependent vasodilatory pathways.

Acetylcholine↗

PubMed2000

Clinical features of and recent advances in therapy for Fabry disease.

Fabry disease is an X-linked recessive lysosomal storage disorder caused by a deficiency of alpha-galactosidase A. Intracellular accumulation of globotriaosylceramide, the glycolipid substrate of this enzyme, leads to severe painful neuropathy with progressive renal, cardiovascular, and cerebrovascular dysfunction and early death. Men are predominantly affected but many female carriers have similar clinical involvement, including increased risk of stroke. Physical stigmata, such as angiokeratomas in skin and mucous membranes and characteristic benign corneal abnormalities, facilitate identification of Fabry disease. The finding of a marked decreased activity of alpha-galactosidase A in white blood cells or cultured skin fibroblasts confirms the diagnosis. Treatment thus far has been symptomatic only. Etiology-based therapies are being developed that include enzyme replacement therapy, gene therapy, and substrate deprivation. Our recently completed double-blind, placebo-controlled trial of intravenous infusions of alpha-galactosidase A in patients with Fabry disease demonstrated the safety and efficacy of this treatment. JAMA. 2000;284:2771-2775.

Adult↗

PubMed2000

Mucolipidosis type IV is caused by mutations in a gene encoding a novel transient receptor potential channel.

Mucolipidosis type IV (MLIV) is a developmental neurodegenerative disorder characterized by severe neurologic and ophthalmologic abnormalities. The MLIV gene, ML4 (MCOLN1), has recently been localized to chromosome 19p13.2-13.3 by genetic linkage. Here we report the cloning of a novel transient receptor potential cation channel gene and show that this gene is mutated in patients with the disorder. ML4 encodes a protein, which we propose to call mucolipin, which has six predicted transmembrane domains and is a member of the polycystin II subfamily of the Drosophila transient receptor potential gene family. The role of a potential receptor-stimulated cation channel defect in the pathogenesis of mucolipidosis IV is discussed.

Amino Acid Sequence↗

PubMed2000

Infusion of alpha-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease.

Fabry disease is a lysosomal storage disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-gal A). This enzymatic defect results in the accumulation of the glycosphingolipid globotriaosylceramide (Gb(3); also referred to as ceramidetrihexoside) throughout the body. To investigate the effects of purified alpha-gal A, 10 patients with Fabry disease received a single i.v. infusion of one of five escalating dose levels of the enzyme. The objectives of this study were: (i) to evaluate the safety of administered alpha-gal A, (ii) to assess the pharmacokinetics of i.v.-administered alpha-gal A in plasma and liver, and (iii) to determine the effect of this replacement enzyme on hepatic, urine sediment and plasma concentrations of Gb(3). alpha-Gal A infusions were well tolerated in all patients. Immunohistochemical staining of liver tissue approximately 2 days after enzyme infusion identified alpha-gal A in several cell types, including sinusoidal endothelial cells, Kupffer cells, and hepatocytes, suggesting diffuse uptake via the mannose 6-phosphate receptor. The tissue half-life in the liver was greater than 24 hr. After the single dose of alpha-gal A, nine of the 10 patients had significantly reduced Gb(3) levels both in the liver and shed renal tubular epithelial cells in the urine sediment. These data demonstrate that single infusions of alpha-gal A prepared from transfected human fibroblasts are both safe and biochemically active in patients with Fabry disease. The degree of substrate reduction seen in the study is potentially clinically significant in view of the fact that Gb(3) burden in Fabry patients increases gradually over decades. Taken together, these results suggest that enzyme replacement is likely to be an effective therapy for patients with this metabolic disorder.

Adult↗

PubMed2000

Five novel mutations in fourteen patients with Fabry Disease.

Fabry disease is an X-linked disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A. The mutations responsible for Fabry disease are diverse and include large rearrangements as well as single base substitutions, and they are dispersed throughout the seven exons of the gene. In this study, we found five novel mutations in four different exons. We have detected the mutations by the PCR-SSCP method and then analysed them by direct sequencing. Three of the novel mutations were deletions: 1205delA, 1238del26 and 5236del18. We also found one novel nonsense mutation: W162X. The final novel mutation was an insertion combined with a deletion: 10995ins24del4.

Fabry Disease↗

PubMed2000

Cutaneous silent periods in patients with Fabry disease.

We assessed the cutaneous silent period (CSP) in 24 patients with Fabry disease with small-fiber sensory neuropathy and 12 normal subjects to test the hypothesis that small-diameter afferents are responsible for producing the CSP. Sensory nerve conduction studies and quantitative sensory testing for cold and vibration detection thresholds were also measured. Overall, Fabry patients had impaired thermal, but not vibration, detection thresholds, with greatest impairment in the feet. In the upper extremity, CSP latencies, duration, and suppression of electromyographic activity (EMG) did not differ. In the lower extremity, patients had reduced suppression of EMG during the CSP compared to normal controls. CSP durations exhibited a bimodal distribution in patients, including a subset of seven patients with durations shorter than all controls. This subset had profound loss of thermal sensation in the feet, but this was also true of some patients who had normal CSPs. Patients with shortened CSPs had modestly elevated vibration thresholds and reduced sensory potentials in comparison to patients with normal CSPs. Reduced CSPs in Fabry patients are associated with, but not entirely explained by, the severity of small-fiber neuropathy as measured by quantitative sensory testing. The possibility that large-diameter fibers provide a minor contribution to producing the CSP should be considered.

Action Potentials↗

PubMed2000

Comparative efficacy of dose regimens in enzyme replacement therapy of type I Gaucher disease.

Gaucher disease is caused by a deficiency of beta-glucocerebrosidase activity. The optimum dose and frequency of enzyme replacement therapy for Gaucher patients have not been determined. We set to compare the therapeutic effects of initiating treatment with macrophage-targeted glucocerebrosidase at a high dose followed by progressive dose reductions with that produced by initial treatment at a low dose in patients with type I Gaucher disease. The study included two parts: (i) Twelve patients received every 2 weeks enzyme replacement therapy at 60 IU/kg body wt for 24 months followed by sequential dose reduction every 6 months to 30 and then to 15 IU/kg body wt. (ii) Thirty-two patients received enzyme replacement therapy at 10 IU/kg every 2 weeks for 12 months. Hematologic parameters and liver and spleen volume were monitored in all patients. All patients had intact spleens. In patients who were started on high-dose enzyme replacement therapy, hemoglobin, acid phosphatase, and organ volume improved or remained unchanged at the end of each dose reduction. Platelet count decreased significantly when the dose of enzyme was reduced from 30 to 15 IU/kg body wt. Initiation of therapy at a low dose led to a significant improvement in all measured parameters at the end of 1 year. We conclude that the minimal effective dose for the nonskeletal manifestations of Gaucher disease can be achieved either by initiating enzyme replacement therapy with a high dose followed by a stepwise dose reduction or by starting treatment at the minimal dose. High dose provides a faster clinical response and should be considered for patients with more aggressive disease. The therapeutic threshold for macrophage-targeted glucocerebrosidase appears to be 10-15 IU/kg body wt every 2 weeks.

Adolescent↗

PubMed2000

Foamy cells with oligodendroglial phenotype in childhood ataxia with diffuse central nervous system hypomyelination syndrome.

Childhood ataxia with diffuse central nervous system hypomyelination syndrome (CACH) is a recently described leukodystrophy of unknown etiology. To characterize the neuropathological features and gain insight as to the pathogenesis of this disorder, we studied cerebral tissue from six patients with the CACH syndrome. Evaluation of toluidine blue-stained, semithin sections of white matter from CACH patients disclosed unusual cells with "foamy" cytoplasm, small round nuclei and fine chromatin. Electron microscopy (EM) revealed cells in the white matter with abundant cytoplasm containing many mitochondria and loosely clustered, membranous structures, but lacking the lysosomal structures seen in macrophages. Further analysis of tissue sections with antibodies and special stains demonstrated that the abnormal cells with abundant cytoplasm labeled with oligodendroglial markers, but did not react with macrophage or astrocytic markers. Double immunolabeling with macrophage and oligodendroglial markers clearly distinguished macrophages from the "foamy" oligodendroglial cells (FODCs). Proteolipid protein (PLP) mRNA in situ hybridization demonstrated PLP mRNA transcripts in a high proportion of oligodendrocytes in CACH patients compared to control patients, and PLP mRNA transcript signal in cells, morphologically consistent with FODCs. Normal and pathological brain control tissues did not contain FODCs. These neuropathological findings will be useful pathological identifiers of CACH, and may provide clues to the pathogenesis of this disorder.

Ataxia↗

PubMed2000

Profile of endothelial and leukocyte activation in Fabry patients.

Fabry disease is an X-linked recessive disorder resulting in the deposition of globotriaosylceramide in numerous cell types including vascular endothelial cells. Because this disease is associated with vascular injury and a high recurrence rate of thrombotic events, measurements of factors regulating endothelium and leukocyte interaction may provide insight into the mechanisms leading to a prothrombotic state. Twenty-five patients with Fabry disease and 25 control subjects participated in the study. Plasma from all 25 Fabry patients and 15 of the 25 controls were studied for multiple endothelial factors. Leukocyte integrins were measured by flow cytometry in 21 Fabry patients and 10 controls. The concentrations of soluble intercellular adhesion molecule-1, vascular cell adhesion molecule-1, P-selectin, and plasminogen activator inhibitor were significantly higher and thrombomodulin was significantly lower in Fabry patients. Expression of the integrin CD11b on monocytes was also significantly higher in the Fabry patients. This study reveals measurable evidence for endothelium and leukocyte activation that is consistent with a prothrombotic state in Fabry patients compared with controls. Further investigations of these findings may help to understand the mechanism of stroke in Fabry disease and provide indicators (or markers) of efficacy of future therapeutic intervention.

Adult↗