Neuronopathic Forms Research Articles

Glucocerebrosidase gene mutations in black South Africans with Gaucher disease

Gaucher disease (GD) is caused by mutations in the glucocerebrocidase gene ( GBA) and presents with variable severity. Type 1 is characterized by the lack of neurological symptoms in childhood, whereas types 2 and 3 are early onset neuronopathic forms and result in premature death. Only type 1 GD has been reported in black South Africans and the cases are clinically severe. In this study both GBA mutations were identified in 18/19 black GD patients. Two mutations accounted for 2/3 of all observed disease causing alleles: p.T36del (c.222–224delTAC) (17/38 alleles) and Rec Ncil (8/38 alleles). Three novel variants were identified and assessed as being likely pathogenic mutations: c.413delC, W357C and D405V. Haplotype analysis supported a single origin for the p.T36del mutation in black South Africans on a haplotype background that is rare in the present population. We hypothesise that the p.T36del results in intracellular mislocalisation of the protein, but confirmation of the altered function of this allele awaits functional studies. A diagnostic test for GD has been implemented for black South Africans.

No evidence for activation of the unfolded protein response in neuronopathic models of Gaucher disease

Gaucher disease (GD), the most common lysosomal storage disorder (LSD), is caused by defects in the activity of the lysosomal enzyme, glucocerebrosidase, resulting in intracellular accumulation of glucosylceramide (GlcCer). Neuronopathic forms, which comprise only a small percent of GD patients, are characterized by neurological impairment and neuronal cell death. Little is known about the pathways leading from GlcCer accumulation to neuronal death or dysfunction but defective calcium homeostasis appears to be one of the pathways involved. Recently, endoplasmic reticulum stress together with activation of the unfolded protein response (UPR) has been suggested to play a key role in cell death in neuronopathic forms of GD, and moreover, the UPR was proposed to be a common mediator of apoptosis in LSDs (Wei et al. (2008) Hum. Mol. Genet. 17, 469-477). We now systematically examine whether the UPR is activated in neuronal forms of GD using a selection of neuronal disease models and a combination of western blotting and semi-quantitative and quantitative real-time polymerase chain reaction. We do not find any changes in either protein or mRNA levels of a number of typical UPR markers including BiP, CHOP, XBP1, Herp and GRP58, in either cultured Gaucher neurons or astrocytes, or in brain regions from mouse models, even at late symptomatic stages. We conclude that the proposition that the UPR is a common mediator for apoptosis in all neurodegenerative LSDs needs to be re-evaluated.

Acid Sphingomyelinase Overexpression Enhances the Antineoplastic Effects of Irradiation In Vitro and In Vivo

Exposure of cells or animals to stress frequently induces acid sphingomyelinase (ASM)-mediated ceramide production that leads to cell death. Consistent with this, overexpression of ASM in subcutaneous B16-F10 mouse melanomas, in combination with irradiation, resulted in tumors that were up to 12-fold smaller than irradiated control melanomas. Similarly, when irradiated melanomas were pretreated with a single, peritumoral injection of recombinant ASM (rhASM), the tumors were up to threefold smaller. The in vivo effect of ASM was likely due to enhanced cell death of the tumor cells themselves, as well as the surrounding microvascular endothelial cells. In vitro, rhASM had little or no effect on the growth of tumor cells, even in combination with irradiation. However, when the culture media was acidified to mimic the acidic microenvironment of solid tumors, rhASM-mediated cell death was markedly enhanced when combined with irradiation. Microscopic analysis suggested that this was associated with an increase in autophagy. rhASM has been produced for the treatment of the lysosomal storage disorder, type B Niemann-Pick disease, and is currently being evaluated in a phase-1 clinical trial. Based on the data presented in this article, we propose that further investigation of this protein and gene as antineoplastic agents also is warranted.

Substrate deprivation therapy: a new hope for patients suffering from neuronopathic forms of inherited lysosomal storage diseases

Lysosomal storage diseases are a group of disorders caused by defects in enzymes responsible for degradation of particular compounds in lysosomes. In most cases, these diseases are fatal, and until recently no treatment was available. Introduction of enzyme replacement therapy was a breakthrough in the treatment of some of the diseases. However, while this therapy is effective in reduction of many somatic symptoms, its efficacy in the treatment of the central nervous system is negligible, if any, mainly because of problems with crossing the blood-brain-barrier by intravenously administered enzyme molecules. On the other hand, there are many lysosomal storage diseases in which the central nervous system is affected. Results of very recent studies indicate that in at least some cases, another type of therapy, called substrate deprivation therapy (or substrate reduction therapy) may be effective in the treatment of neuronopathic forms of lysosomal storage diseases. This therapy, based on inhibition of synthesis of the compounds that cannot be degraded in cells of the patients, has been shown to be effective in several animal models of various diseases, and recent reports demonstrate its efficacy in the treatment of patients suffering from Niemann-Pick C disease and Sanfilippo disease.

Murine models of acute neuronopathic Gaucher disease

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the glucosidase, beta, acid (GBA) gene that encodes the lysosomal enzyme glucosylceramidase (GCase). GCase deficiency leads to characteristic visceral pathology and, in some patients, lethal neurological manifestations. Here, we report the generation of mouse models with the severe neuronopathic form of GD. To circumvent the lethal skin phenotype observed in several of the previous GCase-deficient animals, we genetically engineered a mouse model with strong reduction in GCase activity in all tissues except the skin. These mice exhibit rapid motor dysfunction associated with severe neurodegeneration and apoptotic cell death within the brain, reminiscent of neuronopathic GD. In addition, we have created a second mouse model, in which GCase deficiency is restricted to neural and glial cell progenitors and progeny. These mice develop similar pathology as the first mouse model, but with a delayed onset and slower disease progression, which indicates that GCase deficiency within microglial cells that are of hematopoietic origin is not the primary determinant of the CNS pathology. These findings also demonstrate that normal microglial cells cannot rescue this neurodegenerative disease. These mouse models have significant implications for the development of therapy for patients with neuronopathic GD.

Maladie de Gaucher : particularités cliniques chez l’enfant: Gaucher disease in childhood

Gaucher disease is well-known in adult patients and must be regarded as a pædiatric disease, two thirds of the patients manifesting before the age of 20. Three clinical forms have been defined based on the presence of neurological involvement. Gaucher disease type 1, without neurological signs, generally begins before the five years age with splenomegaly as the main symptom. The bone crises are more frequent than in adulthood. Gaucher disease type 2 or acute neuronopathic form begins between three and six months and do not have any treatment. Type 3 or chronic neuronopathic form appears like a type 1 with progressive horizontal saccade-initiation failure and developmental delay. Onset in childhood is predictive of a severe and progressive phenotype. The presence of neurological symptoms induces important consequences for treatment, prognosis and genetic counselling.

The studies on substrate, product and inhibitor binding to a wild-type and neuronopathic form of human acid-β-glucosidase

Gaucher disease is a lysosomal storage disorder caused by deficiency of human acid beta-glucosidase. Recent x-ray structural elucidation of the enzyme alone and in the presence of its inhibitor was done, which provided an excellent template for further studies on the binding of substrate, product and inhibitor. To draw correlations between the clinical manifestation of the disease driven by point mutations, L444P and L444R, and the placement and function of putative S-binding sites, the presented theoretical studies were undertaken, which comprised of molecular dynamics and molecular docking methods. The obtained results indicate the D443 and D445 residues as extremely important for physiological functionality of an enzyme. They also show, although indirectly, that binding of the substrate is influenced by an interplay of E235 and E334 residues, constituting putative substrate binding site, and the region flanked by D435 and D445 residues.

Determining the frequency of common mutations in the GBA gene in patients with Gaucher disease in Ukraine

A molecular-genetics investigation is conducted on 27 patients from 26 families. Common mutations in the GBA gene (N370S, L444P, and 84GG) are studied. The overall frequency of the common mutations is nearly 58%, with the percentage of alleles that carry the N370S mutation close to 42.3% and the proportion that carry the L444P mutation, 15.4%. No allele containing the 84GG mutation was found. Besides other mutations, the rare mutations P178S, W184R, and Rec Nci I (together with N370S) were also found in the GBA gene in patients with the nonneuronopathic form of the disease, along with the genotypes G377S/c 999GA and D409H/R 120W/G202R in patients with the chronic neuronopathic form. An analysis of the correlation between the genotype and the course of the disease in the patients showed that the genotype-phenotype correlations were close to that described for European populations.

Neurologic Improvement in a Type 3 Gaucher Disease Patient Treated with Imiglucerase/Miglustat Combination

Gaucher disease (GD) is an autosomal recessive lysosomal disorder caused by a deficiency of glucocerebrosidase. The neurologic manifestations of GD patients have to date been refractory to any treatment approach. We present a report of a neuronopathic GD patient whose myoclonic epilepsy improved after combination therapy with imiglucerase and miglustat. In an adult type 3 GD patient who, despite good visceral and analytic response to ERT, developed progressive neurologic deterioration with marked myoclonic epilepsy and dystonia, we added miglustat to the enzyme-replacement therapy. After 2 years of combined miglustat (200 mg, 3 t.i.d.) and imiglucerase (60 IU/kg every 2 weeks), generalized tonic-clonic seizures decreased, speech improved, and the general neurologic clinical picture improved markedly. The EEG showed a reduction in focal and generalized paroxysmal discharges. No significant adverse effects were observed. Combined imiglucerase and miglustat therapy may be beneficial for some neuronopathic forms of GD.

Downregulation of neurotrophic factors in the brain of a mouse model of Gaucher disease: implications for neuronal loss in Gaucher disease

Gaucher disease is a glycosphingolipid storage disease caused by deficiency of glucocerebrosidase, resulting in the accumulation of glucosylceramide in lysosomes. The neuronopathic forms of this disease are associated with neuronal loss and neurodegeneration. However, the pathophysiological mechanisms leading to prenatal and neonatal death remain uncharacterized. To investigate brain dysfunction in Gaucher disease, we studied the effects of neurotrophic factors during development in a mouse model of Gaucher disease. The expression of brain-derived neurotrophic factor and nerve growth factor was reduced in the cerebral cortex, brainstem, and cerebellum of Gaucher mice, compared with that in wild-type mice. Extracellular signal-regulated kinase (ERK) 1/2 expression was downregulated in neurons from Gaucher mice and correlated with a decreased number of neurons. These results suggest that a reduction in neurotrophic factors could be involved in neuronal loss in Gaucher disease.

Miglustat: Substrate Reduction Therapy for Lysosomal Storage Disorders Associated with Primary Central Nervous System Involvement

Difficulties with delivery of functional enzyme to the brain limit the ability to modify neurologic outcome in patients with neuronopathic forms of the lysosomal storage diseases. In a subset of these disorders, which result from a disruption of glycosphingolipid metabolism, the use of a small molecule inhibitor of substrate precursor synthesis may reduce the amount of brain tissue lipid deposition and lead to amelioration of disease. The efficacy of this approach, termed substrate reduction therapy, has been demonstrated in several animal models; with resultant reduction of ganglioside storage in the brain, delayed onset of symptoms and prolonged survival. This pre-clinical 'proof of therapeutic concept' served as the rationale for proceeding with trials in humans using miglustat; an imino-sugar inhibitor of ceramide-specific glucosytransferase (the catalyst for the first committed step in glycosphingolipid synthesis). The glycosphingolipidoses are rare 'orphan' disorders; the limited number of suitable study subjects and the paucity of information on the natural history of these disorders represent major hurdles in the conduct of clinical trials. As treatment potentially constitutes lifelong administration, there will be a need to identify any potential safety considerations attendant to the use of these agents. With greater understanding of disease mechanism, adjunctive therapies may be identified; offering the prospect of modifying these otherwise relentlessly progressive neurodegenerative diseases.

Immunoquantification of β-Glucosidase: Diagnosis and Prediction of Severity in Gaucher Disease

Gaucher disease is an inborn error of glycosphingolipid metabolism resulting from a deficiency of the lysosomal enzyme β-glucosidase (1)(2). Acid β-glucosidase is responsible for the cleavage of the β-glucosidic bond of its primary substrate glucosylceramide, an intermediate in the catabolism of globoside and gangliosides. Gaucher disease is the most prevalent lysosomal storage disorder with an estimated frequency of 1 in 57 000 births in Australia(3). The disease has been broadly classified into 3 clinical subtypes, but a broad spectrum of phenotypes exists within each group(1). Type 1, the most common, is a chronic nonneuronopathic form of the disease associated with various degrees of anemia, thrombocytopenia, hepatosplenomegaly, and bone disease. Clinical onset may occur at any age, but usually occurs after childhood and in some instances does not manifest until later adulthood. Type 2 is an acute neuronopathic form of the disease, characterized by early onset, severe central nervous system impairment, and death, usually by the second year of life. Type 3 is a subacute neuronopathic form, usually with a more chronic course and later onset than type 2. More than 187 mutations in the β-glucosidase gene have been associated with Gaucher disease (4), although there are rare instances of mutations in the prosaposin gene producing a Gaucher phenotype(5). Defined correlations between genotype and phenotype are not overly apparent, and there is broad phenotypic expression among all genotypes. A notable exception is the association of homozygosity for the L444P mutation with neuronopathic disease; similarly, the presence of the N370S allele precludes neuronopathic disease(6)(7). Patients with the nonneuronopathic form of the disease are treated with enzyme replacement therapy (8)(9), which may also slow the progression of neuronopathic disease(10). Early and accurate diagnosis for Gaucher disease, as well as the prediction …

Uncomplicated outcome after anesthesia for pediatric patients with Gaucher disease

The purpose of this retrospective review was to highlight clinical issues relating to anesthetic management in children who present with Gaucher disease-specific features that may impact on anesthetic management and surgical outcome. Previous reports have dealt primarily with neuronopathic forms where neurological dysfunction determined the mode of anesthesia. To date, no series of routine surgeries in pediatric patients with non-neuronopathic Gaucher disease has been published. All surgeries performed in children with Gaucher retrospectively analyzed. There were 31 procedures under anesthesia in 15 pediatric patients. Twenty-seven of these (87%) involved either insertion or removal of a central venous catheter. There was no correlation between disease severity and the need for blood transfusion postoperatively [required in only eight cases (25.8%), including a total hip replacement]. No difficult intubations or other airway problems were recorded. Positioning of two patients, because of gibbus and prior to hip replacement, respectively, required special attention. We record our experience in surgeries in children with mild, non-neuronopathic type I and severe neuronopathic type III Gaucher disease, who had relatively short surgeries under general anesthesia. Attention to hematological parameters in particular can minimize postoperative bleeding, the most serious complication.

TNF-α levels and TNF-α gene polymorphism in type I Gaucher disease

The objective of this pilot study was to determine the levels of Tumor Necrosis Factor (TNF)-α and TNF-α gene polymorphism as a marker of inflammation among patients with type I Gaucher disease as well as to ascertain the relationship between this cytokine and parameters of disease severity and other measures of inflammation. Levels of TNF-α and genotyping for the −308 G → A polymorphism in the promoter of the TNF-α gene were performed in 17 patients with type I Gaucher disease. TNF-α levels were compared with the promoter gene polymorphism, and with hematological and other clinical parameters of Gaucher disease. Eight patients (47.1%) were homozygotes (A/A) for the TNF-α polymorphism, six patients (35.3%) had the wild type (G/G), and three patients (17.6%) were heterozygotes (G/A). A significant correlation was found between serum TNF-α levels and TNF-α genotypes for homozygotes versus heterozygotes patients ( p = 0.02), with patients homozygous for the polymorphism having the lower levels of serum TNF-α relative to heterozygotes with the highest levels. No correlation was found between TNF-α genotypes and chitotriosidase levels, a putative biochemical marker for Gaucher disease severity. Because a significant correlation was found between homozygosity for a common promoter polymorphism of TNF-α and milder expression i.e. non-neuronopathic form, of Gaucher disease (versus the neuronopathic forms), this may be suggestive of an association between genetic variability in TNF-α and phenotypic expression in Gaucher disease. Larger studies will be required.

Homozygosity for a non-pseudogene complex glucocerebrosidase allele as cause of an atypical neuronopathic form of Gaucher disease

American Journal of Medical Genetics Part AVolume 134A, Issue 1 p. 95-96 Research Letter Homozygosity for a non-pseudogene complex glucocerebrosidase allele as cause of an atypical neuronopathic form of Gaucher disease Mirella Filocamo, Corresponding Author Mirella Filocamo dppm@ospedale-gaslini.ge.it http://www.gaslini.org/labdppm.htm Laboratorio Diagnosi Pre-Postnatale Malattie Metaboliche, Istituto G. Gaslini, Genoa, ItalyLaboratorio Diagnosi Pre-Postnatale Malattie Metaboliche, Istituto G. Gaslini, L.go G. Gaslini, 16147 Genova, Italy.Search for more papers by this authorSerena Grossi, Serena Grossi Laboratorio Diagnosi Pre-Postnatale Malattie Metaboliche, Istituto G. Gaslini, Genoa, ItalySearch for more papers by this authorMarina Stroppiano, Marina Stroppiano Laboratorio Diagnosi Pre-Postnatale Malattie Metaboliche, Istituto G. Gaslini, Genoa, ItalySearch for more papers by this authorPaolo Tortori-Donati, Paolo Tortori-Donati Servizio di Neuroradiologia, Istituto G. Gaslini, Genoa, ItalySearch for more papers by this authorStefano Regis, Stefano Regis Laboratorio Diagnosi Pre-Postnatale Malattie Metaboliche, Istituto G. Gaslini, Genoa, ItalySearch for more papers by this authorAnna Allegri, Anna Allegri U.O. Pediatria II, Istituto G. Gaslini, Genoa, ItalySearch for more papers by this authorMaja Di Rocco, Corresponding Author Maja Di Rocco U.O. Pediatria II, Istituto G. Gaslini, Genoa, ItalyLaboratorio Diagnosi Pre-Postnatale Malattie Metaboliche, Istituto G. Gaslini, L.go G. Gaslini, 16147 Genova, Italy.Search for more papers by this author Mirella Filocamo, Corresponding Author Mirella Filocamo dppm@ospedale-gaslini.ge.it http://www.gaslini.org/labdppm.htm Laboratorio Diagnosi Pre-Postnatale Malattie Metaboliche, Istituto G. Gaslini, Genoa, ItalyLaboratorio Diagnosi Pre-Postnatale Malattie Metaboliche, Istituto G. Gaslini, L.go G. Gaslini, 16147 Genova, Italy.Search for more papers by this authorSerena Grossi, Serena Grossi Laboratorio Diagnosi Pre-Postnatale Malattie Metaboliche, Istituto G. Gaslini, Genoa, ItalySearch for more papers by this authorMarina Stroppiano, Marina Stroppiano Laboratorio Diagnosi Pre-Postnatale Malattie Metaboliche, Istituto G. Gaslini, Genoa, ItalySearch for more papers by this authorPaolo Tortori-Donati, Paolo Tortori-Donati Servizio di Neuroradiologia, Istituto G. Gaslini, Genoa, ItalySearch for more papers by this authorStefano Regis, Stefano Regis Laboratorio Diagnosi Pre-Postnatale Malattie Metaboliche, Istituto G. Gaslini, Genoa, ItalySearch for more papers by this authorAnna Allegri, Anna Allegri U.O. Pediatria II, Istituto G. Gaslini, Genoa, ItalySearch for more papers by this authorMaja Di Rocco, Corresponding Author Maja Di Rocco U.O. Pediatria II, Istituto G. Gaslini, Genoa, ItalyLaboratorio Diagnosi Pre-Postnatale Malattie Metaboliche, Istituto G. Gaslini, L.go G. Gaslini, 16147 Genova, Italy.Search for more papers by this author First published: 02 February 2005 https://doi.org/10.1002/ajmg.a.30316Citations: 6Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume134A, Issue11 April 2005Pages 95-96 RelatedInformation

Enhanced calcium release in the acute neuronopathic form of Gaucher disease

Gaucher disease is an inherited metabolic disorder caused by defective activity of the lysosomal enzyme, glucocerebrosidase, resulting in accumulation of the lipids, glucosylceramide (GlcCer), and glucosylsphingosine (GlcSph). Little is known about the mechanism leading from lipid accumulation to disease, particularly in the acute and subacute neuronopathic forms of Gaucher disease, types 2 and 3, respectively. Recent work from our laboratory has shown, in animal models, that GlcCer enhances agonist-induced calcium release from intracellular stores via the ryanodine receptor, which results in neuronal cell death. We now test whether calcium release is altered in human brain tissue obtained post-mortem from Gaucher disease patients. Agonist-induced calcium release via the ryanodine receptor was significantly enhanced (P < 0.05) in brain microsomes from the acute neuronopathic form of Gaucher disease (type 2) (43 +/- 6% of the calcium in microsomes) compared to the subacute (type 3) (27 +/- 3%) and the non-neuronopathic (type 1) (28 +/- 6%) forms, and controls (18 +/- 3%), and correlated with levels of GlcCer accumulation. These findings suggest that defective calcium homeostasis may be a mechanism responsible for neuropathophysiology in acute neuronopathic Gaucher disease, and may potentially offer new therapeutic approaches for disease management.

Global gene expression in a type 2 Gaucher disease brain

Gaucher disease is a member of a family of inherited disorders called sphingolipidoses that among others includes Tay-Sachs and Sandhoff diseases. It is caused by the accumulation of glucosylceramide (glucocerebroside) due to deficient activity of the enzyme glucosylceramide-β-glucosidase (glucocerebrosidase). As with other glycosphingolipidoses, severe neurodegeneration is present in types 2 and 3 Gaucher disease. We have used Serial Analysis of Gene Expression (SAGE) to characterize the gene expression profiles in brain of patients with glycosphingolipid storage diseases to understand the molecular details of neurodegeneration. In the current study we have determined the gene expression profile from the brain of a patient with type 2 Gaucher disease, the acute neuronopathic form of the disorder. We found that the expression profile of the type 2 Gaucher brain is significantly altered relative to the normal control brain profile. There were also differences when compared with profiles from Tay-Sachs and Sandhoff patients, in particular in levels of genes related to macrophage activation. Intriguingly we found that γ-synuclein, a family member of proteins involved the pathogenesis of other neurodegenerative disorders, was elevated in the one Gaucher type 2 patient brain we examined.

Glucosylceramide and Glucosylsphingosine Modulate Calcium Mobilization from Brain Microsomes via Different Mechanisms

We recently demonstrated that elevation of intracellular glucosylceramide (GlcCer) levels results in increased functional Ca2+ stores in cultured neurons, and suggested that this may be due to modulation of ryanodine receptors (RyaRs) by GlcCer (Korkotian, E., Schwarz, A., Pelled, D., Schwarzmann, G., Segal, M. and Futerman, A. H. (1999) J. Biol. Chem. 274, 21673-21678). We now systematically examine the effects of exogenously added GlcCer, other glycosphingolipids (GSLs) and their lyso-derivatives on Ca2+ release from rat brain microsomes. GlcCer had no direct effect on Ca2+ release, but rather augmented agonist-stimulated Ca2+ release via RyaRs, through a mechanism that may involve the redox sensor of the RyaR, but had no effect on Ca2+ release via inositol 1,4,5-trisphosphate receptors. Other GSLs and sphingolipids, including galactosylceramide, lactosylceramide, ceramide, sphingomyelin, sphingosine 1-phosphate, sphinganine 1-phosphate, and sphingosylphosphorylcholine had no effect on Ca2+ mobilization from rat brain microsomes, but both galactosylsphingosine (psychosine) and glucosylsphingosine stimulated Ca2+ release, although only galactosylsphingosine mediated Ca2+ release via the RyaR. Finally, we demonstrated that GlcCer levels were approximately 10-fold higher in microsomes prepared from the temporal lobe of a type 2 Gaucher disease patient compared with a control, and Ca2+ release via the RyaR was significantly elevated, which may be of relevance for explaining the pathophysiology of neuronopathic forms of Gaucher disease.

Adult-onset neuronopathic form of Gaucher's disease: a case report

We report a patient with Gaucher's disease (GD) developing prominent neurological abnormalities in adult life confirming the existence of an adult neuronopathic form of GD. In this adult-onset form, an akinetic-rigid syndrome poorly responsive to dopatherapy, supranuclear gaze palsy, myoclonic jerks, seizures, cerebellar ataxia, cognitive and psychotic disturbances are frequent manifestations. The widely used clinical classification seems inadequate since it does not consider this rare form of GD. Until further understanding of the pathogenesis of the disease is achieved it is not possible to predict accurately which patients will or will not have late-onset nervous system involvement.

Glucosylsphingosine accumulation in tissues from patients with Gaucher disease: correlation with phenotype and genotype

Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase, presents with a wide spectrum of clinical manifestations including neuronopathic and non-neuronopathic forms. While the lipid glucosylceramide is stored in both patients with Gaucher disease and in a null allele mouse model of Gaucher disease, elevated levels of a second potentially toxic substrate, glucosylsphingosine, are also found. Using high performance liquid chromatography, glucosylsphingosine levels were measured in tissues from patients with type 1, 2, and 3 Gaucher disease. Glucosylsphingosine was measured in 16 spleen samples (8 type 1; 4 type 2; and 4, type 3) and levels ranged from 54 to 728 ng/mg protein in the patients with type 1 disease, 133 to 1200 ng/mg protein in the patients with type 2, and 109 to 1298 ng/mg protein in the type 3 samples. The levels of splenic glucosylsphingosine bore no relation to the type of Gaucher disease, the age of the patient, the genotype, nor the clinical course. In the same patients, hepatic glucosylsphingosine levels were lower than in spleen. Glucosylsphingosine was also measured in brains from 13 patients (1 type 1; 8 type 2; and 4 type 3). While the glucosylsphingosine level in the brain from the type 1 patient, 1.0 ng/mg protein, was in the normal range, the levels in the type 3 samples ranged from 14 to 32 ng/mg protein, and in the type 2 samples from 24 to 437 ng/mg protein, with the highest values detected in two fetuses with hydrops fetalis. The elevated levels found in brains from patients with neuronopathic Gaucher disease support the hypothesis that glucosylsphingosine may contribute to the nervous system involvement in these patients.