scholarly journals Two cases of neuronopathic form of Gaucher disease – diagnostic difficulties

2021 ◽  
Author(s):  
Grazina Kleinotiene ◽  
Austeja Ivaskeviciene ◽  
Anna Tylki-Szymanska
Keyword(s):  
Gaucher Disease ◽  
Clinical Manifestations ◽  
Central Nervous System Involvement ◽  
Saccadic Eye Movements ◽  
Neurological Symptoms ◽  
Lysosomal Storage ◽  
Hematopoietic Organ ◽  
Enzyme Replacement ◽  
Type 3

Background: Gaucher disease is one of the most common inherited lysosomal storage diseases caused by the deficiency of the enzyme β-glucocerebrosidase, leading to the accumulation of glucocerebroside. Depending on the clinical manifestations, two different forms of the disease are distinguished – the non-neuronopathic form (type 1) with a variety of presentations – from asymptomatic to symptomatic patients (characterized by hepatosplenomegaly, thrombocytopenia, anemia and osteopenia), and the neuronopathic form (known as types 2 and 3). Besides visceral, osseous, and hematopoietic organ lesions, neuronopathic forms are associated with central nervous system involvement (bulbar and pyramidal signs, horizontal saccadic eye movements, myoclonic epilepsy, progressive development delay). In type 2, the neurological symptoms appear earlier and are more severe, the survival time is shorter. In type 3, the neurological symptoms are milder and allow patients to live a fully productive life. Case presentation: This article includes a review of two cases of neuronopathic Gaucher disease: type 2 and severe type 3. Both patients presented symptoms during infancy and the manifestations were similar but varied in intensity and the dynamics of progress. Enzyme replacement therapy was started in both cases, which decreased visceral symptoms. Conclusions: Both described cases indicate the lack of knowledge and the tendency of doctors to disregard the possibility of Gaucher disease in their paediatrics patients.

scholarly journals Gaucher disease: clinical phenotypes and refining GBA mutational spectrum in Thai patients

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Tim Phetthong ◽  
Thipwimol Tim-Aroon ◽  
Arthaporn Khongkraparn ◽  
Saisuda Noojarern ◽  
Chulaluck Kuptanon ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Age Of Onset ◽  
Lysosomal Storage ◽  
Pathogenic Variants ◽  
Medical Centers ◽  
Neurologic Involvement ◽  
Therapeutic Research ◽  
Type 3

Abstract Background Gaucher disease (GD) is a rare lysosomal storage disorder, characterized by hepatosplenomegaly and pancytopenia, with or without neurologic involvement. The disorder is categorized into three phenotypes: GD type 1 or nonneuronopathic GD; GD type 2 or acute neuronopathic GD; and GD type 3 or chronic neuronopathic GD. The purposes of this study were to describe clinical characteristics of Thai GD in patients diagnosed and/or followed up during 2010–2018 and to perform re-genotyping including analysis of GBA recombinant alleles which had not been investigated in Thai patients before. Results There were 27 patients from seven medical centers, enrolled in the study. All the cases had pediatric onset. GD3 (44.5%) was the most common phenotype, followed by GD2 (40.7%) and GD1 (14.8%), with one case of neonatal GD. The median age of onset for GD1, GD2, and GD3 was 72, 4 and 12 months, respectively, suggesting relatively earlier onset of GD1 and GD3 in Thai patients. All patients with GD1 and most patients with GD3 received ERT. Four patients with GD3 had ERT followed by HSCT. Patients with GD3 who received no or late ERT showed unfavorable outcomes. We identified 14 variants including two novel (p.S384F and p.W533*) and 12 reported pathogenic variants: p.L483P, p.N409S, p.R159W, p.P305A, p.A175G, p.D448H, p.V414L, IVS2+1G>A, IVS6-1G>C, IVS7+1G>C, IVS9-3C>G, and Rec1a. The p.L483P was the most prevalent allele found in this study, at 66% (33/50 alleles), followed by IVS2+1G>A, Rec1a, and IVS6-1G>C. Twenty-four percent of patients were reassigned with validated genotypes, most of whom (4 of 6) were patients with GD2. The [p.S384F + p.W533*] being compounded with p.L483P, was found in the patient with neonatal GD, suggesting that the p.S384F could potentiate the deleterious effect of the p.W533*, and/or vice versa. Conclusions Neuronopathic GD was strikingly prevalent among Thai affected population. Homozygous p.L483P was the most common genotype identified in Thai patients. Recombinant allele Rec1a and splicing mutations were associated with GD2 and severe cases of GD3. Mutation spectrum could be useful for designing stepwise molecular analysis, genetic screenings in population, and new therapeutic research for neuronopathic GD.

Clinical Evaluation of CCL18/PARC and Chitotriosidase Biomarkers in Gaucher Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3885-3885
Author(s):  
Pilar Alfonso ◽  
Paz Latre ◽  
Ignacio de Blas ◽  
Pilar Giraldo ◽  
Manuel Giralt ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Combined Therapy ◽  
Clinical Manifestations ◽  
Therapeutic Interventions ◽  
Substrate Reduction Therapy ◽  
Enzyme Analysis ◽  
Poor Correlation ◽  
Surrogate Markers ◽  
Lysosomal Storage ◽  
Enzyme Replacement

Abstract Gaucher’s disease (GD) is an autosomal recessive lysosomal storage disorder, characterized by accumulation of glycosphingolipid in so-called Gaucher cells. The clinical manifestations of Gaucher disease are highly variable, and although certain genotypes are often associated with mild or severe symtomps, a defined correlation between genotype and phenotype does not exist. Identification of serum biochemical markers characteristic of disease may be useful in the diagnosis and monitoring of GD, nevertheless about 6% of the population does not express the chitotriosidase (CT) gene. In this study, we analyzed using currently available enzyme analysis the relationship among two known surrogate markers: CT, which utility in initiation and optimization of costly therapeutic interventions has been highly demonstrated, and a newly-described chemokine, pulmonary and activation-regulated chemokine (CCL18/PARC) as associated to Gaucher disease. Patients and methods: We have analysed 21 control samples, 149 samples of GD patients on enzyme replacement therapy (ERT), and 52 samples of GD patients on substrate reduction therapy (SRT), 4 samples of GD on combined therapy (ERT+SRT) and 7 samples of GD patients without therapy. The samples were stored at −80°C in the biobank of Biochemistry and Molecular and Cellular Biology Department of Zaragoza University. The CT activity and CCL18/PARC quantification were performed simultaneously in the samples obtained at baseline and yearly during 7 years under ERT. Results: our results concluded that both markers levels similarly fell with time and their variations correlated strongly each other, mainly in patients under ERT. The poor correlation of both variables in the case of SRT might be due to small number of samples. These findings demonstrated that CCL18 is a good biomarker of monitoring GD, comparable to CT and very useful in patients without expression of CT gene. Conclusion: The availability of sensitive plasma surrogate markers may be of great value for monitoring the efficacy of treatment, especially in cases of deficiencies of some marker.

scholarly journals Substrate reduction therapy: clinical evaluation in type 1 Gaucher disease

2003 ◽  
Vol 358 (1433) ◽  
pp. 955-960 ◽  
Author(s):  
Chris Moyses
Keyword(s):  
Gaucher Disease ◽  
Clinical Manifestations ◽  
Residual Activity ◽  
Substrate Reduction Therapy ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Substrate Reduction ◽  
Clinical Consequences ◽  
Type 1 Gaucher Disease

Glycosphingolipid (GSL) lysosomal storage disorders are inherited enzyme deficiencies that result in pathological lysosomal accumulation of glycolipids, with widespread clinical consequences. Type 1 Gaucher disease is the commonest of these; the deficient enzyme in this condition is glucocerebrosidase. Clinical manifestations include hepatosplenomegaly, thrombocytopenia, anaemia, recurrent infections and skeletal lesions. The condition can be treated with intravenous enzyme replacement therapy (ERT). Substrate reduction therapy is a new approach in which glycolipid accumulation is counteracted not by replacing the deficient enzyme but by reducing the substrate level to better balance residual activity of the deficient enzyme. Miglustat is an inhibitor of glucosylceramide synthase, a key enzyme in GSL synthesis. Oral administration of miglustat to patients with type 1 Gaucher disease attenuates the synthesis of glucocerebroside, the substrate of the deficient glucocerebrosidase. In the first clinical study, patients with type 1 Gaucher disease who had enlargement of the liver or spleen and (if present) the spleen at baseline received 12 months treatment with oral miglustat. There were mean decreases in liver and spleen volumes of 12% (7.9–16.4, p < 0.001) and 19% (14.3–23.7, p < 0.001), respectively. Mean haemoglobin increased by 0.26 g dl −1 (−0.5−0.57, not statistically significant) and platelet count by 8.3 × 10 9 l −1 (1.9–14.7, p = 0.014).

scholarly journals Eye Movement Biomarkers Allow for the Definition of Phenotypes in Gaucher Disease

2020 ◽  
Author(s):  
Aimee Donald ◽  
Chong Yew Tan ◽  
Anupam Chakrapani ◽  
Derralyn Hughes ◽  
Reena Sharma ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Gaucher Disease ◽  
Saccadic Eye Movements ◽  
Disease Classification ◽  
Clinical Feature ◽  
Enzyme Replacement ◽  
Clinical Endpoints ◽  
Definition Of ◽  
Type 3

Abstract Background Neurological forms of Gaucher disease, the inherited disorder of b-Glucosylceramidase caused by bi-allelic variants in GBA1, is a progressive disorder which lacks a disease-modifying therapy. Systemic manifestations of disease are effectively treated with Enzyme Replacement Therapy (ERT), however, molecules which cross the blood-brain barrier are still under investigation. Clinical trials of such therapeutics require robust, reproducible clinical endpoints to demonstrate efficacy and clear phenotypic definitions to identify suitable patients for inclusion in trials. The single consistent clinical feature in all patients with neuronopathic disease is the presence of a supranuclear saccadic gaze palsy, in the presence of Gaucher disease this finding serves as diagnostic of ‘type 3’ Gaucher disease. MethodsWe undertook a study to evaluate saccadic eye movements in Gaucher patients and to assess the role of the EyeSeeCam in measuring saccades. The EyeSeeCam is a video oculography device which was used to run a protocol of saccade measures. We studied 39 patients with non-neurological Gaucher disease (type 1), 21 patients with type 3 (neurological) disease and a series of 35 healthy controls. Mean saccade parameters were compared across disease subgroups. ResultsWe confirmed the saccadic abnormality in patients with type 3 Gaucher disease andidentified an unexpected subgroup of patients with type 1 Gaucher disease who demonstrated significant saccade parameter abnormalities. These patients also showed subtle neurological findings and shared aGBA1 variant. ConclusionsThis striking novel finding of a potentially attenuated type 3 Gaucher phenotype associated with a specific GBA1 variant and detectable saccadic abnormality prompts review of current disease classification. Further, this finding highlights the broad spectrum of neuronopathic Gaucher phenotypes relevant when designing inclusion criteria for clinical trials.

scholarly journals Gaucher's Disease- A case report

2014 ◽  
Vol 3 (2) ◽  
pp. 45-48
Author(s):  
ASM Ruhul Quddush ◽  
Md Kamruzzaman ◽  
Md Badruzzaman ◽  
Mirja Hamidul Haque ◽  
Nazma Parvin Ansari ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Abdominal Distension ◽  
Disease Type ◽  
X Ray ◽  
Enzyme Replacement ◽  
Gaucher Disease Type 1 ◽  
Form Type ◽  
Type 3

A 3 years old immunized girl of consanguineous parents presented abdominal distension with hepatosplenomegaly. She was moderately anemic, moderately wasted and stunted. Neurological examination was normal. Musculoskeletal system examination revealed no abnormality. Diagnosis was supported by typical bone involvement in X-ray film (thin cortex in limb bone) and gaucher cell in the bone marrow and also in the splenic aspiration. There are three subtypes Type1: Non neuropathic form, Type 2: Acute neuropathic form, Type 3: Chronic neuropathic form. However some cases do not fit precisely into one of these categories. All forms of Gaucher disease are autosomal recessively inherited. So, this patient more or less correlates with Gaucher disease type 1. Treatment option for type 1 and 3 include medicine and enzyme replacement therapy, which is usually very effective. CBMJ 2014 July: Vol. 03 No. 02 P: 45-48

scholarly journals Gaucher disease: clinical phenotypes and refining GBA mutational spectrum in Thai patients

2021 ◽  
Author(s):  
Tim Phetthong ◽  
Thipwimol Tim-Aroon ◽  
Arthaporn Khongkraparn ◽  
Saisuda Noojarern ◽  
Chulaluck Kuptanon ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Age Of Onset ◽  
Lysosomal Storage ◽  
Pathogenic Variants ◽  
Medical Centers ◽  
Neurologic Involvement ◽  
Therapeutic Research ◽  
Type 3

Abstract Background Gaucher disease (GD is a rare lysosomal storage disorder, characterized by hepatosplenomegaly and pancytopenia, with or without neurologic involvement. The disorder is categorized into three phenotypes: GD type 1 or nonneuronopathic GD; GD type 2 or acute neuronopathic GD; and GD type 3 or chronic neuronopathic GD. The purposes of this study were to describe clinical characteristics of Thai GD in patients diagnosed and/or followed up during 2010–2018 and to perform re-genotyping including analysis of GBA recombinant alleles which had not been investigated in Thai patients before. Results There were 27 patients from seven medical centers, enrolled in the study. All the cases had pediatric onset. GD3 (44.5%) was the most common phenotype, followed by GD2 (40.7%) and GD1 (14.8%), with one case of neonatal GD. The median age of onset for GD1, GD2, and GD3 was 72, 4 and 12 months, respectively, suggesting relatively earlier onset of GD1 and GD3 in Thai patients. All patients with GD1 and most patients with GD3 received ERT. Four patients with GD3 had ERT followed by HSCT. Patients with GD3 who received no or late ERT showed unfavorable outcomes. We identified 14 mutations including two novel (p.S384F and p.W533*) and 12 reported pathogenic variants: p.L483P, p.N409S, p.R159W, p.P305A, p.A175G, p.D448H, p.V414L, IVS2 + 1G > A, IVS6-1G > C, IVS7 + 1G > C, IVS9-3C > G, and Rec1a. The p.L483P was the most prevalent allele found in this study, at 66% (33/50 alleles), followed by IVS2 + 1G > A, Rec1a, and IVS6-1G > C. Twenty-four percent of patients were reassigned with validated genotypes, most of whom (4 of 6) were patients with GD2. The [p.S384F + p.W533*] being compounded with p.L483P, was found in the patient with neonatal GD, suggesting that the p.S384F could potentiate the deleterious effect of the p.W533*, and/or vice versa. Conclusions Neuronopathic GD was strikingly prevalent among Thai affected population. Homozygous p.L483P was the most common genotype identified in Thai patients. Recombinant allele Rec1a and splicing mutations were associated with GD2 and severe cases of GD3. Mutation spectrum could be useful for designing stepwise molecular analysis, genetic screenings in population, and new therapeutic research for neuronopathic GD.

scholarly journals Mass Spectrometry Evaluation of Biomarkers in the Vitreous Fluid in Gaucher Disease Type 3 with Disease Progression Despite Long-Term Treatment

Diagnostics ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 69
Author(s):  
Aizeddin Mhanni ◽  
Michel Boutin ◽  
Frank Stockl ◽  
Janine Johnston ◽  
Jeff Barnes ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Visual Acuity ◽  
Gaucher Disease ◽  
Disease Type ◽  
Substrate Reduction Therapy ◽  
Lysosomal Storage ◽  
High Concentration ◽  
Enzyme Replacement ◽  
Long Term Treatment ◽  
Type 3

Intraocular lesions have been infrequently reported in patients with Gaucher disease type 3 (GD3). We previously reported siblings with GD3 who responded well to the combination of enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). Here we report progressive bilateral vitreous and preretinal deposits with declining visual acuity requiring bilateral vitrectomies in one of these siblings. These ocular manifestations had progressed despite combined ERT and SRT with improvement in visual acuity after vitrectomies. Vitrectomy fluid analysis performed for the first time by ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) identified a high concentration of glucosylceramide (GluCer) in the patient (262.842 nM) compared to a sample (0.428 nM from a patient without a lysosomal storage or known hereditary metabolic disorder). The GluCer detected in our patient was resolved into 12 different isoforms including two methylated ones. No evidence of galactosylceramide (GalCer) was detected. The development of these intraocular manifestations and their characterization by UPLC-MS/MS indicate a need for ongoing ophthalmologic evaluation of all GD patients and for new therapies that can cross the blood–retinal and blood–brain barriers for patients with GD and other neuropathic lysosomal storage disorders.

scholarly journals Genotype/phenotype relationship in Gaucher disease patients. Novel mutation in glucocerebrosidase gene

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Esperanza Lepe-Balsalobre ◽  
José D. Santotoribio ◽  
Ramiro Nuñez-Vazquez ◽  
Salvador García-Morillo ◽  
Pilar Jiménez-Arriscado ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Novel Mutation ◽  
Clinical Manifestations ◽  
University Hospital ◽  
Neurological Involvement ◽  
Lysosomal Storage ◽  
Neurological Alterations ◽  
Form Type ◽  
Monitoring Treatment

AbstractObjectivesGaucher disease (GD) is the most common inherited lysosomal storage disease, caused by mutations in acid β-glucosidase (GBA) gene. This study aimed to identify mutations in Andalusia patients with GD and their genotype-phenotype correlation.MethodsDescriptive observational study. University Hospital Virgen del Rocio patients diagnosed from GD from 1999 to 2019 were included. Demographic and clinical data, β-glucocerebrosidase activity, variants pathogenic in GBA gene and biomarkers for monitoring treatment were collected from digital medical record.ResultsTwenty-six patients with aged between 1 day and 52 years were studied. A total of six mutations described as pathogenic and one mutation not described above [c.937T>C (p.Tyr313His)] were identified in the GBA gene, four patients were homozygotes and 22 compound heterozygotes. Twenty-four patients were diagnosed in non-neuropathic form (type 1) and two cases presented neurological involvement (type 2 or 3). The most common variant was c.1226A>G (p.Asn409Ser), which was detected in 24 patients, followed by c.1448T>C (p.Leu483Pro) variant, identified in 13 patients. The c.1448T>C (p.Leu483Pro) mutation has been presented in the most severe phenotypes with neurological involvement associated with type 2 and 3 GD, while c.1226A>G (p.Asn409Ser) mutation has not been associated with neurological alterations. Splenomegaly and bone disease were the most frequent clinical manifestations, and thrombocytopenia was the most common hematological disorder.ConclusionsThe c.1226A>G (p.Asn409Ser) and c.1448T>C (p.Leu483Pro) mutations were the most common. The c.937T>C (p.Tyr313His) was identified as a novel mutation. The c.1448T>C (p.Leu483Pro) mutation was associated with neurological alterations and c.1226A>G (p.Asn409Ser) mutation has not been associated it.

scholarly journals Eye movement biomarkers allow for the definition of phenotypes in Gaucher Disease

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Aimee Donald ◽  
Chong Y. Tan ◽  
Anupam Chakrapani ◽  
Derralyn A. Hughes ◽  
Reena Sharma ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Gaucher Disease ◽  
Saccadic Eye Movements ◽  
Disease Classification ◽  
Clinical Feature ◽  
Enzyme Replacement ◽  
Clinical Endpoints ◽  
Definition Of ◽  
Type 3

Abstract Background Neurological forms of Gaucher disease, the inherited disorder of β-Glucosylceramidase caused by bi-allelic variants in GBA1, is a progressive disorder which lacks a disease-modifying therapy. Systemic manifestations of disease are effectively treated with enzyme replacement therapy, however, molecules which cross the blood–brain barrier are still under investigation. Clinical trials of such therapeutics require robust, reproducible clinical endpoints to demonstrate efficacy and clear phenotypic definitions to identify suitable patients for inclusion in trials. The single consistent clinical feature in all patients with neuronopathic disease is the presence of a supranuclear saccadic gaze palsy, in the presence of Gaucher disease this finding serves as diagnostic of ‘type 3’ Gaucher disease. Methods We undertook a study to evaluate saccadic eye movements in Gaucher patients and to assess the role of the EyeSeeCam in measuring saccades. The EyeSeeCam is a video-oculography device which was used to run a protocol of saccade measures. We studied 39 patients with non-neurological Gaucher disease (type 1), 21 patients with type 3 (neurological) disease and a series of 35 healthy controls. Mean saccade parameters were compared across disease subgroups. Results We confirmed the saccadic abnormality in patients with type 3 Gaucher disease and identified an unexpected subgroup of patients with type 1 Gaucher disease who demonstrated significant saccade parameter abnormalities. These patients also showed subtle neurological findings and shared a GBA1 variant. Conclusions This striking novel finding of a potentially attenuated type 3 Gaucher phenotype associated with a specific GBA1 variant and detectable saccadic abnormality prompts review of current disease classification. Further, this finding highlights the broad spectrum of neuronopathic Gaucher phenotypes relevant when designing inclusion criteria for clinical trials.

scholarly journals Eye movement biomarkers allow for the definition of phenotypes in Gaucher Disease

2020 ◽  
Author(s):  
Aimee Donald ◽  
Chong Yew Tan ◽  
Anupam Chakrapani ◽  
Derralyn Hughes ◽  
Reena Sharma ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Gaucher Disease ◽  
Saccadic Eye Movements ◽  
Disease Classification ◽  
Clinical Feature ◽  
Enzyme Replacement ◽  
Clinical Endpoints ◽  
Definition Of ◽  
Type 3

Abstract Background Neurological forms of Gaucher disease, the inherited disorder of β-Glucosylceramidase caused by bi-allelic variants in GBA1, is a progressive disorder which lacks a disease-modifying therapy. Systemic manifestations of disease are effectively treated with Enzyme Replacement Therapy (ERT), however, molecules which cross the blood-brain barrier are still under investigation. Clinical trials of such therapeutics require robust, reproducible clinical endpoints to demonstrate efficacy and clear phenotypic definitions to identify suitable patients for inclusion in trials. The single consistent clinical feature in all patients with neuronopathic disease is the presence of a supranuclear saccadic gaze palsy, in the presence of Gaucher disease this finding serves as diagnostic of ‘type 3’ Gaucher disease. Methods We undertook a study to evaluate saccadic eye movements in Gaucher patients and to assess the role of the EyeSeeCam in measuring saccades. The EyeSeeCam is a video oculography device which was used to run a protocol of saccade measures. We studied 39 patients with non-neurological Gaucher disease (type 1), 21 patients with type 3 (neurological) disease and a series of 35 healthy controls. Mean saccade parameters were compared across disease subgroups. Results We confirmed the saccadic abnormality in patients with type 3 Gaucher disease and identified an unexpected subgroup of patients with type 1 Gaucher disease who demonstrated significant saccade parameter abnormalities. These patients also showed subtle neurological findings and shared a GBA1 variant. Conclusions This striking novel finding of a potentially attenuated type 3 Gaucher phenotype associated with a specific GBA1 variant and detectable saccadic abnormality prompts review of current disease classification. Further, this finding highlights the broad spectrum of neuronopathic Gaucher phenotypes relevant when designing inclusion criteria for clinical trials.

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