scholarly journals Age Estimate of the N370S Mutation Causing Gaucher Disease in Ashkenazi Jews and European Populations: A Reappraisal of Haplotype Data

2000 ◽  
Vol 66 (2) ◽  
pp. 692-697 ◽  
Author(s):  
Roberto Colombo
Keyword(s):  
Gaucher Disease ◽  
Ashkenazi Jews ◽  
Haplotype Data ◽  
European Populations ◽  
N370s Mutation

Frequency of carriers of chronic (type I) Gaucher disease in Ashkenazi Jews

1987 ◽  
Vol 27 (3) ◽  
pp. 561-565 ◽  
Author(s):  
Yehuda Maloth ◽  
Sara Chazan ◽  
Avital Cnaan ◽  
Ilana Gelernter ◽  
Chaya Klibansky ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Type I ◽  
Ashkenazi Jews ◽  
Chronic Type

scholarly journals Linkage Disequilibrium Analysis of the Gaucher Disease N370S Mutation

1999 ◽  
Vol 45 (4, Part 2 of 2) ◽  
pp. 137A-137A
Author(s):  
G A Diaz ◽  
B D Gelb ◽  
N Risch ◽  
T Nygaard ◽  
I Maire ◽  
...  
Keyword(s):  
Linkage Disequilibrium ◽  
Gaucher Disease ◽  
Linkage Disequilibrium Analysis ◽  
N370s Mutation

scholarly journals Gaucher Disease: The N370S Mutation in Ashkenazi Jewish and Spanish Patients has a Common Origin and Arose Several Thousand Years Ago

1999 ◽  
Vol 64 (4) ◽  
pp. 1233-1238 ◽  
Author(s):  
Anna Díaz ◽  
Baijin Zeng ◽  
Gregory M. Pastores ◽  
Amparo Chabás ◽  
Lluïsa Vilageliu ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Common Origin ◽  
Ashkenazi Jewish ◽  
N370s Mutation

Variation of Serum Lipid Profile during Enzyme Replacement Therapy, in Patients with Type 1 Gauchers Disease.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3849-3849
Author(s):  
Argiris Symeonidis ◽  
Derralynn Hughes ◽  
Linda Richfield ◽  
Atul Mehta
Keyword(s):  
Platelet Count ◽  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Success Rate ◽  
Gaucher Disease ◽  
Type I ◽  
Success Rates ◽  
Enzyme Replacement ◽  
Pulmonary Manifestations ◽  
N370s Mutation

Abstract Enzyme Replacement Therapy (ERT) has dramatically changed the clinical course and prognosis of patients with Gaucher disease. We have assessed the extent to which the recently defined Goals of Therapy (Pastores et al, Semin Hematol 41(suppl 5):4–14) in 9 major fields (anemia, thrombocytopenia, hepatomegaly, splenomegaly, skeletal pathology,biomarkers, pulmonary manifestations, growth and functional health and well being) were achieved in our cohort of patients with type I Gaucher disease. Fifty-seven patients (27 females, 30 males, median age at diagnosis 30 years (range 2–77 years) and at start of ERT 39 years (range 5–79 years) were assessed. The median period of ERT was 94 months (range 24–155 months). Patients on ERT for less than 2 years were excluded. Twenty five specific goals are defined within the 9 fields. The median overall success rate was 20 of 25 goals or 80% per patient (range 12–25 goals or 60–100%). The success rate for 9 goals was 100% ( normalization of hemoglobin 1 year post-splenectomy, no major bleeding 1 year after ERT start, doubling of baseline platelet count in severely thrombocytopenic patients 2 years after ERT start, maintenance of platelet count in non-thrombocytopenic patients, prevention of bone crises, reversion of hepatopulmonary syndrome and dependence on oxygen, amelioration of pulmonary hypertension and prevention of rapid deterioration of pulmonary disease and sudden death). Higher success rates were achieved for the goals related to thrombocytopenia (97.9%) and pulmonary manifestations (97%) although in the latter case the applicability was low. Lower success rates were achieved for the goals related to bone manifestations (78.7%). There was no significant difference in the success rate between males and females, splenectomised and non-splenectomised patients, and between patients treated less or more than 6 years. However patients started on ERT before the 40th year of age exhibited significantly higher success rate as compared to patients started after the 40th year (p=0.047) and there was a significant inverse correlation between overall success rate and patient’s age at treatment start (r = − 0.437). Finally, the success rate was higher among double heterozygotes, carrying the N370S mutation, as compared to patients homozygous for the N370S mutation (89.2±9.6% vs. 80.2±12.9%, p=0.016).

Base editing of the N370S mutation in Gaucher disease skin fibroblasts

2021 ◽  
Vol 132 (2) ◽  
pp. S26
Author(s):  
Chloe Christensen ◽  
Emma Wells-Durand ◽  
Anna-Maria Hilton ◽  
Jenna Thompson ◽  
Samuel Chu ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Skin Fibroblasts ◽  
Base Editing ◽  
N370s Mutation

scholarly journals Finding and Treating Gaucher Disease Type 1 – The Role of the Haematologist

2018 ◽  
Vol 14 (1) ◽  
pp. 50
Author(s):  
Maria-Domenica Cappellini ◽  
Elena Cassinerio ◽  
Irene Motta ◽  
William Morello ◽  
Jesús Villarubia
Keyword(s):  
Gaucher Disease ◽  
Clinical Symptoms ◽  
Genetic Disorder ◽  
Diagnostic Delay ◽  
Screening Tools ◽  
Substrate Reduction Therapy ◽  
Lysosomal Storage ◽  
Ashkenazi Jews ◽  
Enzyme Replacement

Gaucher disease (GD) type 1 is the most common lysosomal storage disease and the most common genetic disorder among Ashkenazi Jews. The majority of patients with GD present with unexplained splenomegaly and/or thrombocytopenia, and the disorder often affects children; consequently, haematologists and paediatricians are ideally placed to diagnose this condition. Prompt management of GD type 1 using enzyme-replacement therapy or substrate reduction therapy can reduce the risk of developing long-term GD complications and reverse many of the initial signs/symptoms, thereby improving both quality and duration of life. Treatment is most effective when initiated early; consequently, a prompt diagnosis is essential. Despite this, the average time to diagnosis following the onset of clinical symptoms is 4 years. Reasons for the delay include the heterogeneous nature of the disease, together with a lack of awareness of rare haematological disorders and the benefits of early treatment. Indeed, studies show that only 20% of haematologists consider GD type 1 in their differential diagnosis for patients presenting with splenomegaly and/or thrombocytopenia. To help raise awareness of GD, reduce the diagnostic delay and prevent unnecessary tissue biopsies, simple diagnostic algorithms and screening tools have been developed and validated, both in adults and in children.

Multi-Parameter Neurological Study Based on Combined Conventional and Functional Assessments in Gaucher Disease Patients (SENOPRO_GAUCHER Study)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 12-12
Author(s):  
Emanuele Cerulli Irelli ◽  
Carlo Di Bonaventura ◽  
Gianmarco Tessari ◽  
Tiziana Di Pippo ◽  
Rosaria Turchetta ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
Research Funding ◽  
Cognitive Impairments ◽  
Cognitive Test ◽  
Type I ◽  
Brain White Matter ◽  
Neurological Abnormalities ◽  
The Brain ◽  
N370s Mutation ◽  
Sd Oct

Gaucher Disease (GD), a metabolic inherited disorder, includes three clinical phenotypes. Type I GD (GD1), that can mimic a hematologic disease, has been classically considered as a non-neuropathic variant; type II (GD2) and type III (GD3) are classified as acute and chronic neuropathic forms, respectively. A protective role of N370S mutation against neurological impairment had been previously hypothesized in GD1, however, clinical signs of parkinsonism have recently been reported in this category of patients. The aim of our observational, monocentric, and prospective study, called SENOPRO_GAUCHER, was to evaluate in depth the neurological and neuropsychiatric aspects in GD1 patients, using clinical and instrumental investigations, in order to identify clinical and subclinical neurological manifestations, including cognitive impairment and behavioural alterations. Neurological assessments were scheduled for 22 GD patients (19 GD1 and 3 GD3) aged >12 years. Clinical evaluation, including Severity Scoring Tool Unified Parkinson's Disease Rating scale and Epworth Sleepiness scale; psychological tests and psychiatric evaluation, using a cognitive test battery and two psychiatric (BPRS) and psychological (CBA 2.0) questionnaires; somatosensory, motor and visual evoked potential, spectral domain optical coherence tomography (SD-OCT), standard electroretinogram; electroencephalography (EEG), and magnetic resonance (MR) 3Tesla, were planned at baseline, after 12 and 24 months. Results at the baseline evaluation of all 22 enrolled patients (9 males and 13 females; median age at the study: 44.5 years, range 17 - 68) are here reported. Regarding genotyping, all but one of the 19 GD1 pts was heterozygous for the N370S mutation. Parkinsonian motor signs were found in 10/22 patients (9 GD1): 7 pts (6 GD1) had isolated bradykinesia and 3 GD1 patients presented bradykinesia combined with rigidity. Abnormal saccadic movements were found in all GD3 pts and in one GD1. Excessive daytime sleepiness (EDS) was detected in 9/22 patients (8 GD1). EEG revealed focal, or diffuse slow waves in 6 patients (5 GD1). Significant cognitive impairments in attention, language, memory and executive functions were found in 4/19 GD1 and in 2/3 GD3 patients. Moreover, psychological and psychiatric evaluations underlined anxiety, depression and somatic concerns in 10/22 patients (9 GD1), combined with cognitive impairments in 3/12. Sixteen patients (13 GD1) showed slight or moderate sensorineural hearing loss (SNHL), and 4 of them had a cookie and reverse cookie bite morphology, typically associated with genetic SNHL. Ophthalmological evaluation revealed a degree of retinal blood vessel tortuosity in all but one patient, and superficial corneal dystrophies in 3 patients (2 GD1). An increased latency and moderate reduction in the amplitudes of optic nerve function were found in 13/22 patients (10 GD1). The SD-OCT examination showed impairment in retinal nerve fibre layers in 7 patients (6 GD1), combined with macular damage in 2 of them. Qualitative MR 3Tesla examinations revealed unspecific abnormalities in 7/19 (37%) GD1 patients; in particular, cortical and/or subcortical areas of gliosis (4 patients), vascular ectasia extended from the left frontal surface of the brain to the lateral ventricle (1 patient), dilation of perivascular spaces in the sub-cortical and nucleus-basal area (1 patient), diffuse suffering of the brain white matter due to a chronic ischemic vascular damage (1 patient). In summary, all GD3 patients showed a wide spectrum of neurological abnormalities, as expected. Surprisingly, however, all GD1 pts also presented at least two, or more, clinical and/or instrumental, neurological signs. The high prevalence of EDS in our population suggests a possible underlying sleep disorder which should be further investigated. The N370S mutation did not impact the likelihood of developing neurological abnormalities in our cohort of GD1 patients. In conclusion, our results have demonstrated that a multidisciplinary, and in-depth approach is necessary in evaluating GD1 patients. Disclosures Giona: Sanofi Genzyme: Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Novartis: Research Funding.

Gaucher disease: frequency of the N370S mutation in the Greek population

2010 ◽  
Vol 78 (2) ◽  
pp. 195-196 ◽  
Author(s):  
E Dimitriou ◽  
M Moraitou ◽  
C Troungos ◽  
K Schulpis ◽  
H Michelakakis
Keyword(s):  
Gaucher Disease ◽  
Greek Population ◽  
N370s Mutation

scholarly journals Enzyme therapy in Gaucher disease type 1: dosage efficacy and adverse effects in 33 patients treated for 6 to 24 months

Blood ◽  
1993 ◽  
Vol 82 (2) ◽  
pp. 408-416 ◽  
Author(s):  
GM Pastores ◽  
AR Sibille ◽  
GA Grabowski
Keyword(s):  
Gaucher Disease ◽  
Enzyme Therapy ◽  
Lysosomal Storage ◽  
Ashkenazi Jews ◽  
Gaucher Disease Type 1 ◽  
Beta Glucosidase ◽  
Age Range ◽  
Different Doses ◽  
Dose Reductions

Abstract Gaucher disease is the most frequent lysosomal storage disease and the most prevalent genetic disease among the Ashkenazi Jews (q approximately 0.047). The disease results from inherited defects of acid beta-glucosidase and the accumulation of the substrate, glucosylceramide, in cells of monocyte/macrophage origin. The therapeutic response to macrophage-targeted (alpha-mannosyl-terminated) alglucerase (Ceredase, at 60 to 15 IU/kg every 2 weeks) was analyzed in 33 patients (age range, 2 to 63 years; 15 splenectomized) with extensive Gaucher disease over periods of 6 to 24 months. The efficacy of several different doses and dosage reductions was evaluated. In patients with anemia (n = 30) and/or thrombocytopenia (n = 19), hemoglobin levels and platelet counts increased by 0% to 178% and 15% to 155%, respectively, within 3 to 12 months. In patients with splenomegaly (n = 17) and/or hepatomegaly (n = 28), liver and spleen volumes decreased in 6 months from 7% to 64% and 8% to 84% by 12 months, respectively. Hematologic and visceral improvements were noted at any doses between 60 and 15 IU/kg every 2 weeks. Furthermore, these positive initial therapeutic responses were persistent throughout therapy, with doses reduced by 50%. Pulmonary Gaucher disease did not improve clinically in 3 patients. Unrelated cirrhotic (n = 2), cholestatic (n = 1), or renal disease (n = 1) did not influence the rate of patient improvement. Two of five patients who developed serum antibodies against alglucerase during the first 6 to 12 months of therapy had mild antibody reactions. This study shows similar regression of clinical Gaucher disease manifestations with enzyme therapy, using doses between 30 and 60 IU/kg every 2 weeks. Therapeutic efficacy was not diminished after 50% to 75% dose reductions or in the presence of anti-enzyme antibodies.

scholarly journals A Tale of Two Hypotheses: Genetics and the Ethnogenesis of Ashkenazi Jewry

2013 ◽  
Author(s):  
Aram Yardumian
Keyword(s):  
Early Modern ◽  
Genetic Data ◽  
Ashkenazi Jews ◽  
The Caucasus ◽  
Near Eastern ◽  
Arthur Koestler ◽  
Jewish Ancestry ◽  
Per Se ◽  
Analytical Approaches ◽  
European Populations

The debate over the ethnogenesis of Ashkenazi Jewry is longstanding, and has been hampered by a lack of Jewish historiographical work between the Biblical and the early Modern eras. Most historians, as well as geneticists, situate them as the descendants of Israelite tribes whose presence in Europe is owed to deportations during the Roman conquest of Palestine, as well as migration from Babylonia, and eventual settlement along the Rhine. By contrast, a few historians and other writers, most famously Arthur Koestler, have looked to migrations following the decline of the little-understood Medieval Jewish kingdom of Khazaria as the main source for Ashkenazi Jewry. A recent study of genetic variation in southeastern European populations (Elhaik 2012) also proposed a Khazarian origin for Ashkenazi Jews, eliciting considerable criticism from other scholars investigating Jewish ancestry who favor a Near Eastern origin of Ashkenazi populations. This paper re-examines the genetic data and analytical approaches used in these studies of Jewish ancestry, and situates them in the context of historical, linguistic, and archaeological evidence from the Caucasus, Europe and the Near East. Based on this reanalysis, it appears not only that the Khazar Hypothesis per se is without serious merit, but also the veracity of the ‘Rhineland Hypothesis’ may also be questionable.

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