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

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

Gaucher Disease Type 1: Cloning and Characterization of a cDNA Encoding Acid β-Glucosidase from an Ashkenazi Jewish Patient

DNA ◽  
1988 ◽  
Vol 7 (8) ◽  
pp. 521-528 ◽  
Author(s):  
PETER N. GRAVES ◽  
GREGORY A. GRABOWSKI ◽  
ROBIN EISNER ◽  
PETER PALESE ◽  
FRANCES I. SMITH
Keyword(s):  
Gaucher Disease ◽  
Disease Type ◽  
Ashkenazi Jewish ◽  
Jewish Patient ◽  
Gaucher Disease Type 1

scholarly journals The GBA p.G85E mutation in Korean patients with non-neuronopathic Gaucher disease: founder and neuroprotective effects

2020 ◽  
Author(s):  
Yoo-Mi Kim ◽  
Jin-Ho Choi ◽  
Gu-Hwan Kim ◽  
Young Bae Sohn ◽  
Jung-Min Ko ◽  
...  
Keyword(s):  
Founder Effect ◽  
Gaucher Disease ◽  
Clinical Characteristics ◽  
Haplotype Analysis ◽  
Study Cohort ◽  
Ashkenazi Jewish ◽  
Founder Effects ◽  
Neuroprotective Effects ◽  
Shared Haplotype

Abstract Background Gaucher disease (GD) is caused by a deficiency of β-glucocerebrosidase, encoded by GBA. Haplotype analyses previously demonstrated founder effects for particular GBA mutations in Ashkenazi Jewish and French-Canadian populations. This study aimed to investigate the clinical characteristics and mutation spectrum of GBA in Korean GD patients and to identify founder effect of GBA p.G85E in non-neuronopathic GD patients. Results The study cohort included 63 GD patients from 58 unrelated families. Among them, 18 patients from 17 families harboured the p.G85E mutation. Haplotype analysis was performed for 9 probands and their parents for whom DNA samples were available. In 58 unrelated probands, the GBA mutation p.L483P was the most common (30/116 alleles, 26%), followed by p.G85E (16%), p.F252I (13%), and p.R296Q (10%). Of the 18 patients harbouring the p.G85E mutation, their median age at diagnosis was 3.8 (range 1.2–57) years. No patients developed neurological symptoms during follow-up periods of 2.2–20.3 (median 13.9) years. The size of the shared haplotype containing GBA p.G85E was 732 kbp, leading to an estimated age of 3,075 years. Conclusion The GBA p.G85E mutation, which appears to be neuroprotective despite producing distinctive visceromegaly and skeletal symptoms, exhibited a potential founder effect in Korean GD patients.

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 The GBA p.G85E mutation in Korean patients with non-neuronopathic Gaucher disease: founder and neuroprotective effects

2020 ◽  
Author(s):  
Yoo-Mi Kim ◽  
Jin-Ho Choi ◽  
Gu-Hwan Kim ◽  
Young Bae Sohn ◽  
Jung-Min Ko ◽  
...  
Keyword(s):  
Founder Effect ◽  
Gaucher Disease ◽  
Clinical Characteristics ◽  
Haplotype Analysis ◽  
Study Cohort ◽  
Ashkenazi Jewish ◽  
Founder Effects ◽  
Neuroprotective Effects ◽  
Shared Haplotype

Abstract Background Gaucher disease (GD) is caused by a deficiency of β-glucocerebrosidase, encoded by GBA. Haplotype analyses previously demonstrated founder effects for particular GBA mutations in Ashkenazi Jewish and French-Canadian populations. This study aimed to investigate the clinical characteristics and mutation spectrum of GBA in Korean GD patients and to identify founder effect of GBA p.G85E in non-neuronopathic GD patients. Results The study cohort included 62 GD patients from 58 unrelated families. Among them, 18 patients from 17 families harbored the p.G85E mutation. Haplotype analysis was performed for 9 probands and their parents for whom DNA samples were available. In 58 unrelated probands, the GBA mutation p.L483P was the most common (30/116 alleles, 26%), followed by p.G85E (16%), p.F252I (13%), and p.R296Q (9%). The median age at diagnosis of the 18 patients harboring the p.G85E mutation was 3.8 (range 1.2–57) years. No patients developed neurological symptoms during follow-up periods of 2.2–20.3 (median 13.9) years. The size of the shared haplotype containing GBA p.G85E was 732 kbp, leading to an estimated age of 3,075 years. ConclusionThe GBA p.G85E mutation, which appears to be neuroprotective despite producing distinctive visceromegaly and skeletal symptoms, exhibited a potential founder effect in Korean GD patients.

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.

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