Advances in Gaucher Disease: A Model for Rare Lysosomal Disorders

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Cells cells	7.666	6.7	2012	16.4 Days	2400 CHF
Current Issues in Molecular Biology cimb	2.976	2.7	1999	17.2 Days	2000 CHF
Diseases diseases	-	-	2013	23.1 Days	1600 CHF
International Journal of Molecular Sciences ijms	6.208	6.9	2000	15.9 Days	2500 CHF
International Journal of Neonatal Screening IJNS	-	3.2	2015	18.3 Days	1000 CHF
International Journal of Translational Medicine ijtm	-	-	2021	18.8 Days	1000 CHF
Journal of Clinical Medicine jcm	4.964	4.4	2012	18 Days	2600 CHF
Metabolites metabolites	5.581	4.7	2011	12.9 Days	2200 CHF

Open AccessArticle

The Spectrum of Neurological and Sensory Abnormalities in Gaucher Disease Patients: A Multidisciplinary Study (SENOPRO)

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Maria Giulia Tullo

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Emanuele Cerulli Irelli

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Anna Teresa Giallonardo

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Int. J. Mol. Sci. 2023, 24(10), 8844; https://doi.org/10.3390/ijms24108844 - 16 May 2023

Viewed by 315

Abstract

Gaucher disease (GD) has been increasingly recognized as a continuum of phenotypes with variable neurological and sensory involvement. No study has yet specifically explored the spectrum of neuropsychiatric and sensory abnormalities in GD patients through a multidisciplinary approach. Abnormalities involving the nervous system, [...] Read more.

Gaucher disease (GD) has been increasingly recognized as a continuum of phenotypes with variable neurological and sensory involvement. No study has yet specifically explored the spectrum of neuropsychiatric and sensory abnormalities in GD patients through a multidisciplinary approach. Abnormalities involving the nervous system, including sensory abnormalities, cognitive disturbances, and psychiatric comorbidities, have been identified in GD1 and GD3 patients. In this prospective study, named SENOPRO, we performed neurological, neuroradiological, neuropsychological, ophthalmological, and hearing assessments in 22 GD patients: 19 GD1 and 3 GD3. First, we highlighted a high rate of parkinsonian motor and non-motor symptoms (including high rates of excessive daytime sleepiness), especially in GD1 patients harboring severe glucocerebrosidase variants. Secondly, neuropsychological evaluations revealed a high prevalence of cognitive impairment and psychiatric disturbances, both in patients initially classified as GD1 and GD3. Thirdly, hippocampal brain volume reduction was associated with impaired short- and long-term performance in an episodic memory test. Fourthly, audiometric assessment showed an impaired speech perception in noise in the majority of patients, indicative of an impaired central processing of hearing, associated with high rates of slight hearing loss both in GD1 and GD3 patients. Finally, relevant structural and functional abnormalities along the visual system were found both in GD1 and GD3 patients by means of visual evoked potentials and optical coherence tomography. Overall, our findings support the concept of GD as a spectrum of disease subtypes, and support the importance of in-depth periodic monitoring of cognitive and motor performances, mood, sleep patterns, and sensory abnormalities in all patients with GD, independently from the patient’s initial classification. Full article

(This article belongs to the Topic Advances in Gaucher Disease: A Model for Rare Lysosomal Disorders)

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Open AccessBrief Report

The Bone Biomarker of Quantitative Chemical Shift Imaging in Patients with Type 1 Gaucher Disease Receiving Low-Dose Long-Term Enzyme Replacement Therapy

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J. Clin. Med. 2023, 12(6), 2220; https://doi.org/10.3390/jcm12062220 - 13 Mar 2023

Viewed by 524

Abstract

Quantitative chemical shift imaging (QCSI) is the most sensitive imaging biomarker to assess bone marrow involvement in Gaucher disease. Widespread QCSI use is limited by test availability. Anecdotal reports describe two patients demonstrating significant improvement in fat fraction (FF) assessed by QCSI following [...] Read more.

Quantitative chemical shift imaging (QCSI) is the most sensitive imaging biomarker to assess bone marrow involvement in Gaucher disease. Widespread QCSI use is limited by test availability. Anecdotal reports describe two patients demonstrating significant improvement in fat fraction (FF) assessed by QCSI following a switch from imiglucerase to taliglucerase alfa. This analysis evaluated bone marrow involvement in adults with Type 1 Gaucher disease receiving low-dose enzyme replacement therapy (ERT) with imiglucerase and/or velaglucerase alfa. We report baseline data for 30 patients meeting eligibility criteria. Median (range) duration and dose of ERT were 18 (5–26) years and 30 (30–60) U/kg/month, respectively. Low FF scores (<0.30) were observed for seven patients (23%; 95% confidence interval, 10–42%) and were more common in females (n = 6) versus males (n = 1; p < 0.025); one female was menopausal. These baseline data demonstrate that prolonged low-dose ERT with imiglucerase or velaglucerase alfa led to an adequate bone response, assessed by QCSI, in the majority of patients. A minority of such patients with suboptimal bone response require therapeutic change. The next phase of the study will address the effect of switching to taliglucerase alfa on bone status for patients with less than optimal QCSI scores (<0.30). Full article

(This article belongs to the Topic Advances in Gaucher Disease: A Model for Rare Lysosomal Disorders)

Open AccessReview

Global Incidence and Prevalence of Gaucher Disease: A Targeted Literature Review

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Genaro Castillon

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Shun-Chiao Chang

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Yola Moride

J. Clin. Med. 2023, 12(1), 85; https://doi.org/10.3390/jcm12010085 - 22 Dec 2022

Cited by 1 | Viewed by 1570

Abstract

Incidence and prevalence estimates for Gaucher disease (GD) are scarce for this rare disease and can be variable within the same region. This review provides a qualitative synthesis of global GD incidence and prevalence estimates, GD1–3 type-specific and overall, published in the last [...] Read more.

Incidence and prevalence estimates for Gaucher disease (GD) are scarce for this rare disease and can be variable within the same region. This review provides a qualitative synthesis of global GD incidence and prevalence estimates, GD1–3 type-specific and overall, published in the last 10 years. A targeted literature search was conducted across multiple databases from January 2011 to September 2020, including web-based sources and congress proceedings to May 2021. Searches yielded 490 publications, with 31 analyzed: 20 cohort studies (15 prospective, 5 retrospective), 6 cross-sectional studies, 5 online reports (most from Europe (n = 11) or North America (n = 11); one multiregional). Across all GD types, incidence estimates ranged 0.45–25.0/100,000 live births (16 studies), lowest for Asia-Pacific. Incidence of GD1: 0.45–22.9/100,000 live births (Europe and North America) and GD3: 1.36/100,000 live births (Asia-Pacific only). GD type-specific prevalence estimates per 100,000 population were GD1: 0.26–0.63; GD2 and GD3: 0.02–0.08 (Europe only); estimates for GD type unspecified or overall ranged 0.11–139.0/100,000 inhabitants (17 studies), highest for North America. Generalizability was assessed as “adequate”or “intermediate” for all regions with data. GD incidence and prevalence estimates for the last 10 years varied considerably between regions and were poorly documented outside Europe and North America. Data for GD2 and GD3 were limited. Full article

(This article belongs to the Topic Advances in Gaucher Disease: A Model for Rare Lysosomal Disorders)

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Open AccessCase Report

Glucosylsphingosine (Lyso-Gb₁): An Informative Biomarker in the Clinical Monitoring of Patients with Gaucher Disease

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Matthew M. Gayed

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Seung-Hye Jung

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Erin Huggins

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Eleanor Rodriguez-Rassi

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Stephanie DeArmey

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Priya Sunil Kishnani

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Ashlee R. Stiles

Int. J. Mol. Sci. 2022, 23(23), 14938; https://doi.org/10.3390/ijms232314938 - 29 Nov 2022

Viewed by 796

Abstract

Historically, disease burden and treatment responses in patients with Gaucher disease (GD) was assessed by monitoring clinical data, laboratory, imaging, chitotriosidase (CHITO), and other biomarkers; however, these biomarkers lack specificity and CHITO is uninformative in patients heterozygous or homozygous for the CHIT1 c.1049_1072dup24 [...] Read more.

Historically, disease burden and treatment responses in patients with Gaucher disease (GD) was assessed by monitoring clinical data, laboratory, imaging, chitotriosidase (CHITO), and other biomarkers; however, these biomarkers lack specificity and CHITO is uninformative in patients heterozygous or homozygous for the CHIT1 c.1049_1072dup24 variant. Recently, glucosylsphingosine (lyso-Gb₁), a sensitive and specific GD biomarker, has been recommended for patient monitoring. Furthermore, studies measuring lyso-Gb₁ and CHITO in patients on long-term treatment with enzyme replacement therapy (ERT) and/or substrate reduction therapy (SRT) reported as group data show a reduction in both analytes, yet individualized patient data are generally unavailable. We describe seven patients on long-term treatment with longitudinal clinical data with monitoring based on current treatment guidelines. We present four patients who exhibit stable disease with normalized CHITO despite elevated lyso-Gb₁. We present one patient who transitioned from ERT to SRT due to lack of a clinical response with life-threatening thrombocytopenia who responded with marked improvement in platelets, and normalized levels of both CHITO and lyso-Gb₁. Finally, we present two ERT to SRT switch patients with stable disease on ERT who exhibited non-compliance on SRT, one with mirrored marked elevations of CHITO and lyso-Gb₁; and another with normal CHITO and platelets, but increasing lyso-Gb₁ levels and enlarged spleen. These clinical vignettes highlight the role of lyso-Gb₁ as a sensitive biomarker in management of patients with GD, and its further value when CHITO is normal and thus uninformative. We highlight the personalized medicine approach needed to optimize treatment outcomes and recommendations for these patients. Full article

(This article belongs to the Topic Advances in Gaucher Disease: A Model for Rare Lysosomal Disorders)

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Open AccessArticle

Brain-Derived Neurotrophic Factor (BDNF) Is Associated with Platelet Activity and Bleeding Tendency in Patients with Gaucher Disease

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Int. J. Mol. Sci. 2022, 23(22), 13982; https://doi.org/10.3390/ijms232213982 - 12 Nov 2022

Viewed by 820

Abstract

Bleeding tendency, a prominent feature of patients with Gaucher disease (GD), is associated with abnormal platelet function. Brain-derived neurotrophic factor (BDNF) is a protein with neuroprotective potential stored in alpha granules of circulating platelets. Here we studied BDNF levels in 50 patients with [...] Read more.

Bleeding tendency, a prominent feature of patients with Gaucher disease (GD), is associated with abnormal platelet function. Brain-derived neurotrophic factor (BDNF) is a protein with neuroprotective potential stored in alpha granules of circulating platelets. Here we studied BDNF levels in 50 patients with type I GD (GD1) and their correlation with platelet activity and bleeding tendency. Flow cytometry was used to test unstimulated and stimulated measurement of platelet surface-activated expression of αIIbβ3 integrin, P-selectin and lysosomal-associated membrane protein (LAMP3/CD63). Serum and plasma BDNF levels were quantified using ELISA. The bleeding history was recorded by a bleeding questionnaire. Serum BDNF levels were positively correlated with platelet count and moderately correlated with unstimulated and stimulated platelet P-selectin expression. Patients with more than one bleeding manifestation were shown to have lower serum BDNF levels, albeit similar platelet count. Plasma BDNF levels were significantly elevated in splenectomized patients and showed a moderate positive correlation with stimulated platelet CD63 expression. These observations demonstrate the first association between BDNF levels in the peripheral blood with platelet dysfunction and increased bleeding manifestation. The role of measuring serum BDNF for assessing platelet alpha degranulation defects and bleeding risk in patients with GD and the general population needs further study. Full article

(This article belongs to the Topic Advances in Gaucher Disease: A Model for Rare Lysosomal Disorders)

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Open AccessArticle

Real-Life Experience with Oral Eliglustat in Patients with Gaucher Disease Previously Treated with Enzyme Replacement Therapy

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J. Clin. Med. 2022, 11(21), 6265; https://doi.org/10.3390/jcm11216265 - 24 Oct 2022

Cited by 1 | Viewed by 937

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Three types of enzyme replacement therapies (ERTs) and two substrate reduction therapies (SRTs) are approved for symptomatic patients with type 1 Gaucher disease (GD1). Eliglustat is the second SRT approved, yet the first to be approved as first-line therapy for any adult patients [...] Read more.

Three types of enzyme replacement therapies (ERTs) and two substrate reduction therapies (SRTs) are approved for symptomatic patients with type 1 Gaucher disease (GD1). Eliglustat is the second SRT approved, yet the first to be approved as first-line therapy for any adult patients with compatible CYP2D6 metabolizer genotype. Herein we report safety and efficacy data of the first 29 patients switched from ERT to eliglustat from the Gaucher Unit at Shaare Zedek Medical Center (SZMC) between 07/2017 and 06/2022; the median (range) time on ERT was 13 (0.66–30) years, and the median (range) time on eliglustat was 7 (1–52) months. Most patients switched due to oral preference or sub-optimal response to low-dose ERT. Twelve patients stopped eliglustat after a median (range) of 4 (1–18) months; 11 due to adverse events (AEs) and one due to personal request. There were no drug-related serious AEs and no drug-related cardiac events. Most AEs were mild and transient, mainly dyspepsia. Efficacy achievements were reflected by maintaining stability. We concluded that switching from ERT to eliglustat is safe if choosing the appropriate patients. Reassuring patients to tolerate early AEs may reduce discontinuation. Following the response and compliance to therapy is important to ensure long-term efficacy. Full article

(This article belongs to the Topic Advances in Gaucher Disease: A Model for Rare Lysosomal Disorders)

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Open AccessArticle

A Comprehensive Assessment of Qualitative and Quantitative Prodromal Parkinsonian Features in Carriers of Gaucher Disease—Identifying Those at the Greatest Risk

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Int. J. Mol. Sci. 2022, 23(20), 12211; https://doi.org/10.3390/ijms232012211 - 13 Oct 2022

Cited by 4 | Viewed by 955

Abstract

Carriers of GBA1 gene variants have a significant risk of developing Parkinson’s disease (PD). A cohort study of GBA carriers between 40–75 years of age was initiated to study the presence of prodromal PD features. Participants underwent non-invasive tests to assess different domains [...] Read more.

Carriers of GBA1 gene variants have a significant risk of developing Parkinson’s disease (PD). A cohort study of GBA carriers between 40–75 years of age was initiated to study the presence of prodromal PD features. Participants underwent non-invasive tests to assess different domains of PD. Ninety-eight unrelated GBA carriers were enrolled (43 males) at a median age (range) of 51 (40–74) years; 71 carried the N370S variant (c.1226A > G) and 25 had a positive family history of PD. The Montreal Cognitive Assessment (MoCA) was the most frequently abnormal (23.7%, 95% CI 15.7–33.4%), followed by the ultrasound hyperechogenicity (22%, 95% CI 14–32%), Unified Parkinson’s Disease Rating Scale part III (UPDRS-III) (17.2%, 95% CI 10.2–26.4%), smell assessment (12.4%, 95% CI 6.6–20.6%) and abnormalities in sleep questionnaires (11%, 95% CI 5.7–19.4%). Significant correlations were found between tests from different domains. To define the risk for PD, we assessed the bottom 10th percentile of each prodromal test, defining this level as “abnormal”. Then we calculated the percentage of “abnormal” tests for each subject; the median (range) was 4.55 (0–43.5%). Twenty-two subjects had more than 15% “abnormal” tests. The limitations of the study included ascertainment bias of individuals with GBA-related PD in relatives, some incomplete data due to technical issues, and a lack of well-characterized normal value ranges in some tests. We plan to enroll additional participants and conduct longitudinal follow-up assessments to build a model for identifying individuals at risk for PD and investigate interventions aiming to delay the onset or perhaps to prevent full-blown PD. Full article

(This article belongs to the Topic Advances in Gaucher Disease: A Model for Rare Lysosomal Disorders)

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Open AccessArticle

Using the Gaucher Earlier Diagnosis Consensus (GED-C) Delphi Score in a Real-World Dataset

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Int. J. Transl. Med. 2022, 2(3), 506-514; https://doi.org/10.3390/ijtm2030037 - 09 Sep 2022

Viewed by 1339

Abstract

Early and accurate diagnosis of Gaucher disease, a rare, autosomal recessive condition characterized by hepatosplenomegaly, thrombocytopenia, and anemia, is essential to facilitate earlier decision-making and prevent unnecessary tests and procedures. However, diagnosis can be challenging for non-specialists, owing to a wide variability in [...] Read more.

Early and accurate diagnosis of Gaucher disease, a rare, autosomal recessive condition characterized by hepatosplenomegaly, thrombocytopenia, and anemia, is essential to facilitate earlier decision-making and prevent unnecessary tests and procedures. However, diagnosis can be challenging for non-specialists, owing to a wide variability in age, severity of disease, and types of clinical manifestation. The Gaucher Earlier Diagnosis Consensus (GED-C) scoring system was developed by a panel of 22 expert physicians using Delphi methodology on the signs and covariables considered important for diagnosing Gaucher disease. This study aimed to use the scoring system in a real-world dataset. We applied the GED-C scoring system to 265 confirmed cases of Gaucher disease identified in the Maccabi Health Services (MHS) database from 1998 to 2022. Overall Delphi scores were calculated using features applicable to type 1 Gaucher disease. Based on all available patient data up to one year after diagnosis, the median (interquartile range (IQR)) Delphi score was 8.0 (5.5–11.5), with patients reporting up to 15 variables each. A score of 9.5 (6.5–12.5) was determined for 205 patients diagnosed from 2000 to 2022. The overall GED-C score was highly dependent on the extraction of all relevant data. The number of features collected in the MHS database was fewer than those required to achieve a high score on the GED-C score. Full article

(This article belongs to the Topic Advances in Gaucher Disease: A Model for Rare Lysosomal Disorders)

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Open AccessArticle

Biological Variation in Peripheral Inflammation and Oxidative Stress Biomarkers in Individuals with Gaucher Disease

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Siddhee A. Sahasrabudhe

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Int. J. Mol. Sci. 2022, 23(16), 9189; https://doi.org/10.3390/ijms23169189 - 16 Aug 2022

Cited by 2 | Viewed by 1067

Abstract

The lack of reliable biomarkers is a significant challenge impeding progress in orphan drug development. For appropriate interpretation of intervention-based results or for evaluating candidate biomarkers, other things being equal, lower variability in biomarker measurement would be helpful. However, variability in rare disease [...] Read more.

The lack of reliable biomarkers is a significant challenge impeding progress in orphan drug development. For appropriate interpretation of intervention-based results or for evaluating candidate biomarkers, other things being equal, lower variability in biomarker measurement would be helpful. However, variability in rare disease biomarkers is often poorly understood. Type 1 Gaucher disease (GD1) is one such rare lysosomal storage disorder. Oxidative stress and inflammation have been linked to the pathophysiology of GD1 and validated measures of these processes can provide predictive value for treatment success or disease progression. This study was undertaken to investigate and compare the extent of longitudinal biological variation over a three-month period for various blood-based oxidative stress and inflammation markers in participants with GD1 on stable standard-of-care therapy (N = 13), treatment-naïve participants with GD1 (N = 5), and in age- and gender-matched healthy volunteers (N = 18). We utilized Bland–Altman plots for visual comparison of the biological variability among the three measurements. We also report group-wise means and the percentage of coefficient of variation (%CV) for 15 biomarkers. Qualitatively, we show specific markers (IL-1Ra, IL-8, and MIP-1b) to be consistently altered in GD1, irrespective of therapy status, highlighting the need for adjunctive therapies that can target and modulate these biomarkers. This information can help guide the selection of candidate biomarkers for future intervention-based studies in GD1 patients. Full article

(This article belongs to the Topic Advances in Gaucher Disease: A Model for Rare Lysosomal Disorders)

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