The natural history of type 2 Gaucher disease in the 21st century

ObjectiveTo gather natural history data to better understand the changing course of type 2 Gaucher disease (GD2) in order to guide future interventional protocols.MethodsA structured interview was conducted with parents of living or deceased patients with GD2. Retrospective information obtained included disease presentation, progression, medical and surgical history, medications, family history, management, complications, and cause of death, as well as the impact of disease on families.ResultsData from 23 patients were analyzed (20 deceased and 3 living), showing a mean age at death of 19.2 months, ranging from 3 to 55 months. Fourteen patients were treated with enzyme replacement therapy, 2 were treated with substrate reduction therapy, and 3 underwent bone marrow transplantation. Five patients received ambroxol and one was on N-acetylcysteine, both considered experimental treatments. Fifteen patients had gastrostomy tubes placed; 10 underwent tracheostomies. Neurologic disease manifestations included choking episodes, myoclonic jerks, autonomic dysfunction, apnea, seizures, and diminished blinking, all of which worsened as disease progressed.ConclusionsCurrent available therapies appear to prolong life but do not alter neurologic manifestations. Despite aggressive therapeutic interventions, GD2 remains a progressive disorder with a devastating prognosis that may benefit from new treatment approaches.

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

Blood ◽

10.1182/blood.v106.11.3885.3885 ◽

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.

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Impact of Long-Term Enzyme Replacement Therapy on Glucosylsphingosine (Lyso-Gb1) Values in Patients with Type 1 Gaucher Disease: Statistical Models for Comparing Three Enzymatic Formulations

International Journal of Molecular Sciences ◽

10.3390/ijms22147699 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7699

Author(s):

Tama Dinur ◽

Ulrike Grittner ◽

Shoshana Revel-Vilk ◽

Michal Becker-Cohen ◽

Majdolen Istaiti ◽

...

Keyword(s):

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Gaucher Disease ◽

Standard Of Care ◽

Repeated Measurements ◽

Substrate Reduction Therapy ◽

Compound Heterozygous ◽

Type I ◽

Enzyme Replacement ◽

The Impact

For three decades, enzyme replacement therapy (ERT), and more recently, substrate reduction therapy, have been the standard-of-care for type I Gaucher disease (GD1). Since 2012, three different ERTs have been available. No clinical trial or academic study has ever compared these ERTs beyond one year. Herein we compare the impact of the ERTs on repeated measurements of glucosylsphingosine (lyso-Gb1; the most sensitive and GD-specific biomarker). A total of 135 adult patients (77 (57%) female) with GD1, followed from July 2014 to March 2020 and treated with a single ERT (imiglucerase (n = 41, 30.4%), taliglucerase alfa (n = 21, 15.6%) and velaglucerase alfa (n = 73, 54.1%)), were included. Disease severity was defined by genotypes (mild: N370S (c.1226A>G) homozygous and N370S/R496H (c.1604G) compound heterozygous; severe: all other genotypes) and by the severity score index (SSI; mild: <7; severe: ≥7). Lyso-Gb1 testing was performed at Centogene™ on dry blood spot samples collected during routine visits. Patients treated with imiglucerase had higher lyso-Gb1 levels at different time points. A huge variation in lyso-Gb1 levels was noticeable both inter-individually and intra-individually for all three ERTs. A steeper and faster decrease of lyso-Gb1 levels was shown in velaglucerase alfa. Nevertheless, the differences between medications were not very large, and bigger numbers and more pretreatment data are required for more powerful conclusions.

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The RETRIEVE Study: A natural history study of type 2 Gaucher disease, and GM1 and GM2 gangliosidoses with early onset, in preparation of a clinical trial

Molecular Genetics and Metabolism ◽

10.1016/j.ymgme.2020.12.104 ◽

2021 ◽

Vol 132 (2) ◽

pp. S48-S49

Author(s):

Benedicte Heron-Longe ◽

Spyros Batzios ◽

Eugen Mengel ◽

Roberto Giugliani ◽

Marc Patterson ◽

...

Keyword(s):

Clinical Trial ◽

Natural History ◽

Early Onset ◽

Gaucher Disease ◽

Natural History Study ◽

Gm2 Gangliosidoses

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Natural history and effect of therapeutic interventions on subretinal fluid causing foveal detachment in macular telangiectasia type 2

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2016-309237 ◽

2016 ◽

Vol 101 (7) ◽

pp. 955-959 ◽

Cited By ~ 9

Author(s):

Hemal Mehta ◽

Simone Müller ◽

Catherine A Egan ◽

Simona Degli Esposti ◽

Adnan Tufail ◽

...

Keyword(s):

Natural History ◽

Subretinal Fluid ◽

Therapeutic Interventions ◽

Foveal Detachment ◽

Macular Telangiectasia ◽

Macular Telangiectasia Type 2

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Platelet response to enzyme replacement therapy and oral substrate reduction therapy in an adult with Gaucher disease

Molecular Genetics and Metabolism ◽

10.1016/j.ymgme.2015.12.236 ◽

2016 ◽

Vol 117 (2) ◽

pp. S39-S40

Author(s):

Stephanie DeArmey ◽

William Charles ◽

Priya S. Kishnani

Keyword(s):

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Gaucher Disease ◽

Substrate Reduction Therapy ◽

Platelet Response ◽

Enzyme Replacement ◽

Substrate Reduction

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Changing Patterns of Mortality in Gaucher Disease Prior to and Following the Advent of Enzyme Replacement Therapy.

Blood ◽

10.1182/blood.v104.11.3799.3799 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3799-3799

Author(s):

Neal J. Weinreb ◽

Robert E. Lee

Keyword(s):

Cardiovascular Disease ◽

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Cause Of Death ◽

Gaucher Disease ◽

Age At Death ◽

Enzyme Replacement ◽

Number Of Patients ◽

Changing Patterns ◽

The Impact

Abstract Enzyme replacement therapy (ERT) with exogenous glucosylceramide β-glucosidase (alglucerase, [Ceredase®] or imiglucerase, [Cerezyme®]) has been shown to improve anemia, thrombocytopenia, hepatosplenomegaly, bone symptoms and quality of life in patients with Gaucher disease. However, the impact of ERT on mortality has not been assessed since the inception of ERT in 1991. Data from the epoch prior to the availability of ERT were obtained from the University of Pittsburgh Gaucher Disease Registry. Data from the time period following the advent of ERT were obtained from the International Collaborative Gaucher Group (ICGG) Gaucher Registry and the Ceredase/Cerezyme pharmacovigilance database (Genzyme Corporation). Age of death was obtained for patients with reported Type 1 (non-neuronopathic) Gaucher disease. Only patients with a known cause of death were included in this analysis. Pre-ERT Era (R.E.L.) Post-ERT Era Number of patients 31 137 Treated with ERT No Yes Mean age at death (years) 53.2 55.6 Range of age at death (years) 3–85 0.2–89 Cause of death due to: n % n % • Gaucher disease 4 12.9% 1 0.7% • Leukemia 3 9.7% 7 5.1% • Lymphoma 1 3.2% 3 2.2% • Myeloma 3 9.7% 1 0.7% • Solid tumor 12 38.7% 17 12.4% • Hemorrhage 1 3.2% 14 10.2% • Thromboembolism 0 0.0% 4 2.9% • Other cardiovascular disease 2 6.5% 26 19.0% • Infectious disease 3 9.7% 6 10.9% • Other causes 2 6.5% 49 35.8% These descriptive data collected prior to the advent of ERT and following approval of ERT in 1991 raise intriguing questions about the changing pattern of mortality in Gaucher disease. Any direct comparison of these populations must be qualified by the possibility of detection bias or a cohort effect. Therefore, pending further information, it is difficult to attribute significance to the difference in mean age at death between the two populations. However, there have been shifts in the pattern of the causes of death. Most notably, deaths due to the primary manifestations of Gaucher disease and to hematologic cancers and solid tumors appear substantially less common in the post-ERT era whereas the proportion of deaths due to cardiovascular disease and other causes appears to be increasing. More accurate estimates of the patterns of mortality in Gaucher disease remain to be determined, particularly for the pre-ERT era. Additional studies of the changing patterns of mortality in Gaucher disease are ongoing.

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