Development and validation of Gaucher disease type 1 (GD1)-specific patient-reported outcome measures (PROMs) for clinical monitoring and for clinical trials

Background Disease-specific patient-reported outcome measures (PROMs) are fundamental to understanding the impact on, and expectations of, patients with genetic disorders, and can facilitate constructive and educated conversations about treatments and outcomes. However, generic PROMs may fail to capture disease-specific concerns. Here we report the development and validation of a Gaucher disease (GD)-specific PROM for patients with type 1 Gaucher disease (GD1) a lysosomal storage disorder characterized by hepatosplenomegaly, thrombocytopenia, anemia, bruising, bone disease, and fatigue. Results and discussion The questionnaire was initially developed with input from 85 patients or parents of patients with GD1 or GD3 in Israel. Owing to few participating patients with GD3, content validity was assessed for patients with GD1 only. Content validity of the revised questionnaire was assessed in 33 patients in the US, France, and Israel according to US Food and Drug Administration standards, with input from a panel of six GD experts and one patient advocate representative. Concept elicitation interviews explored patient experience of symptoms and treatments, and a cognitive debriefing exercise explored patients’ understanding and relevance of instructions, items, response scales, and recall period. Two versions of the questionnaire were subsequently developed: a 24-item version for routine monitoring in clinical practice (rmGD1-PROM), and a 17-item version for use in clinical trials (ctGD1-PROM). Psychometric validation of the ctGD1-PROM was assessed in 46 adult patients with GD1 and re-administered two weeks later to examine test–retest reliability. Findings from the psychometric validation study revealed excellent internal consistency and strong evidence of convergent validity of the ctGD1-PROM based on correlations with the 36-item Short Form Health Survey. Most items were found to show moderate, good, or excellent test–retest reliability. Conclusions Development of the ctGD1-PROM represents an important step forward for researchers measuring the impact of GD and its respective treatment.

Two cases of neuronopathic form of Gaucher disease – diagnostic difficulties

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.

New correlations between ocular parameters and disease severity in Spanish patients with Gaucher’s disease Type I

Background Gaucher’s disease is associated with a high variety of structural and functional abnormalities in the eye, which do not always affect visual acuity. The purpose of this study was to analyse ocular features in Spanish patients with Gaucher’s disease type I, and to investigate their possible correlation with phenotypic and burden parameters of this entity. Methods This cross-sectional observational study compared parameters belonging to 18 eyes from 9 Spanish patients with Gaucher’s disease Type I with 80 eyes from 40 healthy controls. Complete ophthalmological examination included choroidal and retinal thickness maps with swept source optical coherence tomography. Systemic analysis included genotype, plasmatic biomarkers, [ferritin, chemokine ligand 18 (CCL18) and chitotriosidase (ChT)] and severity scoring systems results [“Gaucher Disease Severity Score Index Type I" (GauSSI-I) and “Gaucher disease severity scoring system” (GD-DS3)]. Results Nine subjects (18 eyes) were cases (female: 55.5%, mean age 45 years; male: 44.5%, mean age 36 years) and 40 subjects (80 eyes) were controls (female: 49%, mean age 50 years; male: 51%, mean age 55 years). There were no statistically significant differences when comparing ocular parameters (visual acuity; axial length, refractive errors, corneal parameters, lens, retinal and choroidal thickness) between case and control subjects (p>0.05). A statistically significant moderate correlation was observed between lower retinal thickness and choroidal quadrants thickness and greater disease severity scores. A lower central retinal thickness also correlates with higher biological plasmatic levels, and has a statistically significant association with the most affected patient with genotype N370S/Del 55pb. Conversely, higher pachymetry involves a more severe plasmatic concentration of biomarkers. Conclusions Our results suggest that pachymetry, and retinal and choroidal thickness, are associated with burden biomarkers and disease severity index scores in Spanish patients with Gaucher’s disease Type I.

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

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.

Long-term safety and effectiveness of velaglucerase alfa in Gaucher disease: 6-year interim analysis of a post-marketing surveillance in Japan

Background Gaucher disease (GD) is caused by reduced lysosomal enzyme β-glucocerebrosidase activity. Heterogeneous genotypes and phenotypes have been observed within GD types and across ethnicities. Enzyme replacement therapy is generally recommended for patients with type 1 GD, the least severe form of GD. In Japan, velaglucerase alfa has a broad indication covering type 1, 2 or 3 GD. Methods All patients with type 1, 2, or 3 GD administered velaglucerase alfa 60 U/kg every 2 weeks via intravenous infusion after its launch date in Japan in 2014, were enrolled in a non-interventional, observational post-marketing surveillance (PMS). Individual patient data were reported via case report forms (CRFs). Key safety endpoints investigated included the incidence of infusion-related reactions (IRRs), the safety of velaglucerase alfa in patients with types 2 and 3 GD, from patients under one year of age to elderly patients (≥ 65 years of age). Long-term efficacy was also assessed. Results In total, 53 patients with GD were registered. CRFs were available for 41 (77.4%) patients at the 6-year interim analysis. Fourteen adverse drug reactions (ADRs) were reported in seven patients. All reported ADRs occurred in patients with type 2 GD. ADRs were reported by 63.6% (7/11) of patients with type 2 GD. Ten ADRs were reported in five patients aged < 4 years. No elderly patients experienced any ADR during the surveillance period. Five ADRs occurring in three (10.0%) patients were classified as IRRs, with one case of vomiting (moderate severity) resulting in treatment discontinuation. Ten serious adverse events were reported in five (16.7%) patients. Three fatal events were considered to be unrelated to treatment with velaglucerase alfa. Platelet counts increased after the administration of velaglucerase alfa and were generally maintained within the normal range over the administration period. Among eleven patients tested for neutralizing anti-velaglucerase alfa antibodies, two (18.2%) were assessed as positive results. Conclusion PMS data from patients with types 1–3 GD in Japan indicate that long-term treatment with velaglucerase alfa was well-tolerated and associated with increased platelet counts, which is consistent with observations made in studies outside of Japan. Trial registration: NCT03625882 registered July 2014.