In-Depth Phenotyping for Clinical Stratification of Gaucher Disease

doi:10.21203/rs.3.rs-543669/v1

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In-Depth Phenotyping for Clinical Stratification of Gaucher Disease

https://doi.org/10.21203/rs.3.rs-543669/v1

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Background

The Gaucher Investigative Therapy Evaluation (GAUCHERITE) is a national clinical cohort of 250 patients aged 5–87 years with Gaucher disease - an ultra-rare genetic disorder. To inform clinical decision-making and improve pathophysiological understanding, we characterized the course of Gaucher disease and explored the influence of costly innovative medication and other interventions. Retrospective and prospective clinical, laboratory and radiological information including molecular analysis of the GBA1 gene and comprising > 2500 variables were collected systematically into a relational database with banking of collated biological samples in a central bioresource. Data for deep phenotyping and life-quality evaluation, including skeletal, visceral, haematological and neurological manifestations were recorded for a median of 17.3 years.

Results

At baseline, 223 of the 250 patients were classified as type 1 Gaucher disease. Intensive neurological phenotyping in a subgroup of 40 originally considered to have only systemic features, revealed neurological involvement in 18: two had Parkinson disease and 16 patients had other neuronopathic features. This revised the number affected by type 3 Gaucher disease to a total to 43. Skeletal manifestations occurred in most patients in the cohort (131 of 201 specifically reported bone pain). Symptomatic osteonecrosis and fragility fractures occurred respectively in 76 and 37 of all 250 patients and the first osseous events occurred significantly earlier in those with neuronopathic disease. Analysis of the longitudinal real-world data permitted stratification of Gaucher disease on the basis of exposure to advanced therapies and splenectomy. Splenectomy was associated with an increased hazard of fragility fractures, osteonecrosis and orthopaedic surgery; after splenectomy, there were marked gender differences in the risk of fragility fractures over time. Combined with associated surgical procedures, the skeletal manifestations represent a heavy burden of illness, especially in patients formerly unable to access disease-modifying therapies.

Conclusion

Gaucher disease has been explored during a period of transformation by disease-modifying interventions. With the introduction of advanced therapies, repeated longitudinal measures in this real-world cohort allowed the condition to be stratified into clear clinical endotypes. Our study reveals diverse and changing phenotypic manifestations with neurological, systemic and skeletal disease as inter-related sources of disability.

Electronic Supplementary Material

The online version of this article contains supplementary material, which is available to authorized users.

Internal Medicine

Gaucher disease

cohort

GAUCHERITE

enzyme replacement therapy

substrate reduction therapy

disease-modifying therapies

Gaucher disease is an ultra-rare, autosomal recessive disease caused by catalytic deficiency of lysosomal acid β-D-glucosylceramidase (ß-glucocerebrosidase; EC 3.2.1.45) (1,2). This protean disorder affects multiple systems but is principally caused by biallelic mutations in the GBA1 gene that maps to chromosome 1q22 (2).

Gaucher disease is an inborn error of sphingolipid metabolism. Impaired lysosomal recycling of ß-glucosylceramides and their unacylated congeners, the ß-glucosylsphingosines, is most apparent in organs rich in macrophages since these cells are responsible for the recycling of exogenous cell membranes from aged blood cells after phagocytosis. Pathological storage of the glycosphingolipid in engorged, often multinuclear histiocytes, gives rise to the characteristic Gaucher cell (3). With the exception of the nervous system, functional disturbances and tissue injury occur at sites where macrophages are most abundant, such as the skeleton (marrow), spleen, liver and sometimes the lung (2–5). Systemic manifestations reflect combinations of bone marrow and visceral involvement related to pathological activation of histiocytes that excite local cellular inflammatory responses; local fibrosis and scarring may follow. This persistent inflammatory state is accompanied by release of cytokines and hepatosplenomegaly: in children there is growth failure and infantilism (6–8) and in the absence of modern therapy, severe splenomegaly complicated by cytopenias or mass effects may necessitate splenectomy. Gaucher disease frequently impairs skeletal development with defective modelling, poor mineralization, osteolytic lesions and osteonecrosis - the latter mainly occurring at the epiphyses of long bones. Osteonecrosis may in part be explained by compromised blood flow in the growth plate microvasculature (Fig. 1 & Supplementary Fig. 1). The neurological complications are less well understood but in essence reflect the imbalance between glucosylceramide biosynthesis in the Golgi compartment and impaired lysosomal recycling of endogenous glycosphingolipids derived from the dynamic turnover of membrane components in long-lived neural cells.

A convenient, but imperfect clinical classification of Gaucher disease, recognises three principal subtypes: type 1 (GD1, OMIM 230800, chronic non-neuronopathic), type 2 (GD2, OMIM 230900, acute neuronopathic) and type 3 (GD3, OMIM 231000, chronic neuronopathic) diseases (2). This operational classification is summarized in Supplementary Table 1.

In resource-rich countries, patients with Gaucher disease have access to transformative molecular therapies which address its systemic and skeletal manifestations. The current choice of treatments involves preparations of human glucosylceramidase modified for preferential targeting to macrophages and administered parenterally, or oral therapies involving small molecules with distinct modes of action (4, 9–12). However, in several regions of the world availability of these advanced medications is restricted by cost and in some instances by the practical requirements for intravenous delivery. The macrophage-targeted enzyme therapies are prescribed on an individualised basis; they are widely used at lower doses than those approved by regulators. Hitherto, two systemically active oral preparations, miglustat and eliglustat, based on the principle of substrate restriction have been approved for type 1 Gaucher disease. These diffusible molecules can decrease the influx of glycosphingolipids into the pathological lysosome by attenuating glucosylceramide biosynthesis (13–19). Targeted enzyme therapy is available for type 1 and the systemic manifestations of type 3 Gaucher disease but decisions about dosing and particular treatments are determined by expert physicians guided by patient preference and local prescribing rules.

With the availability of several molecular therapies with distinct modes of action and the multisystem nature and uncertain behaviour of Gaucher disease, we reasoned that a fuller understanding of its response to different clinical interventions will be a prerequisite for optimal management. Accordingly, to quantify the effects of specific interventions we built a platform based on repeated measures and in-depth clinical phenotyping during the conduct of long-term real-world delivery of care over several decades of practice. With an engaged national cohort of patients attending specialist centres, we collected retrospective and prospective data in those with a confirmed clinical, biochemical and genetic diagnosis. Funded principally by the UK Medical Research Council, the Gaucher Investigative Therapy Evaluation (GAUCHERITE), enrolled 250 patients aged 5 to 87 years. The cohort includes patients with all but the most acute neurological forms of the disease (type 2, OMIM 230900 and the sporadic lethal perinatal form, OMIM 608013).

Once established, the skeletal and neurological features of Gaucher disease become irreversible causes of disability: hence these domains were chosen as the main strands for detailed study. Here we report the clinical and radiological characteristics of the cohort in which the known determinants of outcome are recorded: these include clinical severity scores and the onset and rate of disease progression in the context of different interventions (e.g. splenectomy or molecular therapy). With extensive imaging, exploration of potential biomarkers and longitudinally repeated in-depth determinations, we have established a data-rich analytical platform further to investigate pathogenesis. The ultimate aim of this work is to define novel therapeutic endotypes of Gaucher disease. Combined with extensive haematological and biochemical testing, as well as imaging and DXA studies, these activities meet the expectations and criteria for deep phenotyping (20).

Study design

In the United Kingdom (UK), treatment for Gaucher disease is available only at specialist centres approved by the National Health Service (NHS). All patients attending one of the eight NHS specialist centres in England (Supplementary Table 2) were invited to participate. Clinical, radiological and laboratory data, including case report forms and other study documents, were securely recorded in the bespoke, web-based, relational GAUCHERITE database using unique identifier numbers for specialist centres and patients.

Data were collected at defined intervals and transcribed from GAUCHERITE clinical study forms that include records of structured physical examinations preceded by completion of a dedicated health questionnaire. The clinical interrogation was mainly directed to skeletal events, physical manifestations and specialised neurology; comorbidities were also captured. Separately, patients or carers completed detailed quality-of-life, fatigue, health and anxiety questionnaires; growth measures and the timing of reproductive epochs were also recorded. All treatments were recorded with emphasis on therapies directed to bone disease as well as the dosing of, and adherence to, molecular therapies administered specifically for Gaucher disease.

As set out in Supplementary Table 3, plasma and serum biomarkers have been measured over intervals and these data have been captured - including the tissue-response analytes, chitotriosidase activity and the concentration of CC chemokine pulmonary and activation-regulated chemokine (PARC)/CCL18. From the outset, a tissue biobank was developed (curated by FMP, Gaucherite Co-Principal Investigator). Biological material was collected from 238 patients (182 with serial samples) and frozen. This resource is suitable for analysis of sphingolipid biomarkers, including unacylated metabolites of glucosylceramide; genomic DNA is also retained for future analysis in ethically approved research studies.

Study population

Two hundred and fifty patients with a confirmed diagnosis of Gaucher disease were enrolled between May 2015 to October 2017; this pre-set target, included adults and children and represents ≈ 85% of all those patients known in the UK (< 290). The database was locked in July 2018, allowing 0.5-3 years of prospective data to be collected and retrospective data from > 2–25 years. The patients included those diagnosed with the so-called non-neuronopathic (type 1) and chronic neuronopathic (type 3) disease variants. Patients likely to die within six months, those unable to understand the consent form, or those otherwise judged unsuitable by the investigator, were not recruited.

Definitive diagnosis of Gaucher disease was based on enzymatic assay in leukocytes or skin fibroblasts; this was supported by molecular analysis of the GBA1 gene, except in one adult patient with a genetically confirmed diagnosis of saposin C deficiency (later treated with eliglustat). Conventional nomenclature was used to describe GBA1 mutations and principally employs a traditional protein designation derived from AAC63056.1 (21); in this manuscript, when first describing mutant GBA1 alleles, the 2016 HGVS nomenclature (22) is also used.

Data Collection

Prospective and retrospective clinical data were entered into the GAUCHERITE electronic case report form, including, for adult patients, medical records held at former paediatric specialist centres. The median number of visits was 26.1 (28.1 ± 17.4, mean ± standard deviation, SD) and median follow-up was 17.3 years, range up to 55 years (16.5 ± 9.2, mean ± SD). One child, aged 5 years, had clinical data and investigations entered on enrolment but was not further followed up during the study period. All these data including archived medical imaging studies (Supplementary Table 3) were anonymised. Regular data audits were conducted to ensure quality and completeness. A detailed description of the parameters collected is set out in the supplementary information. Saccadic eye movements were measured prospectively under separate ethical approval in a consented subset of subjects using the EyeSeeCam device with a head-mounted camera for video-oculography (23,24).

Fragility fracture was defined according to the World Health Organization (25) definition of low-impact fractures (see supplementary information). The term “Symptomatic Osteonecrosis”, as used here, represents an event recorded in the clinical record by the treating physician as osteonecrosis or avascular necrosis and supported by a description of characteristic symptoms: radiological confirmation was not required for this purpose.

Statistical analysis

Unless otherwise stated, baseline parameters are described at the time of enrolment into GAUCHERITE for all patients by reporting frequencies and proportions for categorical variables and summary statistics for continuous variables.

Time-to-event outcomes and repeated events data were described using Cox cumulative hazard functions and Andersen-Gill methods, respectively. Time origin for these analyses depended on the outcome and the specific research questions. Subjects were not included if relevant dates were not recorded. For the purpose of these analyses, database lock was July 31 2018. To study the effect of age at initiation of enzyme therapy or substrate reduction therapy on time from presentation with Gaucher disease to bone manifestation, we initially examined six age categories (under 10, 10–19, 20–29, 30–39, 40–49, and 50 years or older). Hazard ratios among the two younger groups and among the four older age groups was similar. Thus, for analytical purposes, age at initiation of specific treatment was stratified into two categories: younger than 20 years, and greater or equal to 20 years. Statistical significance was assessed at the 5% significance level after accounting for the possibility of model misspecification using robust standard errors; where used, 95% confidence limits are shown in parentheses. The STATA SE v14.2 and R software programme was used for all analyses.

Population demographics and disease characteristics

Table 1 shows the baseline characteristics of the cohort: the population is stratified by age (children, up to the age of 18 years; adults, 18 years or older) and the initially assigned subtype of Gaucher disease (type 1 and 3). Of the 250 patients (128 male and 122 female, median age 46 years, range: 5–87), 223 had a clinical diagnosis of non-neuronopathic type 1 Gaucher disease (120 males and 103 females; median age 48 years, range: 5–87) and 27 of neuronopathic type 3 Gaucher disease (8 male and 19 female; median age 23 years, range 5–60), as determined by the participating physician. Of note, 26 patients (13 male and 13 female; 17 type 1 and 9 type 3) were under 18 years of age when enrolled. Of the patients with type 1 Gaucher disease, 7 had Parkinson disease (median age of this diagnosis 52 years, range: 35–70). Eighty-five patients had a family history of Parkinson disease and/or dementia.

Table 1

Clinical characteristics of the GAUCHERITE cohort and subgroups at recruitment
Variables	Categories*	Entire cohort (N = 250) [%]	Children (N = 26) [%]	Adults (N = 224) [%]	Gaucher Type 1 (N = 223) [%]	Gaucher Type 3 (N = 27) [%]
Gender	Male Female	128 [51] 122 [49]	13 [50] 13 [50]	115 [51] 109 [49]	120 [54] 103 [46]	8 [30] 19 [70]
Recruitment age (y)	Mean age ± SD Median (range)	44 ± 19 46 (5–87)	11 ± 4 11 (5-17.8)	48 ± 16 49 (18.7–87)	46 ± 18 48 (5–87)	26 ± 16 23 (5–60)
Jewish descent	Yes No	43 [17] 207 [83]	1 [4] 25 [96]	42 [19] 182 [81]	43 [19] 180 [81]	- 27 [100]
Consanguinity	Yes No	18 [7] 232 [93]	2 [8] 24 [92]	16 [7] 208 [93]	9 [4] 214 [96]	9 [33] 18 [67]
Age at symptom onset (y)	Mean age ± SD Median (range) No symptoms Unknown	16 ± 15 11 (0–72) 13 5	3 ± 2 2 (0–8) - -	18 ± 15 13 (0–72) 13 5	18 ± 15 13 (0–72) 12 4	3 ± 4 1 (0–16) 1 1
First symptoms	Enlarged abdomen Enlarged abdomen plus other symptoms Easy bleeding/bruising Easy bleeding/bruising plus other symptoms Fatigue Fatigue plus other symptoms Bone disease Other non-classical GD symptoms No symptoms Unknown	37 [15] 67 [27] 34 [14] 36 [14] 9 [4] 6 [2] 15 [6] 32 [13] 13 [5] 1 [< 1]	6 [23] 8 [31] 1[4] 4 [15] - - - 7 [27] - -	31 [14] 59 [26] 33 [15] 32 [14] 9 [4] 6 [3] 15 [7] 25 [11] 13 [6] 1 [< 1]	28 [12.5] 56 [25] 34 [15] 35 [16] 9 [4] 6 [3] 15 [7] 28 [12.5] 12 [5] -	9 [33] 11 [40] - 1 [4] - - - 4 [15] 1 [4] 1 [4]
Presentation age (y)	Mean age ± SD Median (range) Missing age	18 ± 16 13 (0–72) 2	3 ± 2 2 (0–8) -	20 ± 16 16 (0–72) 2	20 ± 16 16 (0–72) 1	3 ± 4 2 (0–16) 1
Age at diagnosis (y)	Mean age ± SD Median (range)	21 ± 17 16 (0–73)	4 ± 3 3 (1–10)	23 ± 17 20 (0–73)	23 ± 17 20 (0–73)	3 ± 4 2 (0–16)
Diagnostic pathway	Enzyme assay GBA-gene sequencing Bone marrow histology Liver histology Spleen histology Other histology Combination of these methods Clinical history Unknown	21 [8] 23 [9] 71 [29] 12 [5] 11 [4] 1 [< 1] 105 [42] 5 [2] 1 [< 1]	7 [27] 1 [4] 3 [11] 2 [8] - - 13 [50] - -	14 [6] 22 [10] 68 [30] 10 [5] 11 [5] 1 [< 1] 92 [41] 5 [2] 1 [< 1]	17 [8] 23 [10] 68 [30] 11 [5] 9 [4] 1 [< 1] 89 [40] 5 [2] -	4 [15] - 3 [11] 1 [4] 2 [7] - 16 [59] - 1 [4]
Parkinson disease	Yes Age at diagnosis, years, mean ± SD Median (range) No	7 [3] 54 ± 12 52 (35–70) 243 [97]	- - - 26 [100]	7 [3] 54 ± 12 52 (35–70) 217 [97]	7 [3] 54 ± 12 52 (35–70) 216 [97]	- - - 27 [100]
Family history of Parkinson/dementia	Yes No	85 [34] 165 [66]	4 [15] 22 [85]	81 [36] 143 [64]	76 [34] 147 [66]	9 [33] 18 [67]
GBA1 Genotypes	N370S/N370S L444P/L444P R463C/R463C W184R/W184R N370S/L444P N370S/other L444P/R463C L444P/other R463C/other Other /other Unknown/NA* * heterozygous PSAP mutations	33 20 2 1 38 106 12 7 15 14 2	- 6 - - - 11 2 2 2 2 1	33 14 2 1 38 95 10 5 13 12 1	33 - 2 1 38 106 11 4 13 13 2	- 20 - - - - 1 3 2 1 -
Failure to thrive in childhood	Yes No Unknown/NA	65 [26] 141 [56] 44 [18]	- - 26 [100]	65 [29] 141 [63] 18 [8]	56 [25] 134 [60] 33 [15]	9 [33] 7 [26] 11 [41]
Considered shorter than school peers	Yes No Unknown/NA	86 [35] 123 [49] 41 [16]	- - 26 [100]	86 [38] 123 [55] 15 [7]	77 [34.5] 116 [52] 30 [13.5]	9 [33] 7 [26] 11 [41]
Considered themselves underweight	Yes No Unknown/NA	71 [29] 138 [55] 41 [16]	- - 26 [100]	71 [32] 138 [61] 15 [7]	64 [29] 129 [58] 30 [13]	7 [26] 9 [33] 11 [41]
Delayed puberty	Yes No Unknown/NA	54 [22] 148 [59] 48 [19]	- - 26 [100]	54 [24] 148 [66] 22 [10]	49 [22] 137 [61] 37 [17]	5 [18] 11 [41] 11 [41]
Onset of regular shaving/menses, N.	Male Years, mean age ± SD Median (range) Missing/NA	101 [79] 17 ± 2 16 (9–26) 27	- - - 13	101 [88] 17 ± 2 16 (9–26) 14	96 [80] 17 ± 2 16 (9–23) 24	5 [63] 20 ± 4 18 (16–26) 3
	Female Years, mean age ± SD Median (range) Missing/NA	100 [82] 14 ± 2 14 (6–19) 22	- - - 13	100 [92] 14 ± 2 14 (6–19) 9	89 [86] 14 ± 2 14 (6–19) 14	11 [58] 13 ± 2 13 (11–16) 8
Menopause, N.	Yes Age occurred years mean ± SD Median age (range)	51 [42] 46 ± 7 47 (26–58)	- - -	51 [47] 46 ± 7 47 (26–58)	48 [47] 46 ± 7 47 (26–58)	3 [16] 39 ± 10 36 (31–51)
HRT status	Yes No Missing	20 [39] 29 [57] 2	- - -	20 [39] 29 [57] 2	18 [38] 28 [58] 2	2 [67] 1 [33] -
*Categorical variables are expressed as frequency [percent]. Continuous variables are expressed as mean ± SD and median (range). Abbreviations: HRT, hormone replacement therapy; NA, not applicable; SD, standard deviation.

Forty-three patients (17%) stated that they were of Jewish descent; no patient of Jewish ancestry had neuronopathic (type 3) Gaucher disease. Despite the rarity of the condition, overt consanguinity was identified in only 18 (7%) of the parents. Onset of symptoms or signs attributed to Gaucher disease had occurred earlier in patients with type 3 disease (median at 1 year, range: <1–16) compared with those assigned to the type 1 category (median age 13 years, range: <1–72). The most frequent presenting manifestation was an enlarged abdomen (15%), often with a bleeding tendency (17%). Other manifestations are set out in Table 1.

Most patients were diagnosed in childhood: the median age was 16 (range: <1–73) years. Those with type 3 disease were much younger at diagnosis (median age 2 years, range: <1–16) than type 1 (median age 20 years, range: <1–73). Of note, 13 (5%) patients did not give a history of Gaucher-related symptoms. Although the clinical diagnosis in all cases was suspected by a combination of features, historically the most common primary diagnostic indicator was bone marrow biopsy (29%). Confirmation of the suspected diagnosis required either measurement of acid β-glucosidase activity (typically in peripheral blood leukocytes) or molecular analysis of GBA1. Sequencing of the GBA1-locus in genomic DNA was undertaken in the entire cohort.

Genomic sequencing identified causal mutations of the GBA1 gene in 248 patients: one paediatric patient had deficient leukocyte acid β-glucosidase activity and responded to enzyme therapy but no DNA sample was submitted for analysis; in one adult patient, two mutant PSAP alleles in trans had been identified.

The most common GBA1 variant was p.Asn409Ser (N370S) followed by p.Leu483Pro (L444P) and p.Arg502Cys (R463C), accounting for 42.2, 19.5 and 3.8 percent of the 498 mutant GBA1 alleles, respectively. Genotype frequencies reflected this distribution: 33 patients had a homozygous N370S genotype (all had non-neuronopathic type 1 disease); 20 were L444P homozygotes (all with neuronopathic disease); two patients were homozygous for R463C. Of the most frequent compound heterozygotes, 38 were N370S/L444P and 12 were L444P/R463C. Three of the seven patients with Parkinson disease were homozygous for N370S; of the other four, one was homozygous for R463C, two were N370S/L444P and one had the L444P/R463C compound GBA1 genotype. In patients originally classified as having type 1 disease, four fifths harboured at least one copy of N370S; in those with type 3 disease, nearly 90% had at least one copy of the recurrent L444P allele.

Skeletal manifestations

The skeletal manifestations of Gaucher disease in this study cohort were clinically and radiologically diverse (Fig. 1, Table 2 and Supplementary Fig. 1). Quantification of the periodicity and presence or absence of bone pain entered into the Zimran Severity Score Index (26) was carried out at enrolment in 201 patients. Of these, 131 suffered pain (chronic in 31 patients, frequent in 34, occasional in 41, periodicity not stated in 25); only 70 were pain-free. The severity of skeletal pain, assessed by using the Gaucher Disease Type 1 Severity Scoring System, GD-DS3 (27), was recorded in a subset of patients (n = 129), and was extreme in two, severe in 14, moderate in 47, mild in 41, and was not scored in 25 patients.

Table 2

Bone manifestations and radiological characteristics of the GAUCHERITE cohort and subgroups at recruitment
Variables	Categories*	Entire cohort (N = 250) [%]	Children (N = 26) [%]	Adults (N = 224) [%]	Gaucher Type 1 (N = 223) [%]	Gaucher Type 3 (N = 27) [%]
History of Fragility fracture	Yes 1 fracture > 1 fracture Age at 1st event, years, mean ± SD Median (range) No	37 [15] 22 15 38 ± 19 36 (4–78) 213 [85]	- - - - - 26 [100]	37 [17] 22 15 38 ± 19 36 (4–78) 187 [83]	29 [13] 17 12 42 ± 18 44 (13–78) 194 [87]	8 [30] 5 3 23 ± 16 20 (4–50) 19 [70]
Fracture site	Spine Hip/Femur Ribs Wrist Other bones	24 23 12 5 15	- - - - -	24 23 12 5 15	20 15 10 4 14	4 8 2 1 1
History of Symptomatic Osteonecrosis	Yes 1 event ≥2 events Mean age ± SD at 1st event, years Median age (range) Age unknown No	76 [30] 43 33 26 ± 16 22 (4–64) 4 174 [70]	- - - - - - 26 [100]	76 [34] 43 33 26 ± 16 22 (4–64) 4 148 [66]	70 [31] 39 31 26 ± 16 22 (4–64) 2 153 [69]	6 [22] 4 2 14 ± 2 14 (12–16) 1 21 [78]
Symptoms of Osteonecrosis event	Yes Classical acute bone crisis Pain Symptomatic, other than pain	76 [30] 30 45 1	- - - -	76 [34] 30 45 1	70 [31] 27 42 1	6 [22] 3 3 -
Presence of bone/joint pain	Yes Continuous/chronic Frequently Occasional Pain periodicity not recorded No Unknown	131 [52] 31 34 41 25 70 [28] 49 [20]	4 [15] - 1 3 - 13 [50] 9 [35]	127 [57] 31 33 38 25 57 [25] 40 [18]	118 [53] 27 31 37 23 61 [27] 44 [20]	13 [48] 4 3 4 2 9 [33] 5 [19]
Severity of bone/joint pain (GD1-DS3 score)	Yes Extreme Severe Moderate Mild Pain severity not recorded Unknown	129 [52] 2 14 47 41 25 121 [48]	4 [15] - - 1 1 2 22 [85]	125 [56] 2 14 46 40 23 99 [44]	116 [52] 2 13 41 39 21 107 [48]	13 [48] - 1 6 2 4 14 [52]
Lytic lesions	Yes No	13 [5] 237 [95]	- 26 [100]	13 [6] 211 [94]	11 [5] 212 [95]	2 [7] 25 [93]
Osteoarthritis	Yes No	105 [42] 145 [58]	- 26 [100]	105 [47] 119 [53]	100 [45] 123 [55]	5 [19] 22 [81]
Orthopaedic procedure	Yes No	62 [25] 188[75]	- 26 [100]	62 [28] 162 [72]	55 [25] 168 [75]	7 [26] 20 [74]
DXA
Spine	Number available BMD, g/cm², mean ± SD Median (range)	189 0.984 ± 0.150 0.982 (0.547–1.446)	15 0.836 ± 0.189 0.759 (0.547–1.151)	174 0.997 ± 1.139 0.986 (0.695–1.446)	171 0.989 ± 0.144 0.982 (0.603–1.446)	18 0.937 ± 0.196 0.989 (0.547–1.248)
Total Hip	Number BMD, g/cm², mean ± SD Median (range)	165 0.930 ± 0.153 0.924 (0.600-1.276)	3 0.716 ± 0.133 0.687 (0.600-0.861)	162 0.935 ± 0.151 0.926 (0.607–1.276)	152 0.934 ± 0.153 0.923 (0.607–1.276)	13 0.892 ± 0.1590.874 (0.600-1.253)
Femoral Neck	Number BMD, g/cm², mean ± SD Median (range)	165 0.813 ± 0.152 0.801 (0.464–1.360)	3 0.615 ± 0.120 0.640 (0.485–0.719)	162 0.816 ± 0.151 0.804 (0.464–1.360)	152 0.814 ± 0.153 0.804 (0.464–1.360)	13 0.793 ± 0.152 0.789 (0.485–1.061)
Forearm	Number BMD, g/cm², mean ± SD Median (range)	77 0.658 ± 0.103 0.653 (0.458–0.871)	- - -	77 0.658 ± 0.103 0.653 (0.458–0.871)	70 0.660 ± 0.104 0.654 (0.458–0.871)	7 0.644 ± 0.090 0.632 (0.513–0.778)
*Categorical variables are expressed as frequency [percent]. Continuous variables are expressed as mean ± SD and median (range). Abbreviations: BMD, bone mineral density; DXA, Dual-energy X-ray absorptiometry; GD1-DS3, Gaucher disease type 1 severity scoring system; SD, standard deviation.

Symptomatic osteonecrosis, the most clinically significant and disabling skeletal manifestation of Gaucher disease, occurred in seventy-six patients. Among these, 43 had one episode and 33 had two or more episodes. Osteonecrosis caused bone pain in 45 or classical acute bone crisis in 30 cases, while only one patient had skeletal symptoms that were not painful. The median age at first episode of osteonecrosis in these 76 patients was 22 (range 4–64) years: of these, nearly 90% occurred in the femur (distal or proximal), 4% occurred in the humeral head, 3% in the tibia and 4% at other sites.

Skeletal involvement in Gaucher disease includes reduced bone mineral density (BMD) which can be detected using dual-energy x-ray absorptiometry (DXA) and predisposes to fracture. Although most patients had had multiple DXA measurements between presentation and recruitment to the study, DXA determinations +/- 24 months from enrolment were available in a majority (n = 189 spine; n = 165 hip; n = 77 forearm; Table 2). Overall median vertebral bone mineral density of L1–L4 was 0.982 (range 0.547–1.446) g/cm². The median total hip and femoral neck BMD were 0.924 (0.600-1.276) and 0.801 (0.464–1.360) g/cm², respectively. Median forearm density was 0.653 (0.458–0.871) g/cm². Among postmenopausal women and men aged 50 years and older, 24 had DXA T-scores within the healthy reference range, while 34 had T-scores between − 1 and − 2.5 that are considered osteopaenic and 23 had a T-score of -2.5 or lower - taken to indicate osteoporosis. Among premenopausal women and men younger than 50 years, 94 had DXA Z-scores within the expected range for age, while 17 had a Z-score of -2.0 or lower and thus below the expected range for age.

Sixteen males and 21 females had a history of one or more fragility fractures at any site; the median age at first fragility fracture was 36 (range 4–78) years. The spleen had been removed in twenty-three of the 37. Of the total of 79 fragility fractures at recruitment, 30% had occurred in the spine; 29% in the hip/femur; 16% were in the ribs; 6% in the wrist and 19% occurred elsewhere. Patients with type 3 Gaucher disease who experienced at least one fragility fracture, experienced their first episode earlier (median age 20 years, range: 4–50) than those with type 1 disease who experienced at least one fragility fracture (median age 44 years, range: 13–78 years).

Radiological signs of osteoarthritis and frank osteolytic lesions were reported in 105 and 13 patients, respectively. Erlenmeyer flask deformity based on individual radiographic assessment was present in 80 out of the 125 adult patients for whom radiographs of the knee and distal femur were available for re-analysis. A defining ratio between the diameter of the femoral shaft 4 cm from the physis to the diameter of the physeal baseline of greater than 0.57 was used (28).

Sixty-two patients required orthopaedic surgery: the procedures were carried out mainly for the consequences of joint destruction due to osteonecrosis but also fractures.

Neuronopathic disease

Of the 27 patients with a diagnosis of chronic neuronopathic disease (type 3) at enrolment, the median age was 23 years (range: 5–60); four were older than 40 years. Neuronopathic features had often been detected after Gaucher disease was diagnosed: the most common presenting feature was a horizontal saccadic eye movement defect, typical of the disorder. After Gaucher disease had been diagnosed, formal recognition of the neuronopathic manifestations occurred within one year in 17 of the 27 patients, but in the remaining 10, these manifestations remained undocumented for between 2 and 48 years. In most instances, hepatosplenomegaly was the presenting feature, often in association with neurological signs, or as an incidental finding when a child was undergoing assessment for intercurrent illness, most frequently a respiratory disorder. Four patients had splenomegaly, which led to the diagnosis but in whom clinical hepatomegaly was absent. One patient had been diagnosed with neuronopathic Gaucher disease after the diagnosis had been made in a sibling.

Two patients with neuronopathic Gaucher disease in this cohort had received a bone marrow transplant as a primary intervention at the ages of 18 months and 11 years; the other patients are treated by enzyme therapy. Enzyme therapy was started at various times – before the age of 1 year to 41 years of age; median 3 years. In all four patients for whom longitudinal growth data were available, height velocity improved after enzyme infusions started; catch-up growth was accompanied by salutary changes in peripheral blood counts, hepatosplenomegaly and plasma chitotriosidase activity.

Impaired horizontal saccadic eye movement was present in all patients entering the study with neuronopathic Gaucher disease; more than 70% also had defective vertical saccadic movements. Strabismus was present in 22 (> 80%) of the patients (reflecting abducens nerve palsy); increased muscle tone and tendon reflexes were noted in 18 and intention tremor in 14 patients. Myoclonus and epilepsy, including myoclonic seizures, had occurred in only five patients. Disease severity, as determined by the modified Severity Scoring Tool (mSST) (29;30), ranged from 0.5–19.5 at recruitment (higher scores indicating more severe disease; maximum 36); the mean score was 6.3 ± 5.4.

Patients with neuronopathic Gaucher disease at recruitment had non-neurological comorbidities. The most frequent were kyphosis (and/or scoliosis) and infiltrative lung disease – some patients had recurrent respiratory symptoms in the absence of a formal diagnosis of pulmonary infiltration. Of note, no patients were homozygous for the p.Asp448His (D409H) mutation in GBA1 and, as expected, none had the associated calcific cardiac valve disease nor aorto-coronary involvement.

Other neurological manifestations

Beyond the 27 patients assigned to type 3 disease at baseline as above, during the prospective study period, additional patients with neuronopathic features were found (see Fig. 2). Forty patients previously considered to have non-neuronopathic Gaucher disease at enrolment were examined opportunistically by a neurologist as a convenience sample. This supplementary examination included the assessment of saccadic eye movements as part of a parallel study and in all but one, a video-oculographic assessment was undertaken using EyeSeeCam (31). Twenty-five patients were selected at random and 15 were examined because of clinical features of severe systemic disease and with genotypes recognised to be adverse: L444P, R463C, W184R in homozygous or heterozygous genotypes as well as rare alleles (including the RecNciL complex variant). Three of the 25 patients with normal clinical examination on review had abnormal saccades detected by oculography and on careful scrutiny, neurological features of neuronopathic Gaucher disease (two had an undefined cognitive and behavioural phenotype and the remaining patient suffered seizures and had abnormal magnetic resonance brain imaging).

Of the 15 patients with abnormal neurological signs, two had Parkinson disease. These two require no reclassification since, as set out in Supplementary Table 1, development of Parkinson disease, with or without Lewy body dementia, is an uncommon but now recognised feature of type 1 Gaucher disease; abnormal oculography occurs in Parkinson disease (32). The thirteen (non-Parkinsonian) patients with neurological signs, including abnormal ocular signs, were eligible for reassignment to Gaucher disease type 3 since supranuclear ophthalmoplegia with abnormal saccades are now considered an essential feature of chronic neuronopathic Gaucher disease (type 3) (33). Four of the patients, were found to have florid type 3 disease with additional severe systemic features that included kyphosis. In summary, of the group of forty patients formerly classed as having type 1 disease who were reviewed, sixteen were found to have unequivocal neuronopathic Gaucher disease. The 16 respective GBA1 genotypes were: L444P/R463C (4); R463C/RecNci1 (4); R463C/other (3); L444P/other (2); RecNci1/other (1); RecNci1/splice (1); Other/other (1).

Other manifestations

Haematological findings

Within 30 days of enrolment, the mean haemoglobin was 139 g/L (range 101–178) and the platelet count was 189 x 10⁹/L (range: 39–489). The beneficial effect of splenectomy on the platelet count was evident in the splenectomised subgroup compared with non-splenectomised patients, while no material difference in haemoglobin concentration was noted (Table 3).

Table 3

Laboratory characteristics of the GAUCHERITE cohort and subgroups at recruitment
Variables	Categories*	Entire cohort (N = 250)	Children (N = 26)	Adults (N = 224)	Gaucher Type 1 (N = 223)	Gaucher Type 3 (N = 27)
Haemoglobin	Number g/L, mean ± SD Median (range)	211 139.5 ± 13.9 139 (101–178)	11 133.7 ± 11.6 131 (118–151)	200 139.9 ± 14.0 139 (101–178)	193 140.3 ± 13.6 139 (101–178)	18 131.3 ± 15.2 131 (103–160)
with spleen	Number g/L, mean ± SD Median (range)	157 140 ± 15 139 (101–178)	11 134 ± 12 131 (118–151)	146 141 ± 15 140 (101–178)	146 141 ± 14 140 (101–178)	11 129 ± 17 131 (103–160)
without spleen	Number g/L, mean ± SD Median (range)	54 137 ± 11 138 (116–163)	- - -	54 137 ± 11 138 (116–163)	47 138 ± 11 138 (116–163)	7 135 ± 14 131 (120–153)
Platelet count	Number 10⁹/L, mean ± SD Median (range)	208 200 ± 74 189 (39–489)	11 229 ± 62 213 (151–337)	197 198 ± 74 187 (39–489)	190 196 ± 74 184 (39–489)	18 244 ± 52 234 (147–337)
with spleen	Number 10⁹/L, mean ± SD Median (range)	155 178 ± 56 175 (39–337)	11 229 ± 62 213 (151–337)	144 174 ± 54 175 (39–321)	144 173 ± 53 175 (39–321)	11 242 ± 58 230 (147–337)
without spleen	Number 10⁹/L, mean ± SD Median (range)	53 263 ± 82 253 (87–489)	- - -	53 263 ± 82 253 (87–489)	46 265 ± 87 253.5 (87–489)	7 248 ± 46 236 (197–318)
*Continuous variables are expressed as mean ± SD and median (range). Abbreviations: SD, standard deviation.

Pulmonary disease

Pulmonary manifestations of Gaucher disease have been described but a lack of consensus about the nature of the pathological process and its categorisation has led to inconsistent reporting. Eight patients with type 1 disease had pulmonary disease for which no other cause could be identified: thoracic imaging in this group, revealed bronchiectasis, fibrosis, interstitial disease (with nodules and interlobular septal thickening) and signs of pulmonary hypertension. Twenty-two patients with type 3 disease had intermittent respiratory symptoms: eight had isolated recurrent respiratory infections or symptoms suggesting asthma and had not undergone detailed radiological investigation (e.g. computerized X-ray tomography). One patient had isolated pulmonary hypertension of unknown cause and the 13 remaining had bronchial and interlobular septal thickening, reticular-nodular shadowing with a ground-glass appearance on tomographic scans; cystic changes also occurred. One patient had recurrent pneumothoraces: histology of pulmonary tissue and bronchoalveolar lavage from this patient showed Gaucher cell infiltration. A further patient suffered pulmonary haemorrhages requiring therapeutic embolisation. See Table 4.

Table 4

Other manifestations of the GAUCHERITE cohort and subgroups at recruitment
Variables	Categories*	Entire cohort (N = 250) [%]	Children (N = 26) [%]	Adults (N = 224) [%]	Gaucher Type 1 (N = 223) [%]	Gaucher Type 3 (N = 27) [%]
Gallstones	Yes Age at diagnosis, years, mean ± SD Median (range) Age unknown No	79 [32] 41 ± 13 40 (11–66) 5 171 [68]	1 [4] 16 ± 0 16 (16) - 25 [96]	78 [35] 42 ± 12 40 (11–66) 5 146 [65]	75 [34] 42 ± 12 40 (11–66) 5 148 [66]	4 [15] 35 ± 19 35 (16–55) - 23 [85]
Path to diagnosis of gallstones	Incidental Symptoms prompted investigations Unknown	43 [54] 32 [41] 4 [5]	1 [100] - -	42 [54] 32 [41] 4 [5]	40 [53] 31 [41.5] 4 [5.5]	3 [75] 1 [25] -
Cholecystectomy	Yes Age at cholecystectomy, years, mean ± SD Median (range) Missing age No	37 [15] 39 ± 13 37 (16–69) 1 213 [85]	1 [4] 16 ± 0 16 - 25 [96]	36 [16] 39 ± 12 37 (18–69) 1 188 [84]	35 [16] 39 ± 12 37 (18–69) 1 188 [84]	2 [7] 35 ± 28 35 (16–55) - 25 [93]
Cancer	Yes Haematological Non-haematological Age at diagnosis, years, mean ± SD Median (range) No	23 [9] 4 19 59 ± 15 62 (18–83) 227 [91]	- - - - - 26 [100]	23 [10] 4 (17%) 19 (83%) 58 ± 15 62 (18–83) 201 [90]	23 [10] 4 (17%) 19 (83%) 59 ± 15 62 (18–83) 200 [90]	- - - - - 27 [100]
Hepatic Disease	Yes Age at diagnosis, years, mean ± SD Median (range) No	14 [6] 40 ± 17 41 (6–75) 236 [94]	- - - 26 [100]	14 [6] 40 ± 17 41 (6–75) 210 [94]	9 [4] 47 ± 12 45 (37–75) 214 [96]	5 [19] 27 ± 18 24 (6–55) 22 [81]
Pulmonary disease	Yes Age at diagnosis, years, mean ± SD Median (range) No	29 [12] 19 ± 22 8 (1–72) 221 [88]	8 [31] 5 ± 2 5 (2–9) 18 [69]	21 [9] 24 ± 24 14 (1–72) 203 [91]	7 [3] 39 ± 28 51 (4–72) 216 [97]	22 [81.5] 12 ± 15 6 (1–57) 5 [18.5]
*Continuous variables are expressed as mean ± SD and median (range). Abbreviations: SD, standard deviation.

Table 5

A. Splenectomy and non-haematological cancer
Group	Non-haematological cancer	Total size	Proportion*	P-value†
With spleen	10	188	0.053	0.03
Without spleen	9	62	0.145	0.03
Total	19	250
*Proportion = Non-haematological cancer/Total size. † Fisher's Exact test P-value.

Table 5B. Splenectomy and haematological cancer

Group	Haematological cancer	Total size	Proportion*	P-value†
With spleen	4	188	0.021	0.58
Without spleen	0	62	0	0.58
Total	4	250

*Proportion = Haematological cancer/Total size. †Fisher's Exact test P-value.

Hepatic disease

Clinical features of liver disease with abnormal imaging with or without histopathological findings indicating fibrosis or cirrhosis not clearly attributable to fatty infiltration or alcoholic liver disease, were identified in fourteen patients (9 with type 1, and 5 with type 3 Gaucher disease; Table 4). Eleven of these had been splenectomised and in several, the liver injury had been documented before enzyme therapy was started. In these 14 patients, the median interval between diagnosis of liver disease and Gaucher-specific therapy was 5.5 years but with a wide range - treatment having started 27 years before and up to 8 years after liver disease was recognized. Liver transplantation had been carried out in two patients: one had acute hepatic decompensation and the other, hepato-pulmonary syndrome. These individuals continue to receive enzyme therapy with good effect and alive 19 and 21 years after transplantation. A further fourteen patients had structural liver abnormalities identified on imaging, but a formal diagnosis by biopsy has not been made. The abnormalities include irregularity of the hepatic capsule, focal lesions, atrophy, calcification, and hepatic infarcts. More detailed studies on the hepatic and pulmonary manifestations of patients in the GAUCHERITE cohort will be reported separately.

Malignant disease

Twenty-three patients with type 1 disease (of whom 9 were splenectomised) had documented cancer (median age 62 years, range: 18–83). Of these, > 80% had non-haematological cancer [7 cutaneous, 4 gastro-intestinal, 2 breast, 2 nervous system (cerebral meningioma and spinal cord tumour), one each of hepatic, renal, genito-urinary tract and respiratory]. Of the four patients with haematological cancer, 3 had myeloma and one, B-cell lymphoma - Table 4 and Tables 5A & B.

Treatment status

Splenectomy

Overall, one quarter of the patients had undergone splenectomy (median age of the procedure, 17 years, range: 1–58). The spleen has been removed in one third of those classified with type 3 Gaucher disease - in all instances in infancy and childhood (median age 5 years, range: 1–15). Three quarters of the splenectomies had been carried out before 1992-3, when tissue-derived enzyme therapy first became available in the European region before full regulatory approval: alglucerase was marketed from 1994 in Europe; the recombinant product, imiglucerase, was approved for marketing in 1997, followed by velaglucerase alfa in 2010 (10, 34).

It is noteworthy that of the 15 patients who underwent splenectomy after 1993, cytopenia was an unusual indication. In eight patients, the spleen had been removed for diagnostic purposes (e.g. suspected malignancy) before referral to the specialist services; in a further three, the procedure was carried out for post-traumatic splenic rupture. The spleen was removed for other indications in three patients, including inadequate responses to enzyme therapy and in the management of splenic infarction; in one patient, the indication had not been recorded.

Haematopoietic stem-cell transplantation

Two patients (1 man aged 46 and 1 woman, aged 30 years at recruitment) in the study had undergone haematopoietic stem cell transplantation as a primary intervention for Gaucher disease. Both share the p.Leu483Pro (L444P) homozygous genotype and have a classical “Norrbottnian” type 3 phenotype (3,4;35). Transplantation from HLA-matched related donors was carried out in childhood (aged 11 years and 18 months, respectively). Splenectomy was undertaken before the procedure: growth and haematological parameters responded favourably - although kyphosis and neurological signs have slowly progressed in these patients.

Enzyme and substrate-reduction therapies

Two hundred and forty-three patients were receiving specific treatment for Gaucher disease within 6 months of recruitment to the study: velaglucerase alfa was given to 141 patients, imiglucerase to 89, miglustat to 4 and eliglustat to 7 (Supplementary Table 6). At the time of writing, 65 patients are taking eliglustat. Of note, another three patients were taking enzyme therapy combined with substrate-reduction therapy: velaglucerase alfa and miglustat in a patient with type 1 disease, and imiglucerase with eliglustat in two patients suffering from type 3 Gaucher disease.

Treatment-related adverse events

Sixty-eight treatment-related adverse events (of which 36 were in patients receiving miglustat) had been reported in 43 patients. None of the reactions was life-threatening. As a result of adverse events, 25 users of miglustat had stopped this treatment; 7 patients receiving enzyme therapy had to stop or switch the treatment.

Bone specific therapies

Seventy-five patients had received anti-resorptive and/or anabolic drugs before recruitment. Within 6 months of enrollment, in all 94 patients had received a medication to treat or prevent one aspect of the osseous disease (i.e. supplemental calcium and/or vitamin D, anti-resorptive or anabolic drugs). Seventy-nine patients had received calcium alone or in combination with vitamin D; 14 had received bisphosphonates alone or in combination with calcium and/or vitamin D supplements and one patient had received anabolic treatment in combination with calcium and vitamin D supplements (Supplementary Table 6).

Effect of splenectomy on skeletal manifestations

The occurrence of symptomatic osteonecrosis was strongly associated with splenectomy (Fig. 3A): controlling for gender, the hazard/intensity ratios for first and subsequent events were about 3 times greater in patients after splenectomy (p < 0.0001).

Splenectomy also influenced fracture risk (Fig. 3B). Controlling for gender, the hazard ratio for first fragility fracture in patients after undergoing splenectomy was nearly three-fold greater than those in whom the spleen was, or is intact (p = 0.01). Splenectomy was additionally associated with an approximately 6-fold greater risk of repeated fragility fractures (p < 0.0001). Figure 3 shows the temporal relationship to first skeletal events and the association of splenectomy, from diagnosis onwards: the two panels compare events for osteonecrosis and fragility fracture - depicting the interaction of age and gender in fragility fractures, in which a component risk due to the menopause in women would be predicted. Risk of osteolytic lesions and the occurrence of orthopaedic procedures were about 2.7- and 2-fold respectively higher after splenectomy, when controlled for gender (p = 0.12 and p = 0.01, respectively).

Symptomatic osteonecrosis and fracture in relation to Gaucher-specific therapy

Data from two hundred and forty-six patients were available for analysis of the relationship between the skeletal events and introduction of molecular therapies for Gaucher disease. Fifty-one first episodes of symptomatic osteonecrosis were documented in 242 patients when they were not receiving Gaucher-specific therapy (2136 person-years of follow-up), whereas 13 first events occurred in 180 patients after treatment, which was initially enzyme therapy (2493 person-years of follow-up), hazard ratio 0.2, p < 0.001. At the time of data lock, too few patients have been exposed to the other specific interventions (marrow transplantation or substrate reduction therapy) for such analysis (Fig. 4). Age at which treatment began had no detectable effect.

In an Andersen-Gill analysis of 120 repeated events, the rate of symptomatic osteonecrosis was also reduced after specific treatment was started (hazard ratio 0.45, p < 0.001) and again there was no age effect. In contrast, neither the time to first fragility fracture nor hazard of repeated fragility fractures was associated with any, or all of the combined specific treatments, nor was there an effect of age at which treatment started.

Skeletal complications persist in patients receiving bone-specific treatment

Males with Gaucher disease who had treatment given to improve bone density, on average had a lower fragility fracture rate (p < 0.05) and incidence of lytic lesions (p < 0.01) compared with females receiving bone modifying treatment. When followed over 15 years, the average fracture rate for males was 14.8 (95% confidence interval 6.8 to 32.6) per 100 person-years; the corresponding rate for females was 63.5 (43.5 to 92.7).

In the group of more than eighty inborn lysosomal disorders, Gaucher disease is unique in its susceptibility to treatments and with sustained investment, the transformative efficacy of molecular therapies sets this ultra-rare disorder alongside haemophilia and cystic fibrosis in the Pantheon of orphan diseases. Biotechnological innovation has generated a diverse selection of drugs with distinct modes of action and indications. The competitive success of these ventures and marketing exclusivity of high-cost orphan drugs, mandate the need for academically independent therapeutic research that includes real-world data.

As in other advanced economies, most patients with Gaucher disease in the United Kingdom have received specific treatment but access to molecular therapies was often deferred until long after diagnosis. As a consequence, irreversible injury, especially to the skeleton and larger joints, became an inevitable burden. Emerging products with distinct modes of action will require robust and independent systems that collate clinical, radiological and laboratory data to define clear inflexion points in the illness that will determine their therapeutic position.

GAUCHERITE is a platform concept with a national cohort of patients which seeks (i) to determine clinical burden; (ii) characterize the clinical manifestations by in-depth phenotyping and (iii) ultimately optimize management by therapeutic stratification of Gaucher disease. We focused principally on the skeletal aspects but also indicate the potential importance of timely recognition of neuronopathic features, which are associated with adverse progression of the bone disease. While no effective therapy for the neurological manifestations is as yet available, several molecular therapies have salutary effects on the manifestations in bone: nonetheless, persistent bone pain and disabling skeletal complications remain major unmet needs in many patients (36).

Our study is aligned to current stratification methodology (20): use of longitudinal data of sufficient depth enables the effects of orphan drugs to be analysed even in a rare disease. Our approach has been validated, since patients were readily stratified in respect of two broad interventions: splenectomy, a palliative measure used to overcome the risks of bleeding and infection caused by pancytopenia, and the introduction of molecular therapy.

Although splenectomy was required to ameliorate severe hypersplenism with the risk of life-threatening haemorrhage in the era before specific therapies became available, the procedure is strongly associated with recurrent osteonecrosis and as shown here also fragility fractures with temporal profiles that differ according to gender - a consequence of osteoporosis. Splenectomy thus leads to a readily distinguishable and clinically decisive stratum of Gaucher disease with an increased need for orthopaedic surgery. With respect to cause and effect, it is noteworthy that in a forerunner of the current study (also conducted in the UK population), there was a clear temporal relationship of osteonecrosis skewed to the immediate years after splenectomy, indicating a probable causal relationship (37–42).

The mechanistic explanation for the diverse consequences of splenectomy include: (1) after the procedure, a greater burden of glycosphingolipids derived from the destruction of blood cells will fall on the residence macrophages in the liver (Küpffer cells) and bone marrow. Greater encroachment by pathological macrophages will also induce greater local pro-inflammatory cytokine and chemokine release in the bone marrow. We suggest that this will have adverse effects on the local capillary network at junctional zones related to the growth plate. Poor perfusion will increase the risk of local ischaemia to the bone marrow; (2) splenectomy has multiple effects on the formed elements of the blood and increased viscosity and platelet aggregation index induces a thrombotic tendency (43). Increased platelet numbers consequent upon the abrupt decrease in splenic pooling may also increase the risk of osteonecrosis; splenectomy is likely to amplify the changes in red-cell deformability due to alterations in the lipid composition of red-cell membranes (44). Finally, increased red-cell rigidity will potentiate the effect of removing the spleen on the marrow compartment, since by analogy with sickle-cell disease, it will impair the deformability and flow properties of red cells within the microcirculation at watershed regions of oxygen and nutrient supply in long bones (45).

The greatly increased hazard of fragility fractures showed an incident pattern over time that differs between men and women: neither phenomenon has been reported hitherto. Although splenectomy in Gaucher disease is associated with low bone mineral density (46), we show a strong association with fragility fractures (Table 6 and Fig. 3). Of the 62 patients lacking a spleen, 21 had sustained multiple fragility fractures and 38 had developed osteonecrosis; these data compare with 16 and 38 of 188 Gaucher patients who had intact spleens, respectively. We argue that the link with the three-fold increased hazard of fragility fractures identified here is clinically important. Since completion of our analysis, investigation of an international registry of type 1 Gaucher patients has recently reported a multivariate analysis of fractures in three age cohorts among patients with known splenectomy status and at least one skeletal assessment on treatment (3216 of 6422 patients) (47). Of note, a greater proportion of those splenectomized before enzyme treatment (with alglucerase or imiglucerase), had fractures (56% greater risk of fracture post-splenectomy). The authors state that for patients aged 50 years or older when the therapy was first given the analysis may have been affected by the exclusion of those who had suffered fractures during the long interval between the date of splenectomy and starting enzyme. Nonetheless in this study, the fracture risk attributed to the procedure was found only statistically significant (p = 0.039) in adults aged between 18 and 50 years at the time enzyme treatment started.

The cause is not obvious and may either be a direct or indirect consequence of the procedure. We propose that rapidly progressive inflammatory disease with indications for early splenectomy - especially in young patients not promptly diagnosed and thus not optimally treated - may be the explanation. Florid Gaucher disease activity in childhood is a chronic inflammatory state that stunts growth and delays puberty – not only is modelling impaired with manifest osseous disease as above, but the achievable peak mass of bone is also decreased.

Splenectomy has potential consequences for the skeleton beyond osteonecrosis, risk of fracture and, possibly a trend towards more frequent osteolytic lesions. Since the risk of requiring orthopaedic surgery is also much greater in patients whose spleen has been removed (p = 0.01), the susceptibility to microbial infection and osteomyelitis (which preferentially affects injured bone - see Supplementary Fig. 1B) is likely to be greater. Overall, the findings reinforce the need for vigilant long-term monitoring of bone health in patients with Gaucher disease who have undergone splenectomy.

Splenectomy has other strong associations with clinical behaviour in this condition: there was a marked association with liver disease (48), with or without pulmonary disease, as has been previously reported (49). Indeed, most of the patients with chronic liver disease, including manifest cirrhosis, interstitial lung disease or pulmonary hypertension had had their spleen removed. An unexpected finding was the greater frequency of non-haematological malignancies in patients after removal of the spleen: nine of 62, compared with 10 of 188 in the spleen-intact group (p < 0.03), Table 5A. These differences are not explained by age distribution but confirm in our population, findings reported in other relatively small patient groups (50–53). The possible effect of splenectomy on the development of various cancers in Gaucher disease has been recently reviewed (52) but the mechanism remains unclear (54). We contend that these findings merit further exploration, particularly given the role of pathological sphingolipids in cell death, immune recognition and proliferation. That all four patients with haematological cancers were among the non-splenectomised group in our cohort, is a tantalizing matter of record.

Two hundred and forty-three patients were receiving a specific molecular therapy for Gaucher disease at the time of recruitment; in most cases enzyme therapy (velaglucerase alfa or imiglucerase) was used, but eleven patients were treated with substrate reduction therapy (eliglustat or miglustat). Three had combined therapies (eliglustat and imiglucerase; miglustat and velaglucerase alfa). At the time of writing, 65 patients, more than one quarter of the adult patients with type 1 Gaucher disease, are treated with the orally active, systemic substrate-reducing agent, eliglustat.

Specific treatment for Gaucher disease can reverse bone marrow infiltration, cytopenia and visceromegaly and ameliorate symptoms with improved quality of life. However, persistent skeletal pain is a notorious feature and an important cause of disability (36,37;55–57). In this cohort, despite the emergence of molecular therapies, bone pain was present in more than half of the patients at enrolment, indicating that many UK patients had skeletal disease established before the interventions became generally available (37,40). Many patients - especially women - had persistent fragility fractures, osteonecrosis and lytic lesions requiring orthopaedic surgery. Nonetheless, it is clear that the introduction of specific treatments exerted a protective effect on the disabling and painful consequences of osteonecrosis.

Disease-modifying therapy for Gaucher disease had no effect on fracture rate: this might be explained by the earlier attainment of peak bone mass, which once established, cannot be enhanced further. As a result, the risk of fracture would be more resistant to modification. We also note a lack of effect of the age at which treatment started on either osteonecrosis or fracture, in the era of specific therapy. This might have resulted from the interaction of two opposing effects: once diagnosed in children and young adults, when the disease tends to be severe, early treatment is available to arrest its progress; while in older adults the condition can be severe, the later the age at which treatment is instituted may also imply intrinsically milder disease. In general, however, the interval between diagnosis and starting specific treatment for Gaucher disease is an important determinant of therapeutic outcome in the skeleton (37;40). The unequivocal preventative effects of enzymatic augmentation and other molecular therapies on osteonecrosis events, provides clear evidence that the course of this disease can be substantially modified by treatments that are now available.

Formerly, the diagnosis of patients with type 1 disease was made mainly in adult life and those designated as type 3 Gaucher disease were nearly all identified in childhood. While this distinction reflects the often aggressive presentation of Gaucher type 3 disease, with greater awareness and improved services in the molecular era, this trend has not continued. Ostensibly non-neuronopathic disease is increasingly recognised in children and, as we show, more subtle neuronopathic forms of the disease can be identified in adults. However, as reported in the European and North-American literature (55–58), most patients in this national cohort are considered to have ‘non-neuronopathic’ rather than neuronopathic disease, despite the additional long-term risk of developing Parkinson disease and/or Lewy body dementia.

We uncovered more patients with neuronopathic disease than expected in the UK population; these patients appear to be at a greater risk of developing early skeletal as well as other systemic manifestations of Gaucher disease (8, 59, 60). Twenty-seven of the 250 were noted originally to have neuronopathic disease but a further 16 had features indicative of type 3 disease based principally on proven ophthalmic signs, suggesting an evolving pattern in some patients. The findings point to greater phenotypic variation than generally reported in the literature and further question the wisdom of assigning a subtype and phenotypic classification to a patient with Gaucher disease without neurological review - especially within the early years of diagnosis. The need for intensified clinical monitoring mandated by the high risk of skeletal and other systemic manifestations in patients with neuronopathic disease will allow timely disease-modifying therapy to be introduced (23, 33). It is now clear that diverse neurological features are found in all categories of Gaucher disease and represent a burden of illness globally which has not been fully appreciated in the Western and anglophone literature (2, 4).

The dynamic nature of this cohort introduces an analytical methodology that permits repeated evaluation of the outcomes and complications of the disease over time to facilitate therapeutic stratification (34, 47). Despite the great rarity of Gaucher disease, many clinical publications have depended on data in registries supported by the biopharmaceutical industry, which naturally place emphasis on particular products. We reasoned that an academically established National cohort would be needed to stratify clinical outcomes and disease behaviour in a period of intense commercial therapeutic development and would encourage further independent research. We suggest that the study differs importantly from the international commercial registries and suggest that the GAUCHERITE cohort has advantages which, in toto, differentiate it from non-commercial initiatives in individual countries: (1) the study represents a long-established national disease population in patients attending specialist centres at state-funded University hospitals which, unlike private healthcare, are obliged to follow agreed clinical guidelines and uniform practices; (2) all approved treatments and clinical services are funded by the UK National Health Service; (3) clinical investigators are agnostic with respect to the manufacturer of molecular therapies – all disease-related drugs and nutritional supplements and their doses are captured in the database; (4) the study and clinical research program is subject to a single overarching national ethical review and approval process; (5) high-level data completion across the cohort without incentives such as third-party remuneration to investigators; (6) the study requires detailed completion of structured protocols for clinical history and physical findings with serial patient-reported outcomes, including formal QOL questionnaires; (7) a single database, with mass storage of > 2500 variables, holds all radiological images of radiology and DXA scanning including linked narrative reports downloaded from the study centres; (8) the data are managed by an independently approved Data Management policy, allowing investigators access to anonymised data and curated serial Biobanked blood and tissue samples linked to the relational GAUCHERITE database; (9) the research and publication policy is governed by an independent management oversight committee chaired by senior patient advocate and charity founder.

Scrutiny of this large dataset emphasises the value of systematic phenotyping by investigators with long-term specialist engagement in the care of patients affected by an ultra-rare disease. The strength of the cohort is that it spans the pre-treatment era and subsequent interventions. It has the extent and depth of data founded on repeated year-on-year serial tests (median 26) and utilises comprehensive records in a relational database that allows linear analysis using the repeated mixed measures model of individual timed events. The transformative effects of the therapies combined with intense phenotyping, time-to-event analysis and historical depth in diverse domains of the disease are also notable advantages.

The GAUCHERITE cohort, which comprises 85% of all patients known to have Gaucher disease in the United Kingdom, represents an independent, data-rich platform to study the epidemiology and natural course of this heterogeneous disorder. We show that the database is a source of information that allows clinical effectiveness and appropriateness of care to be investigated in real-world clinical practice; the data can moreover be explored in depth by stratifying patients according to potentially divergent treatment effects. Finally, the cohort is an opportune resource by which to appraise newly introduced and future therapies.

BMD: bone mineral density; DXA: dual-energy x-ray absorptiometry; ERT: enzyme replacement therapy; GAUCHERITE: Gaucher Investigative Therapy Evaluation; GD-DS3: Gaucher Disease Type 1 Severity Scoring System; NHS: National Health Service; SD: standard deviation; SRT: substrate reduction therapy; UK: United Kingdom.

Acknowledgements

The exceptional commitment of patients with Gaucher disease, the UK Gauchers Association, Mr Jeremy Manuel OBE, Ms Tanya Collin-Histed and Ms Sarah Allard, was critical for successful recruitment of the cohort; they engaged enthusiastically with the study from its conception. We are grateful also to Drs Alex Broomfield, James Davison, Elaine Murphy and Uma Ramaswami, for their help with the clinical study, to Iguazu Ltd for helping to develop and implement the GAUCHERITE database and Fjola Johannesdottir for image retrieval. Senior representatives from the biopharmaceutical partners: Actelion (now Johnson and Johnson), SHIRE (now part of Takeda) & Sanofi (formerly Genzyme) for pro bono advice and expertise on logistics and support for team-building. EQ-5D-5L © EuroQol Research Foundation. EQ-5D™ is a trademark of the EuroQol Research Foundation, mSST NGD, NART, FAB, ACE_R were provided free of charge. We thank Dr Lucy Collins for help with UPDRS and the Core Biochemical Assay Laboratory (Mr Keith Burling and Mr Peter Barker) at Cambridge University hospitals for CCL-18/PARC assays. GBA1 genotyping was done by sequencing genomic DNA at University of Manchester Centre for Integrated Genomic Medical Research (Dr Siddharth Banka); the Oxford Laboratory stored study samples for further biomarker development. We thank Sister Elizabeth Morris of the Lysosomal Disorders Unit at Addenbrooke’s hospital and other specialist nurses and support staff for their sustained advice and assistance. Picture Archiving and Communication System (PACS) team members kindly facilitated image downloading. Sooyoung Lee diligently extracted, transcribed and handled the clinical and laboratory data. Dr Bill Newman kindly helped to supervise the neurology.

Availability of Data

The data that support the findings of this study are held by the University of Cambridge under an MRC approved Data Management Policy. Restrictions apply and data are not publicly available: applications from bona fide organizations will be considered by the University of Cambridge and clinical governance of Cambridge University NHS Foundation Trust Hospitals and also subject to approval by the Gaucherite Consortium Management Committee.

Authors’ contributions

All authors contributed materially to the work of this project: conceptualization of the research questions, study design and/or interpretation of the results. All reviewed the manuscript. SD, KP and AD contributed equally to the conduct of the research and KP first drafted the manuscript; KT and BT conducted the statistical analyses. All authors approved the final manuscript.

Ethical approval

This study was conducted according to the principles of the Declaration of Helsinki (2013) (61). Ethical approval was given by the national ethics review committee (14/EE/1168) under the purview of the NHS Research and Development (R&D) in the United Kingdom and from the local R&D boards at each of the eight participating specialist clinical centres.

Informed consent was obtained from all subjects at the time of enrolment into GAUCHERITE.

The research cohort is registered with ClinicalTrials.gov, NCT code, 03240653

Consent to publish

No restrictions.

Competing interests

SHIRE Biopharmaceuticals UK (now part of Takeda) supported the license fee for the SF-36v2 questionnaire (<$6000). The authors confirm that neither SHIRE nor any other external agency played any part in the study design, data collection, analysis - nor interpretation. The named authors are solely responsible for the manuscript and the decision to submit it for publication.

Footnotes (supplementary material)

Detailed procedures (Ethical considerations and Patients, GAUCHERITE database, Variables, Questionnaires, Cognitive Assessment) are provided in the Supplementary Information.

Contributor information

Simona D’Amore [email protected]

Kathleen Page [email protected]

Aimée Donald [email protected]; [email protected]

Khadijeh Taiyari [email protected]

Brian Tom [email protected]

Patrick Deegan [email protected]; [email protected]

Chong Y Tan [email protected]

Kenneth Poole [email protected]

Simon A Jones [email protected]

Atul Mehta [email protected]; [email protected]

Derralynn Hughes [email protected]; [email protected]

Reena Sharma [email protected]

Robin H Lachmann [email protected]

Anupam Chakrapani [email protected]

Tarekegn Geberhiwot [email protected]

Saikat Santra [email protected]

Timothy M Cox [email protected]

Simona D’Amore^1,*, Kathleen Page^,1*, Aimée Donald^1,4 ^,*^,†, Khadijeh Taiyari ^2,‡, Brian Tom² , Patrick Deegan³, Chong Y Tan³, Kenneth Poole¹, Simon A Jones⁴ , Atul Mehta⁵ , Derralynn Hughes⁵, Reena Sharma⁶, Robin H Lachmann⁷, Anupam Chakrapani⁸, Tarekegn Geberhiwot⁹, Saikat Santra¹⁰, Siddarth Banka⁴, Timothy M Cox^1,3and the MRC GAUCHERITE Consortium. *These authors contributed equally to the manuscript.

¹Department of Medicine, University of Cambridge, Cambridge, UK; ²Medical Research Council Biostatistics Unit, University of Cambridge, Cambridge, UK; ³Cambridge University Hospitals, Cambridge, UK; ⁴Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University NHS Foundation Trust, University of Manchester, UK; ⁵Royal Free Hospital, London, UK; ⁶Salford Royal NHS Foundation Trust, Salford, UK;⁷National Hospital for Neurology and Neurosurgery, London, UK; ⁸Great Ormond Street Hospital, London, UK; ⁹Birmingham Queen Elizabeth Hospital, Birmingham, UK; ¹⁰Birmingham Children’s Hospital, Birmingham, UK

Current addresses: †Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester, UK; ‡ Centre for Trials Research, Cardiff University, Cardiff, UK.

GAUCHERITE: Chief Investigator, TM Cox, University of Cambridge; co-Principal Investigator, FM Platt, Department of Pharmacology, University of Oxford; Principal clinical investigators (listed in alphabetical order followed by the specialist centre): S Banka, Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester; A Chakrapani, Great Ormond Street Hospital; P B Deegan, Cambridge University Hospital; T Geberhiwot, Birmingham Queen Elizabeth Hospital; DA Hughes, Royal Free Hospital University College London; S Jones, Manchester University NHS Foundation Trust, Manchester; RH Lachmann, National Hospital for Neurology and Neurosurgery, Queen’s Square London; S Santra, Birmingham Women’s and Children’s Hospital, R Sharma, Hope hospital Salford, Manchester; A Vellodi, Great Ormond Street London.

Funding

The UK Medical Research Council funded this study (2013-9) under the Stratified Medicine Programme scheme, (GAUCHERITE, MR/K015338/1); the research was co-funded by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (grant number IS-BRC-1215-20014) that in part supported SD, AD and KP. An add-on contribution to independent statistical support (KT) was kindly donated by Shire International GmbH (2018-9). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

Brady RO, Kanfer JN, Shapiro D. Metabolism of glucocerebrosides. Evidence of an enzymatic deficiency in Gaucher's disease. Biochem Biophys Res Commun 1965 Jan 18;18:221–5.
Beutler E, Grabowski GA. The Metabolic and Molecular Basis of Inherited Disease. 8th ed. New York: ed. McGraw-Hill Book Co.; 2001.
Cox TM, Schofield JP. Gaucher's disease: clinical features and natural history. Baillieres Clin Haematol. 1997 Dec;10(4):657–89.
Grabowski GA. Phenotype, diagnosis, and treatment of Gaucher's disease. Lancet 2008 Oct 4;372(9645):1263–71.
Mistry PK, Cappellini MD, Lukina E, Ozsan H, Mach PS, Rosenbaum H, et al. A reappraisal of Gaucher disease-diagnosis and disease management algorithms. Am J Hematol. 2011 Jan;86(1):110–5.
Aerts JM, Hollak CE. Plasma and metabolic abnormalities in Gaucher's disease. Baillieres Clin Haematol. 1997 Dec;10(4):691–709.
Cox TM. Gaucher disease: understanding the molecular pathogenesis of sphingolipidoses. J Inherit Metab Dis. 2001;24(Suppl 2):106–21.
Stirnemann J, Belmatoug N, Camou F, Serratrice C, Froissart R, Caillaud C, et al. A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments. Int J Mol Sci 2017 Feb 17;18(2).
Cox TM. Gaucher disease: clinical profile and therapeutic developments. Biologics 2010 Dec 6;4:299–313.
Deegan PB, Cox TM. Imiglucerase in the treatment of Gaucher disease: a history and perspective. Drug Des Devel Ther. 2012;6:81–106.
Rosenbloom BE, Weinreb NJ. Gaucher disease: a comprehensive review. Crit Rev Oncog. 2013;18(3):163–75.
Pastores GM, Hughes DA. Gaucher Disease. In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2020. 2000 Jul 27 [updated 2018 Jun 21].
Cox T, Lachmann R, Hollak C, Aerts J, van WS, Hrebicek. M, et al. Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis. Lancet 2000 Apr 29;355(9214):1481–5.
Shayman JA. Developing novel chemical entities for the treatment of lysosomal storage disorders: an academic perspective. Am J Physiol Renal Physiol 2015 Dec 15;309(12):F996-F999.
Mistry PK, Lukina E, Ben TH, Amato D, Baris H, Dasouki M, et al. Effect of oral eliglustat on splenomegaly in patients with Gaucher disease type 1: the ENGAGE randomized clinical trial. JAMA 2015 Feb 17;313(7):695–706.
Mistry PK, Lukina E, Ben TH, Shankar SP, Baris H, Ghosn M, et al. Outcomes after 18 months of eliglustat therapy in treatment-naive adults with Gaucher disease type 1: The phase 3 ENGAGE trial. Am J Hematol. 2017 Nov;92(11):1170–6.
Cox TM, Drelichman G, Cravo R, Balwani M, Burrow TA, Martins AM, et al. Eliglustat maintains long-term clinical stability in patients with Gaucher disease type 1 stabilized on enzyme therapy. Blood 2017 Apr 27;129(17):2375–83.
Lukina E, Watman N, Dragosky M, Lau H, Avila AE, Rosenbaum H, et al. Outcomes after 8 years of eliglustat therapy for Gaucher disease type 1: Final results from the Phase 2 trial. Am J Hematol. 2019 Jan;94(1):29–38.
Mistry PK, Balwani M, Charrow J, Kishnani P, Niederau C, Underhill LH, et al. Real-world effectiveness of eliglustat in treatment-naive and switch patients enrolled in the International Collaborative Gaucher Group Gaucher Registry. Am J Hematol. 2020 Sep;95(9):1038–46.
Robinson PN. Deep phenotyping for precision medicine. Hum Mutat. 2012 May;33(5):777–80.
Cozar M, Bembi B, Dominissini S, Zampieri S, Vilageliu L, Grinberg D, et al. Molecular characterization of a new deletion of the GBA1 gene due to an inter Alu recombination event. Mol Genet Metab. 2011 Feb;102(2):226–8.
den Dunnen JT. Sequence Variant Descriptions: HGVS Nomenclature and Mutalyzer. Curr Protoc Hum Genet 2016 Jul 1;90:7.
Bremova-Ertl T, Schiffmann R, Patterson MC, Belmatoug N, Billette d V, Bardins S, et al. Oculomotor and Vestibular Findings in Gaucher Disease Type 3 and Their Correlation with Neurological Findings. Front Neurol. 2017;8:711.
Schneider E, Villgrattner T, Vockeroth J, Bartl K, Kohlbecher S, Bardins S, et al. EyeSeeCam: an eye movement-driven head camera for the examination of natural visual exploration. Ann N Y Acad Sci. 2009 May;1164:461–7.
Bonjour JP, Ammann P, Rizzoli R. Importance of preclinical studies in the development of drugs for treatment of osteoporosis: a review related to the 1998 WHO guidelines. Osteoporos Int. 1999;9(5):379–93.
Zimran A, Kay A, Gelbart T, Garver P, Thurston D, Saven A, et al. Gaucher disease. Clinical, laboratory, radiologic, and genetic features of 53 patients. Med (Baltim). 1992 Nov;71(6):337–53.
Weinreb NJ, Cappellini MD, Cox TM, Giannini EH, Grabowski GA, Hwu WL, et al. A validated disease severity scoring system for adults with type 1 Gaucher disease. Genet Med 2010 Jan;12(1):44–51.
Carter A, Rajan PS, Deegan P, Cox TM, Bearcroft P. Quantifying the Erlenmeyer flask deformity. Br J Radiol. 2012 Jul;85(1015):905–9.
Davies EH, Surtees R, DeVile C, Schoon I, Vellodi A. A severity scoring tool to assess the neurological features of neuronopathic Gaucher disease. J Inherit Metab Dis. 2007 Oct;30(5):768–82.
Davies EH, Mengel E, Tylki-Szymanska A, Kleinotiene G, Reinke J, Vellodi A. Four-year follow-up of chronic neuronopathic Gaucher disease in Europeans using a modified severity scoring tool. J Inherit Metab Dis. 2011 Oct;34(5):1053–9.
Donald A, Tan CY, Chakrapani A, Hughes DA, Sharma R, Cole D, et al. Eye movement biomarkers allow for the definition of phenotypes in Gaucher Disease. Orphanet J Rare Dis 2020 Dec 17;15(1):349.
MacAskill MR, Anderson TJ, Jones RD. Adaptive modification of saccade amplitude in Parkinson's disease. Brain 2002 Jul;125(Pt 7):1570–82.
Schiffmann R, Sevigny J, Rolfs A, Davies EH, Goker-Alpan O, Abdelwahab M, et al. The definition of neuronopathic Gaucher disease. J Inherit Metab Dis. 2020 Sep;43(5):1056–9.
Barton NW, Brady RO, Dambrosia JM, Di Bisceglie AM, Doppelt SH, Hill SC, et al. Replacement therapy for inherited enzyme deficiency–macrophage-targeted glucocerebrosidase for Gaucher's disease. N Engl J Med 1991 May 23;324(21):1464-70.
Desnick RJ. Gaucher disease: a century of delineation and understanding. Prog Clin Biol Res. 1982;95:1–30.
Hughes D, Mikosch P, Belmatoug N, Carubbi F, Cox T, Goker-Alpan O, et al. Gaucher Disease in Bone: From Pathophysiology to Practice. J Bone Miner Res. 2019 Jun;34(6):996–1013.
Deegan PB, Pavlova E, Tindall J, Stein PE, Bearcroft P, Mehta A, et al. Osseous manifestations of adult Gaucher disease in the era of enzyme replacement therapy. Med (Baltim). 2011 Jan;90(1):52–60.
Pastores GM, Patel MJ, Firooznia H. Bone and joint complications related to Gaucher disease. Curr Rheumatol Rep. 2000 Apr;2(2):175–80.
Pastores GM, Weinreb NJ, Aerts H, Andria G, Cox TM, Giralt M, et al. Therapeutic goals in the treatment of Gaucher disease. Semin Hematol. 2004 Oct;41(4 Suppl 5):4–14.
Mistry PK, Deegan P, Vellodi A, Cole JA, Yeh M, Weinreb NJ. Timing of initiation of enzyme replacement therapy after diagnosis of type 1 Gaucher disease: effect on incidence of avascular necrosis. Br J Haematol. 2009 Nov;147(4):561–70.
Khan A, Hangartner T, Weinreb NJ, Taylor JS, Mistry PK. Risk factors for fractures and avascular osteonecrosis in type 1 Gaucher disease: a study from the International Collaborative Gaucher Group (ICGG) Gaucher Registry. J Bone Miner Res. 2012 Aug;27(8):1839–48.
Mistry PK, Weinreb NJ, Kaplan P, Cole JA, Gwosdow AR, Hangartner T. Osteopenia in Gaucher disease develops early in life: response to imiglucerase enzyme therapy in children, adolescents and adults. Blood Cells Mol Dis 2011 Jan 15;46(1):66–72.
Bax BE, Richfield L, Bain MD, Mehta AB, Chalmers RA, Rampling MW. Haemorheology in Gaucher disease. Eur J Haematol. 2005 Sep;75(3):252–8.
Franco M, Collec E, Connes P, van den Akker E, Billette d V, Belmatoug N, et al Abnormal properties of red. blood cells suggest a role in the pathophysiology of Gaucher disease. Blood 2013 Jan 17;121(3):546 – 55.
Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med 1997 Sep 11;337(11):762-9.
Pastores GM, Wallenstein S, Desnick RJ, Luckey MM. Bone density in Type 1 Gaucher disease. J Bone Miner Res. 1996 Nov;11(11):1801–7.
Deegan P, Khan A, Camelo JS Jr, Batista JL, Weinreb N. The International Collaborative Gaucher Group GRAF (Gaucher Risk Assessment for Fracture) score: a composite risk score for assessing adult fracture risk in imiglucerase-treated Gaucher disease type 1 patients. Orphanet J Rare Dis 2021 Feb 18;16(1):92.
Lachmann RH, Wight DG, Lomas DJ, Fisher NC, Schofield JP, Elias E, et al. Massive hepatic fibrosis in Gaucher's disease: clinico-pathological and radiological features. QJM 2000 Apr;93(4):237–44.
Mistry PK, Sirrs S, Chan A, Pritzker MR, Duffy TP, Grace ME, et al. Pulmonary hypertension in type 1 Gaucher's disease: genetic and epigenetic determinants of phenotype and response to therapy. Mol Genet Metab. 2002 Sep;77(1–2):91–8.
Fleshner PR, Aufses AH Jr, Grabowski GA, Elias R. A 27-year experience with splenectomy for Gaucher's disease. Am J Surg. 1991 Jan;161(1):69–75.
Lo SM, Stein P, Mullaly S, Bar M, Jain D, Pastores GM, et al. Expanding spectrum of the association between Type 1 Gaucher disease and cancers: a series of patients with up to 3 sequential cancers of multiple types–correlation with genotype and phenotype. Am J Hematol. 2010 May;85(5):340–5.
Mistry PK, Taddei T, vom DS, Rosenbloom. BE. Gaucher disease and malignancy: a model for cancer pathogenesis in an inborn error of metabolism. Crit Rev Oncog. 2013;18(3):235–46.
Zimran A, Liphshitz I, Barchana M, Abrahamov A, Elstein D. Incidence of malignancies among patients with type I Gaucher disease from a single referral clinic. Blood Cells Mol Dis. 2005 May;34(3):197–200.
Dubot P, Astudillo L, Therville N, Sabourdy F, Stirnemann J, Levade T, et al. Are Glucosylceramide-Related Sphingolipids Involved in the Increased Risk for Cancer in Gaucher Disease Patients? Review and Hypotheses. Cancers (Basel) 2020 Feb 18;12(2).
Charrow J, Andersson HC, Kaplan P, Kolodny EH, Mistry P, Pastores G, et al. The Gaucher registry: demographics and disease characteristics of 1698 patients with Gaucher disease. Arch Intern Med 2000 Oct 9;160(18):2835-43.
Giraldo P, Alfonso P, Irun P, Gort L, Chabas A, Vilageliu L, et al. Mapping the genetic and clinical characteristics of Gaucher disease in the Iberian Peninsula. Orphanet J Rare Dis 2012 Mar 19;7:17.
Stirnemann J, Vigan M, Hamroun D, Heraoui D, Rossi-Semerano L, Berger MG, et al. The French Gaucher's disease registry: clinical characteristics, complications and treatment of 562 patients. Orphanet J Rare Dis 2012 Oct 9;7:77.
Zimran A, Belmatoug N, Bembi B, Deegan P, Elstein D, Fernandez-Sasso D, et al. Demographics and patient characteristics of 1209 patients with Gaucher disease: Descriptive analysis from the Gaucher Outcome Survey (GOS). Am J Hematol. 2018 Feb;93(2):205–12.
Biegstraaten M, van Schaik IN, Aerts JM, Hollak CE. 'Non-neuronopathic' Gaucher disease reconsidered. Prevalence of neurological manifestations in a Dutch cohort of type I Gaucher disease patients and a systematic review of the literature. J Inherit Metab Dis. 2008 Jun;31(3):337–49.
Detollenaere C, Benghergbia M, Brassier A, de Villemeur TB, Amsallem D, Berger M, et al. Type 3 Gaucher disease, diagnostic in adulthood. Mol Genet Metab Rep. 2017 Dec;13:1–2.
World Medical Association. Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 2013 Nov 27;310(20):2191–4.

Additionalfile1DeepPhenotypingGaucherdise.docx
Additional file 1 (.docx) of Deep Phenotyping of Gaucher disease: supplementary material and methods, supplementary results, supplementary references, legend to supplementary figure 1, six supplementary tables.
Additionalfile2SupplFigure1DeepPhenotypingGaucher.tif
Additional file 2 (.tiff) of Deep Phenotyping of Gaucher disease: Supplementary Figure 1 Magnetic resonance imaging of skeletal manifestations in Gaucher disease.

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You are reading this latest preprint version

In-Depth Phenotyping for Clinical Stratification of Gaucher Disease

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Version 1

Abstract

Background

Results

Conclusion

Electronic Supplementary Material

Figures

Background

Materials And Methods

Study design

Study population

Data Collection

Statistical analysis

Results

Population demographics and disease characteristics

Skeletal manifestations

Neuronopathic disease

Other neurological manifestations

Other manifestations

Haematological findings

Pulmonary disease

Hepatic disease

Malignant disease

Treatment status

Splenectomy

Haematopoietic stem-cell transplantation

Enzyme and substrate-reduction therapies

Treatment-related adverse events

Bone specific therapies

Effect of splenectomy on skeletal manifestations

Symptomatic osteonecrosis and fracture in relation to Gaucher-specific therapy

Skeletal complications persist in patients receiving bone-specific treatment

Discussion

Conclusions

Abbreviations

Declarations

References

Supplementary Files

Status:

Version 1