Adult type I Gaucher disease with splenectomy caused by a compound heterozygous GBA1 mutation in a Chinese patient: a case report.

Gaucher disease (GD) is an autosomal recessive ailment resulting from glucocerebrosidase deficiency caused by a mutation in the GBA1 gene, leading to multi-organ problems in the liver, spleen, and bone marrow. In China, GD is extremely uncommon and has a lower incidence rate than worldwide. In this study, we report the case of an adult male with an enlarged spleen for 13 years who presented with abdominal distension, severe loss of appetite and weight, reduction of the three-line due to hypersplenism, frequent nosebleeds, and bloody stools. Regrettably, the unexpected discovery of splenic pathology suggestive of splenic Gaucher disease was only made after a splenectomy due to a lack of knowledge about rare disorders. Our patient's delayed diagnosis may have been due to the department where he was originally treated, but it highlights the need for multidisciplinary consultation in splenomegaly of unknown etiology. We then investigated the patient's clinical phenotypes and gene mutation features using genetically phenotypical analysis. The analysis of the GBA1 gene sequence indicated that the patient carried a compound heterozygous mutation consisting of two potentially disease-causing mutations: c.907C > A (p. Leu303Ile) and c.1448 T > C (p. Leu483Pro). While previous research has linked the p. Leu483Pro mutation site to neurologic GD phenotypes (GD2 and GD3), the patients in this investigation were identified as having non-neuronopathic GD1. The other mutation, p. Leu303Ile, is a new GD-related mutation not indexed in PubMed that enriches the GBA1 gene mutation spectrum. Biosignature analysis has shown that both mutations alter the protein's three-dimensional structure, which may be a pathogenic mechanism for GD1 in this patient.

VITREOUS HEMORRHAGE IN TYPE 3 GAUCHER DISEASE: AN ANGIOGRAPHIC AND PATHOLOGIC ANALYSIS.

PURPOSE: To describe the case of a 12-year-old woman with vitreoretinal manifestations of Type 3 Gaucher disease. METHODS: A retrospective case report including multimodal imaging and histologic examination of the vitreous. RESULTS: A 12-year-old woman with a history of Gaucher disease Type 3 was referred to the ophthalmology service for evaluation of vitreous deposits in both eyes. Funduscopic examination was notable for white vitreous opacities in both eyes. Ultra-widefield fluorescein angiography demonstrated areas of blockage associated with the deposits and focal areas of leakage. Optical coherence tomography angiography showed shadow artifact without intrinsic flow at these sites. Three years after presentation, she developed a right hemorrhagic posterior vitreous detachment, requiring pars plana vitrectomy with scleral buckle. A vitreous sample was sent to pathology, which demonstrated Gaucher cells. CONCLUSION: Gaucher disease is a rare metabolic condition caused by an autosomal recessive deficiency of glucocerebrosidase. To the best of our knowledge, this is the first report of hemorrhagic posterior vitreous detachment in Type 3 Gaucher disease, including ultra-widefield imaging, optical coherence tomography angiography, and histopathology.

Direct and indirect effects of the SARS-CoV-2 pandemic on Gaucher Disease patients in Spain: Time to reconsider home-based therapies?

OBJECTIVE: An analysis of the SARS-CoV-2 pandemic impact in the Spanish Gaucher Disease (GD) community is presented here. PATIENTS & METHODS: The Spanish GD foundation (FEETEF) surveyed 113 GD patients from March 30 to April 27; all patients provided a verbal consent. RESULTS: 110 surveys were analyzed. The median age was 47 years old (y.o.), 31 patients were ≥ 60 y.o.; and 34% of patients reported comorbidities. 46% (51/110) of patients were treated by enzyme replacement therapy (ERT), 48 of them at hospitals; 45.1% (45/110) were on substrate reduction therapy (SRT) and 9% (10/110) receive no therapy. 25% (11/48) of ERT-hospital-based patients reported therapy interruptions, while SRT-patients did not report missing doses. No bone crises were reported. However, 50% (55/110) of patients reported being worried about their predisposition to a severe SARS-COV-2 infection and 29% (16/55) of them took anxiolytics or antidepressants for this. While 6 patients reported to have contact with an infected person, another two confirmed SARS-CoV-2 infections were reported in splenectomyzed patients, one of them (a 79-year-old diabetic) died. CONCLUSIONS: One quarter of the patients treated at hospitals reported dose interruptions. Home-based therapy may need to be considered in order to minimize the impact of the COVID-19 pandemic.

Liver transplantation for Gaucher disease presenting as neonatal cholestasis: Case report and literature review.

BACKGROUND: We present a rare case of neonatal cholestasis in a female infant with Gaucher Disease (GD), who received liver transplantation. We review the relevant literature on similar disease presentations. METHODS: A chart review of the index case was performed. PubMed and Medline databases were searched to identify other cases. RESULTS: A 4-day-old female was referred with conjugated hyperbilirubinemia. Physical examination revealed icterus with hepatosplenomegaly and normal neurologic examination. The diagnosis of GD was confirmed through liver biopsy, low glucocerebrosidase enzyme activity, and two pathogenic mutations in GBA gene. Despite early initiation of ERT, the patient had worsening of her liver failure and underwent a left lateral segment liver transplant from a living donor at 7 months of age. She experienced improvement of her liver enzymes and coagulation, but passed away at 8 months due to the late onset of neurologic involvement. Nine other cases of GD presenting with neonatal cholestasis have been reported. Forty-four percent (4/9) of cases received ERT and none were considered for transplant. Overall, the literature suggests a poor prognosis with death reported in 77% (7/9) cases. CONCLUSIONS: Neonatal presentation of GD represents a poor prognosis despite early initiation of treatment. Diagnosis remains a challenge as the presentation is rare and multiple tests such as BM biopsy, liver biopsy with both light and electron microscopy, enzymology, and genetic testing may need to be completed to reach a diagnosis. Neurological sequelae may manifest later making the decision to proceed with liver transplantation a difficult one.

Longevity of total hip arthroplasty implants in patients with Gaucher disease.

BACKGROUND: Total hip replacement (THR) is performed for arthritic hip joints, which in Gaucher disease results from osteonecrosis of the femoral head. This procedure was recommended as valid and safe for this group of patients. Nevertheless, long term outcome has not been evaluated in a large cohort. METHODS: Data regarding all patients having hip replacement in a relatively large Gaucher clinic was collected. Specifically, details such as patient background and quality of life, implant types, radiographic signs of implant-loosening, and success of implant revision were gathered. RESULTS: The cohort included 48 patients (females 42%, mean age at operation 42 ± 14 years), having 54 hip implants. 15 years survival was 60% and an average implant life was 12.8 years. Longevity was related to implant type, with cementless implants using ceramic-on-ceramic bearing surfaces performing better than other types (no revisions so-far). Older age at surgery also involved a lower revision risk. Gender, disease genotype, and use of cement during the procedure did not have significant effect on longevity. As expected, quality of life and hip related function were better for patients who did not undergo revision. This implies the importance of long-term implant survival. CONCLUSION: Based on these results we recommend THR as a viable treatment for symptomatic hip arthrosis, especially at older age. Specifically, the utilisation of ceramic on ceramic bearing surfaced shows promising result in patients with Gauchers disease.

Cauda equina syndrome in a patient diagnosed with type 1 Gaucher disease: a rare case.

BACKGROUND: Gaucher disease is a rare hereditary glycolipid storage disease. One of the rare complications is neurodeficits due to vertebral involvement. CASE PRESENTATION: An 18-year-old female patient presented to the outpatient clinic with cauda equina syndrome due to sacral involvement of type 1 GD. Bilateral laminectomy via posterior approach without posterior stabilization was performed. CONCLUSION: Maximum excision of the mass avoiding destabilization of the spinal column can provide long-term vertebral stability and improvement in neurodeficits.

Prevalence and predictors of liver fibrosis evaluated by vibration controlled transient elastography in type 1 Gaucher disease.

BACKGROUND & AIMS: Long-term liver-related complications of Gaucher disease (GD) include cirrhosis, portal hypertension and hepatocellular carcinoma. Although liver fibrosis is the main determinant of adverse liver-related clinical outcomes, it has rarely been evaluated in previously published cohorts of GD patients. We aimed at: assessing the prevalence of significant liver fibrosis in a cohort of patients with type 1 GD; identifying its predictors among GD-related variables, enzyme replacement therapy (ERT) and metabolic features. METHODS: 37 adult type 1 GD patients from two Italian academic referral centers were prospectively submitted to vibration controlled transient elastography (Fibroscan®); significant fibrosis was defined as liver stiffness ≥7 kPa. RESULTS: Median liver stiffness was 4.6 [3-15.1] kPa and 7 patients (19%) had significant fibrosis. Significant fibrosis was associated with splenectomy (p = .046) and with scores (DS3: p = .002; SSI: p = .026) and biomarkers (ACE: p = .016; HDL cholesterol: p = .004) of GD severity. Length of ERT was significantly lower in GD patients with significant fibrosis. In the subgroup of 29 patients who were on stable ERT for at least 24 months, further to splenectomy, GD severity and non-N370S GBA1 genotypes, also diastolic blood pressure, BMI and the number of metabolic syndrome (MetS) components emerged as factors significantly associated with significant fibrosis. CONCLUSIONS: Significant fibrosis is present in a remarkable proportion of adult type 1 GD patients. Splenectomy, GD severity and GBA1 genotypes are major GD-related predictors of liver fibrosis. Length of ERT is inversely correlated with liver disease in GD patients, suggesting a beneficial effect of ERT on liver fibrosis. However, GD patients on stable ERT should be monitored for metabolic complications, since MetS features may enhance liver disease progression despite optimal GD control.

Splenectomy in Gaucher Disease: A Call for Minimally Invasive Surgery.

OBJECTIVE: The objective of this article was to demonstrate that Gaucher disease (GD) patients with refractory hypersplenism and massive splenomegaly may successfully undergo hand-assisted laparoscopic splenectomy (HALS). METHODS: This was a retrospective audit conducted at the Gaucher clinic at a national referral center over a 10-year period. PATIENT POPULATION: This study included 8 GD patients who underwent hand-assisted or conventional laparoscopic splenectomy for massive or complicated splenomegaly between the years 2007 and 2017. RESULTS: Seven patients underwent an elective HALS procedure because of refractory hypersplenism, whereas 1 patient underwent an urgent conventional laparoscopic splenectomy because of torsion of a wandering spleen. Only 1 patient required conversion to open surgery because of multiple adhesions from a previous partial splenectomy. The mean weight of the removed spleens was 2373 g (range, 480 to 4900 g), mean craniocaudal length of the removed spleens was 25 cm (range, 20 to 33.5 cm), and mean operating time was 150 minutes (range, 96 to 280 min). Postoperative complications were limited to 2 patients and included thrombosis of the splenic vein stump in 1 patient, and propagation of a preoperative splenic vein thrombus to the portal system, as well as an accumulation of an intra-abdominal hematoma in another patient. There was no mortality. Mean length of hospital stay was 5 days (range, 2 to 11 d). CONCLUSION: HALS for GD patients with refractory hypersplenism and massive splenomegaly is safe and feasible in experienced hands.

Hematopoietic stem cell transplantation for Gaucher disease.

BACKGROUND: Gaucher disease is the most common lysosomal storage disorder caused by a deficiency of the enzyme glucocerebrosidase. Current treatment of the disease involves a choice from enzyme replacement therapy, substrate reduction therapy and hemotopoietic stem cell transplantation (HSCT). HSCT is a high risk procedure with possible long-term benefits in the regression of skeletal and neurological changes in people with Gaucher disease. This is an update of a previously published Cochrane Review. OBJECTIVES: To determine the role of HSCT in people with Gaucher disease in relation to: mortality risk associated with the procedure; efficacy in modifying the course of the disease; and arrest or regression of neurological manifestations in neuronopathic forms (types 2 and 3). SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Inborn Errors of Metabolism Trials Register which comprises of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 19 January 2017.We also searched the websites: www.clinicaltrials.gov; WHO International Clinical Trials Registry Platform portal and www.genzymeclinicalresearch.com. Date of most recent search of these sites: 02 March 2017. SELECTION CRITERIA: All randomised, quasi-randomised and controlled clinical trials comparing stem cell transplantation with enzyme replacement therapy, substrate reduction therapy, symptomatic treatment or no treatment in people with Gaucher disease of all ages. DATA COLLECTION AND ANALYSIS: We independently assessed trials for inclusion, however, no relevant trials were identified. MAIN RESULTS: Thirty two trials were identified by the searches; however, these were not suitable for inclusion in the review. AUTHORS' CONCLUSIONS: HSCT is a form of treatment that offers the potential of permanent cure. However, there are no clinical trials that have assessed the safety and efficacy of this treatment in comparison to other conservative measures (enzyme replacement therapy, substrate reduction therapy) now in use.There are no trials included in the review and we have not identified any relevant trials up to March 2017. We therefore do not plan to update this review until new trials are published.

The Exeter Universal cemented femoral stem at 20 to 25 years: A report of 382 hips.

AIMS: We present a minimum 20-year follow-up study of 382 cemented Exeter Universal total hip arthroplasties (350 patients) operated on at a mean age of 66.3 years (17 to 94). PATIENTS AND METHODS: All patients received the same design of femoral component, regardless of the original diagnosis. Previous surgery had been undertaken for 33 hips (8.6%). During the study period 218 patients with 236 hips (62%) died, 42 hips (11%) were revised and 110 hips (29%) in 96 patients were available for review. The acetabular components were varied and some designs are now obsolete, however they were all cemented. RESULTS: With an endpoint of revision for aseptic loosening or lysis, survivorship of the stem at 22.8 years was 99.0% (95% confidence interval (CI) 97.0 to 100). One stem was revised 21 years post-operatively in a patient with Gaucher's disease and proximal femoral osteolysis. Survivorship with aseptic loosening or lysis of the acetabular component or stem as the endpoint at 22.8 years was 89.3% (95% CI 84.8 to 93.8). With an endpoint of revision for any reason, overall survivorship was 82.9% (95% CI 77.4 to 88.4) at 22.8 years. Radiological review showed excellent preservation of bone stock at 20 to 25 years, and no impending failures of the stem. CONCLUSION: The Exeter femoral stem continues to perform well beyond 20 years. Cite this article: Bone Joint J 2016;98-B:1441-9.

Persistent immune alterations and comorbidities in splenectomized patients with Gaucher disease.

Gaucher disease (GD) is an autosomal recessive disorder caused by mutations in the gene encoding acid-ß-glucosidase, resulting in functional disruptions in degradation of glycosphingolipids and lysosomal accumulation of the substrates. The most frequent clinical presentations of GD are thrombocytopenia, splenomegaly and bone pain. Prior to advent of enzyme replacement therapy, splenectomy was performed for complications of hypersplenism such as severe thrombocytopenia and transfusion dependency. Though there is evidence about worsening bone disease after splenectomy, there is no systematic study to assess its effects on the immune system in GD patients. In order to investigate the long-term immunological effects of splenectomy, we used flow cytometry to compare the immunophenotypes of GD patients who had undergone splenectomy (SGD) to those with intact spleen. The results show that SGD patients have significantly fewer CD27(+)/IgM(+) B-cells but more CD4(+)/CD45RO(+) and CD8(+)/CD45RO(+) T-cells. The most surprising finding was an almost complete absence of circulating dendritic cells in SGD patients. In addition, splenectomized subjects had comorbidities, the most common being monoclonal gammopathy of undetermined significance (MGUS). Taken together, these results highlight the persistence of multiple immune alterations and comorbidities coexisting in higher frequency in the SGD group and they are not affected by GD specific therapy.

Lung Transplantation in Gaucher Disease: A Learning Lesson in Trying to Avoid Both Scylla and Charybdis.

Gaucher disease (GD), a lysosomal storage disorder, may result in end-stage lung disease. We report successful bilateral lung transplantation in a 49-year-old woman with GD complicated by severe pulmonary hypertension and fibrotic changes in the lungs. Before receiving the lung transplant, the patient was undergoing both enzyme replacement therapy (imiglucerase) and triple pulmonary hypertension treatment (epoprostenol, bosentan, and sildenafil). She had a history of splenectomy, severe bone disease, and renal involvement, all of which were related to GD and considered as relative contraindications for a lung transplantation. In the literature, lung transplantation has been suggested for severe pulmonary involvement in GD but has been reported only once in a child. To our knowledge, until now, no successful procedure has been reported in adults, and no reports deal with the severe potential posttransplantation complications specifically related to GD.

Case Report Serious pulmonary infection in a splenectomized patient with adult type 1 Gaucher disease.

A 49-year-old man with a history of Gaucher disease type 1, resulting in serious splenomegaly and eating disorder, was referred to our department and underwent a splenectomy under general anesthesia. Gaucher disease is very rare, and its first signs are unexplained splenomegaly and hypersplenism. On preoperative examination, the patient's platelet count was slightly low, and his other test results were normal. Surprisingly, on the first postoperative day, the patient developed a lung infection. This gradually progressed to acute respiratory distress syndrome with respiratory failure, requiring intubation and mechanical ventilation. The patient eventually recovered, and he was discharged after receiving antibiotics and other treatments to enhance immunity. However, his postoperative lung infection led to a significantly prolonged and expensive hospital stay. This case suggests that we must pay close attention to the immune dysfunction of patients with Gaucher disease type 1. Anesthesia and surgery with accompanying post-traumatic stress can weaken patients' immunity and cause susceptibility to severe lung infections. Pulmonary signs and functions should be monitored closely during the perioperative period, and, if necessary, gamma globulin and thymosin should be administered early in the preoperative or postoperative period to enhance immunity.

Liver fibrosis in type I Gaucher disease: magnetic resonance imaging, transient elastography and parameters of iron storage.

Long term liver-related complications of type-1 Gaucher disease (GD), a lysosomal storage disorder, include fibrosis and an increased incidence of hepatocellular carcinoma. Splenectomy has been implicated as a risk factor for the development of liver pathology in GD. High ferritin concentrations are a feature of GD and iron storage in Gaucher cells has been described, but iron storage in the liver in relation to liver fibrosis has not been studied. Alternatively, iron storage in GD may be the result of iron supplementation therapy or regular blood transfusions in patients with severe cytopenia. In this pilot study, comprising 14 type-1 GD patients (7 splenectomized, 7 non-splenectomized) and 7 healthy controls, we demonstrate that liver stiffness values, measured by Transient Elastography and MR-Elastography, are significantly higher in splenectomized GD patients when compared with non-splenectomized GD patients (p = 0.03 and p = 0.01, respectively). Liver iron concentration was elevated (>60±30 µmol/g) in 4 GD patients of whom 3 were splenectomized. No relationship was found between liver stiffness and liver iron concentration. HFE gene mutations were more frequent in splenectomized (6/7) than in non-splenectomized (2/7) participants (p = 0.10). Liver disease appeared more advanced in splenectomized than in non-splenectomized patients. We hypothesize a relationship with excessive hepatic iron accumulation in splenectomized patients. We recommend that all splenectomized patients, especially those with evidence of substantial liver fibrosis undergo regular screening for HCC, according to current guidelines.

Velaglucerase alfa enzyme replacement therapy compared with imiglucerase in patients with Gaucher disease.

Enzyme replacement therapy for Gaucher disease (GD) has been available since 1991. This study compared the efficacy and safety of velaglucerase alfa with imiglucerase, the previous standard of care. A 9-month, global, randomized, double-blind, non-inferiority study compared velaglucerase alfa with imiglucerase (60 U/kg every other week) in treatment-naïve patients aged 3-73 years with anemia and either thrombocytopenia or organomegaly. The primary endpoint was the difference between groups in mean change from baseline to 9 months in hemoglobin concentration. 35 patients were randomized: 34 received study drug (intent-to-treat: 17 per arm), 20 were splenectomized. Baseline characteristics were similar in the two groups. The per-protocol population included 15 patients per arm. The mean treatment difference for hemoglobin concentration from baseline to 9 months (velaglucerase alfa minus imiglucerase) was 0.14 and 0.16 g/dL in the intent-to-treat and per-protocol populations, respectively. The lower bound of the 97.5% one-sided confidence interval in both populations lay within the pre-defined non-inferiority margin of -1.0 g/dL, confirming that velaglucerase alfa is non-inferior to imiglucerase. There were no statistically significant differences in the secondary endpoints. Most adverse events were mild to moderate. No patient receiving velaglucerase alfa developed antibodies to either drug, whereas four patients (23.5%) receiving imiglucerase developed IgG antibodies to imiglucerase, which were cross-reactive with velaglucerase alfa in one patient. This study demonstrates the efficacy and safety of velaglucerase alfa compared with imiglucerase in adult and pediatric patients with GD clinically characterized as Type 1. Differences in immunogenicity were also observed.

Pilot study using ambroxol as a pharmacological chaperone in type 1 Gaucher disease.

The purpose of this pilot was to assess the tolerability and efficacy of ambroxol as a pharmacological chaperone in patients with symptomatic, type 1 Gaucher disease who present with measurable disease parameters but are not receiving enzyme replacement therapy (ERT) in order to provide proof of concept and/or ascertain the suitability of ambroxol for a larger clinical trial. The Israeli Ministry of Health Form 29c was employed to prescribe ambroxol for off-label use. Twelve patients were dispensed 2 capsules of 75 mg of ambroxol daily for 6 months. There were 8 females (66.7%). Mean age at entry was 41.1 (range: 24-63) years. Mean body weight at entry was 66.4 (range: 46.5-100) kg. One patient withdrew because of a hypersensitivity reaction, one because of elective splenectomy. No patient experienced clinically relevant deterioration in disease parameters measured. One patient achieved a robust response relative to baseline: +16.2% hemoglobin; +32.9% platelets; -2.8% liver volume; and -14.4% spleen volume. Three patients, including the above one, elected to continue on ambroxol for a further 6 months: hemoglobin levels and liver volumes were relatively stable, but platelet counts further increased in the above patient (+52.6% from baseline) and spleen volumes decreased further in all three patients (-6.4%, -18.6%, and -23.4% from baseline). Thus, ambroxol may be a safe option for Gaucher disease patients with potential disease-specific efficacy and should be expanded into a clinical trial using higher doses and placebo-controlled design.

Hematopoietic stem cell transplantation for Gaucher disease.

BACKGROUND: Gaucher disease is the most common lysosomal storage disorder caused by a deficiency of the enzyme glucocerebrosidase. Current treatment of the disease involves a choice among enzyme replacement therapy, substrate reduction therapy and stem cell transplantation. Stem cell transplantation is a high risk procedure with possible long-term benefits in the regression of skeletal and neurological changes in people with Gaucher disease. OBJECTIVES: To determine the role of hematopoietic stem cell transplantation in people with Gaucher disease in relation to: mortality risk associated with the procedure; efficacy in modifying the course of the disease; and arrest or regression of neurological manifestations in neuropathic forms (Types 2 and 3). SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Inborn Errors of Metabolism Trials Register which comprises of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 26 March 2012.We also searched the websites www.clinicaltrials.gov and www.genzymeclinicalresearch.com. Date of most recent search of these sites: 16 February 2012. SELECTION CRITERIA: All randomised, quasi-randomised and controlled clinical trials comparing stem cell transplantation with enzyme replacement therapy, substrate reduction therapy, symptomatic treatment or no treatment in people with Gaucher disease of all ages. DATA COLLECTION AND ANALYSIS: We independently assessed trials for inclusion, however, no relevant trials were identified. MAIN RESULTS: Twelve trials were identified by the searches, however, these were not suitable for inclusion in the review. AUTHORS' CONCLUSIONS: Stem cell transplantation is a form of treatment that offers the potential of permanent cure. However, there are no clinical trials that have assessed the safety and efficacy of stem cell transplantation in comparison to other conservative measures (enzyme replacement therapy, substrate reduction therapy) now in use.