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.

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.

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.

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.

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.

Gaucher disease: outcome following total hip replacements and effect of enzyme replacement therapy in a cohort of UK patients.

Only a limited number of reports of total hip replacements (THRs) in patients with Gaucher disease (GD) have been published, with the majority showing high rates of early aseptic loosening as well as an increased number of peri-operative complications. We present a series of twelve THRs in nine affected patients, with a mean age of 39 years at the time of surgery (median 37 years; range 27-60 years). We examine the medium- to long-term results and present the outcome scores, survival, and assess the effect of enzyme replacement therapy (ERT). Four hips (33.3%) required revision for aseptic loosening at a mean time of 11.5 years. There was no significant difference in survival between the group on ERT at the time of surgery and group not on ERT. Those on ERT did, however, have fewer peri-operative complications and there was a trend to better outcome scores. Five of the 12 THRs were performed when the diagnosis of GD was unknown and all of these had early complications.?Our results show better survival of THRs in patients with GD than previously thought. The use of ERT pre-operatively did not have an effect on survival, nor outcome scores, but did reduce the peri-operative complication rate. Those not on ERT at the time of surgery were commenced on it at some point in their treatment (at an average of 8.6 years following THR) and we believe the use of ERT, at any time in the treatment, could have contributed to the improved survival seen in our series compared to historical results in the literature.

Vitrectomy for vitreous opacities and macular pucker in Gaucher disease.

PURPOSE: To report significant surgical results in an uncommon ophthalmologic complication of a rare disease. METHODS: Interventional case report. RESULTS: A 16-year-old girl with type III Gaucher disease experienced visual loss in both eyes. Ophthalmologic examination revealed dense whitish vitreous opacities and macular pucker OU. Visual acuity (VA) OD was 20/63 and OS was 20/25. She underwent 25-gauge vitrectomy with removal of the vitreous core, posterior vitreous cortex, and indocyanine green?stained internal limiting membrane OD. Visual acuity improved, reaching 20/25 1 year after surgery despite the appearance of small preretinal flecks. Visual acuity OS decreased some time later and vitrectomy was performed when VA OS was 20/100. Three years after surgery, BCVA was 20/25 OD and 20/20 OS 1 year after surgery. CONCLUSIONS: We describe a young patient with Gaucher disease with severe bilateral vitreous opacities and macular pucker. After surgery, vitreous opacities partially and progressively recurred, but the overall favorable outcome strongly supports a surgical approach in cases of this kind.

Hip arthroplasty in patients with Gaucher disease.

Patients with Gaucher disease suffering from the consequences of femoral head osteonecrosis deserve a treatment modality that will eliminate pain, preserve ambulation and hopefully will endure long enough to allow satisfactory daily life. Total hip arthroplasty fulfills these 3 objectives. The rate of complications during anesthesia and during surgical procedure is comparable to otherwise healthy population if the Gaucher patients are carefully evaluated pre-surgery and prepared by a medical team familiar with all aspects of the disease. With prompt preparation, meticulous procedure, and careful post-operative care, patients with Gaucher disease may benefit from long-lasting hip prostheses. It is to be hoped that newer types of implants would allow longer revision-free periods even in this young patient population who have developed avascular necrosis, and a greater hope for patients with Gaucher disease would be that early administration of bone-specific therapies may prevent osteonecrosis.

Gaucher disease with communicating hydrocephalus and cardiac involvement.

A 14-year-old female with Gaucher disease presented with hydrocephalus, corneal opacities, cirrhosis, and cardiac valvular involvement. A homozygous D409H mutation was identified. She underwent surgery for aortic and mitral valve replacement. Because of severe calcification of the aortic root, no successful valve replacement was performed. She died on the third day after the explorative cardiac surgery. Cardiac abnormalities represent a life-threatening presentation of the homozygous D409H mutation. Identification of this type is essential prior to initiating appropriate therapy with enzyme replacement and cardiac corrective surgery.

Proximal femoral allograft: prognostic indicators.

Between 1972 and 1999, the Orthopedic Oncology Service treated 150 patients with resection and allograft transplantation of the proximal femur. Of the group, 121 patients had malignant tumors of the proximal femur and 29 had benign disorders. Four types of allografts were used: osteoarticular (46 patients), allograft-prosthesis (73), intercalary (20), and allograft-arthrodesis (5). Only 16% of the patients died of disease and 3% required amputation. The overall success rate for the series was 77% with the best results for the allograft prosthetic (82%) and intercalary procedures (87%). Graft infection (15 patients), allograft fracture (26 patients), and local recurrence (11 patients) most markedly affected outcome. With the exception of deaths of disease, no significant outcome difference occurred between the patients with malignant and benign disorders. In conclusion, allograft implantation especially for aggressive or malignant tumors of the proximal femur appears to be a competent system for therapy.

A patient with parkinsonism related to Gaucher's disease type I successfully treated by unilateral pallidotomy - a 3-year follow-up.

Gaucher's disease is the most common hereditary lysosomal storage disorder and presents with a wide clinical spectrum including parkinsonism. We present a patient first diagnosed with idiopathic Parkinson's disease at the age of 38 due to left-sided bradykinesia and rigidity. But thereafter the diagnosis of Gaucher's disease type I according to clinical pictures and clinical genetic testing was made. Despite the optimal enzyme replacement therapy, the parkinsonian symptoms worsened. He was referred for consideration for surgical treatment of his severe parkinsonism. At the age of 54 he underwent right-sided posteroventrolateral pallidotomy. The surgery was uneventful and he immediately improved. On the last examination performed 3 years later, he had mild parkinsonism and was independent in all activities of daily living. This case demonstrates a benefit of surgical treatment for genetically proven Gaucher's disease type I.

Poor results of drilling in early stages of juxta-articular osteonecrosis in 12 joints affected by Gaucher disease.

BACKGROUND AND PURPOSE: Gaucher disease is heterogeneous. One of the most devastating complications is bone involvement, ranging from mild osteopenia to osteonecrosis, but no markers have been discovered to predict onset and/or progression. We describe our experience in a large referral center using drilling for juxta-articular osteonecrosis in young patients with Gaucher disease. PATIENTS AND METHODS: We retrospectively reviewed medical data from all patients who were recommended to undergo drilling for osteonecrosis of juxta-articular bone of the femoral head, the humeral head, or upper tibia for acute osteonecrosis at a pre-collapse stage. RESULTS: 11 patients (mean age 34 years) underwent drilling of 12 joints with juxta-articular osteonecrosis; 3 (mean age 51 years) refused intervention. 9 joints that were drilled showed advancing joint degeneration within 0.5 to 4 years. 3 joints have undergone replacement. Of the 3 joints that did not undergo drilling, 2 have undergone replacement and 1 has collapsed with osteoarthritis. INTERPRETATION: We found equally poor outcome with and without drilling. Effective intervention can only be achieved by improving our understanding of bone physiology and pathophysiology in Gaucher disease.