New prospects for the treatment of lysosomal storage diseases

Although individually rare, lysosomal storage disorders constitute a significant burden on society. To date, enzyme replacement therapy (ERT) has been the most successful therapeutic approach for lysosomal storage disorders. ERT reverses systemic manifestations of Gaucher disease but does not effectively treat the neurological complications. Recently, ERT produced a reduction of severe neuropathic pain, stabilisation of renal disease, and improved vascular function and structure in short-term, placebo-controlled trials in patients with Fabry's disease. Long-term studies are necessary to evaluate the full potential of ERT in this disease. In patients with Pompe disease, a fatal cardiac and skeletal muscle disorder, ERT improved cardiac function and structure, and increased overall muscle strength. It has already increased survival in a small number of affected infants. ERT also decreased liver and spleen size, joint mobility and quality of life in patients with mucopolysaccharidosis type I, but when the therapeutic protein is administered intravenously, it is unlikely to modify the neurological outcome in this or in other similar disorders. Bone marrow transplantation continues to be effective in Gaucher disease, in some forms of mucopolysaccharidosis and in mild forms of Krabbé disease, but it has high morbidity and mortality that limits its use in lysosomal storage disorders. Drugs that slow the rate of formation of accumulating glycolipids are being developed and one of them, OGT-918 (N-butyldeoxynojirimycin), is showing promise in patients with Gaucher disease. Gene therapy for lysosomal storage disorders holds promise as a replacement for the other therapies described here but requires much more development before clinical efficacy trials.     

Evidence-based recommendations for monitoring bone disease and the response to enzyme replacement therapy in Gaucher patients

BACKGROUND: Bone disease is a serious complication of Gaucher disease. Untreated, it can result in pain, permanent bone damage and disability. Enzyme replacement therapy reverses many of the clinical signs of Gaucher bone disease but early assessment and treatment, and regular monitoring, are essential in optimising outcomes. SCOPE: In September 2005, a group of European experts met to review current knowledge and identify best practice and unmet needs in the monitoring of Gaucher bone disease and the response to enzyme replacement therapy. METHODS: Medline searches of peer-reviewed literature (no date restrictions) were conducted and supplemented by additional information considered relevant by panellists to furthering discussions. FINDINGS AND CONCLUSIONS: The group's recommendations included: currently used biochemical bone markers are not clinically practical or reliable; plain X-rays should not be the sole method of assessing bone disease; MRI is the most sensitive method for monitoring bone marrow infiltration by Gaucher cells; semi-quantitative methods for assessing bone marrow infiltration in routine clinical practice should use readily available technology, include an assessment of Gaucher cell infiltration in the lumbar spine and femur, and be validated for inter-rater reliability and in comparison to other methods; a multidisciplinary approach is required for the treatment of Gaucher patients; all Gaucher patients should receive a comprehensive initial radiologic evaluation for bone disease and ongoing radiological monitoring at least once every 2 years.     

Evidence-based recommendations for monitoring bone disease and the response to enzyme replacement therapy in Gaucher patients

ABSTRACT

Background: Bone disease is a serious complication of Gaucher disease. Untreated, it can result in pain, permanent bone damage and disability. Enzyme replacement therapy reverses many of the clinical signs of Gaucher bone disease but early assessment and treatment, and regular monitoring, are essential in optimising outcomes.

Scope: In September 2005, a group of European experts met to review current knowledge and identify best practice and unmet needs in the monitoring of Gaucher bone disease and the response to enzyme replacement therapy.

Methods: Medline searches of peer-reviewed literature (no date restrictions) were conducted and supplemented by additional information considered relevant by panellists to furthering discussions.

Findings and conclusions: The group's recommendations included: currently used biochemical bone markers are not clinically practical or reliable; plain X‐rays should not be the sole method of assessing bone disease; MRI is the most sensitive method for monitoring bone marrow infiltration by Gaucher cells; semi-quantitative methods for assessing bone marrow infiltration in routine clinical practice should use readily available technology, include an assessment of Gaucher cell infiltration in the lumbar spine and femur, and be validated for inter-rater reliability and in comparison to other methods; a multidisciplinary approach is required for the treatment of Gaucher patients; all Gaucher patients should receive a comprehensive initial radiologic evaluation for bone disease and ongoing radiological monitoring at least once every 2 years.     

Selective action of the iminosugar isofagomine, a pharmacological chaperone for mutant forms of acid-beta-glucosidase

Gaucher disease is a lysosomal glycolipid storage disorder characterized by defects in acid-beta-glucosidase (GlcCerase), the enzyme responsible for the catabolism of glucosylceramide. We recently demonstrated that isofagomine (IFG), an iminosugar that binds to the active site of GlcCerase, enhances the folding, transport and activity of the N370S mutant form of GlcCerase. In this study we compared the effects of IFG on a number of other glucosidases and glucosyltransferases. We report that IFG has little or no inhibitory activity towards intestinal disaccharidase enzymes, ER alpha-glucosidase II or glucosylceramide synthase at concentrations previously shown to enhance N370S GlcCerase folding and trafficking in Gaucher fibroblasts. Furthermore, treatment of wild type fibroblasts with high doses of IFG did not alter the processing of newly synthesized N-linked oligosaccharides. These findings support further evaluation of IFG as a potential therapeutic agent in the treatment of some forms of Gaucher disease.     

Secondary G-CSF mobilized blood stem cell transplantation without preconditioning in a patient with Gaucher disease: Report of a new approach which resulted in complete reversal of severe skeletal involvement

Gaucher disease has been treated by allogeneic bone marrow transplantation (BMT), however, severe bone involvement that is probably the most disabling aspect of this disease is difficult to reverse. Other problem of BMT is the use of intensive preconditioning that adversely affects growth and development of the patients. In this study, a patient with type I Gaucher disease was treated by allogeneic BMT from HLA-matched sibling donor. However, the treatment resulted in late graft failure and the patient developed severe bone involvement. Fifty months after the first BMT, the patient was treated by allogeneic peripheral blood stem cell (PBSC) transplantation without preconditioning. Recombinant human granulocyte-colony stimulating factor (rhG-CSF) was used to mobilize PBSC. Cyclosporine A (CyA) was administered for the prophylaxis of graft-versushost disease (GVHD). Full donor-derived hematopoiesis was obtained, and clinical symptoms including severe bone involvement improved completely with increased glucocerebrosidase activity. It was shown that an engraftment could be obtained without intensive preconditioning when a recipient receives an rhG-CSF-mobilized PBSCs infusion as a secondary transplant. Another important finding of this study is the complete reversal of severe bone involvement by the supply of abundant glucocerebrosidase from high proliferating PBSC graft.     

戈谢病3例临床分析及文献复习

目的 探讨戈谢病的临床特点、诊断和治疗方法.方法 总结3例戈谢病患儿的临床表现、骨髓或组织病理特点等临床资料.结果 3例患儿的共同临床表现为生长发育落后、脾肿大、肝肿大、血小板减少、贫血,骨髓细胞学检查可见大量典型戈谢细胞.例1伴有智力低下及骨质疏松;例2伴有惊厥等神经系统症状及骨痛,脾病理检查可见典型戈谢细胞;例1和例3外周血白细胞葡萄糖脑苷脂酶活性均明显下降（＜正常值的15％）.例1诊断后即予足量酶替代治疗,6个月后肝脾肿大等临床表现明显缓解,治疗6年后由于没有足量用药而逐渐出现骨骼损害;例2经脾切除及对症治疗后神经系统症状仍进行性加重;例3暂未开始治疗.结论 对以肝脾肿大就诊的患儿,要注意戈谢病的可能性,避免漏诊和误诊.骨髓细胞学及酶学检查具有诊断意义.治疗上以对症为主,有条件者予酶替代治疗.     

Potent aminocyclitol glucocerebrosidase inhibitors are subnanomolar pharmacological chaperones for treating gaucher disease

Amino-myo-inositol derivatives have been found to be potent inhibitors of glucocerebrosidase (GCase), the β-glucosidase enzyme deficient in Gaucher disease (GD). When tested using lymphoblasts derived from patients with GD homozygous for N370S or L444P mutations, the compounds enhanced GCase activity at very low concentrations. The most potent inhibitor, (1R,2S,3R,4S,5S,6R)-5-(nonylamino)-6-(nonyloxy)cyclohexane-1,2,3,4-tetraol had a K(i) of 1 nM using isolated enzyme and an IC(50) of 4.3 nM when assayed in human fibroblast cell culture. This aminocyclitol produced maximum increases of GCase activities of 90% in N370S lymphoblasts at 1 nM and 40% in L444P at 0.01 nM following a three-day incubation. In addition to inhibitory potency, this compound has the permeability, subcellular distribution, and cell metabolism characteristics that are important for use as a pharmacological chaperone. It is a remarkable finding that picomolar concentrations of aminocyclitols are sufficient to enhance activity in the L444P variant, which produces a severe neuronopathic form of GD without clinical treatment.     

部分脾动脉栓塞与脾切除治疗脾功能亢进症的疗效比较

目的通过对部分脾动脉栓塞和脾切除治疗脾功能亢进症的治疗费用、疗效及并发症进行分析,评价两种方法治疗脾功能亢进症的特点。方法92例脾功能亢进症行部分脾动脉栓塞治疗患者作为脾栓塞组,208例脾功能亢进症行脾切除治疗患者作为脾切除组。比较两组患者住院天数及住院费用;术前、术后的白细胞(WBC)、红细胞(RBC)、血小板(PLT)水平;并发症发生情况。结果两组患者手术均安全、顺利、成功。脾栓塞组住院天数(23.39±10.15)d短于脾切除组的(31.54±11.08)d,住院费用中位数2.77万元少于脾切除组的4.82万元,差异均具有统计学意义(P<0.05)。术前,两组患者的WBC、RBC、PLT水平比较,差异均无统计学意义(P>0.05);脾栓塞组术后3、7、14、21 d的WBC、PLT水平均低于脾切除组,术后3 d的RBC水平高于脾切除组,差异均具有统计学意义(P<0.05);两组患者术后7、14、21 d的RBC水平比较,差异均无统计学意义(P>0.05)。脾栓塞组患者的腹水感染、脾周脓肿、门静脉血栓形成、发热、肝性脑病、腹泻发生率分别为25.00%、2.17%、0、88.04%、1.09%、2.17%,与脾切除组的42.79%、0、25.00%、98.08%、19.71%、0比较,差异均具有统计学意义(P<0.05);两组患者的腹水、腹痛、左下肺不张、肺炎、腹腔血肿、其他发生率比较,差异均无统计学意义(P>0.05)。结论部分脾动脉栓塞和脾切除均为治疗脾功能亢进症的有效方法,近期治疗效果明确。部分脾动脉栓塞更适合肝功能差、不能耐受外科手术的患者。     

Surgical treatment of hepatocellular carcinoma with cirrhotic esophageal varices and hypersplenism:a 184 case report

In treating hepatocellular carcinoma (HCC) patients with advanced cirrhosis, one of the most difficult problems is concomitant esophageal varices and hypersplenism. Whether these conditions should be treated surgically in association with HCC resection is still in debate. To elucidate whether esophageal devascularization or splenectomy is beneficial when simultaneously performed with liver resection in HCC patients with both varices and hypersplenism, HCC patients (n = 184) with esophageal varices and hypersplenism received one of the three treatments: simultaneous liver resection and esophageal devascularization (Group I, n = 41); simultaneous liver resection and splenectomy (Group II, n = 61); liver resection only (Group III, n = 82). The incidences of postoperative complications of the three groups were 31.7%, 29.5% and 24.4%, respectively, with no significant difference among them. The 5-year tumor-free survival rates for the group I, group II and group III were 34.1%, 36.1% and 37.8%, respectively. Variceal bleeding caused death by only 4.2% in group I, but by 14.3% in group II and 23.2% in group III. The survival rates in the group I and the group II were comparable to those in the group III, however, the recurrences of postoperative fatal variceal bleeding in group I and group II were significantly lower than those in group III. The results suggest that HCC patients with esophageal varices and hypersplenism should undergo hepatic resection plus esophageal devascularization or splenectomy if radical resection of HCC can be expected.     

A further case of Gaucher's disease in a black Zimbabwean

We present a further case of Gaucher's disease in a 23 year old black Zimbabwean woman treated in Bulawayo. The patient underwent a splenectomy for hypersplenism due to massive splenomegaly. The patient did well post-operatively and has continued to honour her outpatient follow-up appointments. At the last review, 8 months after splenectomy, she still continues to enjoy good health. There was no family history suggestive of Gaucher's disease and there is no possibility that this patient could be related to the other 2 cases (sisters) reported by Muguti et al in 1987.     

肝癌合并肝硬化脾亢同期行肝脾联合切除20例分析

目的探讨原发性肝癌并肝硬化脾功能亢进患者行肝癌切除联合脾切除的临床疗效。方法对1999年1月至2005年12月手术治疗的20例肝癌并肝硬化脾功能亢进患者的临床资料分析。结果 20例患者行原发性肝脏癌肿一期切除联合脾切除,手术基本顺利,无手术死亡;术后脾亢症状基本消失。无严重手术并发症。结论对肝癌合并肝硬化脾功能亢进患者行原发性肝癌切除联合脾切除是安全有效的;远期疗效也是较好的。     

Macrophage-derived soluble CD163 level in young patients with Gaucher disease: Relation to phenotypes,disease severity and complications

ObjectivesBone and lung involvement are two major causes of morbidity in Gaucher disease (GD). The soluble form of CD163 (sCD163) is a valuable diagnostic biomarker for monitoring diseases with increased macrophage activation. We determined sCD163 levels in 30 children and adolescence with GD compared with 30 healthy controls and assessed the relation to phenotypes, disease severity and complications.MethodsThirty GD patients (10 had type 1 and 20 had type 3) were studied stressing on skeletal, pulmonary or neurological manifestations, enzyme replacement therapy (ERT), hematological profile, plasma chitotriosidase activity, D-dimer and sCD163. Liver and spleen volumes and bone mineral density (BMD) were assessed.ResultssCD163 levels were markedly elevated in patients compared with controls. D-dimer, chitotriosidase activity and sCD163 levels were significantly increased in type 3 GD patients compared with type 1. sCD163 was significantly elevated in GD patients with dysphagia, developmental delay, pulmonary hypertension risk or abnormal BMD (osteopenia/osteoporosis) than those without. GD patients receiving ERT every 2 weeks had lower levels than those under ERT for more than 2 weeks. sCD163 was positively correlated with age, disease duration, severity score index, D-dimer and chitotriosidase activity. The cutoff value of sCD163 at 9400 ng/mL could differentiate GD patients with and without pulmonary hypertension risk with a sensitivity of 90% and specificity of 95%.ConclusionssCD163 is a biomarker for the clinical assessment of macrophage proliferation and activity that would help in risk prediction of bone and lung involvement and monitoring treatment response.     

Substrate reduction therapy for glycosphingolipid storage disorders

Substrate reduction therapy is a novel approach to treating glycosphingolipid (GSL) lysosomal storage disorders. These diseases are caused by mutations in the genes coding for enzymes involved in GSL catabolism and are characterised by the accumulation of GSL substrates within the lysosomes of cells. The aim of substrate reduction therapy is to inhibit the rate of synthesis of GSLs to levels where the residual activity of the mutant catabolic enzyme is sufficient to prevent pathological storage. In this review we discuss the development of N-butyldeoxynojirimycin (NB-DNJ), an imino sugar that inhibits the ceramide-specific glucosyltransferase which catalyses the first committed step of GSL synthesis. This agent has been shown to slow accumulation of stored glycolipid in an in vitro model of Gaucher’s disease and in knockout mouse models of Tay-Sachs and Sandhoff diseases. Furthermore, administration of NB-DNJ to Sandhoff mice delays the onset of neurological disease and also slows its progression. We discuss safety and efficacy data from the clinical trial of substrate reduction with NB-DNJ which has been undertaken in patients with Type 1 Gaucher’s disease. This trial provides a proof-of-principle for the use of this approach in a wide range of GSL lysosomal storage diseases.     

以血细胞减少为特征的非血液系统疾病临床分析

目的：分析以血细胞减少为特征的非血液系统疾病特点,开阔临床医师思维,避免误诊、漏诊。方法对108例以血细胞减少为特征的非血液系统疾病患者的临床特征、实验室检查及诊断进行回顾性分析。结果所有患者中感染性疾病31例,其中疟疾28例,流行性出血热2例,伤寒1例;脾功能亢进21例;结缔组织病21例,以系统性红斑狼疮最为多见;骨髓转移癌18例;甲状腺机能减退症7例;甲状腺机能亢进症5例;胃肠道肿瘤5例。结论以血细胞减少为特征的非血液系统疾病临床以感染性疾病最为多见,其次为脾功能亢进、结缔组织病和骨髓转移癌,应引起临床医师重视,减少误诊、漏诊。     

脾动脉盗血综合征的临床研究

目的研究门静脉高压症时是否存在脾动脉盗血及手术前后肝动脉血流动力学变化,为该类患者是否行脾切除术提供依据。方法54例正常人为对照组,69例门静脉高压症患者为试验组,门静脉高压症患者均行脾切除加贲门周围血管离断术,术前根据脾功能亢进状况分为轻度脾亢组（28例）和中重度脾亢组（41例）,采用TOSHIBAaplio50型彩色多普勒超声诊断仪,清晨空腹进行检查。常规检查肝胆脾情况,测量门静脉、脾动脉及肝动脉内径、血流参数（包括平均流速V、血流量F）。结果门静脉高压组门静脉内径明显大于对照组（P〈0.05）,血流量高于对照组（P〈0.05）,平均流速低于对照组（P〈0.05）。门静脉高压组血流量较对照组降低（P〈0.05）,中重度脾亢组肝动脉血流量较对照组有明显下降（P〈0.05）。中重度脾亢组患者脾动脉内径、平均流速及血流量较对照组均有明显升高（P〈0.01）。中重度脾亢患者脾切除后肝动脉血流量明显增加（P〈0.01）。结论门静脉高压症时门静脉血流增加,肝动脉血流量减少,脾动脉血流量明显增加,中重度脾亢时存在脾动脉盗血,脾切除后肝动脉血流量明显增加。     

手术治疗肝豆状核变性并脾功能亢进的疗效评价

目的：评价脾切除术联合胃底贲门周围血管离断术治疗肝豆状核变性并脾功能亢进的疗效。方法148例肝豆状核变性并脾功能亢进患者行脾切除术联合胃底贲门周围血管离断术治疗,检测患者的血常规、肝功能变化,评定手术疗效。结果手术后1周,患者血小板（PLT）、白细胞（WBC）较手术前显著升高（P ＜0．05）,甚至超过正常范围;手术后1月的 PLT、WBC水平则显著回落,恢复正常水平。谷丙转氨酶、谷草转氨酶、总胆红素术前处于较高水平,术后1周较术前进一步升高（P ＜0．05）,而术后1月时其水平较术前及术后1周均有显著下降（P ＜0．05）。结论脾切除术联合胃底贲门周围血管离断术治疗肝豆状核变性并脾亢,对恢复外周血细胞数量、保护肝功能均有显著作用。     

Fabry disease: recent advances in enzyme replacement therapy

Fabry disease is an X-linked inherited disorder of metabolism due to mutations in the gene encoding alpha-galactosidase A, a lysosomal enzyme. The enzymatic defect leads to the systemic accumulation of incompletely metabolised glycosphingolipids, primarily globotriaosylceramide, in plasma and lysosomes within various tissues. Inability to prevent the progression of glycosphingolipid deposition causes significant morbidity, associated with significant impact on quality of life and diminished lifespan from early onset strokes, heart attack and progressive renal failure. The disease manifests primarily in hemizygous males; however, there is increasing recognition that heterozygous (carrier) females may also develop disease-related complications. Indeed, most heterozygotes present with cardiac, renal or neurological symptoms, although with later-onset and to a lesser extent than is observed in hemizygotes. Until recently, medical management was symptomatic, consisting of partial pain relief with analgesic drugs (carbamazepin, gabapentin), kidney and vascular protection with angiotensin-converting enzyme inhibitors, statins and folic acid, whereas renal transplantation or dialysis is available for patients experiencing end stage renal failure. The ability to produce high doses of alpha-galactosidase A has opened the way to preclinical studies, and enzyme replacement therapy has recently been validated as a therapeutic agent in clinical trials. Long-term safety and efficacy of replacement therapy are currently being investigated. Increasing knowledge of the natural history of Fabry disease and greater experience with enzyme therapy should enable optimal patient care. The complexity and relative rarity of Fabry disease necessitates a multi-disciplinary team approach that may be facilitated by a disease registry.     

肝癌合并门脉高压脾功能亢进11例外科治疗

目的 探讨肝癌合并门静脉高压脾功能亢进患者外科治疗的方法。方法 回顾分析2001～2002年经手术治疗的肝癌合并门脉高压脾功能亢进患者11例，切除肝癌病灶同时行脾切除，或加行贲门周围血管离断术。结果 全组无手术死亡。术后并发症有腹水、低钠血症、上消化道出血、腹腔内出血。结论 肝癌合并门静脉高压脾功能亢进一期进行手术治疗是安全可行的。     

聚乙二醇干扰素α-2a联合利巴韦林对丙型肝炎肝硬化患者抗病毒治疗的疗效观察

目的观察聚乙二醇干扰素(Peg-IFN)α-2a联合利巴韦林对丙型肝炎肝硬化合并脾功能亢进患者在脾切除或部分脾栓塞术后抗病毒治疗的疗效。方法将31例丙型肝炎肝硬化(基因Ⅰ型HCV感染)合并脾功能亢进而未作抗病毒治疗的患者,在行脾切除术或部分脾栓塞术,脾功能亢进改善2个月后,给予Peg-IFNα-2a 135μg或180μg皮下注射,每周1次,联合利巴韦林800~1200mg/d治疗,疗程48周。治疗期间,第1、2、4、6、8、12周随访,之后每4周随访1次,停药后继续观察24周。治疗及随访期间观察肝功能、血常规、肾功能、HCV RNA及用药期间的不良反应。结果丙型肝炎肝硬化合并脾功能亢进患者采用脾切除或部分脾栓塞术治疗脾功能缓解后,给予Peg-IFNα-2a联合利巴韦林抗病毒治疗其持续病毒学应答率为64.51%。结论丙型肝炎肝硬化合并脾功能亢进的患者,在脾切除或部分脾栓塞术后给予Peg-IFNα-2a联合利巴韦林治疗有较好的SVR,延缓了丙型肝炎肝硬化的进展,减少了肝衰竭及肝癌的发生。     

Intensive investigation in management of Hodgkin's disease.

Ninety-eight patients with clinically localised Hodgkin's disease underwent laparotomy and splenectomy to determine the extent of microscopic spread. In 68 patients the procedure was carried out for untreated disease apparently confined above the diaphragm. Abdominal disease cannot be confidently excluded on the basis of non-invasive investigation at presentation. Clinical assessment of splenic disease was unreliable unless gross splenomegaly was present. Pedal lymphography was accurate in assessing para-aortic and iliac disease but of no value in assessing other intra-abdominal lymph node involvement, including that of the mesenteric lymph node. Trephine bone marrow biopsy findings were normal in all patients before surgery, and only one patient was found to have diseased bone marrow by Stryker-saw biopsy at operation. Liver disease was identified at operation in nine patients, some of whom were asymptomatic with clinically undetectable splenic and nodal disease. Detailed clinical staging failed to detect disease in one-third of patients who underwent laparotomy. These studies show that if radiotherapy is to remain the treatment of choice for disease truly localised to lymph nodes a detailed staging procedure, including laparotomy and splenectomy, remains essential. The value of this potentially curative treatment is considerably diminished in the patient who has been inadequately staged.