Gaucher's disease: a paradigm for interventional genetics.

Enzyme replacement therapy (ERT) has been shown to be effective at reducing the accumulation of undegraded substrates in lysosomal storage diseases. Most ERT studies have been performed with recombinant proteins that are mixtures of phosphorylated and non-phosphorylated enzyme. Because different cell types use different receptors to take up phosphorylated or non-phosphorylated enzyme, it is difficult to determine which form of enzyme contributed to the clinical response. Here we compare the uptake, distribution, and efficacy of highly phosphorylated and non-phosphorylated beta-glucuronidase (GUSB) in the MPS VII mouse. Highly phosphorylated murine GUSB was efficiently taken up by a wide range of tissues. In contrast, non-phosphorylated murine GUSB was taken up primarily by tissues of the reticuloendothelial (RE) system. Although the tissue distribution was different, the half-lives of both enzymes in any particular tissue were similar. Both preparations of enzyme were capable of preventing the accumulation of lysosomal storage in cell types they targeted. An important difference in clinical efficacy emerged in that phosphorylated GUSB was more efficient than non-phosphorylated enzyme at preventing the hearing loss associated with this disease. These data suggest that both forms of enzyme contribute to the clinical responses of ERT in MPS VII mice but that enzyme preparations containing phosphorylated GUSB are more broadly effective than non-phosphorylated enzyme.

In this issue, Banikazemi and colleagues' landmark trial on Fabry disease provides a crucial path toward lowering the morbidity of this disease. Among other findings, they determined that hemizygou...

Designing Protein Therapies: Lessons Learned from Cerezyme® for Gaucher Disease

Gaucher disease (GD) has been classically divided into three phenotypes primarily according to the absence (type 1 GD or nonneuronopathic GD) or presence and severity (types 2 and 3 GD or neuronopathic GD) of neurological involvement. Despite such distinction, neurological manifestations have been recorded also in patients with type 1 GD: in this latter form, however, such manifestations are different and, in the majority of cases, of much less severity than those associated with types 2 and 3 GD. Significant advances in therapy have been achieved, primarily after the advent of enzyme replacement therapy (ERT). As it occurs in patients with type 1 GD, ERT is able to reverse systemic and extraneurological manifestations of type 3 GD, although evidence suggests that ERT is not able to prevent the progression of neurological involvement in the long term. Thus, it is necessary to better understand the pathophysiological mechanism underlying neurological involvement in GD patients, allowing the development of new therapeutic approaches capable of improving central nervous system manifestations in GD.

Rationale:Gaucher disease (GD) is an autosomal recessive disorder that leads to multiorgan complications caused by β-glucocerebrosidase deficiency due to mutations in the β-glucocerebrosidase-encoding gene (GBA). GD morbidity in Japan is quite rare and clinical phenotype and gene mutation patterns of patients with GD in Japan and Western countries differ considerably. Of Japanese patients with GD, 57% develop types 2 or 3 GD with neurologic manifestations and younger onset, whereas only 6% of patients with GD develop those manifestations in Western countries. Thus, it is relatively difficult to find and diagnose GD in Japan.Patient concerns:A 69-year-old Japanese female with mild anemia and thrombocytopenia but without neurologic symptoms was initially referred for gastric cancer. Preoperative 18F-deoxyglucose positron emission tomography/computed tomography (FDG PET/CT) showed accumulation in the bone marrow and paraabdominal lymph nodes. Following bone marrow aspiration found, abnormal foamy macrophages in the bone marrow and electron microscopy revealed that the macrophages were filled with tubular-form structures. Adding to these signs suggestive of a lysosomal disease, serum β-glucocerebrosidase activity test found decreased. Sequencing of the patient's GBA gene revealed a RecNciI recombinant mutation and the novel mutation K157R (c.587A>G).Diagnoses:On the basis of these findings and clinical manifestations, the final diagnosis of type 1 GD was made.Interventions:Enzyme replacement therapy (ERT) with velaglucerase α was started after the diagnosis of type 1 GD.Outcomes:The patient's β-glucocerebrosidase activity as well as hemoglobin and platelet levels were restored by ERT without any side effects. Bone marrow aspirations 10 months after the start of the treatment with velaglucerase α showed reduction of Gaucher cells in bone marrow to 2% from 4% of total cellularity.Lessons:This is the first report of 18F-FDG PET/CT application providing a clue for GD diagnosis. A novel mutation in GBA is described, which implies a potential pool of patients with GD with this mutation in Japan.

Journal of Inherited Metabolic DiseaseVolume 30, Issue 6 p. 843-844 EditorialFree Access No justification for very high-dose enzyme therapy for patients with type III Gaucher disease Ari Zimran, Ari Zimran Gaucher Clinic, Shaare Zedek Medical Center, Jerusalem, 91031 IsraelSearch for more papers by this authorDeborah Elstein, Corresponding Author Deborah Elstein [email protected] Gaucher Clinic, Shaare Zedek Medical Center, Jerusalem, 91031 Israel [email protected]Search for more papers by this author Ari Zimran, Ari Zimran Gaucher Clinic, Shaare Zedek Medical Center, Jerusalem, 91031 IsraelSearch for more papers by this authorDeborah Elstein, Corresponding Author Deborah Elstein [email protected] Gaucher Clinic, Shaare Zedek Medical Center, Jerusalem, 91031 Israel [email protected]Search for more papers by this author First published: 19 November 2007 https://doi.org/10.1007/s10545-007-0783-8Citations: 18AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References Altarescu G, Brooks B, Margalioth E, Eldar Geva T, Levy-Lahad E, Renbaum P (2007) Simultaneous preimplantation genetic diagnosis for Tay–Sachs and Gaucher disease. Reprod Biomed Online, 15: 83– 88, . Barton NW, Brady RO, Dambrosia JM, et al (1991) Replacement therapy for inherited enzyme deficiency: macrophage-targeted glucocerebrosidase for Gaucher's disease. N Engl J Med, 324: 1464– 1470, . Beutler E (2006) Lysosomal storage diseases: natural history and ethical and economic aspects. Mol Genet Metab, 88: 208– 215, . Beutler E (2007) Consensus recommendations. Br J Haematol, 138 (6): 673– 675, . Cox T, Lachmann R, Hollak C, et al (2000) Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis. Lancet, 355: 1481– 1485, . Davies EH, Erikson A, Collin-Histed, et al (2007) Outcome of type 3 Gaucher on enzyme replacement therapy: review of 55 cases J Inherit Metab Dis doi:10.1007/s10545-007-0577-z. Elstein D, Abrahamov A, Zimran A (1998) Ethical considerations for enzyme replacement therapy in neuronopathic Gaucher disease. Clin Genet, 54: 179– 184, . Elstein D, Guedalia J, Doniger GM, et al (2005) Computerized cognitive testing in patients with type I Gaucher disease: effects of enzyme replacement and substrate reduction. Genet Med, 7: 124– 130, . Patterson MC, Horowitz M, Abel RB, et al (1993) Isolated horizontal supranuclear gaze palsy as a marker of severe systemic involvement in Gaucher's disease. Neurology, 43: 1993– 1997. Prows CA, Sanchez N, Daugherty C, Grabowski GA (1997) Gaucher disease: enzyme therapy in the acute neuronopathic variant. Am J Med Genet, 71: 16– 21, . Vellodi A, Bembi B, deVillemeur TB, et al (2001) Management of neuronopathic Gaucher disease: a European consensus. J Inherit Metab Dis, 24: 319– 327, . Weinreb NJ, Charrow J, Andersson HC, et al (2002) Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher Registry. Am J Med, 113: 112– 119, . Zimran A, Elstein D, Beutler E (2006) Low-dose therapy trumps high-dose therapy again in the treatment of Gaucher disease. Blood, 108: 802– 803, . Citing Literature Volume30, Issue6November 2007Pages 843-844 ReferencesRelatedInformation

To review the epidemiology, pathophysiology, and treatments of Gaucher disease (GD), focusing on the role of enzyme replacement therapy (ERT), andsubstrate reduction therapy (SRT). A literature search through PubMed (1984-May 2013) of English language articles was performed with terms: Gaucher's disease, lysosomal storage disease. Secondary and tertiary references were obtained by reviewing related articles. All articles in English identified from the data sources, clinical studies using ERT, SRT and articles containing other interesting aspects were included. GD is the most common inherited LSD, characterized by a deficiency in the activity of the enzyme acid β-glucosidase, which leads to accumulation of glucocerebroside within lysosomes of macrophages, leading to hepatosplenomegaly, bone marrow suppression, and bone lesions. GD is classified into 3 types: type 1 GD (GD1) is chronic and non-neuronopathic, accounting for 95% of GDs, and types 2 and 3 (GD2, GD3) cause nerve cell destruction. Regular monitoring of enzyme chitotriosidase and pulmonary and activation-regulated chemokines are useful to confirm the diagnosis and effectiveness of GD treatment. There are 4 treatments available for GD1: 3 ERTs and 1 SRT. Miglustat, an SRT, is approved for mild to moderate GD1. ERTs are available for moderate to severe GD1 and can improve quality of life within the first year of treatment. The newest ERT, taliglucerase alfa, is plant-cell derived that can be produced on a large scale at lower cost. Eliglustat tartrate, another SRT, is under phase 3 clinical trials. No drugs have been approved for GD2 or GD3.

Type 1 Gaucher disease (GD) is the most common lysosomal storage disorder. Previously, treatment for GD was limited to intravenous enzyme replacement therapies (ERTs). More recently, oral substrate reduction therapies (SRTs) were approved for treatment of GD. Although both therapies alleviate disease symptoms, attitudes toward SRTs and patient perceptions of health while using SRT have not been well established. Electronic surveys were administered to adults with GD and asked about treatment history, attitudes toward SRTs, and perception of health while using SRTs as compared to ERTs, if applicable to the participant. ERT users that were offered treatment with SRTs cited potential side effects, wanting more research on SRTs, and satisfaction with their current treatment regimen as reasons for declining SRTs. SRT users expressed convenience and less invasiveness as reasons for choosing SRTs. Additionally, those using SRTs most often perceived their health to be similar to when they previously used ERT. Participant responses illustrate that attitudes toward SRTs can be variable and that one particular treatment may not be ideal for all patients with GD depending on individual perceptions of factors such as convenience, invasiveness, or side effects. Thus, individuals with GD should be counseled adequately by healthcare providers about both ERTs and SRTs for treatment of GD now that SRTs are clinically available.

Gaucher disease (GD) is the most common type of lysosomal storage disease, with type 2 being the most severe subtype. Type 2 GD patients suffer significant progressive neurological impairment, including spasticity, opisthotonus, seizure, and apnea. The recently developed enzyme replacement therapy (ERT) has shown therapeutic benefit for GD. However, as the enzymes do not cross the blood-brain barrier, ERT does not ameliorate neurological impairment in GD. Intrathecal baclofen therapy (IBT) is indicated for spastic neurological diseases, such as cerebral palsy, and studies have shown its therapeutic benefit in improving several manifestations of GD, such as scoliosis caused by muscle spasticity and respiratory function. To date, the potential benefits of IBT for treating lysosomal storage diseases such as GD have not been examined. Here we provide the first report of a patient with type 2 GD treated with IBT, and demonstrate its therapeutic benefit in ameliorating the neurological aspects of this disease.

Gaucher disease (GD) is a lysosomal storage disorder caused by the deficient activity of acid beta glucosidase, with consequent accumulation of glucosylceramide in the spleen, liver, bone marrow, and various organs and tissues. Currently, the gold standard for GD treatment is enzyme replacement therapy (ERT). The efficacy of ERT in improving or stabilizing the visceral and hematological symptoms of GD is well-proven. However, since ERT has to be administered by frequent intravenous infusions, this therapeutic approach has an important impact on the patient’s quality of life. Eliglustat tartrate is a new substrate reduction therapy for GD, which acts as a specific and potent inhibitor of glucosylceramide synthase and can be administered orally. This review summarizes the results of the preclinical and clinical trials, which experimented with eliglustat, and discusses its possible role in the management of GD, when compared to the currently available treatments and the new experimental approaches.

Pulmonary hypertension in type 1 Gaucher’s disease: genetic and epigenetic determinants of phenotype and response to therapy

Introduction to Brazilian Guidelines to Diagnosis, Treatment, and Monitoring for Gaucher Disease, Fabry Disease, Mucopolysaccharidosis I, and Pompe Disease

In Gaucher disease, the infiltration of the bone marrow by glucocerebroside-laden macrophages (Gaucher cells) triggers a diverse pattern of skeletal disease that results in crippling complications. Reliable ascertainment of the severity and pattern of skeletal disease is essential to determine disease status and the response to enzyme replacement therapy (ERT). Although there is ample documentation of reversal of haematological and visceral disease by ERT, there is a paucity of data on skeletal response to ERT in children. To delineate the pattern of bone disease in children with Gaucher disease in Egypt and to evaluate its response to ERT. Twenty-two children with Gaucher disease were treated with ERT. Phenotyping by clinical, laboratory and radiological criteria was performed at baseline and following 11.2 +/- 4 months of ERT. Genotyping for glucocerebrosidase (GBA) mutations was performed by gene sequencing, and genotype-phenotype correlations were performed.Results. Two-thirds of the patients were from consanguineous pedigrees and 14/22 patients were homozygous or compound heterozygous for L444P and D409H mutations. Bone involvement was detected by plain radiology in 11 children (50%) and in 16 (73%) by magnetic resonance imaging (MRI). There was no correlation of severity of bone involvement and GBA genotype. ERT ameliorated bone disease: 10 of the 11 children with abnormal radiographic findings at baseline showed improvement in skeletal lesions; while 9/16 showed improvement of marrow disease by MRI. Radiographic sensitivity and specificity were 62% and 82% compared to MRI for detection of bone involvement in this patient population. At baseline, bone pain was present in 5 patients and ERT resulted in complete symptomatic remission in all of them. ERT was associated with significant improvement in growth parameters and amelioration of haematological and visceral involvement. Symptomatic and radiological skeletal disease is common in children with Gaucher disease in Egypt. MRI is the most accurate technique for detecting early skeletal involvement. There was no correlation between severity of skeletal involvement and GBA genotype. ERT was effective in ameliorating radiological manifestations of skeletal disease and achieving complete remission of bone pain.

Objective: To analyze the clinical and genetical characteristics of children with Gaucher disease and to explore the relationship between genotype and phenotype. Methods: In this retrospective study, the clinical data of 14 children with Gaucher disease diagnosed in Children's Hospital of Nanjing Medical University from August 2016 to October 2021 were analyzed. Their general conditions, clinical manifestations, laboratory tests and gene variations were collected, followed by the analysis of the clinical phenotypes and genotypes. Results: Among 14 children diagnosed with Gaucher disease, 9 were males and 5 were females, with the age of diagnosis ranging from 0.7 to 15.8 years. There were 10 patients with type 1 Gaucher disease, 2 patients with type 2, and 2 patients with type 3. The most common clinical manifestations were splenomegaly, thrombocytopenia (14 cases), hepatomegaly (8 cases) and anemia (8 cases). There were 6 patients with growth retardation, and 5 patients lag in height compared with their peers. Bone abnormalities were revealed by magnetic resonance imaging in 7 type 1 Gaucher disease patients, but only 1 patient experienced bone pain. Patients with type 2 and type 3 Gaucher disease also presented with convulsions, nystagmus and hearing loss. Gaucher cells were found in bone marrow smears in 12 patients. The glucocerebrosidase gene variations identified in 13 patients were heterozygous and in 1 type 1 patient was homozygous of L483P. L483P variation accounted for 33%(10/30) of the variation alleles, followed by V414L, D448H and R159W. The variation alleles were L483P and L422R, F252I and L483P in 2 children with severe neurological manifestations of Gaucher disease. A novel variation c.22A>G was detected. Conclusions: Splenomegaly and thrombocytopenia are the main clinical presentations of Gaucher disease in children and bone lesions revealed by radiologic imaging appear prior to the occurrence of bone diseases, type 2 and type 3 Gaucher disease also present growth retardation and neurological manifestation. The most frequent variant allele is L483P, which are detected in all 3 subtypes of Gaucher disease. The L422R, F252I gene variants correlated with the neuronopathic phenotype.

The human lysosomal enzymes alpha-galactosidase (alpha-GAL, EC 3.2.1.22) and alpha-N-acetylgalactosaminidase (alpha-NAGAL, EC 3.2.1.49) share 46% amino acid sequence identity and have similar folds. The active sites of the two enzymes share 11 of 13 amino acids, differing only where they interact with the 2-position of the substrates. Using a rational protein engineering approach, we interconverted the enzymatic specificity of alpha- GAL and alpha-NAGAL. The engineered alpha-GAL (which we call alpha-GAL(SA)) retains the antigenicity of alpha-GAL but has acquired the enzymatic specificity of alpha-NAGAL. Conversely, the engineered alpha-NAGAL (which we call alpha-NAGAL(EL)) retains the antigenicity of alpha-NAGAL but has acquired the enzymatic specificity of the alpha-GAL enzyme. Comparison of the crystal structures of the designed enzyme alpha-GAL(SA) to the wild-type enzymes shows that active sites of alpha-GAL(SA) and alpha-NAGAL superimpose well, indicating success of the rational design. The designed enzymes might be useful as non-immunogenic alternatives in enzyme replacement therapy for treatment of lysosomal storage disorders such as Fabry disease.