Gaucher disease: studies of phenotype, molecular diagnosis and treatment

This report summarizes the results on 39 patients with Gaucher disease who have been genotyped, evaluated, and/or followed at this center. Mutation analysis for 4 common mutations; N370S, L444P, 84gg and IVS2 (+1), was performed for all patients. Mutation analysis identified both mutant alleles in 69% and at least one mutant allele in 90% of all chromosomes. This study group of 39 patients included 32 type 1, four type 2 and three type 3 patients. We include the details of the clinical course of two patients with Gaucher disease treated with enzyme replacement therapy (ERT). One patient with chronic neuronopathic Gaucher disease has been treated with enzyme replacement therapy (ERT) at a dose of 60 U/kg every 2 weeks since 2.5 years of age and has shown no progression of neurologic involvement. A second patient with non-neuronopathic Gaucher disease has demonstrated an unusually delayed response to ERT. No clinical response was noted following 17 months of treatment at 60 U/kg every 2 weeks. Only after the dose was increased to 60 U/kg every week was a clinical response evident. Response to treatment at 15 U/kg every 2 weeks was variable in the four type 1 patients treated at the lower dose. In two of these patients with identical genotypes, one patient demonstrated a positive clinical response to low dose treatment while the other patient did not.     

Progressive mesenteric lymphadenopathy with protein-losing enteropathy; a devastating complication in Gaucher disease

Mesenteric lymphadenopathy has been rarely reported in pediatric patients with Gaucher disease, developing despite the enzyme replacement therapy. The clinical implication of this condition is undetermined, with no consensus on treatment strategies. However, this condition can reflect the progression of Gaucher disease. Moreover, it can be accompanied by the serious complication, protein-losing enteropathy. Our experience underlines the importance of careful monitoring and early intervention for mesenteric lymphadenopathy, especially in pediatric patients with neuronopathic Gaucher disease.     

Divergent phenotypes in Gaucher disease implicate the role of modifiers

Background: Gaucher disease is classified into neuronopathic and non-neuronopathic forms with wide phenotypic variation among patients sharing the same genotype. While homozygosity for the common L444P allele usually correlates with the neuronopathic forms, how a defined genotype leads to a phenotype remains unknown. Results: Residual enzyme activity was highly variable and did not correlate with the observed clinical course. There was also a wide spectrum of phenotypes. Average age at diagnosis was 15 months, and slowed saccadic eye movements were the most prevalent finding. The most severe systemic complications and highest mortality occurred in splenectomised patients before the advent of enzyme replacement therapy (ERT). On ERT, as morbidity and mortality decreased, developmental and language deficits emerged as a major issue. Some trends related to ethnic background were observed. Conclusion: The wide clinical spectrum observed in the L444P homozygotes implicates the contribution of genetic modifiers in defining the phenotype in Gaucher disease.     

Long-term follow-up of a patient with neonatal form of Gaucher disease

Gaucher disease is the most common of the lysosomal storage diseases. It presents a wide phenotypic continuum, in which one may identify the classically described phenotypes, including type 1 form with visceral involvement, type 2 acute neuropathic early-infantile form, and type 3 subacute neuronopathic form. At the most severe end there is the perinatal form with onset in utero or during the neonatal period. The very few reported cases of neonatal onset Gaucher disease presented high and early mortality, due to neurological or visceral involvement, including liver failure. We report our experience treating a patient with the neonatal form of Gaucher disease who presented at birth with thrombocytopenia, hepatosplenomegaly and cholestasis. Despite early enzyme replacement therapy, liver disease was progressive. Liver biopsy showed hepatocellular giant-cell transformation, a nonspecific finding consistent with inflammation. The lack of response to enzyme replacement therapy and the microscopic findings suggested that mechanisms apart from substrate accumulation and Gaucher cells may play a role in the hepatic pathogenesis in Gaucher disease. An attempt to use corticosteroids at the age of 3 months resulted in a dramatic improvement in liver function and resulted in long-term survival. The patient is alive and 2 years old at this writing. Our case suggests that inflammatory processes may be important in the early pathogenesis of Gaucher disease and that early use of corticosteroids may open the way to a new therapeutic approach.     

New Directions in Gaucher Disease

In Gaucher disease (GD), mutant lysosomal acid β‐glucocerebrosidase fails to properly hydrolyze its substrate, glucosylceramide, which accumulates in the lysosomes. Due to its phenotypic heterogeneity, GD has been classified into type 1, non‐neuronopathic, and types 2 and 3, the neuronopathic forms, based on the primary involvement of the central nervous system. Neuroinflammation and necroptotic death may appear in the neuronopathic forms of GD, whereas type 1 GD patients may develop Parkinson disease (PD), a prototype of protein misfolding disorders of the nervous system. PD is significantly more prevalent among GD carriers and patients than among the non‐GD populations. It is apparent that the amount of mutant enzyme present in lysosomes depends on the amount of mutant enzyme recognized as correctly folded in the endoplasmic reticulum (ER) for physiologically correct transport through the Golgi apparatus to the lysosome. Mutant enzyme recognized as misfolded is retained in the ER, inducing the Unfolded Protein Response. In the current review, we present three discrete areas of interest: molecular and cellular mechanisms underlying the association between GD and PD; the clinical and genetic associations between GD and PD; and treatment options for GD. We also discuss the relevance of induced pleuripotent stem cells to the above associations.     

Gaucher disease: Enzyme therapy in the acute neuronopathic variant

The responses to regular intravenous enzyme infusions were compared in two sibs with Gaucher disease type 2, the acute neuronopathic variant. Enzyme administration was begun at 7 months in patient 1 who had severe progressive visceral and neuronopathic disease. No significant effect of enzyme infusions was noted. Death occurred at 9 months. Patient 2 was prenatally diagnosed and enzyme infusions were initiated at age 4 days. Overall development progressed at a rate similar to her unaffected full sib until her death at 15.1 months. Slowly progressive esotropia, ocular paresis and dysphagia began at 8 months as did infiltrative pulmonary disease. Comparison of these clinical courses show significant visceral and neurologic effects of anticipatory enzyme therapy, but with unaltered outcome, for Gaucher disease type 2. Am. J. Med. Genet. 71:16–21, 1997. © 1997 Wiley-Liss, Inc.     

The identification of eight novel glucocerebrosidase (GBA) mutations in patients with Gaucher disease

Mutations in the gene encoding for the lysosomal enzyme glucocerebrosidase (GBA) result in Gaucher disease. In this study, seven novel missense mutations in the glucocerebrosidase gene (A136E, H162P, K198E, Y205C, F251L, Q350X and I402F) and a splice site mutation (IVS10+2T-->A) were identified by direct sequencing of three amplified segments of the glucocerebrosidase gene. Five of the novel mutations were found in patients with neuronopathic forms of Gaucher disease, two of which, K198E and F251L, appear to be associated with type 2 Gaucher disease.     

Gaucher disease: diagnosis and treatment

Gaucher's disease is the most common lysosomal storage disorder. It was identified in 1882 by Phillipe Gaucher, a French dermatologist. However, it was not until 1965 that Gaucher disease was found to be due to a deficiency in the enzyme glucocerebrosidase (EC 3.2.1.45) which breaks down glucocerebroside, a cell membrane component. The deficiency in this enzyme leads to an accumulation of glucocerebroside within the lysosomes of macrophages throughout the body. Gaucher's disease is classified into three types: type 1 (non-neuronopathic), type 2 (acute neuronopathic), and type 3 (subacute neuronopathic). Of the three, type 1 is the most common, affecting one in 40,000-200,000 people and having a high prevalence among Ashkenazi Jews, affecting one in 450-1500. The signs and symptoms of type 1 disease demonstrate marked heterogeneity, from asymptomatic or mildly symptomatic, to severe disability with disfigurement and even death. Hepatosplenomegaly and thrombocytopenia are well documented. Less well-recognized are often insidious skeletal complications which affect the majority of type 1 patients and which are its most debilitating feature. In addition to clinical suspicion, some morphologic, hematologic and biochemical indicators can help establish the diagnosis. However, definitive diagnosis is only made by determining the catalytic activity of the lysosomal enzyme glucocerebrosidase. Confirmation of heterozygosity requires the use of molecular biotechnology methods. About 150 mutations of the glucocerebrosidase gene have been identified in patients with Gaucher's disease, some of which are predictive of phenotype. The history of treatment of Gaucher disease started with splenectomy and continued with bone marrow transplantation, before the recent introduction of safe and effective enzyme replacement therapy. In Croatia, nine patients with type 1 Gaucher's disease have been identified so far. Seven patients are on enzyme replacement therapy, and past results demonstrated significant improvement in all clinical symptoms, without development of any side effects. However, new treatments, such as substrate balance therapy and gene therapy, may become available within the next few years. The place, if any, that such therapies will have in the treatment of patients with Gaucher's disease will be dependent on the results of clinical studies currently in progress.     

Mutation analysis of 28 Gaucher disease patients: The Australasian experience

Gaucher disease is the most common lysosomal storage disease. It is an autosomal recessive disorder that results from a deficiency of β-glucocerebrosidase. Three clinical phenotypes have been described: non-neuronopathic, acute neuronopathic, and subacute neuronopathic. Genomic DNA from 28 Australasian patients of diverse ethnic origin with Gaucher disease was screened for 3 common mutations (1226G, 1448C and 84GG) using the amplification refractory mutation system (ARMS), and one uncommon mutation (1504T) by restriction enzyme digestion. Thirty-eight of the 56 independent alleles in these patients were characterized, with 1448C present in 42% and 1226G in 28% of the alleles. The 1226G mutation was associated only with the non-neuronopathic phenotype and 7 of the 15 patients who carried the 1448C mutation developed neuronopathic disease. Three infants who died in the neonatal period following a rapidly progressive neurodegenerative course carried no identifiable mutations. The 84GG mutation was carried by 2 Jewish patients and 1504T was present in one patient. It is now possible to rapidly identify the common Gaucher mutations using ARMS and restriction enzyme digestion, and our findings confirm the heterogeneity of mutations in Gaucher disease. It is also possible to predict in part the phenotypic outcome when screening patients for these mutations. We consider mutation analysis to be of most use in prenatal diagnosis and for carrier detection within affected families. © 1994 Wiley-Liss, Inc.     

Creating genetics-based infusion centers: a case study of two models

In 1993, the first effective enzyme replacement therapy for a genetic disease, Ceredase (Genzyme Corporation, Cambridge, MA), was approved for use in patients with Gaucher disease. Over the next 13 years, enzyme replacement therapy became clinically available for the treatment of Fabry disease, mucopolysaccharidosis Type I, mucopolysaccharidosis Type II, mucopolysaccharidosis Type VI, and glycogen storage disease Type II. The development of enzyme replacement therapy to treat lysosomal storage diseases has resulted in an increasing number of genetic patients undergoing weekly or biweekly intravenous enzyme replacement therapy and an expanded role of the genetics team to include comprehensive care involving therapeutic intervention for lysosomal storage diseases. This article describes the development of two outpatient genetics-based infusion centers: the Northshore Genetics Infusion Clinic as part of the Children's Hospital of Wisconsin Lysosomal Diseases Treatment Center in conjunction with the Medical College of Wisconsin and the Emory Lysosomal Storage Disease Center for Genetic Infusions in the Emory University Department of Human Genetics.     

Therapy for Gaucher disease: don't stop thinking about tomorrow

While enzyme replacement therapy for Gaucher disease has been widely used and appears to be an efficacious and safe treatment, this success should not be a reason for complacency. Other treatment strategies currently under consideration for patients with Gaucher disease include gene therapy, substrate reduction therapy and chaperone therapy. Furthermore, improvements in enzyme therapy could also have a significant clinical impact. Individuals with Gaucher disease and other lysosomal disorders will greatly benefit from continual refinement and optimization of the current therapy, as well as from the development of new treatment modalities that offer improvements in efficacy, cost, safety and availability.     

The outcome of clinical parameters in adults with severe Type I Gaucher disease using very low dose enzyme replacement therapy

Enzyme replacement therapy is now well established as the treatment of choice in Type I Gaucher disease. Historically higher dosage regimens have been used in preference to lower doses despite the little clinical evidence in the way of large controlled clinical trials to support this. Moreover, the extraordinary cost of therapy means that not all eligible patients are able to be treated at the higher dose. Twelve type I adult patients with relatively severe disease were commenced on a very low dose of 7.5U of alglucerase/imiglucerase per kg every two weeks (initially given thrice weekly and later weekly). Follow-up 5 year data reveal a good visceral and haematological response with outcomes consistent with recently published treatment guidelines. Satisfactory clinical and radiological skeletal improvement was also demonstrated in most patients. Three patients had an inadequate overall skeletal response to therapy. Biomarkers also steadily improved although perhaps not quite at the same rate as that seen in higher doses. Very low dose enzyme replacement therapy may be appropriate for adult type I Gaucher patients with mild-moderate skeletal disease.     

Długotrwała pancytopenia po chemioterapii jako objaw demaskujący chorobę Gauchera u pacjentki z rakiem płuca

The diagnosis of congenital metabolic disease can be very difficult and often extends in time. This applies particularly to metabolic diseases of milder phenotype, such as an adult form (type 1) of Gaucher disease caused by the inherited (autosomal recessive) deficiency of the lysosomal enzyme glucocerebrosidase.In this work, we present a case of 48-year-old Polish patient (living in Sweden) with lung cancer, who developed a prolonged pancytopenia complicated by sepsis after each cycle of chemotherapy. These symptoms led to initiation of hematological diagnostic work-up and the assumption that the complications are caused by Gaucher disease. Definitive diagnosis of Gaucher disease was confirmed by results of enzymatic analyses, which revealed reduced activity of glucocerebrosidase in peripheral blood lymphocytes to 0.44 μkat/kg protein (ref.: 2.1–3.8), increased activity of plasma chitotriosidase to 1241 nkat/L (ref.: <40), and elevated plasma concentrations of chemokine CCL18/PARC to 1228 μg/L (ref.: <100). Direct DNA sequencing of the GBA1 gene revealed the presence of heterozygous mutation c.604C>T (R163X) and c.1226A>G (N370S), confirming diagnosis of type 1 Gaucher disease in the patient. The presence of the mutation c.604C>T has never been previously reported in a Polish patient with Gaucher disease. Administration of enzyme replacement therapy with imiglucerase (Cerezyme™) led to a rapid improvement of peripheral blood counts and enabled further continuation of intensive chemotherapy for lung cancer.In conclusion, the authors would like to emphasize that knowledge of the symptoms and the principles of diagnosis of Gaucher disease among hematologists is very important for efficient diagnostics of patients affected by this rare disease.     

Enzyme Replacement Therapy in a Gaucher Family

Gaucher disease is a lipid storage disorder due to deficiency of beta glucocerebrosidase. It's an autosomal recessive disease and as a result of this enzyme deficiency, glucocerebroside accumulates in various types of tissues like liver, brain spleen and bone marrow. We aimed to describe the effects of enzyme replacement therapy in three members of a family with Gaucher disease and to emphasize screening of the family members of the patients with Gaucher disease. Furthermore, late diagnosis and treatment in these patients have a minimal effect on improvement of the quality of life, and early diagnosis and treatment are very important in Gaucher disease.     

Gaucher disease: complexity in a "simple" disorder

Gaucher disease, the recessively inherited deficiency of the enzyme glucocerebrosidase and the most common sphingolipidosis, has both non-neurological and neuronopathic forms and a continuum of diverse clinical manifestations. Studies of genotype-phenotype correlations reveal significant genotypic heterogeneity among clinically similar patients, and vastly different phenotypes among patients with the same mutations. The region surrounding the glucocerebrosidase gene (GBA) on chromosome 1q is particularly gene-rich, with a highly homologous pseudogene sequence 16 kb downstream. Recombination events within the GBA locus contribute to the etiology of some mutations in Gaucher disease. Studies of patients with Gaucher disease and atypical manifestations, including parkinsonism, myoclonic epilepsy, cardiac involvement and collodion skin, seek to define other genetic or environmental factors contributing to the phenotypes. Recent reports demonstrating an association between Gaucher disease and parkinsonism provide an example of heterozygosity for a Mendelian disorder acting as a risk factor for a complex disease. There are rare patients with Gaucher disease and differing genotypes who develop early onset, treatment-refractory parkinsonism. Neuropathology in a group of these patients showed alpha-synuclein-reactive Lewy bodies in brain regions specifically associated with Gaucher disease. Family studies of these probands suggested that the incidence of parkinsonism might be more frequent in obligate heterozygotes. In a complementary finding, the examination of GBA in autopsy samples from individuals with sporadic Parkinson disease identified alterations in the GBA sequence in 14% of the cohort. These studies provide evidence that altered glucocerebrosidase may contribute to a vulnerability to parkinsonism. Moreover, this research demonstrates how insights from rare, single gene disorders like Gaucher disease can provide a window into the etiology of more common, multifactorial genetic diseases.     

Clinical and genetic study of Japanese patients with type 3 Gaucher disease

Information on the phenotypic variations seen in patients with type 3 (chronic neuronopathic) Gaucher disease (GD) is still limited compared with type 1 GD. We retrospectively investigated the clinical features of 42 Japanese patients with type 3 GD. The 42 patients classified as type 3 fell into two groups: those diagnosed as having type 3 GD at diagnosis (group A; n = 24) and those thought to have type 1 at diagnosis but who later developed neurological symptoms (group B; n = 18). The genotype of group A patients varied widely; however, L444P/L444P and L444P/F213I genotypes accounted for 83% in group B. All the patients who did not receive enzyme replacement with alglucerase or imiglucerase (4 in group A, 2 in group B) died. Nineteen patients received enzyme replacement in group A; however, 7 of these died despite the therapy. On the other hand, 14 patients received enzyme replacement alone in group B and 13 of them survived. Among the ERT-treated patients who survived, only one of 12 in group A and 12 out of 13 in group B can walk unaided. In conclusion, some Japanese GD patients who are thought to have type 1 at diagnosis develop neurological symptoms during their clinical course, and careful observation is essential for patients with characteristic genotypes. Moreover, enzyme replacement alone might not have a sufficient effect on the early onset neurological symptoms in type 3 patients. A different treatment strategy is needed to improve the prognosis of these patients.     

White vitreous opacities in five patients with Gaucher disease type 3

Fundal abnormalities, including preretinal and retinal changes, are a rare finding in patients with the autosomal recessive lysosomal storage disorder Gaucher disease, most often described in patients with the chronic neuronopathic form (type 3). We evaluated whether these ophthalmological findings correlated with other manifestations of type 3 Gaucher disease. Reviewing the records of 40 patients with type 3 Gaucher disease, we identified five with white vitreous opacities and reviewed their clinical course in depth. Each of the patients described decreased visual acuity and “floaters” obstructing their vision. The development and/or progression of these fluffy‐appearing white opacities in each patient were tracked longitudinally in the context of their neurological and other clinical findings. It was noted that all five patients shared genotype p.L483P/p.L483P (L444P/L444P) and had significant neurological, oculomotor and bone involvement and two had undergone splenectomy. Enzyme replacement therapy with recombinant glucocerebrosidase did not prevent the development or progression of these ocular opacities. Since preretinal findings, in addition to other neuro‐ophthalmological findings, can be a feature of Gaucher disease, it is recommended that patients be monitored by regular eye examinations.     

Global gene expression in a type 2 Gaucher disease brain

Gaucher disease is a member of a family of inherited disorders called sphingolipidoses that among others includes Tay-Sachs and Sandhoff diseases. It is caused by the accumulation of glucosylceramide (glucocerebroside) due to deficient activity of the enzyme glucosylceramide-beta-glucosidase (glucocerebrosidase). As with other glycosphingolipidoses, severe neurodegeneration is present in types 2 and 3 Gaucher disease. We have used Serial Analysis of Gene Expression (SAGE) to characterize the gene expression profiles in brain of patients with glycosphingolipid storage diseases to understand the molecular details of neurodegeneration. In the current study we have determined the gene expression profile from the brain of a patient with type 2 Gaucher disease, the acute neuronopathic form of the disorder. We found that the expression profile of the type 2 Gaucher brain is significantly altered relative to the normal control brain profile. There were also differences when compared with profiles from Tay-Sachs and Sandhoff patients, in particular in levels of genes related to macrophage activation. Intriguingly we found that gamma-synuclein, a family member of proteins involved the pathogenesis of other neurodegenerative disorders, was elevated in the one Gaucher type 2 patient brain we examined.     

Marked clinical and histologic improvement in a patient with type-1 Gaucher's disease following long-term glucocerebroside substitution. A case report and review of current diagnosis and management

Type-1 Gaucher's disease represents the most common lysosomal storage disorder. With the introduction of enzyme replacement therapy, many of the clinical manifestations can be controlled. The functional deficiency of the lysosomal beta-glucocerebrosidase leads to deposition of glycosylceramide in the liver, spleen, and bone marrow. We report the clinical and pathologic presentation of a patient with a florid type-1 Gaucher's disease who received long-term enzyme replacement therapy, which led to marked clinical improvement. A repeat liver biopsy performed at the time of a cholecystectomy several years after initiation of enzyme replacement therapy revealed complete resolution of Gaucher cells.