Neonatal cholestasis and infantile Gaucher disease: a case report

AIM: To report on clinical complications of liver disease occurring during Gaucher disease. METHODS: A case of Gaucher disease was revealed by neonatal cholestasis and early onset of portal hypertension. RESULTS: At 7 d of age, a newborn was admitted for cholestasis associated with hepatosplenomegaly and thrombocytopenia. At that time, bone marrow aspirate and liver biopsy did not reveal any engorged cells. The clinical course was marked by early progressive portal hypertension, and the patient died of uncontrollable upper gastrointestinal bleeding. The histological results of the postmortem showed that Gaucher cells were present in the liver, spleen and bone marrow. The diagnosis was confirmed by enzymatic studies. CONCLUSION: Isolated neonatal cholestasis could be the first sign of Gaucher disease. Gaucher disease should always be considered in such circumstances, even if, initially, the bone marrow aspirate and liver biopsy do not reveal any engorged cells.     

Effect of splenectomy on destructive bone changes in children with chronic (Type I) Gaucher disease

The incidence and severity of osteolytic bone changes in patients with chronic (Type I) Gaucher disease splenectomized in the first decade of life were compared to those in patients of the same age group and similar degree of severity of the disease in whom the spleen remained intact at least until the second half of the second decade. The size of the spleen, measured by palpation, was used as an index of severity. In the splenectomized group osteolytic changes appeared within a few months following splenectomy in six out of eight cases. The changes were severe in five cases and moderate in one. In contrast, in the non-splenectomized group, evidence of bone destruction was found in two out of eight patients and classified as mild in both cases. Furthermore, in three patients in this group, who remained free of bone destruction until splenectomy in the second half of the second decade, osteolytic lesions appeared soon after the operation. Children with chronic Gaucher disease can be spared a great deal of suffering caused by bone disease, if splenectomy is avoided or postponed as far as possible.Abbreviation CGD chronic, nonneuropathic (Type I) Gaucher disease     

Perinatal Lethal Gaucher Disease

Perinatal Lethal Gaucher Disease (PLGD) is a rare form of Gaucher disease and is often considered a distinct form of type 2 Gaucher disease. The authors report on an infant who presented with progressive hepatosplenomegaly, ichthyosis, generalized skin edema and neonatal encephalopathy and died at 6 h of age. Autopsy revealed massive hepatosplenomegaly, ichthyosis, a diffuse collodion picture and histological evidence of infiltration by Gaucher cells in the liver, spleen, lung, thymus, lymph node and bone marrow. Genetic testing of the parents revealed both to be carriers of Gaucher disease.     

Roles of specific cytokines in bone remodeling and hematopoiesis in Gaucher disease

BACKGROUND: Gaucher disease type 1 and type 3 are characterized by bone disease and hematological symptoms. It is known that monocyte/macrophage lineage is activated in Gaucher disease, and accordingly certain cytokines are elevated in blood. The aim of the present study was to explore the possible relationships between cytokines and bone remodeling and hematological abnormalities in this disease. METHODS: The concentrations of seven cytokines and two related proteins were measured in patients with Gaucher disease type 1 and type 3 (n= 8; age range, 2-50 years) who had received enzyme replacement therapy. RESULTS: Concentrations of interleukin-18 and transforming growth factor-beta1 were elevated in patients of all clinical types. Elevation of these cytokines in Gaucher disease has not been previously reported. Analysis of correlation among cytokines and bone-turnover markers showed that interleukin-18 concentration was correlated with each of two bone formation markers of bone-specific alkaline phosphatase activity and osteocalcin concentration, whereas macrophage colony-stimulating factor concentration correlated with the bone absorption marker of N-telopeptide to helix in urine. Concentrations of macrophage colony-stimulating factor and tumor necrosis factor-alpha were inversely correlated with hemoglobin concentration. CONCLUSIONS: Interleukin-18 and monocyte macrophage colony-stimulating factor are cytokines mainly involved in the mechanism of bone disease, while macrophage colony-stimulating factor and tumor necrosis factor-alpha may play a role in the development of hematological abnormalities in Gaucher disease.     

Gaucher disease: multiple lessons from a single gene disorder

Gaucher disease is the most common lysosomal storage disease. It is caused by a deficiency in the lysosomal enzyme glucocerebrosidase, a beta-glucosidase, which results in the accumulation of the lipid glucocerebroside in macrophages throughout the body. Gaucher disease is most common in the Ashkenazi Jewish population, and three mutations of the gene encoding glucocerebrosidase (GBA) have been shown to be prevalent in this population (c.1226 A > C [N370S], 84GG and IVS2[+1]). In non-Jewish patients, the most common mutation is c.1448 G > C (L444P). Until 15 years ago, treatment has been restricted to symptomatic interventions, such as splenectomy or hip replacement. However, there are now specific treatment options - enzyme replacement therapy and substrate reduction therapy. Future developments may include the use of chaperone therapy.Conclusion: The lessons that we have learned from Gaucher disease may well be applicable to the development of therapies for some of the other less common lysosomal storage diseases.     

Gaucher disease: multiple lessons from a single gene disorder

Gaucher disease is the most common lysosomal storage disease. It is caused by a deficiency in the lysosomal enzyme glucocerebrosidase, a β-glucosidase, which results in the accumulation of the lipid glucocerebroside in macrophages throughout the body. Gaucher disease is most common in the Ashkenazi Jewish population, and three mutations of the gene encoding glucocerebrosidase ( GBA ) have been shown to be prevalent in this population (c.1226 A > C [N370S], 84GG and IVS2[+1]). In non-Jewish patients, the most common mutation is c.1448 G > C (L444P). Until 15 years ago, treatment has been restricted to symptomatic interventions, such as splenectomy or hip replacement. However, there are now specific treatment options – enzyme replacement therapy and substrate reduction therapy. Future developments may include the use of chaperone therapy.
Conclusion: The lessons that we have learned from Gaucher disease may well be applicable to the development of therapies for some of the other less common lysosomal storage diseases.     

Outcome of enzyme replacement therapy in Turkish patients with Gaucher disease: does late intervention affect the response?

We aimed to evaluate the outcome of enzyme replacement therapy (ERT) in Turkish Gaucher patients since it first became available in our country. Eleven patients with type I and one patient with type III Gaucher disease (GD) received therapy as 30-60 U/kg and 120 U/kg every two weeks, respectively, for at least six months, starting a mean period of 4.2 years after the diagnosis. Assessment of response included serial measurements of hematological and biochemical parameters and liver and spleen volumes. Symptoms and signs of bone disease, growth and severity scores were also evaluated. ERT in Turkish patients led to marked improvement in hematological parameters and organomegaly in the majority of them. Patients with growth failure demonstrated catch-up growth. Progression of bone disease was not observed except in two patients who experienced a delay of 15 and 8.6 years, respectively, between the diagnosis and the start of ERT.     

Improvement of bone disease with increased dose of glucocerebrosidase in a Gaucher disease patient who had a bone lesion presenting during low-dose enzyme replacement therapy

In recent years, enzyme replacement therapy has been shown to be useful for the treatment of Gaucher disease. A 10 year old Japanese boy with Gaucher disease underwent splenectomy at the age of 5 years and received enzyme replacement therapy from the age of 6 years. He had avascular necrosis of the bilateral femoral heads, which was not seen at the beginning of the therapy, without deterioration of hematological variables during maintenance therapy. The enzyme dosage was increased from 20 to 120 IU/kg per month resulting in an improvement of the clinical symptoms and bone lesion. In enzyme replacement therapy, dose increase is considered to be essential for improvement in bone disease; however, it is important to watch for the development of bone lesion.     

Allogenic bone marrow transplantation in severe Gaucher disease.

Gaucher disease is the most prevalent lysosomal storage disease. This autosomal recessive disease is caused by the defective activity of the enzyme acid beta-glucosidase and the resultant accumulation of glucosylceramide primarily within cells of the reticuloendothelial system. Because the primary manifestations of Gaucher disease are due to involvement of monocyte/macrophage-derived cells, this disease is thought to be an excellent candidate for curative intervention via bone marrow transplantation (BMT). A Hispanic female with subacute neuronopathic Gaucher disease and rapidly progressing visceral manifestations underwent BMT at 23 mo of age using her histocompatible normal brother as the donor. Cytogenetic analyses demonstrated complete, stable engraftment by 1 mo post-BMT. During the subsequent 24 mo, clinical, biochemical, enzymatic, and histologic studies demonstrated nearly complete correction in the viscera. Her neuropathic manifestations did not progress. Complete reconstitution of enzymatic activity in peripheral blood leukocytes was achieved by 1 mo. Cytogenetic analyses demonstrated complete engraftment by d 79 and nearly complete loss of bone marrow Gaucher cells was observed by 8 mo. Plasma glucosylceramide levels normalized by 8-12 mo. Nearly coincident improvements in hepatic size, enzyme levels, and histology were found by 12-24 mo post-BMT. Fatal sepsis occurred at 24 mo post-BMT. Autopsy revealed sparse Gaucher cells in clusters in the liver, lymph nodes, and lungs as well as the lack of periadventitial Gaucher cells surrounding brain vessels. The findings provide the time course and rationale for studies directed to gene therapy via BMT for this disease after introduction of acid beta-glucosidase gene constructs into autologous pluripotent stem cells of selected Gaucher disease patients.     

酶替代治疗戈谢病72例

目的通过对戈谢病患者的用药跟踪监测,综合评估酶制剂伊米苷酶(Imiglucerase)替代疗法(ERT)治疗戈谢病的效果。方法 1999年5月至2005年10月,ERT 治疗戈谢病72例,男46例、女26例,年龄1岁4个月～22岁。Ⅰ型57例、Ⅱ型2例、Ⅲ型13例。伊米苷酶初剂量60 U/kg,每2周1次静脉滴注,2年后剂量改为45 U/kg。每用药3～6个月,对患者进行身高、体重、血常规、肝脾容积测定、长骨 X 线等检查。结果 3例失访,4例死亡,正接受治疗65例。ERT 治疗12个月起,未切除脾脏患者的 Hb 和血小板值显著增加(P<0.01);ERT 治疗30个月时,已切除脾脏患者的Hb 值明显增加(P<0.01),而血小板值在 ERT 治疗中无明显改变(P>0.05)。肝、脾体积随时间显著回缩(P<0.01),治疗24个月肝脏缩小(39±17)%、脾脏缩小(59±21)%。治疗12个月,2～12岁患儿身高增长(8.6±4.3)cm,体重增加(2.6±1.7)kg,12～18岁患儿身高增长(5.2±3.9)cm,体重增加(4.5±3.3)kg。复查骨 X 线征象无明显改变、16例合并骨痛经治疗3个月即缓解;Ⅱ、Ⅲ型神经系统症状无改善;全部病例未发现严重的毒副作用。结论 ERT 可改善戈谢病患者全身症状:纠正贫血、血小板减少,使肝脾体积回缩,体格发育,骨痛缓解,从而提高其生存质量。     

A disease severity scoring system for children with type 1 Gaucher disease

Almost half of patients with Gaucher disease are diagnosed by the age of 10 years, and approximately two thirds are diagnosed by the age of 20 years. Besides symptomatic children, some presymptomatic children are being diagnosed through community screening programs and because of affected siblings. In addition, it is anticipated that in the near future, newborn screening for lysosomal diseases such as Gaucher disease will be introduced in the USA, identifying additional pre/nonsymptomatic children. Currently, there is no severity scoring system for children. A validated disease severity scoring system in the pediatric Gaucher population will be essential for classifying disease severity in these children, monitoring their disease progression, making decisions about when to treat them, and monitoring disease improvement with therapy. A severity scoring system will also be helpful in comparing therapeutic options as new therapies are designed. Therefore, a Pediatric Gaucher Severity Scoring System (PGS3) was devised using expert opinion and validated in 26 patients with type 1 Gaucher disease. The PGS3 correlates well with disease severity in patients at diagnosis and over time. Conclusion: A practical system that will help clinical management, based on signs and symptoms in children with type 1 Gaucher disease, is presented.     

Type 2 Gaucher disease: the collodion baby phenotype revisited

The association of Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase (EC 3.2.1.45), and congenital ichthyosis was first noted a decade ago. Subsequently, a null allele type 2 Gaucher mouse was generated that also exhibited ichthyotic skin, confirming that the skin disorder and enzyme deficiency were directly related. This paper details the clinical and molecular characterisation of 6 cases of type 2 Gaucher disease presenting with the collodion baby phenotype. The identified mutant glucocerebrosidase alleles include two novel mutations (S196P and R131L) and two rare point mutations (R120W and R257Q), as well as alleles resulting from recombination with the nearby glucocerebrosidase pseudogene. There is significant genotypic heterogeneity in this rare subset of patients with type 2 Gaucher disease. Gaucher disease should be considered in the differential diagnosis of congenital ichthyosis in the newborn period.     

Aminohydroxypropylidene-biphosphonate in the treatment of bone lesions in a case of Gaucher's disease type 3

Bembi B, Agosti E, Boehm P, Nassimbeni G, Zanatta M, Vidoni L. Aminohydroxypropylidene-biphosphonate in the treatment of bone lesions in a case of Gaucher's disease type 3. Acta Pædiatr 1994;83:122–4. Stockholm. ISSN 0803–5253
Gaucher disease is the most prevalent lysosomal storage disorder. It is characterized by an autosomal recessive inheritance of a deficiency of lysosomal acid glucocerebrosidase. Three clinical phenotypes are recognized: type 1 (non-neuronopathic), type 2 (acute neuronopathic), type 3 (subacute neuronopathic). Bone lesions are associated with type 1 and type 3 Gaucher disease. Skeletal involvement is secondary to the progressive accumulation of histiocytes and macrophages laden with glucosylceramide in bone marrow. Our patient was a female type 3 Gaucher patient who was referred to us at the age of 3 years with a neurological symptomatology and severe bone lesions (bilateral fracture of the femur heads, lytic process of the bone matrix of the femurs and distal flask deformity, kyphoskoliosis and chest deformity). The baby was constrained to a wheel-chair. The use of (3-amino-1-hydroxypropylidene)-1,1-biphosphonate (APD) was described in a case of Gaucher disease with very severe bone lesions. We used periodic iv infusions of APD (10 mg every 3 weeks) in our patient for a period of 20 months; after that, enzyme replacement therapy (alglucerase) was commenced. APD treatment showed normalization of bone density, formation of bone callus at the femural heads, positive calcium balance. The urinary Ca/Cr ratio and TRP were consistently normal during therapy. After 9 months of algucerase therapy the patient was able to walk again. The data indicate that APD therapy can find an indication in Gaucher patients with severe bone involvement.     

Gaucher Disease: Treatment of Hypersplenism with Splenic Embolization

ABSTRACT. Hypersplenism is a frequent complication of Gaucher disease requiring splenectomy. A patient with Gaucher disease and severe hypersplenism was treated with partial splenic embolization to avoid the increased risk of serious infectious complications and deterioration of the disease associated with splenectomy. A first embolization (25% ablation) was performed at 4 years. Because of persisting abdominal discomfort, failure to thrive and signs of hypersplenism a second embolization (40–50% ablation) was performed 18 months later. Subsequently, the patient's health improved remarkably and 4 years later he achieved normal growth, maintains normal haematologic parameters, is free of symptoms and has no skeletal abnormalities. No serious infections have occurred. The size of the liver and the spleen has not changed appreciably. It appears that partial splenic embolization may be preferable to splenectomy in patients with Gaucher disease, especially in those of young age.     

Gaucher disease: treatment of hypersplenism with splenic embolization

Hypersplenism is a frequent complication of Gaucher disease requiring splenectomy. A patient with Gaucher disease and severe hypersplenism was treated with partial splenic embolization to avoid the increased risk of serious infectious complications and deterioration of the disease associated with splenectomy. A first embolization (25% ablation) was performed at 4 years. Because of persisting abdominal discomfort, failure to thrive and signs of hypersplenism a second embolization (40-50% ablation) was performed 18 months later. Subsequently, the patient's health improved remarkably and 4 years later he achieved normal growth, maintains normal haematologic parameters, is free of symptoms and has no skeletal abnormalities. No serious infections have occurred. The size of the liver and the spleen has not changed appreciably. It appears that partial splenic embolization may be preferable to splenectomy in patients with Gaucher disease, especially in those of young age.     

Analysis of the densitometric method of hand bone radiograms and assessment of early changes of bone structure in the children with Gaucher s disease on enzyme replacement therapy (ERT)

In the study of changes of bone structure eighteen children with Gaucher s disease (ERT) at the 4 to 19.8 years, used was densitometric in vivo method of hand bone radiograms. On the basis of the radiogram assessed was the bone age of patient also optical bone density and dimension in the second metacarpal bone. Differential diagnostics was produced based on standardized cortical thickness and optical bone density, according to the norm of Polish population (1989, 2004). The analysis of hand bone radiograms in children with Gaucher's (ERT) shows that 55.5% of patients had normal skeletal status, 38.8% indicated osteopenia traits, one patient had osteoporotic traits.     

Clinical and Biochemical Outcome of Marrow Transplantation for Gaucher Disease of the Norrbottnian Type

ABSTRACT. Three children, two girls and one boy, with Gaucher disease of the Norrbottnian type were treated by allogeneic bone marrow transplantation (BMT). Two of the donors were heterozygotes for Gaucher disease, and the third did not carry the gene. Engraftment was achieved in all three children but the boy became a chimera. The children have been followed from 1.5 to 6 years after transplantation. In each case the outcome was favourable, and in two children (patients 1 and 3) the BMT has been life saving. In all three cases a positive biochemical effect was apparent. Almost all biochemical parameters normalized within one year. The authors conclude that BMT is the treatment of choice in severe cases of Gaucher disease. BMT should be considered early in the course of disease and vigorous efforts made to find a suitable donor.     

GAUCHER DISEASE: PATHOPHYSIOLOGY AND TREATMENT

D A Hughes, M C Reed, R J Baker, L Richfield, A Milligan, S Evans, M Blincoe, A B Mehta
Lysosomal Storage Disorders Unit, Royal Free and University College Medical School, London, UK
Background: Gaucher disease is an autosomal recessive disorder caused by deficiency in β-glucocerebrosidase resulting in storage of glucosylceramide in reticuloendothelial cells. This results in multiorgan pathology including cytopenias, hepatosplenomegaly and bone disease. Bone disease may remain problematic despite treatment with recombinant enzyme. While features of bone pathology such as osteopenia and osteonecrosis have been described, their underlying pathophysiology is not well understood and the role of monocyte-derived osteoclasts is unknown.
Aim: To isolate, culture and characterize osteoclasts from patients with Gaucher disease and to compare kinetics of in vitro osteoclastogenesis and bone resorptive activity with cells derived from healthy subjects.
Methods: Peripheral blood mononuclear cells were isolated from patients with Gaucher disease and healthy controls, cultured with macrophage colony-stimulating factor and receptor activator of NF-κB ligand to induce osteoclastic differentiation and analysed for evidence of osteoclast markers and activity.
Results: Multinucleated giant cells expressing markers of osteoclast differentiation occurred earlier and in greater numbers in cultures derived from Gaucher patients. In addition, the functional capacity of osteoclasts for bone resorption was enhanced in Gaucher patients. Increases in both osteoclast number and activity correlated with clinical markers of severity of bone disease in individual patients.
Conclusion: Patients with Gaucher disease-related bone disease exhibit enhanced capacity for osteoclast differentiation. Elucidating the underlying mechanisms will suggest rational therapies for the most disabling aspect of this condition.     

Clinical and biochemical outcome of marrow transplantation for Gaucher disease of the Norrbottnian type

Three children, two girls and one boy, with Gaucher disease of the Norrbottnian type were treated by allogeneic bone marrow transplantation (BMT). Two of the donors were heterozygotes for Gaucher disease, and the third did not carry the gene. Engraftment was achieved in all three children but the boy became a chimera. The children have been followed from 1.5 to 6 years after transplantation. In each case the outcome was favourable, and in two children (patients 1 and 3) the BMT has been life saving. In all three cases a positive biochemical effect was apparent. Almost all biochemical parameters normalized within one year. The authors conclude that BMT is the treatment of choice in severe cases of Gaucher disease. BMT should be considered early in the course of disease and vigorous efforts made to find a suitable donor.