Clinical evaluation of biomarkers in Gaucher disease

Novel or candidate biomarkers require thorough evaluation to establish their utility in a clinical setting. This paper describes an evaluation of several established enzyme markers of Gaucher disease and a newly-described chemokine, pulmonary and activation-regulated chemokine (PARC). The ability of the biomarkers to rank patients with Gaucher disease in order of disease severity and organ bulk, and to reflect changes in key clinical parameters in response to enzyme replacement therapy were evaluated. PARC concentrations were found to be reliably correlated with visceral disease and with key clinical responses to enzyme replacement in an unbiased manner. Unlike chitotriosidase and serum angiotensin-converting enzyme activity, genetic variation in serum PARC did not appear to influence its utility as a biomarker.
Conclusion: For each new candidate biomarker of lysosomal storage diseases, a similar clinical evaluation will be required, though the approach will need to be modified according to the clinical features and natural history of each disorder.     

Identification and use of biomarkers in Gaucher disease and other lysosomal storage diseases

The value of biomarkers in the clinical management of lysosomal storage diseases is best illustrated by the present use of plasma chitotriosidase levels in the diagnosis and monitoring of Gaucher disease. The enzyme chitotriosidase is specifically produced and secreted by the pathological storage macrophages (Gaucher cells). Plasma chitotriosidase levels are elevated on average 1000-fold in symptomatic patients with Gaucher disease and reflect the body burden on storage cells. Changes in plasma chitotriosidase reflect changes in clinical symptoms. Monitoring of plasma chitotriosidase levels is nowadays commonly used in decision making regarding initiation and optimization of costly therapeutic interventions (enzyme replacement therapy or substrate reduction therapy). A novel substrate has been developed that further facilitates the measurement of chitotriosidase in plasma samples. Moreover, an alternative Gaucher-cell marker, CCL18, has been very recently identified and can also be employed to monitor the disease, particularly in those patients lacking chitotriosidase due to a genetic mutation. There is a need for comparable surrogate markers for other lysosomal storage diseases and the search for such molecules is an area of intense investigation.
Conclusion: The use of biomarkers can provide valuable insight into the molecular pathogenesis of LSDs, such as Gaucher disease and Fabry disease.     

Identification and use of biomarkers in Gaucher disease and other lysosomal storage diseases

The value of biomarkers in the clinical management of lysosomal storage diseases is best illustrated by the present use of plasma chitotriosidase levels in the diagnosis and monitoring of Gaucher disease. The enzyme chitotriosidase is specifically produced and secreted by the pathological storage macrophages (Gaucher cells). Plasma chitotriosidase levels are elevated on average 1000-fold in symptomatic patients with Gaucher disease and reflect the body burden on storage cells. Changes in plasma chitotriosidase reflect changes in clinical symptoms. Monitoring of plasma chitotriosidase levels is nowadays commonly used in decision making regarding initiation and optimization of costly therapeutic interventions (enzyme replacement therapy or substrate reduction therapy). A novel substrate has been developed that further facilitates the measurement of chitotriosidase in plasma samples. Moreover, an alternative Gaucher-cell marker, CCL18, has been very recently identified and can also be employed to monitor the disease, particularly in those patients lacking chitotriosidase due to a genetic mutation. There is a need for comparable surrogate markers for other lysosomal storage diseases and the search for such molecules is an area of intense investigation. Conclusion: The use of biomarkers can provide valuable insight into the molecular pathogenesis of LSDs, such as Gaucher disease and Fabry disease.     

戈谢病的治疗进展

戈谢病 (Ｇａｕｃｈｅｒｄｉｓｅａｓｅ ,ＧＤ)是溶酶体贮积病 (ｌｙｓｏｓｏｍａｌｓｔｏｒａｇｅｄｉｓｅａｓｅ ,ＬＳＤ)中最常见的一种 ,为常染色体隐性遗传。 1882年由法国医生ＰｈｉｌｉｐｅＧａｕｃｈｅｒ首先报道而得名。 5 0年后Ａｇｈｉｏｎ发现由于葡萄糖脑苷酶 (ｇｌｕｃｏｃｅｒｅｂｒｏｓｉｄａｓｅ ,ＧＣ)在肝、脾、骨骼和中枢神经系统的单核 巨噬细胞内蓄积所致。Ｂｒａｄｙ等[1] 在 196 4年发现葡萄糖脑苷脂的贮积是由于β 葡萄糖苷酶 (β ｇｌｕｃｏｓｉｄａｓｅ ) 葡萄糖脑苷脂酶(ｇｌｕｃｅｒｅｂｒｏｓｉｄａｓｅ ,Ｇ…     

Recent clinical progress in Gaucher disease

PURPOSE OF REVIEW: Major clinical advances in Gaucher disease focus on detection, prediction and treatment of variant phenotypes. RECENT FINDINGS: The advent of efficacious enzyme therapy has emphasized the importance of early diagnosis and intervention to prevent the morbid manifestations of the disease including organomegaly, growth and pubertal retardation, and osteopenia/osteoporosis. Genotype/phenotype correlations provide some guidance for prognosis by categorical distinctions of nonneuronopathic (type 1) and neuronopathic (types 2 and 3) variants. Early detection of children genetically predisposed to severe disease are a management challenge for the pediatrician and metabolic physician. The development of specific therapeutic goals provides a framework for assessments of visceral therapeutic and palliative responses in children with type 1, and types 2 and 3, respectively. SUMMARY: The pediatrician plays a major role in these clinical and genetically based decisions.     

戈谢病研究进展

戈谢病(Gaucher disease)是溶酶体贮积症(lysosomal storage disorder)中最常见的一种,为常染色体隐性遗传病.该病为溶酶体中葡糖脑苷脂酶(glucocerebrosidase)的结构基因变异,导致该酶缺乏,致使葡糖脑苷脂(glucocerebroside)不能被水解而聚积在巨噬细胞溶酶体中,导致细胞失去原有的功能而产生一系列症状,戈谢病是溶酶体贮积症中首先应用酶替代治疗(enzyme replacement therapy,ERT),并取得了很好疗效的疾病之一.在此将戈谢病研究进展综述如下.     

Gaucher disease—Norrbottnian type

Neurodevelopmental, neurological and neurophysiological aspects of the Norrbottnian type of Gaucher disease (type III) were studied in 22 patients. The findings were related to clinical stages and to whether or not the patients had been splenectomized. Neurological abnormalities were mainly found in splenectomized patients who had passed the first decade of life. The EEG findings were not diagnostic for the disease, but changes were more common in the advanced stages and among splenectomized patients. The patterns of development of neurological and neurophysiological features indicate that CNS deposition of glucosylceramide increases after splenectomy, and favor a restrictive attitude towards surgery.     

戈谢病1例

<正> 患者,男,1岁3个月,间断抽搐4次,发现腹胀半月余就诊。患儿4～5月龄时曾间断性惊厥4次,发作时突然头后仰,口周发绀,眼球凝视,意识丧失,四肢抽动,大小便失禁,抽搐时体温正常,持续时间     

Insulin-like growth factors in childhood-onset Gaucher disease

There is a high prevalence of growth retardation in children with type 1 Gaucher disease. The cause of this poor growth is not yet known; however, studies have shown acceleration of growth with enzyme replacement therapy (ERT). IGF are recognized as important determinants of somatic growth. It has been proven that chronic diseases with liver involvement might cause IGF deficiency. The aim of this study was to assess the IGF system in patients with childhood-onset Gaucher disease, before and after ERT, and its association with other clinical and analytical parameters. Twenty-two patients with type I Gaucher disease were included. The diagnosis was established before 14 y of age in all patients. Baseline determinations of total IGF-I, free IGF-I, and IGF binding protein 3 (IGFBP-3) were obtained in 19 patients before starting ERT at a mean age of 13.8 +/- 11.2 y. A Spearman test was performed to establish the association with other clinical and analytical parameters. In a group of 13 patients receiving IGF, changes were evaluated during the initial 2 y of treatment. A Wilcoxon test was performed for the statistical analysis. Total IGF-I, free IGF-I, and IGFBP-3 were expressed as SD scores (SDS). We found low levels of IGF and its binding proteins before ERT. A significant association was found between the total IGF-I SDS before treatment and the age-adjusted severity score index: r = -0.62, p < 0.05. Total IGF-I and IGFBP-3 SDS correlated negatively with the presence of the L444P mutation (r = -0.53 and -0.5, respectively, p < 0.05). Height SDS correlated with total IGF-I and IGFBP-3 SDS in eight children (r = 0.84 and 0.78, respectively, p < 0.05). Total IGF-I SDS increased from -1.8 +/- 0.8 to -0.8 +/- 1.4 (p = 0.005) and free IGF-I increased from -1.2 +/- 1 to 1.1 +/- 2.1 after 12 +/- 6.8 mo (p = 0.011) of ERT. IGFBP-3 SDS increased from -1.3 +/- 0.6 to -0.2 +/- 1.2 (p = 0.012) after 12 +/- 4.5 mo of ERT. Type 1 Gaucher disease is associated with low levels of IGF and its binding proteins, which could be a consequence of liver involvement. Total IGF-I deficiency is associated with the severity of the illness. Growth retardation in pediatric patients with Gaucher disease is related to the alterations in IGF axis. Total IGF-I and IGFBP-3 are the two parameters that better correlate with height before treatment. ERT results in significant increase of total IGF-I, free IGF-I, and IGFBP-3 during the first year of treatment.     

Clinical and genetic studies of five fatal cases of Japanese Gaucher disease type 1

Five fatal cases of Japanese patients with type 1 Gaucher disease were studied. The causes of death included hemorrhage secondary to esophageal varices (two cases), respiratory distress (one case), hepatic failure (one case) and postoperative sepsis (one case). All of the patients had previous splenectomies, four patients had bone involvement and hepatic cirrhosis. The identified Gaucher genotypes were 1448C/1213G, 1603T/1603T, 1448C/1390G, ?/? and 1213G/1213G. The prognosis of type 1 Gaucher disease is generally good. We propose that patients with a similar clinical course and genotype to those presented in the present study should receive prompt comprehensive treatment. Patients with the 1213G mutation, pulmonary and liver involvement and a previous splenectomy should be considered as candidates for early vigorous treatment.     

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.