Biomarkers in the diagnosis of lysosomal storage disorders: proteins, lipids, and inhibodies

Aerts, Johannes M. F. G.; Kallemeijn, Wouter W.; Wegdam, Wouter; Ferraz, Maria J.; Breemen, Mariëlle J. van; Dekker, Natashe Lemos; Kramer, Gertjan; Poorthuis, Ben J. H. M.; Groener, J.E.M.; Cox-Brinkman, Josanne; Rombach, Saskia M.; Hollak, Carla E. M.; Linthorst, Gabor E.; Witte, Martin D.; Gold, Henrik; Marel, Gijs A. van der; Overkleeft, Herman S.; Boot, Rolf G.

doi:10.1007/s10545-011-9308-6

Cited by 101 publications

(73 citation statements)

References 169 publications

(210 reference statements)

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“…26,27 In contrast to the strikingly low acid ␤-glucosidase activity measured in peripheral blood leukocytes using the 4MU-Glc substrate (Table 1), functional enzyme activity measured by inhibody probes and fluorescein di-␤-D-galactopyranoside substrate in intact fibroblasts was less severely impaired ( Figure 5A). In vitro inhibody labeling using skin fibroblasts revealed a marked reduction of active GBA1 in parent and patient fibroblasts compared with control: approximately 70% and 15%, respectively ( Figure 5B).…”

Section: Functional Analysis Of D137n Mutant Gbamentioning

confidence: 88%

“…Acid ␤-glucosidase activity in peripheral blood leukocytes on 2 separate occasions was almost undetectable: 0.01 units/10 10 cells and 0 units/10 10 cells (normal range, 0.080-0.235 units/10 10 ), which was diagnostic of GD. Serum biomarkers of GD 27 were elevated: chitotriosidase activity was elevated 104-fold (6147 nmol/h/mL) and CCL18 approximately 20-fold (749 ng/mL). Serum ferritin was elevated 9-fold at 2710 ng/mL, a common finding in untreated GD.…”

Section: Genetic Modifier For Cancer In Gaucher Disease 4733mentioning

confidence: 98%

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Phenotype diversity in type 1 Gaucher disease: discovering the genetic basis of Gaucher disease/hematologic malignancy phenotype by individual genome analysis

Choi

et al. 2012

Blood

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Gaucher disease (GD), an inherited macrophage glycosphingolipidosis, manifests with an extraordinary variety of phenotypes that show imperfect correlation with mutations in the GBA gene. In addition to the classic manifestations, patients suffer from increased susceptibility to hematologic and nonhematologic malignancies. The mechanism(s) underlying malignancy in GD is not known, but is postulated to be secondary to macrophage dysfunction and immune dysregulation arising from lysosomal accumulation of glucocerebroside. However, there is weak correlation between GD/cancer phenotype and the systemic burden of glucocerebroside-laden macrophages. Therefore, we hypothesized that genetic modifier(s) may underlie the GD/cancer phenotype. In the present study, the genetic basis of GD/T-cell acute lymphoblastic lymphoma in 2 affected siblings was deciphered through genomic analysis. GBA gene sequencing revealed homozygosity for a novel mutation, D137N. Wholeexome capture and massively parallel sequencing combined with homozygosity mapping identified a homozygous novel mutation in the MSH6 gene that leads to constitutional mismatch repair deficiency syndrome and increased cancer risk. Enzyme studies demonstrated that the D137N mutation in GBA is a pathogenic mutation, and immunohistochemistry confirmed the absence of the MSH6 protein. Therefore, precise phenotype annotation followed by individual genome analysis has the potential to identify genetic modifiers of GD, facilitate personalized management, and provide novel insights into disease pathophysiology.

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Section: Functional Analysis Of D137n Mutant Gbamentioning

confidence: 88%

Section: Genetic Modifier For Cancer In Gaucher Disease 4733mentioning

confidence: 98%

Phenotype diversity in type 1 Gaucher disease: discovering the genetic basis of Gaucher disease/hematologic malignancy phenotype by individual genome analysis

Choi

et al. 2012

Blood

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“…17,18 Individual lysosomal diseases exhibit great variability in clinical expression that contributes to the current inability to predict their rate of progression, severity, and response to therapy, which underscores the need for biomarkers. 19 A biomarker is defined as a laboratory measurement that reflects the activity of a disease process.…”

Section: Discussionmentioning

confidence: 99%

Changes in plasma and urine globotriaosylceramide levels do not predict Fabry disease progression over 1 year of agalsidase alfa

Schiffmann¹,

Ries

Blankenship

et al. 2013

Genetics in Medicine

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Original research articleGlobotriaosylceramide (Gb 3 ) is often elevated in the urine of patients with Fabry disease, 1 and some studies support its use as a diagnostic biomarker. [2][3][4] Plasma Gb 3 concentration has been found to be consistently elevated in hemizygous males with classic Fabry disease but variably elevated in some variant hemizygous males with residual enzyme activity and in heterozygous females. 5,6 No evidence has been published supporting the use of plasma or urine Gb 3 concentrations as a biomarker for disease progression or response to treatment. For patients with elevated plasma or urine Gb 3 concentrations before treatment, enzyme replacement therapy (ERT) results in an initial drop in Gb 3 concentrations. 5,7 The lower Gb 3 concentrations do not remain low in all patients and do not always coincide with clinical improvement. 8 Biomarkers are generally defined as measurements that reflect the activity of a disease process 9 and can be (i) prognostic, (ii) predictive, or (iii) pharmacodynamic. 10 The goal of this study was to assess the relationship of plasma and urine Gb 3 concentrations with renal or cardiac outcome measures. A previous analysis of pooled data from three randomized, placebo-controlled clinical trials and their open-label extensions (sponsored by Shire Human Genetic Therapies) of male patients with Fabry disease suggested a stabilizing effect of agalsidase alfa (agalα) on renal function assessed by measured glomerular filtration rate (GFR). 11 In that analysis, baseline GFR or elevated proteinuria category (≥1 g/24 h) significantly predicted GFR decline during treatment. Using a suitable selection approach of pooled data Purpose: Globotriaosylceramide concentrations were assessed as potential predictors of change from baseline after 12 months by estimated glomerular filtration rate and left-ventricular mass index using pooled data from three randomized, placebo-controlled agalsidase alfa trials and open-label extensions of patients with Fabry disease.Methods: Males (aged 18 years or older) with Fabry disease received agalsidase alfa (0.2 mg/kg every other week for 12 months). A backward-elimination approach evaluated potential predictors (baseline estimated glomerular filtration rate and left-ventricular mass index; age at first dose; baseline and change from baseline at 12 months of globotriaosylceramide (urine, plasma); urine protein excretion; and systolic and diastolic blood pressure). Subgroups included patients randomized to placebo or agalsidase alfa (double-blind phase), then to agalsidase alfa (open-label extensions; placebo→agalsidase alfa or agalsidase alfa→agalsidase alfa, respectively) and stage 2/3 chronic kidney disease patients.Results: Baseline estimated glomerular filtration rate, age at first dose, baseline urine globotriaosylceramide excretion, and baseline and change from baseline urine protein excretion significantly predicted change from baseline estimated glomerular filtration rate in the analysis population (N = 73; all P<0.05), although not in...

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“…Using this method, in cases and controls, we compared the percentages of patients who have the highest biomarker values, as the magnitude of the biomarker chitotriosidase elevation correlates with disease severity. (27,28) We were interested in analyzing WBC count because the severity of leukopenia in GD1 patients tends to parallel GD1 severity. We performed a similar analysis, categorizing patients into those with a WBC count <25th percentile and those with a WBC count !25th percentile.…”

Section: Discussionmentioning

confidence: 99%

Risk factors for fractures and avascular osteonecrosis in type 1 Gaucher disease: A study from the International Collaborative Gaucher Group (ICGG) Gaucher Registry

Khan

Hangartner

Weinreb³

et al. 2012

Journal of Bone and Mineral Research

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We hypothesized that overall disease activity or the severity of involvement of individual disease compartments, as measured by clinical and surrogate markers, predict the risk of avascular osteonecrosis (AVN) or fractures in type 1 Gaucher disease (GD1). We applied our risk‐set matched case‐control method to identify four patient groups within the International Collaborative Gaucher Group (ICGG) Gaucher Registry based on the presence and absence of AVN and fractures. Characteristics of GD1 were examined by comparing the distributions of each risk factor in cases versus matched controls using conditional logistic regression to calculate adjusted odds ratios (OR). Potential risk factors included hematological and visceral parameters, GD1 biomarkers, white blood cells, GBA1 genotype, and spine and femur dual‐energy X‐ray absorptiometry (DXA) Z‐scores. In the total population of 5894 ICGG Gaucher Registry patients, 544 experienced at least one episode of AVN; 2008 reported no history of AVN. Clinical and surrogate markers of disease activity were similar in patients with and without AVN; patients with AVN were 1.6 times more likely to be anemic compared to matched controls (OR = 1.59; 95% confidence interval [CI], 1.06–2.38, p < 0.05). For fractures, 319 patients suffered fractures and 1233 had no prior history of fractures. Clinical and surrogate markers of disease in patients with and without fractures were similar, except for mean lumbar spine DXA Z‐scores. Among patients with fractures, 49.3% had DXA Z‐scores ≤ −1 compared to 31.0% in the control group. Compared to controls with Z‐scores > −1.0, GD1 patients exhibiting Z‐scores ≤ −1 had an OR of 5.55 (95% CI, 1.81–17.02, p < 0.01) for fracture. In GD1, after controlling for gender, year of birth, treatment status, and splenectomy status, we identified new risk factors for AVN and fractures. Concurrent anemia was associated with an increased risk for AVN. Low bone mineral density of the lumbar spine was a strong risk factor for fractures of the spine and femur in GD1. © 2012 American Society for Bone and Mineral Research.

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Biomarkers in the diagnosis of lysosomal storage disorders: proteins, lipids, and inhibodies

Cited by 101 publications

References 169 publications

Phenotype diversity in type 1 Gaucher disease: discovering the genetic basis of Gaucher disease/hematologic malignancy phenotype by individual genome analysis

Phenotype diversity in type 1 Gaucher disease: discovering the genetic basis of Gaucher disease/hematologic malignancy phenotype by individual genome analysis

Changes in plasma and urine globotriaosylceramide levels do not predict Fabry disease progression over 1 year of agalsidase alfa

Risk factors for fractures and avascular osteonecrosis in type 1 Gaucher disease: A study from the International Collaborative Gaucher Group (ICGG) Gaucher Registry

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