scholarly journals Treatment Efficiency in Gaucher Patients Can Reliably Be Monitored by Quantification of Lyso-Gb1 Concentrations in Dried Blood Spots

2020 ◽  
Vol 21 (13) ◽  
pp. 4577 ◽  
Author(s):  
Claudia Cozma ◽  
Paskal Cullufi ◽  
Guido Kramp ◽  
Marina Hovakimyan ◽  
Virtut Velmishi ◽  
...  
Keyword(s):  
Early Stage ◽  
Subsequent Development ◽  
High Sensitivity ◽  
Dried Blood Spots ◽  
Lysosomal Storage ◽  
Treatment Efficiency ◽  
Blood Spots ◽  
Enzyme Replacement ◽  
Treatment Conditions ◽  
Clinical Consequences

Gaucher disease (GD) is a lysosomal storage disorder that responds well to enzyme replacement therapy (ERT). Certain laboratory parameters, including blood concentration of glucosylsphingosine (Lyso-Gb1), the lyso-derivate of the common glycolipid glucocerebroside, correlate with clinical improvement and are therefore considered candidate-monitoring biomarkers. Whether they can indicate a reduction or loss of treatment efficiency, however, has not been systematically addressed for obvious reasons. We established and validated measurement of Lyso-Gb1 from dried blood spots (DBSs) by mass spectrometry. We then characterized the assay’s longitudinal performance in 19 stably ERT-treated GD patients by dense monitoring over a 3-year period. The observed level of fluctuation was accounted for in the subsequent development of a unifying data normalization concept. The resulting approach was eventually applied to data from Lyso-Gb1 measurements after an involuntary treatment break for all 19 patients. It enabled separation of the “under treatment” versus “not under treatment” conditions with high sensitivity and specificity. We conclude that Lyso-Gb1 determination from DBSs indicates treatment issues already at an early stage before clinical consequences arise. In addition to its previously shown diagnostic utility, Lyso-Gb1 thereby qualifies as a monitoring biomarker in GD patients.

scholarly journals Determination of Acid α-Glucosidase Protein: Evaluation as a Screening Marker for Pompe Disease and Other Lysosomal Storage Disorders

2000 ◽  
Vol 46 (9) ◽  
pp. 1318-1325 ◽  
Author(s):  
Kandiah Umapathysivam ◽  
Alison M Whittle ◽  
Enzo Ranieri ◽  
Colleen Bindloss ◽  
Elaine M Ravenscroft ◽  
...  
Keyword(s):  
Pompe Disease ◽  
Screening Program ◽  
Dried Blood Spots ◽  
Lysosomal Storage Disorders ◽  
Lysosomal Storage ◽  
Total Acid ◽  
Blood Spots ◽  
Enzyme Replacement ◽  
Storage Disorders

Abstract Background: In recent years, there have been significant advances in the development of enzyme replacement and other therapies for lysosomal storage disorders (LSDs). Early diagnosis, before the onset of irreversible pathology, has been demonstrated to be critical for maximum efficacy of current and proposed therapies. In the absence of a family history, the presymptomatic detection of these disorders ideally can be achieved through a newborn screening program. One approach to the development of such a program is the identification of suitable screening markers. In this study, the acid α-glucosidase protein was evaluated as a marker protein for Pompe disease and potentially for other LSDs. Methods: Two sensitive immunoquantification assays for the measurement of total (precursor and mature) and mature forms of acid α-glucosidase protein were used to determine the concentrations in plasma and dried blood spots from control and LSD-affected individuals. Results: In the majority of LSDs, no significant increases above control values were observed. However, individuals with Pompe disease showed a marked decrease in acid α-glucosidase protein in both plasma and whole blood compared with unaffected controls. For plasma samples, this assay gave a sensitivity of 95% with a specificity of 100%. For blood spot samples, the sensitivity was 82% with a specificity of 100%. Conclusions: This study demonstrates that it is possible to screen for Pompe disease by screening the concentration of total acid α-glucosidase in plasma or dried blood spots.

scholarly journals Reliability of enzyme assays in dried blood spots for diagnosis of 4 lysosomal storage disorders

2011 ◽  
Vol 01 (03) ◽  
pp. 58-64 ◽  
Author(s):  
Romina Ceci ◽  
Pablo N. de Francesco ◽  
Juan M. Mucci ◽  
Lorena N. Cancelarich ◽  
Carlos A. Fossati ◽  
...  
Keyword(s):  
Dried Blood Spots ◽  
Lysosomal Storage Disorders ◽  
Enzyme Assays ◽  
Lysosomal Storage ◽  
Blood Spots ◽  
Storage Disorders

Cholesteryl ester storage disease: a rare and possibly treatable cause of premature vascular disease and cirrhosis

2013 ◽  
Vol 66 (11) ◽  
pp. 918-923 ◽  
Author(s):  
Tim Reynolds
Keyword(s):  
Enzyme Activity ◽  
Cholesteryl Ester ◽  
Storage Disease ◽  
Treatment Options ◽  
Failure To Thrive ◽  
Early Death ◽  
Dried Blood Spots ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Reduced Activity

Cholesteryl ester storage disease (CESD) is an autosomal recessive lysosomal storage disorder caused by a variety of mutations of the LIPA gene. These cause reduced activity of lysosomal acid lipase, which results in accumulation of cholesteryl esters in lysosomes. If enzyme activity is very low/absent, presentation is in infancy with failure to thrive, malabsorption, hepatosplenomegaly and rapid early death (Wolman disease). With higher but still low enzyme activity, presentation is later in life with hepatic fibrosis, dyslipidaemia and early atherosclerosis.Identification of this rare disorder is difficult as it is essential to assay leucocyte acid phosphatase activity. An assay using specific inhibitors has now been developed that facilitates measurement in dried blood spots. Treatment of CESD has until now been limited to management of the dyslipidaemia, but this does not influence the liver effects. A new enzyme replacement therapy (Sebelipase) has now been developed that could change treatment options for the future.

A Rare Condition in Haematological Practice – Gaucher Disease

2015 ◽  
Vol 11 (1) ◽  
pp. 15 ◽  
Author(s):  
Maria-Domenica Cappellini ◽  
Keyword(s):  
Gaucher Disease ◽  
Growth Failure ◽  
Rare Condition ◽  
Dried Blood Spots ◽  
Severe Bleeding ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Population Type ◽  
Increased Risk

Gaucher disease, which is caused by an inherited glucocerebrosidase deficiency, is the most prevalent lysosomal storage disease worldwide. Estimated prevalence of Gaucher disease is 1:50,000 in most countries and the disease has its highest incidence in the Ashkenazi Jewish population. Type 1 (non-neuropathic) Gaucher disease is by far the most common form. Gaucher disease type 1 should be considered in cases of unexplained splenomegaly with or without bleeding diathesis, skeletal manifestations or hepatomegaly. Diagnosis is made by demonstrating decreased glucocerebrosidase activity in peripheral blood leucocytes. Dried blood spots can be used for screening but conventional enzyme assay on heparinised blood is essential. Patients with Gaucher disease may have extensive organ involvement despite relatively minor overt symptomatology. Evidence suggests that Gaucher disease may remain undiagnosed for years, leading to severe complications that are preventable or reversible with enzyme replacement therapy. These complications include avascular necrosis, severe bleeding, chronic bone pain, pathological fractures, growth failure, liver pathology and life-threatening sepsis. Most patients with Gaucher disease are initially evaluated by a haematologist–oncologist. Improved education is needed to enable prompt detection of Gaucher disease. An increased risk of multiple myeloma and haematological and non-haematological malignancies has been reported in type 1 Gaucher disease. This review aims to offer familiarisation with a rare disorder in haematological practice, focusing on adult patient management.

scholarly journals Substrate reduction therapy: clinical evaluation in type 1 Gaucher disease

2003 ◽  
Vol 358 (1433) ◽  
pp. 955-960 ◽  
Author(s):  
Chris Moyses
Keyword(s):  
Gaucher Disease ◽  
Clinical Manifestations ◽  
Residual Activity ◽  
Substrate Reduction Therapy ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Substrate Reduction ◽  
Clinical Consequences ◽  
Type 1 Gaucher Disease

Glycosphingolipid (GSL) lysosomal storage disorders are inherited enzyme deficiencies that result in pathological lysosomal accumulation of glycolipids, with widespread clinical consequences. Type 1 Gaucher disease is the commonest of these; the deficient enzyme in this condition is glucocerebrosidase. Clinical manifestations include hepatosplenomegaly, thrombocytopenia, anaemia, recurrent infections and skeletal lesions. The condition can be treated with intravenous enzyme replacement therapy (ERT). Substrate reduction therapy is a new approach in which glycolipid accumulation is counteracted not by replacing the deficient enzyme but by reducing the substrate level to better balance residual activity of the deficient enzyme. Miglustat is an inhibitor of glucosylceramide synthase, a key enzyme in GSL synthesis. Oral administration of miglustat to patients with type 1 Gaucher disease attenuates the synthesis of glucocerebroside, the substrate of the deficient glucocerebrosidase. In the first clinical study, patients with type 1 Gaucher disease who had enlargement of the liver or spleen and (if present) the spleen at baseline received 12 months treatment with oral miglustat. There were mean decreases in liver and spleen volumes of 12% (7.9–16.4, p < 0.001) and 19% (14.3–23.7, p < 0.001), respectively. Mean haemoglobin increased by 0.26 g dl −1 (−0.5−0.57, not statistically significant) and platelet count by 8.3 × 10 9 l −1 (1.9–14.7, p = 0.014).

scholarly journals Determination of Oligosaccharides in Pompe Disease by Electrospray Ionization Tandem Mass Spectrometry

2002 ◽  
Vol 48 (1) ◽  
pp. 131-139 ◽  
Author(s):  
Tina Rozaklis ◽  
Steven L Ramsay ◽  
Phillip D Whitfield ◽  
Enzo Ranieri ◽  
John J Hopwood ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Tandem Mass Spectrometry ◽  
Electrospray Ionization ◽  
Pompe Disease ◽  
Dried Blood Spots ◽  
Tandem Mass ◽  
Lysosomal Storage ◽  
Blood Spots ◽  
Limited Application ◽  
Ionization Tandem Mass Spectrometry

Abstract Background: The development of therapies for lysosomal storage disorders has created a need for biochemical markers to monitor the efficacy of therapy and methods to quantify these markers in biologic samples. In Pompe disease, the concentration of a tetrasaccharide, consisting of four glucose residues, is reputedly increased in urine and plasma, but faster and more sensitive methods are required for the analysis of this, and other oligosaccharides, from biologic fluids. Methods: We optimized the derivatization of storage oligosaccharides with 1-phenyl-3-methyl-5-pyrazolone for the measurement, by electrospray ionization tandem mass spectrometry, of oligosaccharide concentrations in urine (n = 6), plasma (n = 11), and dried-blood spots (n = 17) from Pompe-affected individuals. Age-matched control samples of urine (n = 10), plasma (n = 28), and blood spots (n = 369) were also analyzed. Results: The mean tetrasaccharide concentration was increased in urine from infantile-onset (0.69–12 mmol/mol of creatinine) and adult-onset (0.22–3.0 mmol/mol of creatinine) Pompe individuals compared with age-matched controls. In plasma samples, an increased tetrasaccharide concentration was observed in some infantile patients (up to 22 μmol/L) compared with age-matched controls (mean, 2.2 μmol/L). The method developed was sensitive enough to determine oligosaccharide concentrations in a single 3-mm blood spot, but no differences were observed between blood spots from control and Pompe-affected individuals. Conclusions: Measurements of oligosaccharide concentrations in urine by this new method have potential application for the diagnosis and monitoring of patients with Pompe disease. Plasma analysis may have limited application for infantile patients, but analysis of blood spots does not discriminate between controls and affected individuals.

Biotinidase determination in serum and dried blood spots—high sensitivity fluorimetric ultramicro-assay

2001 ◽  
Vol 314 (1-2) ◽  
pp. 175-185 ◽  
Author(s):  
Elke Broda ◽  
E.Regula Baumgartner ◽  
Sabine Scholl ◽  
Marina Stopsack ◽  
Anton Horn ◽  
...  
Keyword(s):  
High Sensitivity ◽  
Dried Blood Spots ◽  
Blood Spots
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