Various guidelines for Gaucher disease have been developed, each stating that a diagnosis is based on the measurement of glucocerebrosidase enzyme activity in leukocytes or skin fibroblasts; enzymatic activity can also be measured using a screening assay in dried blood spots.1-8 A genetic analysis can identify the mutations or alterations in the GBA1 gene.1-5,7,9 The most frequent GBA1 mutations are N370S (c.1226A>G; p.Asp409Ser) and L444P (c.1448T>C; p.Leu483Pro). The N370S (c.1226A>G; p.Asp409Ser) mutation is associated with Gaucher disease Type 1 and the L444P (c.1448T>C; p.Leu483Pro) mutation with Gaucher disease Type 3.10,11 There may be overlap in glucocerebrosidase enzyme activity between heterozygote carriers of GBA1 gene mutations and healthy unaffected individuals without Gaucher disease. Therefore, genetic analysis studies are useful, especially in cases where measurement of glucocerebrosidase activity is inconclusive.12 Genetic analysis can also highlight the disease phenotype and risk for the neuronopathic forms of the disease (Types 2 and 3), as patients homozygous for the L444P (c.1448T>C; p.Leu483Pro) mutation have a higher risk for neurological impairment.13
Since Gaucher disease Type 1 has a higher birth incidence in the Ashkenazi Jewish population,14,15 carrier testing and prenatal screening can be offered to couples of Ashkenazi Jewish ethnicity, generally in a primary care obstetrical setting, to determine the risk for having children affected with Gaucher disease.16 Carrier couples are offered genetic consultations to discuss their reproductive options, where prenatal diagnosis is explained.17
Although the ‘gold standard’ for Gaucher disease diagnosis is the measurement of glucocerebrosidase enzyme activity,12,18 plasma levels of glucosylsphingosine (lyso-Gb1), chitotriosidase and CC chemokine ligand 18 (CCL18) have been shown to be elevated in patients with Gaucher disease, highlighting their use as disease biomarkers.19-26 In one study, levels of glucosylsphingosine (lyso-Gb1) in dried blood spots have also been used to identify patients with Gaucher disease. Patients with the neuronopathic form of the disease (Types 2 or 3) exhibited significantly higher levels of glucosylsphingosine (lyso-Gb1) than patients with non-neuronopathic Gaucher disease Type 1. This finding suggests that, in addition to being a biomarker of Gaucher disease, glucosylsphingosine (lyso-Gb1) may be useful for prenatal diagnosis and in screening programmes using dried blood spots.27
The availability of tests for Gaucher disease varies worldwide; more information is provided on the Genetic Testing Registry (https://www.ncbi.nlm.nih.gov/gtr/conditions/C0017205/).
To aid clinicians in reaching a diagnosis of Gaucher disease, diagnostic algorithms have been published, and validated disease severity indexes are available to aid symptom monitoring.28-32 Following a diagnosis of Gaucher disease, subsequent evaluations may also include5:
- Clinical and laboratory tests (blood count, clinical chemistry including transaminases, renal function and blood gas analysis)
- Diagnostic imaging to determine liver and spleen sizes, and of skeletal pathology depending on symptoms.
- Additional clinical and neurological examinations including neuro-ophthalmological testing, electroencephalogram (EEG; if necessary), brainstem auditory evoked potentials (AEP), magnetic resonance imaging (MRI) and cognitive performance tests.
- Additional neurological examinations including eye movement tests to check for oculomotor apraxia, MRI, EEG, AEP, neuropsychological tests and cognitive performance tests.
C-ANPROM/INT//7567; Date of preparation: September 2020
- Weinreb NJ, Aggio MC, Andersson HC, et al. Gaucher disease type 1: revised recommendations on evaluations and monitoring for adult patients. Semin Hematol 2004; 41: 15-22.
- Deegan P, Hughes D, Mehta A, et al. UK National Guideline for adult Gaucher disease. April 2005. Available at https://www.researchgate.net/publication/265282933_UK_National_Guideline_for_Adult_Gaucher_Disease_April_2005. Accessed September 2020.
- The Belgian Working Group on Gaucher disease. Guidelines for diagnosis, treatment and monitoring of Gaucher's disease. May 2016. Available at https://cema.uza.be/static/documenten/informatie_metabole_ziekten/Belgian%20Expert%20Opinion%20for%20Diagnosis,%20Treatment%20an%20Monitoring%20of%20Gaucher.pdf. Accessed September 2020.
- Haute Autorité de Santé. Gaucher disease: national diagnosis and treatment protocol. January 2007. Available at https://www.has-sante.fr/upload/docs/application/pdf/ven_gaucher_web.pdf. Accessed September 2020.
- German Society for Child and Youth Medicine Working Group on Pediatric Metabolic Disorders. Gaucher's disease guidelines. March 2006. Available at https://www.ggd-ev.de/wp-content/uploads/mgaucher-22-12-2007.pdf. Accessed September 2020.
- Ontario guidelines for the treatment of Gaucher disease by enzyme replacement with imiglucerase or velaglucerase, or substrate reduction therapy with miglustat. August 2011. Available at http://garrod.ca/wp-content/uploads/2011/11/ONTARIO-GUIDELINES-FOR-TREATMENT-OF-GAUCHER-August-2011-2.pdf. Accessed September 2020.
- Fundaciόn Española para el Estudio y Tratamiento de la Enfermedad de Gaucher y otras Lisosomales. Medical care guide for patients with Type 1 Gaucher's disease. April 2011. Available at http://www.feeteg.org/docs/GC_Gaucher3.pdf. Accessed September 2020.
- Johnson BA, Dajnoki A, Bodamer O. Diagnosis of lysosomal storage disorders: Gaucher disease. Curr Protoc Hum Genet 2014; 82: 17.15.1-17.15.6.
- Aviezer D, Brill-Almon E, Shaaltiel Y, et al. A plant-derived recombinant human glucocerebrosidase enzyme–a preclinical and phase I investigation. PLoS One 2009; 4: e4792.
- Dandana A, Ben Khelifa S, Chahed H, et al. Gaucher disease: clinical, biological and therapeutic aspects. Pathobiology 2016; 83: 13-23.
- Charrow J, Andersson HC, Kaplan P, et al. The Gaucher registry: demographics and disease characteristics of 1698 patients with Gaucher disease. Arch Intern Med 2000; 160: 2835-2843.
- Nagral A. Gaucher disease. J Clin Exp Hepatol 2014; 4: 37-50.
- Stirnemann J, Belmatoug N, Camou F, et al. A review of Gaucher disease pathophysiology, clinical presentation and treatments. Int J Mol Sci 2017; 18: 441.
- Zimran A, Gelbart T, Westwood B, et al. High frequency of the Gaucher disease mutation at nucleotide 1226 among Ashkenazi Jews. Am J Hum Genet 1991; 49: 855-859.
- Zimran A, Elstein D. Gaucher disease and related lysosomal storage diseases. In: Kaushansky K, Lichtman M, Prchal J, et al., eds. Williams Hematology. 9th ed; New York, NY: McGraw-Hill, 2016.
- Gross SJ, Pletcher BA, Monaghan KG, et al. Carrier screening in individuals of Ashkenazi Jewish descent. Genet Med 2008; 10: 54-56.
- Vallance H, Ford J. Carrier testing for autosomal-recessive disorders. Crit Rev Clin Lab Sci 2003; 40: 473-497.
- Ho MW, Seck J, Schmidt D, et al. Adult Gaucher's disease: kindred studies and demonstration of a deficiency of acid beta-glucosidase in cultured fibroblasts. Am J Hum Genet 1972; 24: 37-45.
- Dekker N, van Dussen L, Hollak CE, et al. Elevated plasma glucosylsphingosine in Gaucher disease: relation to phenotype, storage cell markers, and therapeutic response. Blood 2011; 118: e118-e127.
- Zhang W, Oehrle M, Prada CE, et al. A convenient approach to facilitate monitoring Gaucher disease progression and therapeutic response. Analyst 2017; 142: 3380-3387.
- Hollak CE, van Weely S, van Oers MH, et al. Marked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease. J Clin Invest 1994; 93: 1288-1292.
- van Dussen L, Hendriks EJ, Groener JE, et al. Value of plasma chitotriosidase to assess non-neuronopathic Gaucher disease severity and progression in the era of enzyme replacement therapy. J Inherit Metab Dis 2014; 37: 991-1001.
- Ries M, Schaefer E, Luhrs T, et al. Critical assessment of chitotriosidase analysis in the rational laboratory diagnosis of children with Gaucher disease and Niemann-Pick disease type A/B and C. J Inherit Metab Dis 2006; 29: 647-652.
- Boot RG, Verhoek M, de Fost M, et al. Marked elevation of the chemokine CCL18/PARC in Gaucher disease: a novel surrogate marker for assessing therapeutic intervention. Blood 2004; 103: 33-39.
- Deegan PB, Moran MT, McFarlane I, et al. Clinical evaluation of chemokine and enzymatic biomarkers of Gaucher disease. Blood Cells Mol Dis 2005; 35: 259-267.
- Raskovalova T, Deegan PB, Mistry PK, et al. Accuracy of chitotriosidase activity and CCL18 concentration in assessing type I Gaucher disease severity. A systematic review with meta-analysis of individual participant data. Haematologica 2020; Epub ahead of print.
- Saville JT, McDermott BK, Chin SJ, et al. Expanding the clinical utility of glucosylsphingosine for Gaucher disease. J Inherit Metab Dis 2020; 43: 558-563.
- Di Rocco M, Andria G, Deodato F, et al. Early diagnosis of Gaucher disease in pediatric patients: proposal for a diagnostic algorithm. Pediatr Blood Cancer 2014; 61: 1905-1909.
- Weiss K, Gonzalez A, Lopez G, et al. The clinical management of Type 2 Gaucher disease. Mol Genet Metab 2015; 114: 110-122.
- Mistry PK, Cappellini MD, Lukina E, et al. A reappraisal of Gaucher disease-diagnosis and disease management algorithms. Am J Hematol 2011; 86: 110-115.
- Weinreb NJ, Cappellini MD, Cox TM, et al. A validated disease severity scoring system for adults with type 1 Gaucher disease. Genet Med 2010; 12: 44-51.
- Davies EH, Surtees R, DeVile C, et al. A severity scoring tool to assess the neurological features of neuronopathic Gaucher disease. J Inherit Metab Dis 2007; 30: 768-782.