Gaucher Disease Treatment & Management
- Author: Ellen Sidransky, MD; Chief Editor: Maria Descartes, MD more...
Enzyme replacement therapy (ERT) for type 1 Gaucher disease includes imiglucerase (Cerezyme), velaglucerase alfa (VPRIV), and taliglucerase alfa (Elelyso). Historically, most patients received the recombinant enzyme imiglucerase. This preparation is highly effective in reversing the visceral and hematologic manifestations of Gaucher disease. However, skeletal disease is slow to respond, and pulmonary involvement is relatively resistant to the enzyme. Treatment is typically administered once every other week at a high dose, but, in some patients, treatment is administered every week at a medium dose or as many as 3 times per week at low doses. Good responses have been described with all dose regimens, and the issue of the most suitable initial and maintenance dosages remains controversial.
ERT is indicated for patients with type 1 Gaucher disease who exhibit clinical signs and symptoms of the disease, including anemia, thrombocytopenia, skeletal disease, or visceromegaly. Severity and rate of disease progression widely varies, especially in adults, which makes treatment decisions extremely difficult in some patients. Generally, children who present symptomatically, rather than because of family history, may have severe disease manifestations that require early treatment. Presymptomatic treatment with ERT remains controversial because of the lack of prognostic correlation between genotype and disease severity and the high cost of the therapy.
For most patients with Gaucher disease in the United States, treatment with ERT is typically guided by a geneticist or a hematologist. Patients should receive periodic follow-up at a center familiar with Gaucher disease, if possible.
ERT has a remarkable effect on hepatosplenomegaly, with an average overall decrease of 25% in liver and spleen volume after 6 months of therapy. In most patients with anemia, hemoglobin levels rise by 1.5 g/dL during the first 4-6 months of therapy. An additional increase of 1 g/dL is observed in the subsequent 9-18 months in patients with persistent anemia. The platelet count responds more slowly, doubling on average over 1 year. The hematologic status of patients with splenomegaly must be closely monitored, and splenectomy is still occasionally necessary.
Skeletal disease is the slowest to respond, with symptomatic improvement described by some within the first year of treatment, although a much longer period of ERT is required to achieve a radiologic response. Patients with bone crises require pain relief, hydration, and close monitoring. A bone scan is sometimes needed to differentiate between a bone crisis and infection.
Other effects of ERT in children with Gaucher disease include an increased growth velocity, weight gain, increased energy levels, and a correction of both delayed puberty and hypermetabolic state.
The response of patients to ERT widely varies and does not correlate with genotype, disease severity, splenectomy, or age. However, a number of factors, including cirrhosis and portal hypertension, extensive infarction and fibrosis of the spleen, and lung involvement, portend a poor response to therapy.
The symptoms of patients with Gaucher disease who have associated hematologic malignancies respond relatively poorly to ERT. To overcome these difficulties, increased dosage and frequency of enzyme infusions have been attempted. The symptoms of patients with decompensated liver disease do not appear to respond well to ERT, and these patients remain at risk for life-threatening hemorrhage due to variceal bleeding.
No evidence shows that ERT results in neurologic improvement. Although the enzyme affects the visceral involvement in types 2 and 3 disease, the associated brain involvement may persist or progress.
Glucosylceramide synthase inhibitors
Glucosylceramide synthase inhibitors include miglustat (Zavesca) and eliglustat (Cerdelga). Miglustat was approved in 2003 as monotherapy for treatment of adults with mild-to-moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option.
Eliglustat was approved in August 2014 as first-line treatment for the long-term treatment of adults with Gaucher disease type 1. The dose of eliglustat is determined by establishing the patient’s CYP2D6 phenotype (ie, extensive metabolizers [EM], intermediate metabolizers [IM], or poor metabolizers [PM]).
Approval was based on efficacy data from 2 positive phase 3 studies involving 199 patients. One study involved patients new to therapy (trial 1), and the other involved patients switching from approved enzyme replacement therapies (trial 2). Efficacy data from 4 years of the Cerdelga phase 2 study also contributed to the approval. Improvements in study participants were observed in spleen size, platelet levels, hemoglobin levels, and liver volume, and noninferiority to enzyme replacement therapy (imiglucerase) was established in trial 2.[8, 9]
Partial and total splenectomy was once advocated in the treatment of patients with Gaucher disease. However, with the availability of ERT, this procedure is no longer necessary in most patients.
In addition, patients with Gaucher disease may require hip replacements or other orthopedic procedures to treat skeletal disease. This is best undertaken after the patient has undergone several months of ERT.
Consultations with the following specialists are indicated:
No dietary manipulation has been found to affect disease progression.
Patients with massive splenomegaly or severe thrombocytopenia should avoid contact sports and any other activities that place them at risk for splenic rupture or bleeding.
Harrison L. Evidence Mounting for Eliglustat in Gaucher's Disease. Medscape Medical News. Available at http://www.medscape.com/viewarticle/834451. Accessed: November 10, 2014.
Vitner EB, Farfel-Becker T, Eilam R, Biton I, Futerman AH. Contribution of brain inflammation to neuronal cell death in neuronopathic forms of Gaucher's disease. Brain. 2012 Jun. 135(Pt 6):1724-35. [Medline].
Grabowski GA. Phenotype, diagnosis, and treatment of Gaucher's disease. Lancet. 2008 Oct 4. 372(9645):1263-71. [Medline].
Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med. 2009 Oct 22. 361(17):1651-61. [Medline]. [Full Text].
Nalls MA, Duran R, Lopez G, Kurzawa-Akanbi M, McKeith IG, Chinnery PF, et al. A multicenter study of glucocerebrosidase mutations in dementia with Lewy bodies. JAMA Neurol. 2013 Jun. 70(6):727-35. [Medline]. [Full Text].
Cerdelga (eliglustat) prescribing information. [package insert]. IDA Industrial Park, Old Kilmeaden Road, Waterford, Ireland: Genzyme Ireland, Ltd. August 2014.
Lowes, R. Medscape Medical News. FDA Clears Eliglustat (Cerdelga) for Gaucher Disease. Available at http://www.medscape.com/viewarticle/830172.
Zimran A, Altarescu G, Phillips M, Attias D, Jmoudiak M, Deeb M. Phase I/II and extension study of velaglucerase alfa (Gene-ActivatedTM human glucocerebrosidase) replacement therapy in adults with type 1 Gaucher disease: 48-month experience. Blood. 2010 Mar 18. [Medline].
Andersson H, Kaplan P, Kacena K, Yee J. Eight-year clinical outcomes of long-term enzyme replacement therapy for 884 children with Gaucher disease type 1. Pediatrics. 2008 Dec. 122(6):1182-90. [Medline].
Hruska KS, LaMarca ME, Scott CR, Sidransky E. Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA). Hum Mutat. 2008 May. 29(5):567-83. [Medline].
Weinreb NJ, Deegan P, Kacena KA, Mistry P, Pastores GM, Velentgas P, et al. Life expectancy in Gaucher disease type 1. Am J Hematol. 2008 Dec. 83(12):896-900. [Medline].
Mamopoulos AM, Hughes DA, Tuck SM, Mehta AB. Gaucher disease and pregnancy. J Obstet Gynaecol. 2009 Apr. 29(3):240-2. [Medline].
AH Futerman and A Zimran. Gaucher Disease. Boca Raton, FL: CRC Press; 2006.
Amato D, Stachiw T, Clarke JT, Rivard GE. Gaucher disease: variability in phenotype among siblings. J Inherit Metab Dis. 2004. 27(5):659-69. [Medline].
Andersson HC, Charrow J, Kaplan P, et al. Individualization of long-term enzyme replacement therapy for Gaucher disease. Genet Med. 2005 Feb. 7(2):105-10. [Medline].
Barton NW, Brady RO, Dambrosia JM, et al. Replacement therapy for inherited enzyme deficiency--macrophage-targeted glucocerebrosidase for Gaucher's disease. N Engl J Med. 1991 May 23. 324(21):1464-70. [Medline].
Beutler E. Lysosomal storage diseases: natural history and ethical and economic aspects. Mol Genet Metab. 2006 Jul. 88(3):208-15. [Medline].
Beutler E, Gelbart T, Scott CR. Hematologically important mutations: Gaucher disease. Blood Cells Mol Dis. 2005 Nov-Dec. 35(3):355-64. [Medline].
Beutler E, Grabowski GA, CR Scriver, et al Eds. The Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill, New York. 2001. 3635-68.
Bohlega S, Kambouris M, Shahid M, et al. Gaucher disease with oculomotor apraxia and cardiovascular calcification (Gaucher type IIIC). Neurology. 2000 Jan 11. 54(1):261-3. [Medline].
Charrow J, Andersson HC, Kaplan P, et al. Enzyme replacement therapy and monitoring for children with type 1 Gaucher disease: consensus recommendations. J Pediatr. 2004 Jan. 144(1):112-20. [Medline].
Cox TM, Aerts JM, Andria G, et al. The role of the iminosugar N-butyldeoxynojirimycin (miglustat) in the management of type I (non-neuronopathic) Gaucher disease: a position statement. J Inherit Metab Dis. 2003. 26(6):513-26. [Medline].
Depaolo J, Goker-Alpan O, Samaddar T, Lopez G, Sidransky E. The association between mutations in the lysosomal protein glucocerebrosidase and parkinsonism. Mov Disord. 2009 May 7. [Medline]. [Full Text].
Futerman AH, Zimran A. Gaucher Disease. CRC Press, Boca Raton, FL. 2006.
Goker-Alpan O, Schiffmann R, Park JK, et al. Phenotypic continuum in neuronopathic Gaucher disease: an intermediate phenotype between type 2 and type 3. J Pediatr. 2003 Aug. 143(2):273-6. [Medline].
Grabowski GA, Kacena K, Cole JA, et al. Dose-response relationships for enzyme replacement therapy with imiglucerase/alglucerase in patients with Gaucher disease type 1. Genet Med. 2009 Feb. 11(2):92-100. [Medline].
Grabowski GA, Leslie N, Wenstrup R. Enzyme therapy for Gaucher disease: the first 5 years. Blood Rev. 1998 Jun. 12(2):115-33. [Medline].
Itzchaki M, Lebel E, Dweck A, et al. Orthopedic considerations in Gaucher disease since the advent of enzyme replacement therapy. Acta Orthop Scand. 2004 Dec. 75(6):641-53. [Medline].
Jmoudiak M, Futerman AH. Gaucher disease: pathological mechanisms and modern management. Br J Haematol. 2005 Apr. 129(2):178-88. [Medline].
Koprivica V, Stone DL, Park JK, et al. Analysis and classification of 304 mutant alleles in patients with type 1 and type 3 Gaucher disease. Am J Hum Genet. 2000 Jun. 66(6):1777-86. [Medline]. [Full Text].
[Guideline] Langlois S, Wilson RD. Carrier screening for genetic disorders in individuals of Ashkenazi Jewish descent. J Obstet Gynaecol Can. 2006 Apr. 28(4):324-43. [Medline].
Lwin A, Orvisky E, Goker-Alpan O, et al. Glucocerebrosidase mutations in subjects with parkinsonism. Mol Genet Metab. 2004 Jan. 81(1):70-3. [Medline].
Mistry PK, Abrahamov A. A practical approach to diagnosis and management of Gaucher's disease. Baillieres Clin Haematol. 1997 Dec. 10(4):817-38. [Medline].
Mitsui J, Mizuta I, Toyoda A, Ashida R, et al. Mutations for Gaucher disease confer high susceptibility to Parkinson disease. Arch Neurol. 2009 May. 66(5):571-6. [Medline].
NIH Technology Assessment Panel on Gaucher Disease. Gaucher disease. Current issues in diagnosis and treatment. JAMA. 1996 Feb 21. 275(7):548-53. [Medline].
Park JK, Orvisky E, Tayebi N, et al. Myoclonic epilepsy in Gaucher disease: genotype-phenotype insights from a rare patient subgroup. Pediatr Res. 2003 Mar. 53(3):387-95. [Medline].
Sidransky E. Gaucher disease: complexity in a "simple" disorder. Mol Genet Metab. 2004 Sep-Oct. 83(1-2):6-15. [Medline].
Svennerholm L, Erikson A, Groth CG, et al. Norrbottnian type of Gaucher disease--clinical, biochemical and molecular biology aspects: successful treatment with bone marrow transplantation. Dev Neurosci. 1991. 13(4-5):345-51. [Medline].
Tayebi N, Stone DL, Sidransky E. Type 2 Gaucher disease: an expanding phenotype. Mol Genet Metab. 1999 Oct. 68(2):209-19. [Medline].
Tayebi N, Stubblefield BK, Park JK, et al. Reciprocal and nonreciprocal recombination at the glucocerebrosidase gene region: implications for complexity in Gaucher disease. Am J Hum Genet. 2003 Mar. 72(3):519-34. [Medline].
Weinreb NJ, Aggio MC, Andersson HC, et al. Gaucher disease type 1: revised recommendations on evaluations and monitoring for adult patients. Semin Hematol. 2004 Oct. 41(4 Suppl 5):15-22. [Medline].
Zimran A. How I treat Gaucher disease. Blood. 2011 Aug 11. 118(6):1463-71. [Medline].
Zimran A, Altarescu G, Rudensky B, et al. Survey of hematological aspects of Gaucher disease. Hematology. 2005 Apr. 10(2):151-6. [Medline].