- Author: Ellen Sidransky, MD; Chief Editor: Maria Descartes, MD more...
Gaucher disease is a rare genetic disorder characterized by the deposition of glucocerebroside in cells of the macrophage-monocyte system. The disorder results from the deficiency of the enzyme glucocerebrosidase.
Essential update: New drug eliglustat proving to work for Gaucher disease
The oral glucosylceramide (glucocerebroside) synthase inhibitor eliglustat, approved by the FDA for treatment of Gaucher disease type 1 (GD1) in August 2014, has proven as effective as intravenous enzyme replacement therapy with imiglucerase.
In a study of 159 patients with Gaucher’s disease, researchers found that fewer patients treated with eliglustat (85%) than imiglucerase (94%) met criteria for hemoglobin level, platelet count, spleen volume, and liver volume indicating stable disease for 12 months. Adverse events were more common with eliglustat, but most were mild.
In three other studies, eliglustat was superior to placebo over nine months of treatment, outcomes were similar for patients treated with eliglustat or imiglucerase for 4 years, and outcomes of eliglustat treatment were similar when dosing regimens were determined based on CYP2D6-genotype-predicted phenotype or plasma eliglustat concentrations.
Signs and symptoms
Gaucher disease has traditionally been divided into the following three clinical subtypes, delineated by the absence or presence of neurologic involvement and its progression:
Type 1 - Nonneuronopathic form
Type 2 - Acute neuronopathic form
Type 3 - Chronic neuronopathic form
Patients with type 1 disease commonly present with painless splenomegaly, anemia, or thrombocytopenia. They may also have chronic fatigue, hepatomegaly (with or without abnormal liver function test findings), bone pain, or pathologic fractures and may bruise easily because of thrombocytopenia. Bleeding secondary to thrombocytopenia may manifest as nosebleeds, bruising, or both.
Patients with type 2 disease may present at birth or during infancy with increased tone, seizures, strabismus, and organomegaly. Failure to thrive, swallowing abnormalities, oculomotor apraxia, hepatosplenomegaly, and stridor due to laryngospasm are typical in infants with type 2 disease.
In addition to organomegaly and bony involvement, individuals with type 3 disease have neurologic involvement.
See Clinical Presentation for more detail.
Diagnosis can be confirmed through measurement of glucocerebrosidase activity in peripheral blood leukocytes. A finding of less than 15% of mean normal activity is diagnostic. Minor elevations of liver and angiotensin-converting enzyme levels are common.
See Workup for more detail.
Enzyme replacement therapy (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. An oral glucosylceramide inhibitor is an alternate efficacious therapy.
Gaucher disease is a lipid storage disease characterized by the deposition of glucocerebroside in cells of the macrophage-monocyte system. The disorder results from the deficiency of a specific lysosomal hydrolase, glucocerebrosidase (also termed acid beta-glucosidase, glucosylceramidase). The disease is characterized by a continuum of phenotypes. The severity widely varies; some patients present in childhood with virtually all the complications of Gaucher disease, whereas others remain asymptomatic into the eighth decade of life.
Gaucher disease has traditionally been divided into the following 3 clinical subtypes, delineated by the absence or presence of neurologic involvement and its progression:
Type 1 - Nonneuronopathic form
Type 2 - Acute neuronopathic form
Type 3 - Chronic neuronopathic form
However, some cases do not fit precisely into one of these categories. All forms of Gaucher disease are autosomal recessively inherited.
Type 1 Gaucher disease is more common among individuals of Ashkenazi Jewish descent, although all 3 types are panethnic in their distribution.
Glucosylceramide, the accumulated glycolipid, is primarily derived from the phagocytosis and degradation of senescent leukocytes and, to a lesser extent, from erythrocyte membranes. The glycolipid storage gives rise to the characteristic Gaucher cells, macrophages engorged with lipid with a crumpled–tissue-paper appearance and displaced nuclei. The factors that contribute to neurologic involvement in patients with types 2 and 3 disease are still unknown but may be related to the accumulation of a cytotoxic glycolipid, glucosylsphingosine, in the brain due to the severe deficiency of glucocerebrosidase activity or to neuroinflammation.
Glucosylceramide accumulation in the bone marrow, liver, spleen, lungs, and other organs contributes to pancytopenia, massive hepatosplenomegaly, and, at times, diffuse infiltrative pulmonary disease. Progressive infiltration of Gaucher cells in the bone marrow may lead to thinning of the cortex, pathologic fractures, bone pain, bony infarcts, and osteopenia. These bony features may also be related to macrophage-produced cytokines.
Disruption of the ceramide-to-glucosylceramide ratio can affect barrier formation in the epidermal layer of the skin, leading to ichthyosis or a collodion skin presentation in individuals who are severely affected (those with type 2).
Type 1 Gaucher disease more common among Jewish people of Eastern European origin; the carrier frequency in these individuals is approximately 1 per 15 population, whereas the disease frequency is 1 per 855 population. Gaucher disease is rare in the non-Jewish population, with an estimated frequency of 1 per 40,000 population.
International disease frequency is similar to that in the United States, except for areas of the world with large Ashkenazi Jewish populations. Most patients worldwide are non-Jewish. As many as 60% of patients of Ashkenazi origin are estimated to be homozygous for the mild N370S mutation, which accounts for 75% of disease alleles in this population. Many individuals with this genotype never seek medical attention, contributing to an underestimation of the disease frequency. Type 3 disease is more common in the Norrbottnian region of Sweden (1 per 50,000 population), which has been traced to a common founder in the 17th century.
Mortality and morbidity varies with the different types.
Type 1 Gaucher disease often presents in childhood with hepatosplenomegaly, pancytopenia, and skeletal disease, although striking clinical variability occurs in disease severity.
Type 2 Gaucher disease causes rapidly progressive neurovisceral storage disease and death during infancy or during the first years of life. A subset of this type, associated with congenital ichthyosis and hydrops fetalis, is described as neonatal lethal and results in perinatal or in utero death.
Type 3 Gaucher disease is often a less rapidly progressive neurovisceral storage disease. Various associated clinical courses have been reported, some of which cause death in childhood or early adulthood.
All forms of Gaucher disease are panethnic. Type 1 Gaucher disease is the most common lysosomal storage disease and is the most prevalent genetic disorder in individuals of Ashkenazi Jewish descent. Type 3 disease is more common in the Norrbottnian region of Sweden.
All 3 types of Gaucher disease are inherited as autosomal recessive traits and have an equal sex distribution.
Patients with type 1 Gaucher disease may present in childhood with hepatosplenomegaly, pancytopenia, and crippling skeletal disease. Some patients are not diagnosed until adulthood, when they present with low blood counts or bone involvement, whereas others are diagnosed in the seventh to ninth decades of life after an incidental finding of thrombocytopenia or splenomegaly. Many affected individuals never develop signs or symptoms and do not seek medical attention. Types 2 and 3 Gaucher disease typically present in early childhood. Some subjects with parkinsonism have been found to have Gaucher disease at a later age.
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].