Gaucher Disease 

  • Author: Ellen Sidransky, MD; Chief Editor: Bruce Buehler, MD   more...
 
Updated: May 4, 2012
 

Background

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.

Autosomal recessive inheritance pattern. Autosomal recessive inheritance pattern.

Type 1 Gaucher disease is more common among individuals of Ashkenazi Jewish descent, although all 3 types are panethnic in their distribution.

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Pathophysiology

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.

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).

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Epidemiology

Frequency

United States

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

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 persons 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/Morbidity

Mortality and morbidity varies with the different types.[1]

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.

Race

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.

Sex

All 3 types of Gaucher disease are inherited as autosomal recessive traits and have an equal sex distribution.

Age

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.

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Contributor Information and Disclosures
Author

Ellen Sidransky, MD  Senior Investigator, Chief, Section on Molecular Neurogenetics, Medical Genetics Branch, National Human Genome Research Institute, NIH

Ellen Sidransky, MD is a member of the following medical societies: American Society of Human Genetics, Movement Disorders Society, Society for Inherited Metabolic Disorders, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Specialty Editor Board

Robert D Steiner, MD  Credit Unions for Kids Professor of Pediatric Research, Professor of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Department of Pediatrics, Faculty, Program in Molecular and Cellular Biosciences, Oregon Health and Science University School of Medicine; Attending Physician, Doernbecher Children's Hospital; Staff Consultant, Director of Metabolic Bone Disease Clinic, Shriners Hospital Portland

Robert D Steiner, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Medical Genetics, American Society of Human Genetics, Oregon Medical Association, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism, and Western Society for Pediatric Research

Disclosure: Amicus Honoraria Consulting; Actelion Honoraria Consulting; Actelion Honoraria Speaking and teaching; Biomarin Honoraria Consulting; Genzyme Honoraria Consulting; Shire Honoraria Consulting

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Hagop Youssoufian, MD, MSc  Vice President of Clinical Research, ImClone Systems Incorporated

Hagop Youssoufian, MD, MSc is a member of the following medical societies: American Society for Clinical Investigation, American Society of Clinical Oncology, American Society of Hematology, and American Society of Human Genetics

Disclosure: Nothing to disclose.

Paul D Petry, DO, FACOP, FAAP  Consulting Staff, Freeman Pediatric Care, Freeman Health System

Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

References

  1. Grabowski GA. Phenotype, diagnosis, and treatment of Gaucher's disease. Lancet. Oct 4 2008;372(9645):1263-71. [Medline].

  2. [Best Evidence] 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. Oct 22 2009;361(17):1651-61. [Medline].

  3. Sidransky E, Pastores GM, Mori M. Dosing enzyme replacement therapy for Gaucher disease: older, but are we wiser?. Genet Med. Feb 2009;11(2):90-1. [Medline].

  4. 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. Mar 18 2010;[Medline].

  5. Sidransky E, Pastores GM, Mori M. Dosing enzyme replacement therapy for Gaucher disease: older, but are we wiser?. Genet Med. Feb 2009;11(2):90-1. [Medline].

  6. 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. Dec 2008;122(6):1182-90. [Medline].

  7. Mitsui J, Mizuta I, Toyoda A, Ashida R, et al. Mutations for Gaucher disease confer high susceptibility to Parkinson disease. Arch Neurol. May 2009;66(5):571-6. [Medline].

  8. Weinreb NJ, Deegan P, Kacena KA, Mistry P, Pastores GM, Velentgas P, et al. Life expectancy in Gaucher disease type 1. Am J Hematol. Dec 2008;83(12):896-900. [Medline].

  9. Mamopoulos AM, Hughes DA, Tuck SM, Mehta AB. Gaucher disease and pregnancy. J Obstet Gynaecol. Apr 2009;29(3):240-2. [Medline].

  10. 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].

  11. Andersson HC, Charrow J, Kaplan P, et al. Individualization of long-term enzyme replacement therapy for Gaucher disease. Genet Med. Feb 2005;7(2):105-10. [Medline].

  12. 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. May 23 1991;324(21):1464-70. [Medline].

  13. Beutler E. Lysosomal storage diseases: natural history and ethical and economic aspects. Mol Genet Metab. Jul 2006;88(3):208-15. [Medline].

  14. Beutler E, Gelbart T, Scott CR. Hematologically important mutations: Gaucher disease. Blood Cells Mol Dis. Nov-Dec 2005;35(3):355-64. [Medline].

  15. Beutler E, Grabowski GA, CR Scriver, et al Eds. The Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill, New York. 2001;3635-68.

  16. Bohlega S, Kambouris M, Shahid M, et al. Gaucher disease with oculomotor apraxia and cardiovascular calcification (Gaucher type IIIC). Neurology. Jan 11 2000;54(1):261-3. [Medline].

  17. Charrow J, Andersson HC, Kaplan P, et al. Enzyme replacement therapy and monitoring for children with type 1 Gaucher disease: consensus recommendations. J Pediatr. Jan 2004;144(1):112-20. [Medline].

  18. 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].

  19. Depaolo J, Goker-Alpan O, Samaddar T, Lopez G, Sidransky E. The association between mutations in the lysosomal protein glucocerebrosidase and parkinsonism. Mov Disord. May 7 2009;[Medline].

  20. Futerman AH, Zimran A. Gaucher Disease. CRC Press, Boca Raton, FL. 2006.

  21. 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. Aug 2003;143(2):273-6. [Medline].

  22. 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. Feb 2009;11(2):92-100. [Medline].

  23. Grabowski GA, Leslie N, Wenstrup R. Enzyme therapy for Gaucher disease: the first 5 years. Blood Rev. Jun 1998;12(2):115-33. [Medline].

  24. Itzchaki M, Lebel E, Dweck A, et al. Orthopedic considerations in Gaucher disease since the advent of enzyme replacement therapy. Acta Orthop Scand. Dec 2004;75(6):641-53. [Medline].

  25. Jmoudiak M, Futerman AH. Gaucher disease: pathological mechanisms and modern management. Br J Haematol. Apr 2005;129(2):178-88. [Medline].

  26. 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. Jun 2000;66(6):1777-86. [Medline]. [Full Text].

  27. [Guideline] Langlois S, Wilson RD. Carrier screening for genetic disorders in individuals of Ashkenazi Jewish descent. J Obstet Gynaecol Can. Apr 2006;28(4):324-43. [Medline].

  28. Lwin A, Orvisky E, Goker-Alpan O, et al. Glucocerebrosidase mutations in subjects with parkinsonism. Mol Genet Metab. Jan 2004;81(1):70-3. [Medline].

  29. Mistry PK, Abrahamov A. A practical approach to diagnosis and management of Gaucher's disease. Baillieres Clin Haematol. Dec 1997;10(4):817-38. [Medline].

  30. NIH Technology Assessment Panel on Gaucher Disease. Gaucher disease. Current issues in diagnosis and treatment. JAMA. Feb 21 1996;275(7):548-53. [Medline].

  31. Park JK, Orvisky E, Tayebi N, et al. Myoclonic epilepsy in Gaucher disease: genotype-phenotype insights from a rare patient subgroup. Pediatr Res. Mar 2003;53(3):387-95. [Medline].

  32. Sibille A, Eng CM, Kim SJ, et al. Phenotype/genotype correlations in Gaucher disease type I: clinical and therapeutic implications. Am J Hum Genet. Jun 1993;52(6):1094-101. [Medline]. [Full Text].

  33. Sidransky E. Gaucher disease: complexity in a "simple" disorder. Mol Genet Metab. Sep-Oct 2004;83(1-2):6-15. [Medline].

  34. 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].

  35. Tayebi N, Stone DL, Sidransky E. Type 2 gaucher disease: an expanding phenotype. Mol Genet Metab. Oct 1999;68(2):209-19. [Medline].

  36. 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. Mar 2003;72(3):519-34. [Medline].

  37. Weinreb NJ, Aggio MC, Andersson HC, et al. Gaucher disease type 1: revised recommendations on evaluations and monitoring for adult patients. Semin Hematol. Oct 2004;41(4 Suppl 5):15-22. [Medline].

  38. Wenstrup RJ, Roca-Espiau M, Weinreb NJ, Bembi B. Skeletal aspects of Gaucher disease: a review. Br J Radiol. 2002;75 Suppl 1:A2-12. [Medline]. [Full Text].

  39. Zimran A, Altarescu G, Rudensky B, et al. Survey of hematological aspects of Gaucher disease. Hematology. Apr 2005;10(2):151-6. [Medline].

 
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