Final Diagnosis -- Gaucher Disease type II


Gaucher Disease type II

Gaucher disease is an autosomal recessive, lysosomal storage disease due to a dysfunction of acid beta-glucosidase (GBA, glucocerebrosidase, glucosylceramidase) located on chromosome 1q22(1). GBA functions to break glucocerebroside into glucose and lipid components. Mutations of both copies of GBA lead to accumulations of glucocerebroside in lysosomes, notably in macrophages. Over 200 mutations have been associated with the disease(2). The resulting phenotype is a continuum (3), but it is traditionally divided into type 1, 2, and 3. Type 1 is the most common and lacks central nervous system involvement. Patients often present in childhood. While there is variability in the severity of symptoms, it includes anemia, thrombocytopenia, hepatosplenomegaly, skeletal deformities, osteopenia, and osteonecrosis (4). Type 2 Gaucher disease is also called acute neuropathic or infantile Gaucher disease as the patients often present in the first year of life with neurological defects. The patients have CNS and visceral involvement. Oculomotor dysfunction symptoms are first followed by brainstem involvement (5). Patients develop severe hypertonia, rigidity, arching of the back, and seizures. Neuropathology shows neuronal loss, gliosis, and widespread periadventitial Gaucher cells. The expected lifespan is two to three years.

Type 3 Gaucher disease, or chronic neuropathic Gaucher disease, also has CNS involvement like type 2 but it less severe. Patients can survive to adulthood in comparison to the shorter life expectancy seen in Type 2. Patients usually present in childhood, and they may have dementia, oculomotor dysfunction, seizures, ataxia and severe visceral involvement (6).

It is not entirely clear how lipid accumulation leads to cellular and organ dysfunction. In all types the accumulation of glucocerebroside within macrophages leads to Gaucher cells in many tissues. The lipid-laden macrophages accounts for only 2% of viscera mass increase. The pathogenesis is in part thought to be due to inflammatory mediators secreted by the affected macrophages, which can lead to chronic inflammation and fibrosis. Marrow fibrosis and osteosclerosis result in loss of hematopoesis. While pathologic findings are seen in many organs, the extent of the macrophage role is unclear (7).

The diagnosis can be made with a leukocyte enzyme assay, which measures activity against 4-methylumbiliferyl-beta-glucoside (8). Gaucher disease will result in 15% or less of the expected activity.

Molecular methods can be used to confirm the diagnosis if mutations are identified in both copies of GBA. While there have been over 200 described mutations in GBA, there is poor correlation between genotype and phenotype. The most common mutation is c.1226A>G (p.Asn409Ser), and is associated with Type 1. This patient was found to be heterozygous for two missense mutations, c.701G>A (p.Gly234Glu) and c.721G>A (p.Gly241Arg), located in exon 6. Both mutations have been described in the literature in patients with Type 2 Gaucher disease and have demonstrated severely reduced specific activity using cross-reactive immunologic material compared to the wild type (9, 10).


  1. Barneveld RA, Keijzer W, Tegelaers FP, Ginns EI, Geurts van Kessel A, Brady RO, et al. Assignment of the gene coding for human beta-glucocerebrosidase to the region q21-q31 of chromosome 1 using monoclonal antibodies. Hum Genet 1983;64:227-31.
  2. Hruska KS, LaMarca ME, Scott CR, Sidransky E. Gaucher disease: Mutation and polymorphism spectrum in the glucocerebrosidase gene (gba). Hum Mutat 2008;29:567-83.
  3. Goker-Alpan O, Schiffmann R, Park JK, Stubblefield BK, Tayebi N, Sidransky E. Phenotypic continuum in neuronopathic gaucher disease: An intermediate phenotype between type 2 and type 3. J Pediatr 2003;143:273-6.
  4. Zimran A. Gaucher's disease. Baillière's Clinical Haematology 1997;10.
  5. Beutler E, Grabowski GA, eds. Gaucher's disease. Eight ed. New York: McGraw-Hill, 2001.
  6. Erikson A, Bembi B, Schiffmann R. Neuronopathic forms of gaucher's disease. Baillière's Clinical Haematology 1997;10:711-23.
  7. Jmoudiak M, Futerman AH. Gaucher disease: Pathological mechanisms and modern management. Br J Haematol 2005;129:178-88.
  8. aghavan SS, Topol J, Kolodny EH. Leukocyte beta-glucosidase in homozygotes and heterozygotes for gaucher disease. Am J Hum Genet 1980;32:158-73.
  9. Stone DL, Tayebi N, Orvisky E, Stubblefield B, Madike V, Sidransky E. Glucocerebrosidase gene mutations in patients with type 2 gaucher disease. Hum Mutat 2000;15:181-8.
  10. Grace ME, Desnick RJ, Pastores GM. Identification and expression of acid beta-glucosidase mutations causing severe type 1 and neurologic type 2 gaucher disease in non-jewish patients. J Clin Invest 1997;99:2530-7.

Contributed by Aaron Berg, MD and Steven Dobrowolski, PhD

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