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1130 Part VIII: Monocytes and Macrophages Chapter 72: Gaucher Disease and Related Lysosomal Storage Diseases 1131

juvenile dystonic lipidosis with neonatal icterus and hepatosplenomeg- COURSE AND PROGNOSIS
aly. In infants and toddlers, hepatosplenomegaly may be the only sign. The prognosis in type A Niemann-Pick disease is dire; death nearly
In patients with a later-onset, there are variable presentations, but psy- always occurs before the third year of life. Patients with type B dis-
chiatric signs and symptoms (disinhibition and deteriorating executive ease may survive into childhood or longer and there is now hope for
function) predominate. 165
a disease-specific ERT. Patients with type C disease usually die in
the second decade of life, but some patients with mild disease have
LABORATORY FEATURES AND DIFFERENTIAL a normal life span. New hope for patients with type C emanates from
DIAGNOSIS the potential for identification of disease-specific oxysterols as both
biomarkers of the disease and as harbingers of PC therapy for mis-
180
Hemoglobin values may be normal, or mild anemia may be present. folded variants. 181
Approximately 75 percent of lymphocytes contain one to nine vacuoles
with a diameter of 2 μm. Electron microscopy reveals that these vac- REFERENCES
uoles are lipid-filled lysosomes. The marrow contains typical foam
166
cells whose diameter ranges between 20 and 100 μm. Small droplets are 1. Gaucher PCE: De L’epithelioma Primitif de la Rate, Hypertrophie Idiopathique del la Rate
scattered throughout the cytoplasm (see Fig. 72–6). The cytoplasm of San Leucemie. University of Paris, Paris, 1882.
these cells stains only very faintly with the periodic acid-Schiff reagent. 2. Brill N, Mandelbaum F, Libman E: Primary splenomegaly-Gaucher type. Report on one
of four cases occurring in a single generation in a family. Am J Med Sci 129:491, 1905.
Phase microscopy of unstained preparations clearly reveals droplets in 3. Aghion H: La maladie de Gaucher dans l’enfance [PhD thesis]. Paris, 1934.
the cytoplasm of Niemann-Pick foam cells that distinguish them from 4. Brady RO, Kanfer JN, Shapiro D: Metabolism of glucocerebrosides: II. Evidence of an
Gaucher cells. Sea-blue histiocytes may be present in the spleen and enzymatic deficiency in Gaucher’s disease. Biochem Biophys Res Commun 18:221, 1965.
marrow. 158,164 5. Patrick AD: Short communications: A deficiency of glucocerebrosidase in Gaucher’s
disease. Biochem J 97:17C, 1965.
Type A and type B disease can be distinguished from other dis- 6. Sorge J, West C, Westwood B, Beutler ED: Molecular cloning and nucleotide sequence
orders by identification of the lipid as sphingomyelin and by demon- of human glucocerebrosidase cDNA. Proc Natl Acad Sci U S A 82:7289, 1985.
stration of sphingomyelinase deficiency in leukocytes or cultured 7. Horowitz M, Wilder S, Horowitz Z, et al: The human glucocerebrosidase gene and
pseudogene: Structure and evolution. Genomics 4:87, 1989.
fibroblasts. 166,167 Patients with type A disease have acid sphingomyeli- 8. Hruska KS, LaMarca ME, Scott CR, Sidransky E: Gaucher disease: Mutations and poly-
nase activity levels less than 5 percent of normal in in vitro cultures of morphism spectrum in the glucocerebrosidase gene (GBA). Hum Mutat 29:567, 2008.
lymphoblasts or fibroblasts. In type B disease, acid sphingomyelinase 9. Barton NW, Brady RO, Dambrosia JM, et al: Replacement therapy for inherited enzyme
deficiency—Macrophage-targeted glucocerebrosidase for Gaucher’s disease. N Engl J
activity levels range between 2 and 10 percent of normal levels. Mono- Med 324:1464, 1991.
specific antibodies against sphingomyelinase are used to differentiate 10. Beutler E, Nguyen NJ, Henneberger MW, et al: Gaucher disease: Gene frequencies in
168
between type A and type B disease. Heterozygotes may be detected the Ashkenazi Jewish population. Am J Hum Genet 52:85, 1993.
by measurement of sphingomyelinase activity of cultured fibroblasts. 11. Svennerholm L, Erikson A, Groth CG, et al: Norrbottnian type of Gaucher disease—
169
Clinical, biochemical and molecular biology aspects: Successful treatment with bone
For patients with type C disease, the presence of foam cells is the only marrow transplantation. Dev Neurosci 13:345, 1991.
indication of the disease. 12. Abrahamov A, Elstein D, Gross-Tsur V, et al: Gaucher’s disease variant characterized by
progressive calcification of heart valves and unique genotype. Lancet 346:1000, 1995.
Prenatal diagnosis of the three types of the disease is possible, but 13. Meikle PJ, Fuller M, Hopwood JJ: Gaucher Disease: Epidemiology and screening policy,
is difficult in type C. 170 in Gaucher Disease, edited by AH Futerman, A Zimran, p 321. CRC Press, Boca Raton,
FL, 2007.
14. Bronstein S, Karpati M, Peleg L: An update of Gaucher mutations distribution among
TREATMENT Ashkenazi Jewish population: Prevalence and country of origin of the mutation R496H.
Isr Med Assoc J 16:683, 2014.
There is no effective treatment for types A and B disease, but there has 15. Kannai R, Elstein D, Weiler-Razell D, Zimran A: The selective advantage of Gaucher’s
been an announcement of a successful phase 1b trial with ERT for type disease: TB or not TB? Isr Med Assoc J 30:911, 1994.
B disease and plans for continuation into a phase 2 trial. 171 16. Cochran G, Hardy J, Harpending H: Natural history of Ashkenazi intelligence. J Biosoc
Sci 38:659, 2006.
Splenectomy is only rarely required, because death usually occurs 17. Ilan Y, Elstein D, Zimran A: Glucocerebroside-an evolutionary advantage for patients
from other manifestations of the disease before hypersplenism becomes with Gaucher disease: A new immunomodulatory agent. Immunol Cell Biol 3:407, 2009.
clinically important. Liver transplantation in type A disease corrects 18. Boot RG, Verhoek M, Donker-Koopman W, et al: Identification of the non-lysosomal
glucosylceramidase as beta-glucosidase 2. J Biol Chem 282:1305, 2007.
hepatic pathology but has little long-term benefit ; similarly, allogeneic 19. Yildiz Y, Hoffmann P, Vom Dahl S, et al: Functional and genetic characterization of the
172
hematopoietic stem cell transplantation does not ameliorate the neu- non-lysosomal glucosylceramidase 2 as a modifier for Gaucher disease. Orphanet J Rare
rologic deterioration in type B disease, nor does it affect the course Dis 8:151, 2013.
173
of type C disease. Somatic cell gene therapy has been attempted in 20. Mistry PK, Liu J, Sun L, et al: Glucocerebrosidase 2 gene deletion rescues type 1
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Gaucher disease. Proc Natl Acad Sci U S A 111:4934, 2014.
knockout type B mice and was effective in ameliorating visceral signs 21. Schnabel D, Schröder M, Sandhoff K: Mutation in the sphingolipid activator protein 2
175
but had no effect on neurologic signs. in a patient with a variant of Gaucher disease. FEBS Lett 284:57, 1991.
SRT was attempted in a patient with type C disease. Depletion 22. Tylki-Szymaska A, Czartoryska B, Vanier MT, et al: Non-neuronopathic Gaucher dis-
176
ease due to saposin C deficiency. Clin Genet 72:538, 2007.
of glycosphingolipids by miglustat despite having no direct effect 23. Lieberman RL: A guided tour of the structural biology of Gaucher disease: Acid-
130
on cholesterol metabolism, corrected abnormal lipid trafficking and β-glucosidase and saposin C. Enzyme Res 2011:973231, 2011.
177
indicated that glycosphingolipid accumulation is a primary pathoge- 24. Fairley C, Zimran A, Phillips M, et al: Phenotypic heterogeneity of N370S homozygotes
netic event in type C disease. with type I Gaucher disease: An analysis of 798 patients from the ICGG Gaucher Reg-
istry. J Inherit Metab Dis 31:738, 2008.
A clinical trial using miglustat at a dose of 200 mg three times daily 25. Beutler E, Gelbart T, Kuhl W, et al: Mutations in Jewish patients with Gaucher disease.
in an open-label 12-month trial with extension to 66 months in juvenile Blood 79:1662, 1992.
and adult patients with type C disease and in some children, resulted 26. Beutler E, Gelbart T: Gaucher disease mutations in non-Jewish patients. Br J Haematol
85:401, 1993.
in improvement or stabilization. Subsequent long-term exposure in 27. Horowitz M, Pasmanik-Chor M, Borochowitz Z, et al: Prevalence of glucocerebrosidase
177
adults, and some children led to its commercial approval and use clin- mutations in the Israeli Ashkenazi Jewish population. Hum Mutat 12:240, 1998.
179
ically in many countries. Miglustat improved neurologic manifestations 28. Zuckerman S, Lahad A, Shmueli A, et al: Carrier screening for Gaucher disease: Les-
sons for low-penetrance, treatable diseases. JAMA 298:1281, 2007.
such as ambulation, manipulation, speech, and swallowing; there are 29. Falcone D, Wood EM, Mennuti M, et al: Prenatal healthcare providers’ Gaucher disease
some gastrointestinal side effects. 177–179 carrier screening practices. Genet Med 14:844, 2012.
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