Gaucher

Epidemiology and Etiology:

· cluster of autosomal recessive disorders

· mutations in the GBA gene (1q21) encoding glucocerebrosidase (glucosylceramidase)

· enzyme that normally cleaves the glucose residue from ceramide

· Glucocerebrosides are continually formed from the catabolism of glycolipids derived mainly from the cell membranes of senescent leukocytes and erythrocytes

· As a result, glucocerebroside accumulates principally in the phagocytic cells of the body but in some forms also in the central nervous system

· most common lysosomal storage disorder

· type I (chronic non-neuronopathic)

· reduced but detectable levels of glucocerebrosidase activity

· glucocerebrosides is limited to the mononuclear phagocytes throughout the body without involving the brain

· principally in Jews of European stock

· type II (acute neuronopathic)

· virtually no detectable glucocerebrosidase activity

· no predilection for jews

· type III

· intermediate form

·

Common sites:

· type I

· spleen

· bone marrow

· type II

· hepatosplenomegaly

· progressive CNS involvement begins in infancy

· type III

· progressive CNS involvement begins in teens or twenties

Gross features:

· splenomegaly (type I)

· uniformly pale or mottled

· lymphadenopathy (mild to moderate, generalized)

· bone

· pathologic fractures (type I)

Histologic features:

· Distended phagocytic cells (Gaucher cells) in spleen, liver, bone marrow, lymph nodes, tonsils, thymus, Peyer’s patches

· Crumpled tissue paper appearance of cytoplasm (not vacuolated)

Immunophenotype & Special Stains:

Marker:	Sensitivity:	Specificity:
PAS (intense)

Molecular features:

· GBA gene (1q21) mutations

· more than 150 allelic mutations

· N370S, 84GG, IVS2+1G>A, and L444P account for 90% of the mutant alleles in Ashkenazi Jewish individuals with type 1 GD and for 50%-60% of mutant alleles in non-Jewish individuals with type 1 GD

Other features:

· Diagnosis by measurement of glucocerebrosidase activity in peripheral blood leukocytes or in extracts of cultured skin fibroblasts

· Chitotriosidase, an enzyme synthesized by macrophages, is markedly elevated (reasonably specific)

· EM:

· Elongated, distended lysosomes containing stored lipid in stacks of bilayers

· Pancytopenia or thrombocytopenia due to hypersplenism

· Progressive CNS dysfunction (types II and III)

· Convulsions

· Progressive mental deterioration

· Prognosis:

· Type I

· Longevity is shortened but not markedly

· Type II

· Death at an early age due to progressive CNS involvement

References:

· Kumar V, Fausto N, Abbas A. Robbins & Cotran Pathologic Basis of Disease, Seventh Edition. 7th ed. Saunders; 2004:1552.