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  • Gaucher disease is a lysosomal glycolipid storage disorder characterized by the accumulation of glucosylceramide (glucocerebroside) and other glucosphingolipids that are normal intermediates in the catabolism of globoside and gangliosides.

  • Three variants of Gaucher disease have been delineated. Type 1 is the most common in the Western world and is distinguished from type 2 and type 3 disease by the lack of early onset primary CNS deterioration. Types 2 and 3 represent a continuum of primary CNS involvement, but clinically are separated. Type 2, the acute neuronopathic form of the disease, has onset with severe CNS involvement in the first months and with death at <2 years. Type 3, subacute neuronopathic, has several subtypes with variable degrees of CNS disease and visceral disease. Hepatosplenomegaly, bone lesions, and, more rarely, lungs and other organs are affected by all forms of Gaucher disease.

  • Gaucher disease has its highest prevalence/frequency in the Ashkenazi Jewish population, in which Gaucher disease-causing alleles have a frequency of ~0.0343. The L444P allele, the most common mutation worldwide, is at polymorphic levels in northern Sweden and is highly associated with neuronopathic disease in all populations.

  • The gene coding for acid β-glucosidase maps to chromosome 1q21. A pseudogene that has maintained a high degree of homology is ~16 kb downstream from the functional gene. A number of other active genes have been identified in the duplicated flanking regions, including thrombospondin and metaxin.

  • Most of the >300 disease alleles in Gaucher disease are missense mutations that lead to acid β-glucosidases with decreased catalytic function and/or stability. A variety of complex mutations/rearrangements also causes Gaucher disease. Included are missense mutations, frame shift mutations, splicing mutations, deletions, gene fusions with the pseudogene, examples of gene conversions, and total deletions. While genotype/phenotype correlations exist for type 1 disease (N370S) and types 2 and 3 (L444P), within these categories there is variable penetrance and expressivity between individuals and ethnic groups.

  • Detailed structures, catalytic mechanism, processing, lysosomal trafficking, and stabilities of acid β-glucosidases have been delineated for wild type and some variant enzyme forms.

  • The quality of life of patients with Gaucher disease can be greatly improved by comprehensive, personalized therapy that includes medical and surgical interventions and, in sufficiently affected patients, enzyme and/or substrate reduction therapies. Repeated infusions of macrophage-mannose-receptor-targeted acid β-glucosidase provide for significant stabilization and reversal of many visceral manifestations. Adjunctive therapies for treatment of bone and other involvement may be needed.

  • The variable penetrance and expressivity of Gaucher disease significantly impacts the complexity of patient care and genetic counseling. Ethnic-specific genotype/phenotype correlations are needed to provide accurate information to affected patients and families.


The eponym “Gaucher disease” encompasses the heterogeneous sets of signs and symptoms in patients with defective intracellular hydrolysis of glucosylceramide (Fig. 183-1) and related glucosphingolipids. At the molecular level, these autosomal recessively inherited disorders most commonly result from mutations of the gene that encodes the lysosomal hydrolase ...

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