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The marked phenotypic variation within and among the Gaucher disease clinical types has been known for several decades, but the characterization of this variation has generally been limited to relatively small patient populations (Sibille et al,148; Zimran et al,194; Zimran et al,191; Zimran et al,192). In addition, these characterizations are skewed because of the ascertainment bias in European-derived and, specifically, Ashkenazi Jewish populations. With broader knowledge about the major phenotypes, known as types 1, 2, and 3, the understanding of a spectrum or continuum has evolved with regard to clinical/pathologic involvement, particularly for the neuronopathic variants (Table 184-1; Fig. 184-1A). Excluding CNS involvement, the continuum extends to the variation in the visceral disease of overlapping involvement among and between type 1, 2, and 3 diseases (Fig. 184-1B). The advent of specific therapies for, the need for early prognostication in, and the search for modifying agents of Gaucher disease make complex phenotyping not merely an academic nosologic exercise, but of major practical and basic import. Thus, such distinctions impact whole-life medical care delivery, reproductive decisions, and therapeutic choices for affected families. Importantly, approaches to presymptomatic or prospective intervention therapies and/or use of therapies with significant risk require accurate risk-benefit analyses based on the prognosis for individual patients. Detailed phenotyping and correlations to genotype could provide insight into individual susceptibility to varying disease severity. This need represents a prime motivation to correlate phenotypes and genotypes in Gaucher disease as well as other inherited disorders.

Fig. 184-1

Schematic of the continuum of Gaucher disease variants. A and B represent the categorical separation of the neuronopathic (types 2 and 3) and nonneuronopathic (type 1) variants. In A the rate of progression of the neuronopathic manifestations varies with age at onset. The more rapidly progressing neuronopathic disease with degeneration and regression occurring during the first year corresponds in general to the type 2 variants. The later-onset, less rapidly progressing CNS involvement occurs in the type 3 variants. The acceleration in manifestations may indicate that progression is compounded by synergy between developing signs and/or the development of new signs/symptoms. In addition, not all signs/symptoms progress at similar rates, e.g., saccadic initiation deficits may be unchanged for years whereas myoclonic seizures may progress rapidly in a later-onset variant. The continuum of neuronopathic variants makes categorical distinctions between types 2 and 3 difficult, but the terms retain clinical significance for physicians and counselors.

Table 184-1:Classic Nosology for Gaucher Disease Phenotypes

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