Types Of Gaucher Disease

Gaucher disease has classically been divided into three clinical types based on the absence or presence of neurological involvement.

Type I is defined by the absence of neurological involvement and, usually, the presence of the N370S (1226G) mutation on at least one allele. Although pan-


The genomic area near the p-glucocerebrosidase locus on human chromosome 1q21 includes its pseudogene and several other gene loci. Enzyme and mRNA activities vary among species and tissues, the import of which is unclear. Before the advent of a biochemical assay of p-glucocerebrosidase activity, demonstration of Gaucher cells in the bone marrow was used for diagnosis. Since 1970, routine enzymatic assay (pH 4) of leukocytes that hydrolyze 4-methylumbelliferyl-p-glucocerebrosidase to <15% of normal is the gold standard for diagnosis.[1] A limitation of the test is the overlap of activity of heterozygotes with normal values, and the inability of the enzyme level to predict neuronopathic involvement.

Therefore, mutation analysis based on routine polymerase chain reaction (PCR)-based technology has been added as an adjunct for diagnosis because some mutations have been associated with mild, severe, or lethal disease. Primers target the gene fraction of interest and amplify it (but not the pseudogene). Restriction digestion reveals mutations by gel electrophoresis; alternative approaches include allele-specific oligonucleotide hybridization,[2] and mismatched PCR methods by amplification refractory mutation systems[1] or by direct sequencing, if necessary. A new kit assay, the PRONTOâ„¢ procedure (Savyon Diagnostics, Israel), detects single-nucleotide polymorphisms in DNA sequences via multistep reactions using biotin-labeled primers, and the final results are read either visually (substrate remains clear or turns blue) or colorimetrically using enzyme-linked immunosorbent assay (ELISA).

Whereas the majority of disease alleles are single-base substitutions resulting in missense mutations, there are also nonsense mutations and rearrangements. Of the more than 200 disease-associated alleles (most of which cluster toward the 3' end of the gene), fewer than 10 have significant frequencies in various populations, among them N370S (1226G), 84GG, L444P (1448C), IVS 2+1, D409H (1342C), R486H (1604A), and F213I (754T), and the two recombinant alleles, RecNciI and RecTL.[2]

Allele distribution reveals that the common N370S mutation is detected in 71.8% of Ashkenazi Jews (which, in homozygosity, is invariably associated with mild disease), but only in 43.6% of non-Jews;[2] indeed, among non-Jews, the prognostic information of large numbers of private/rare mutations also decreases the usefulness of mutation analysis. Thus genotype-phenotype correlations and genetic and/or environmental modifiers are areas of intense research for improved genetic counseling and open avenues of therapeutic intervention. Currently, chorionic villous sampling and amniocentesis are available for prenatal diagnosis. As a rule of thumb for broad outlines for prediction of phenotype: null/null mutations are incompatible with life, whereas mild/mild mutations generally result in mild type I disease; mild/ severe or mild/null mutations often result in symptomatic, nonneuronopathic disease; and combinations of severe/ severe or severe/null mutations result in neuronopath-ic forms.

Mutation analysis for detection of carrier status among Ashkenazi Jews is robust, being nearly 98% reliable.[1]

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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