The prevalence of seven different mutations (84GG, IVS2 + 1, 754A, 1226G, 1342C, 1448C, and 1504T) was investigated in 32 unrelated Japanese Gaucher patients of which 20 were type I, 6 were type II, and 6 were type III). These mutations constitute 95% of the mutations observed in Jewish patients with Gaucher disease and 75% of the mutations in non-Jews (European). The most frequent mutation, 1448C (L444P), accounted for 26 alleles (40.6%); the second most prevalent mutation was 754A (F213I), accounting for 7 alleles (10.9%); 27 alleles (42.2%) were unidentified. To data, neither the 1226G (N370S) nor 84GG mutations have been identified in the Japanese population though these alleles account for approximately 70% and 10% of mutations in the Jewish population. These data suggest that mutant alleles identified from the Japanese population are distinct from those observed in Jewish and non-Jewish (European) patients with Gaucher disease.

In patients originally genotyped as homoallelic for the Gaucher disease (GD) L444P (1448C) mutation, we sought to confirm previously reported phenotypic differences between Caucasians and Japanese, to determine the prevalence and phenotypic impact of recombinant alleles, and to explore the phenotypic influence of genetic background. We therefore analyzed data from longer-term clinical follow-up, more comprehensive genotyping and polymorphism and mitochondrial DNA (mtDNA) testing in all known Japanese L444P homozygotes (n=15). Our studies demonstrated that, of 12 patients in our series originally diagnosed with non-neuronopathic GD, 9 developed neurological signs/symptoms during follow-up (at a mean of 14 years 11 months +/- 11 years 4 months). Of three patients originally diagnosed with acute neuronopathic (type 2) GD, all three were compound heterozygotes for L444P and the complex allele RecNci I. In the entire series, Pvu II and liver erythrocyte pyruvate kinase (PKLR) polymorphism and prevalence of the 9 bp mtDNA deletion were heterogeneous, and these background genetic factors could not predict phenotypic expression. Our data suggest that, in Japanese as in Caucasian patients, the L444P/L444P genotype is highly associated with subacute neuronopathic (type 3) GD, and the presence of a complex allele together with an L444P allele leads to type 2 disease. Our findings also underline the importance of comprehensive genotyping (particularly testing for recombinant alleles), long-term follow-up and careful neurological examination in patients with early-onset GD. Such measures ultimately may improve genotype/phenotype correlations and, with them, genetic counseling and therapeutic decision making.

Gaucher disease (GD) can be caused by any of over 50 mutations of the gene of glucocerebrosidase (D‐glucosyl acylsphingosine glucohydrolase; EC 3.2.1.45). The 1448T to C mutation is found among all ethnic groups. In Ashkenazi Jews, the patients who are homozygous for the 1448C mutation are associated with the neuropathic form of the disease, but this is not the case in Japanese patients. This present study was the analysis of the two haplotypes, the Pv1.1 and the liver/erythrocytes pyruvate kinase (PKLR), in Japanese GD patients who were homo‐ or heterozygous for the 1448C mutation, and comparison of the results with other ethnic patients with the same genotypes in order to show ethnic differences. Of 28 patients, 20 had type I disease (7 were homozygous for the 1448C), five had type II (1 was homozygous) and 3 had type III (all were heterozygous). In Japanese GD patients with the 1448C mutation, the two haplotypes showed complete matching in (+) or (‐). The Pv1.1/PKLR(+) alleles accounted for 84.0% and this frequency was opposite to that reported in Ashkenazi Jews and other Caucasians. The 1448C homozygous state showed no obvious linkage with either of the haplotypes. From this haplotype analysis, it is postulated that the origin of the 1448C mutation in Japanese GD patients is different from that reported in other ethnic groups.