Clinical and genetic studies of Japanese homozygotes for the Gaucher disease L444P mutation

Abstract

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.

Mutation analysis and genotype/phenotype relationships of Gaucher disease patients in Spain

“…Of the eight GD3 patients in our series, three were homozygous (two for L444P and one for D409H), and five compound heterozygote (Ida et al 1999). …”

Clinical and genetic characteristics of Korean patients with Gaucher disease

“…Indeed, 5 patients had homozygous mutations of these 4 alleles; 2 patients with L444P/L444P and 1 patient each with G46E/G46E, F213I/F213I, or R257Q/R257Q. Several reports have suggested that L444P compound heterozygous mutations are associated with type 2 GD (severe type) and that the L444P/L444P homozygous mutation is more frequently associated with type 3 GD than with types 1 and 2 [10,[12][13][14][15][16]. In Korean GD patients, the L444P/L444P mutation was detected in 2 patients (cases No.…”

Velaglucerase alfa enzyme replacement therapy compared with imiglucerase in patients with Gaucher disease

“…This genotype is typically associated with neuronopathic GD [16,17]. At the time of enrollment, the genotype of these patients was unknown.…”