Mapping the genetic and clinical characteristics of Gaucher disease in the Iberian Peninsula

Abstract

BackgroundGaucher disease (GD) is due to deficiency of the glucocerebrosidase enzyme. It is panethnic, but its presentation reveals ethnicity-specific characteristics.MethodsWe evaluated the distribution, and clinical and genetic characteristics of GD patients in the Iberian Peninsula (IP). We analysed geographical distribution, demographic, genetic and clinical data, age at diagnosis, type, and years of therapy in 436 GD patients from the IP.ResultsThe prevalence of GD was 1/149,000 inhabitants; 88.3% were type 1, 6.7% type 2, and 5.0% type 3. The mean age at diagnosis in type 1 was 28.7 years. A total of 72.7% were classified as having mild forms, 25.5% moderate, and 1.7% severe. Anemia and thrombocytopenia were present in 56% and 55%, respectively. Bone disease and hepatomegaly were reported in 62% and 68%, respectively, and were more likely in asplenic than in non-splenectomized patients. Sixty-nine mutant alleles were identified, and five mutations accounted for 75% of the GBA alleles. Several patients described in our series had interesting phenotypes. A total of 58.7% of patients had received enzyme replacement therapy and 12.6% were treated with miglustat.ConclusionsA broad spectrum of GBA mutations is present in the IP, with 98.2% of type 1 GD being mild and 23.0% never treated. These data highlight genetic and phenotypic heterogeneities among geographic populations.

Consanguinity and founder effect for Gaucher disease mutation G377S in a population from Tabuleiro do Norte, Northeastern Brazil

“…Initially, it was believed to be neuroprotective owing to its mild effect, high residual enzyme activity and the fact that all known Portuguese homozygotes for G377S have type 1 GD (17). However, the G377S mutation has been observed in patients with type 3 GD in both Brazil and the Iberian Peninsula (2,14). Although cardiac valvulopathies have been observed in a homozygous patient from Croatia, all our subjects had type 1 GD and no cardiovascular symptoms.…”

“…Although cardiac valvulopathies have been observed in a homozygous patient from Croatia, all our subjects had type 1 GD and no cardiovascular symptoms. This suggests that individuals with the same genotype may have different phenotypes and highlights the influence of other genetic and/or environmental factors on the clinical manifestations of GD (2,18).…”

“…These may be classified into three types (null, severe and mild) according to their phenotypic effect (2).…”

Nine-year experience in Gaucher disease diagnosis at the Spanish reference center Fundación Jiménez Díaz

“…After extracting DNA from peripheral leukocytes using standard methods ( Bio robot EZ1 Qiagen ), the diagnostic algorithm (Fig.1) starts by analyzing the DNA by mutational screening for the 8 most frequent Gaucher mutations in the European population [22]: 84GG [452   +   G], IVS2 + 1 [484 G > A], N370S [1226 A   >   G], V394L [1297 G > T], D409H [1342 G   >   C] , L444P [1448 T > C], R463C [1504 C   >   T] , R496H [1604 G > A] (Gaucher disease StripAssay® - ViennaLab Diagnostics GmbH, Vienna, Austria).…”

“…It is well-known that there is a higher prevalence among Ashkenazi Jews, with a carrier frequency of 8.9% and a birth incidence of 1:450 [21]. However, in the Iberian Peninsula, the prevalence of GD is 1 in 149,000 inhabitants, with c.1226A > G (N370S) and c.1448T > C (L444P) as the most frequent mutations [22].…”