Phenotypic heterogeneity of N370S homozygotes with type I Gaucher disease: An analysis of 798 patients from the ICGG Gaucher Registry

Abstract

Gaucher disease is a lysosomal storage disorder caused by a deficiency of the enzyme acid beta-glucosidase. The most prevalent mutant genotype in type I Gaucher disease, N370S/N370S, is commonly thought to confer a mild phenotype presenting in adulthood. To characterize a subset of more severely affected N370S homozygotes, we assessed the phenotypes at or near the time of diagnosis of all N370S homozygotes with available data enrolled in the International Collaborative Gaucher Group Gaucher Registry. N370S compound heterozygotes were analyzed for comparison, as they are expected to present with a more severe phenotype. Of 798 N370S homozygotes and 1,278 N370S compound heterozygotes identified, 32% (251/788) and 65% (820/1269), respectively, were diagnosed before age 20 years. At diagnosis, N370S homozygotes as compared to N370S compound heterozygotes had the following clinical characteristics: irreversible skeletal lesions 17% (34/198) for N370S homozygotes versus 26% (76/290) for N370S compound heterozygotes; anaemia 18% (59/327) versus 29% (145/494); thrombocytopenia 52% (170/327) versus 62% (281/453); hepatomegaly 44% (83/190) versus 72% (141/195); splenomegaly 73% (142/194) versus 91% (178/195); and osteopenia or osteoporosis 48.6% (34/70) versus 51% (25/49). Some N370S homozygotes exhibited more severe clinical manifestations: 9% (29/327) had severe thrombocytopenia; 3% (5/190) had severe hepatomegaly; 11% (22/194) had severe splenomegaly; 7% (18/255) reported bone crises; 11% (8/70) had osteoporosis. In conclusion, N370S homozygosity does not consistently confer a mild, adult-onset phenotype. Gaucher disease patients with the N370S/N370S genotype exhibit a high degree of phenotypic heterogeneity and some may be at risk for early disease onset and severe clinical manifestations.

Risk factors for fractures and avascular osteonecrosis in type 1 Gaucher disease: A study from the International Collaborative Gaucher Group (ICGG) Gaucher Registry

“…However, N370S homozygous patients constituted 23.8% of all patients with AVN, confirming previous reports that, even in this apparently milder genotype, there is significant risk of AVN. (3,31) Consistent with our findings that the burden of visceral disease was not a predictor of AVN, Taddei and colleagues (31) found an unexpectedly high incidence of AVN among older N370S homozygous patients, even though they exhibited minimal, or even no, visceral or hematologic disease. We found that, compared to N370S homozygous patients, AVN was more prevalent among heteroallelic genotypes (eg, N370S/L444P, N370S/84GG).…”

“…(29) The identification of osteopenia as a risk factor for fractures in GD1 is important for the management of patients because osteopenia is highly prevalent in symptomatic GD1 patients, as well as asymptomatic N370S homozygous patients diagnosed through genetic screening programs. (3,4,30,31) We found that fractures occur in patients with GD1 in the range of relatively young median ages, from 29 to 57 years, as well as in older patients.…”

“…Presence of anemia was determined based on age and gender norms for hemoglobin (g/dL) concentrations as follows: <12 g/dL for males older than 12 years; <11 g/dL for females older than 12 years; <10.5 g/dL for children aged >2 to 12 years; <9.5 g/dL for children aged 6 months to 2 years; and <10.1 g/dL for children younger than 6 months of age. Thrombocytopenia was defined as platelet count <120 Â 10 3 /mm 3 . Liver and spleen volumes were determined by volumetric imaging and the results were expressed as multiples of normal (MN) volume, based on body weight; eg, normal liver volume is 2.5% of body weight and normal spleen volume is 0.2% of body weight.…”

“…(1) The conspicuous sites of pathology in GD1 are the liver, the spleen, the bone marrow, and the skeleton, (1,2) although considerable phenotypic heterogeneity exists between patients, even among those with the same GBA1 genotype. (3,4) Clinical and radiological evidence of skeletal involvement is found in the vast majority of patients. (1,2,5) Although clinical observations indicate that severe skeletal manifestations may occur in the absence of commensurate severe visceral and hematological disease, it is not known whether, in general, there is a relationship between the severity of skeletal disease and the severity of visceral/hematological disease.…”

The history and accomplishments of the ICGG Gaucher registry

“…There is some attrition of patients lost to follow-up and missing data that may not necessarily be random or recoverable. Although the Registry is not restricted to patients treated with imiglucerase, with the advent of Demographics and disease characteristics in 1,698 patients prior to treatment [8] Recommendations for initial evaluation and serial monitoring in adult patients [9,10] Phenotypic and genetic variation worldwide and in specific populations (e.g., Latin American, Asian, N370S homozygous patients) [1,[11][12][13][14][15] Estimation of life expectancy for Gaucher disease patients based largely on years alive in the pre-ERT era [16] Gaucher disease and incidence of cancer [17] Gaucher disease and increased risk for parkinsonism [ Growth and development prior to and after initiation of alglucerase/imiglucerase enzyme replacement therapy (ERT) [27] Clinical and demographic characteristics of nearly 900 children with Gaucher disease type 1 and their response to ERT [28,29] Recommendations for initial and serial monitoring in untreated and treated pediatric patients [30][31][32][33] Outcomes in pediatric patients from Latin America where previous work has shown that severity of Gaucher disease is often greater than usually encountered in the U.S. [11,12] Clinical characteristics and effectiveness of imiglucerase/alglucerase in 443 children with Gaucher disease type 1 from Latin America after 8 years of treatment [34] …”