Novel G377S (c.1246G&gt;T) mutation associated with Gaucher disease type 1
Authors: Yaolin Zhou, Ryan R. Kraemer, Deniz Peker, Dara N. Wakefield, Diego A. de Idiaquez Bakula
Journal: American Journal of Hematology (2013)

Gaucher disease (GD) is the classical autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme glucocerebrosidase. More than 350 GBA (glucosidase, β, acid) mutations have been reported, with frequencies that vary by ethnicity and disease type 1. In all cases of GD, glucocerebroside accumulation in macrophages leads to potential clinical manifestations. The phenotype of adult-onset GD type 1 includes bone disease, hepatosplenomegaly, anemia, and thrombocytopenia. Plasma cell disorders and other hematologic malignancies also appear to be more frequent in these patients 2. We report a case of a previously healthy 61-year-old white man who presented with easy bruisability and thrombocytopenia (Platelet 77,000/μL). Physical examination was within normal limits; however, abdominal imaging revealed mild hepatosplenomegaly. Urine protein electrophoresis showed a paraprotein (M-spike of 21.4%, total protein 14 mg/dL). Free lambda light chain monoclonal band was identified by urine immunofixation electrophoresis. In view of these findings, a bone marrow evaluation was performed. The biopsy showed scattered plasma cells, accounting for 5% of cellularity. There were, however, numerous foamy macrophages alongside lipid-engorged macrophages with clear blue “tissue paper” cytoplasm and eccentric nuclei (Fig. 1), consistent with “Gaucher cells” 3. These cells were strongly positive with Prussian Blue iron stain. GD was confirmed by undetectable β-glucosidase activity. Full gene analysis demonstrated heterozygous mutations: previously described N370S (c.1226A>G) and a novel mutation (c.1246G>T) at the G377S allele. MRI of the lumbar spine and bilateral hips showed diffuse marrow changes consistent with GD, but no osteonecrosis. Skeletal survey revealed no osteolytic lesions. DEXA scan showed osteopenia. Chitotriosidase, ferritin, and angiotensin-converting enzyme levels were elevated. Treatment with enzyme replacement was recommended. GD is now recognized as a pan-ethnic condition with variable genotypes and phenotypes. The four most common mutations (N370S, 84GG, IVS2+1G>A, and L444P) account for approximately 90% of the disease-causing alleles in Ashkenazi Jewish populations 3. These four mutations also account for 50–60% of disease-causing alleles in non-Jewish patients, who often have compound heterozygous genotypes with one rare or unique mutation 3, as seen here. Individuals with homozygous N370S mutations tend to show a milder phenotype; they may even be asymptomatic and not diagnosed until much later in life 3, 4. In contrast, heterozygous patients with N370S/other present earlier and show predominantly visceral disease and more severe skeletal involvement 4. Our patient has heterozygous mutation N370S/G377S. Unlike N370S, the G377S mutation is rare and usually seen in patients of Portuguese and Spanish descent 1 and is also seen in type 3 GD (neuropathic GD) 5. The N370S (c.1226A>G) and G377S (c.1246G>A) mutations are known mutations 3, but to our knowledge, G377S (c.1246G>T) has not been previously described. The predicted replacement of a nonpolar amino acid glycine for polar amino acid cysteine would have deleterious effects, leading to a GD type 1 phenotype. We describe the contribution of a novel G377S mutation in a patient with adult-onset GD. The patient's significant thrombocytopenia, monoclonal gammopathy, and osteopenia illustrate the importance of evaluating and monitoring GD patients for associated bone disease and potential hematologic cancers. Yaolin Zhou1 Ryan R. Kraemer2 Deniz Peker1 Dara N. Wakefield1 Diego A. de Idiaquez Bakula2 1Departments of Pathology, University of Alabama at Birmingham,West Pavilion P220, Birmingham, Alabama 2Medicine, University of Alabama at Birmingham, 1808 7th Ave S,Birmingham, Alabama