A novel mutation causing type 1 Gaucher disease found in a Japanese patient with gastric cancer: A case report

Abstract

Rationale: Gaucher disease (GD) is an autosomal recessive disorder that leads to multiorgan complications caused by β-glucocerebrosidase deficiency due to mutations in the β-glucocerebrosidase-encoding gene (GBA). GD morbidity in Japan is quite rare and clinical phenotype and gene mutation patterns of patients with GD in Japan and Western countries differ considerably. Of Japanese patients with GD, 57% develop types 2 or 3 GD with neurologic manifestations and younger onset, whereas only 6% of patients with GD develop those manifestations in Western countries. Thus, it is relatively difficult to find and diagnose GD in Japan.

Patient concerns: A 69-year-old Japanese female with mild anemia and thrombocytopenia but without neurologic symptoms was initially referred for gastric cancer. Preoperative F-deoxyglucose positron emission tomography/computed tomography (FDG PET/CT) showed accumulation in the bone marrow and paraabdominal lymph nodes. Following bone marrow aspiration found, abnormal foamy macrophages in the bone marrow and electron microscopy revealed that the macrophages were filled with tubular-form structures. Adding to these signs suggestive of a lysosomal disease, serum β-glucocerebrosidase activity test found decreased. Sequencing of the patient's GBA gene revealed a RecNciI recombinant mutation and the novel mutation K157R (c.587A>G).

Diagnoses: On the basis of these findings and clinical manifestations, the final diagnosis of type 1 GD was made.

Interventions: Enzyme replacement therapy (ERT) with velaglucerase α was started after the diagnosis of type 1 GD.

Outcomes: The patient's β-glucocerebrosidase activity as well as hemoglobin and platelet levels were restored by ERT without any side effects. Bone marrow aspirations 10 months after the start of the treatment with velaglucerase α showed reduction of Gaucher cells in bone marrow to 2% from 4% of total cellularity.

Lessons: This is the first report of F-FDG PET/CT application providing a clue for GD diagnosis. A novel mutation in GBA is described, which implies a potential pool of patients with GD with this mutation in Japan.

Figure 1

(A) Preoperative ¹⁸F-deoxyglucose positron emission tomography/computed tomography scan shows atypical accumulation at the bilateral brachia and thigh bones and the paraabdominal aortic lymph nodes in addition to weaker accumulation in the stomach without accumulation in the gastric lymph nodes. (B) Histopathologic findings in a bone marrow clot. Large foamy histiocytes constitute sheet-like pattern (hematoxylin and eosin stain; original magnification, ×100). (C) Histopathologic findings in a bone marrow smear. The histiocytes have weekly basophilic enlarged cytoplasm containing wrinkled structures (Wright−Giemsa stain; original magnification, ×1000). (D) Histopathologic findings in a bone marrow smear. The cytoplasm of the abnormal histiocytes is strongly positive for acid phosphatase stain (original magnification, ×1000).

Figure 2

(A) Electron microscopy findings in the bone marrow. The abnormal histiocyte distorted by enlarged cytoplasm contained enlarged lysosomes (A-1, ×2000). Further magnification shows that the lysosomes are filled with various tubular structures (A-2, ×25,000). (B) Histopathologic findings in the excised paraabdominal lymph node. Atypical large histiocytes with foamy cytoplasm proliferated and occupied most of the lymph node in the absence of gastric cancer cell invasion (hematoxylin and eosin stain; original magnification, ×100).

Figure 3

Mutation analysis of the GBA gene in the patient shows heterozygous point mutation K157R (c.587A>G) on exon 6 (A) and heterozygous recombinant mutations of RecNciI, including L444P (c.1448T>C), A456P (c.1483G>C), and V460 (c.1497G>C) on exon 11 (B).