Three mutations of adult type 1 Gaucher disease found in a Chinese patient: A case report.

RATIONALE: Gaucher disease (GD), characterized by glucosylceramide accumulation in the macrophage-monocyte system, is caused by glucosidase b acid (GBA) gene mutations which lead to the deficiency of lysosomal enzyme glucocerebrosidase. The mutation spectrum of GBA in Chinese patients is quite different from those seen in Jewish and non-Jewish Caucasian patients. Thus, it is relatively hard to diagnose GD in Chinese. PATIENT CONCERNS: A 24-year-old Chinese female with intermittent abdominal distension and progressive decrease in strength but without neurologic symptoms was initially referred for femoral head necrosis on the right feet. Laboratory examinations results indicated panhematopenia. Bone marrow aspiration smear and biopsy specimen found typical "wrinkled" Gaucher cells. Molecular-genetic testing of GBA gene revealed 3 mutations including R159W (c. 475 C > T), V1230G (c. 689T > G), and G241A (c. 721G > A). 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 carried out after the diagnosis of type 1 GD. OUTCOMES: The platelet and hemoglobin levels were restored by ERT. LESSONS: To our knowledge, this is the first report of GD patient carrying 3 mutations in Chinese. These mutations in GBA in the present case imply a potential pool of patients with GD with this mutation in Chinese.

Introduction

Gaucher disease (GD) is an autosomal-recessive disorder caused by the deficiency of acid β-glucosidase, due to mutations in the GBA gene.[ Three major clinical types of GD have been described based on the clinical signs, age of onset, and central nervous system involvement.[ Type 1 GD is called non-neuronopathic subtype and accounts for 90% of known GD cases worldwide, and characterized by hepatosplenomegaly, frequent bone fractures, hematological complications.[ To date, more than 250 mutations in GBA gene have been reported to associate with GD.[

Here, we present a case of an adult patient with type 1 GD, whose diagnosis was made based on the findings of Gaucher Cells in the bone marrow aspiration and genetic testing of GBA gene. We report a case of GD1 in a 24-year-old female with 3 exon mutations of the GBA gene: R159W (c. 475 C > T), V1230G (c. 689T > G), and G241A (c. 721G > A).

Case presentation

A 24-year-old female was admitted to our hospital with intermittent abdominal distension and progressive lacking in strength in July 2014. According to the medical history, the patient was diagnosed with femoral head necrosis on the right feet in 2011. She was pregnant 7 times and delivered 3 times including 2 dead fetuses and a neonatal death 3 days later. Physical examination revealed abdomen flat and soft; no tenderness or rebound tenderness; splenic tip palpable 5 cm below the left costal margin; liver impalpable; no abnormalities in heart and lung; right foot 2 cm shorter than the left, and no signs of primary central nervous systemic symptoms.

Laboratory examinations showed the number of white blood cell (WBC) was 3.37 × 109/L (normal level, 4.0–11.0 × 109/L), the hemoglobin (HGB) level was 106 × 109/L (normal level, 110–150 × 109/L) and the number of platelets (PLT) was 75 × 109/L (normal level, 100–300 × 109/L). Laboratory examinations results indicated panhematopenia. Computed tomography (CT) showed large liver and enlarged spleen. Bone marrow aspiration smear showed many large, ovoid cells with small eccentric nuclei (Fig. 1), whose cytoplasm was pale blue and had the “wrinkled” appearance typical in Gaucher cells.[ Further examination of bone marrow biopsy specimen confirmed typical Gaucher Cells. Due to lack of accessible methods to detect the enzymatic activity of leukocyte β-glucosidase, we performed molecular genetic testing of GBA gene. Analytical results showed 3 exon mutations of the GBA gene including R159W (c. 475 C > T), V1230G (c. 689T > G), and G241A (c. 721G > A) (Fig. 2). Based on the clinical and biological examination results described above, we diagnosed the patient with GD 1. Enzyme replacement therapy (ERT) with velaglucerase α was carried out after the diagnosis of type 1 GD. The platelet and hemoglobin levels were restored by ERT.

Figure 1

Typical Gaucher cell with a “wrinkled tissue pattern” on bone marrow aspirate smear (×200, Wright–Giemsa stain) (arrowhead) (A). Bone marrow biopsy specimen presenting with several Gaucher cells (×200, hematoxylin and eosin stain) (B).

Figure 2

The analysis results showed 3 mutations of the GBA gene.

Discussion

The overall frequency of GD variants is 1:40,000 to 1:50,000.[ A patient is suspected to suffer from GD when there are several unexplained symptoms, such as hepatosplenomegaly, anemia, thrombocytopenia, or detection of Gaucher cells in bone marrow aspiration smear sample.[ Definite diagnosis can be made by measuring acid β-glucosidase activity in fresh peripheral blood leukocytes or skin biopsy specimens. Confirmation and better characterization of the condition may subsequently be afforded by molecular analysis of the human GBA gene, which encodes lysosomal GBA.[ Genetic testing of GBA gene not only improves the diagnostic accuracy of GD patients, but also improves the detection efficiency of underlying carrier.[ In our case, the patient had large liver and enlarged spleen. Bone marrow aspiration smear and biopsy specimen both showed the typical “wrinkled” Gaucher cells (Fig. 1). Molecular genetic testing of GBA gene further revealed 3 new exon mutation sites within GBA gene (Fig. 2). Additionally, the patient showed no signs of primary central nervous systemic symptoms. Taking all factors stated into consideration, we diagnosed the patient with type 1 GD.

According to an academic review previously published in 2008, more than 250 mutation sites have been identified in GBA gene,[ among which mutations c.1448T > C (L444P) and c.1226A > G (N370S) are the prevalent mutant alleles.[ In our present study, we reviewed the new mutations reported from 2008 to 2018 (Table 1).[ As shown in Table 1, more mutations were identified in type 1 GD than type 2 and 3 GD in recent years. The mutation spectrum of GBA in Chinese patients was quite different from those seen in Jewish and non-Jewish Caucasian patients.[ Our results further confirmed that the mutation spectrum of GBA in Chinese patients was quite different from those seen in Jewish and non-Jewish Caucasian patients.[ Long-term follow-up study would be necessary in determining the association between GD severity and those newly found mutations.

Table 1

New GBA mutations found in the recent years (from 2008 to 2018).

Author contributions

Guarantor of integrity of entire study: Qing Wang

Data acquisition: Xiaoli Du and Qian Ding

Data analysis: Xiaoli Du

Literature research: Xiaoli Du, Pengxiang Guo and Qian Ding

Manuscript definition of intellectual content: Qing Wang

Manuscript preparation: Xiaoli Du

Manuscript revision: Xiaoli Du, Qian Ding and Qi Chen

Manuscript final version approval: Qing Wang

Data curation: Xiaoli Du.

Formal analysis: Qian Ding, Qing Wang.

Funding acquisition: Xiaoli Du.

Investigation: Xiaoli Du, Pengxiang Guo.

Methodology: Qian Ding.

Project administration: Qing Wang.

Writing – original draft: Xiaoli Du.

Writing – review & editing: Xiaoli Du, Qi Chen.