The patient did not develop any neurologic symptoms, and no abnormalities were found by head magnetic resonance imaging, which confirmed the classification of GD as type 1.
The ERT with every-other-week intravenous infusion of 60 units per kilogram of velaglucerase α, a recombinant β-glucocerebrosidase that was most recently approved in Japan, was started after the diagnosis of GD. Hemoglobin and platelet levels were restored at 2 and 3 months after velaglucerase α administration, respectively. Bone marrow samples collected 10 months after velaglucerase α administration showed reduction of Gaucher cells in bone marrow to 2% of total cellularity. The patient has received ERT for 16 months without any side effect up to the present.
This case report was approved by the ethics committee of Shiga University of Medical Science, Shiga, Japan and written informed consent was obtained.
To the best of our knowledge, this is the first report of the novel K157R (c.587A>G) mutation in GBA that caused GD and of the use of 18F-FDG PET/CT for suggestive diagnosis of GD in a patient with slight anemia and thrombocytopenia but no complaints.
The morbidity of GD in Japan is much less than in Western countries (1 per 3.3 × 105 and 1.16 per 1 × 105 live births, respectively), and the information about Japanese patients with GD is relatively limited.[11,12] Tajima et al reported that 58% of Japanese patients with GD develop types 2 or 3 GD, which is accompanied by neurologic symptoms (24% and 34% of cases, respectively). In contrast, only 1% or 5% of patients with GD globally are diagnosed as types 2 or 3 GD, respectively, according to the worldwide registry reported by Charrow et al. As the age at diagnosis for the patients with types 2 and 3 GD is usually younger than that of patients with type 1 GD, Japanese patients are diagnosed with GD at a relatively younger age. Thus, in Japan, it is quite difficult to diagnose GD in adult individuals who present with slight anemia and thrombocytopenia but exhibit no neurologic manifestations, splenomegaly, bone pain, or other typical GD symptoms.
In our case, 18F-FDG uptake in the bone marrow was the important clue to suspect GD. The correlation between 18F-FDG accumulation in bone marrow and GD was previously reported by Erba et al. In their report, all 7 enrolled patients who had been diagnosed previously as type 1 GD had 18F-FDG accumulation in the bone marrow. Furthermore, the score based on the extension and magnitude of 18F-FDG uptake in the bone marrow was highly correlated to the clinical severity score. However, we believe that no case reports that actually utilized 18F-FDG PET/CT for GD diagnosis had been published before our present case.
Moreover, our case is the first report of K157R mutation in GBA. GBA is located on 1q21; its total length is 7 kb, and it has 11 exons, and there is a highly homozygous pseudogene that easily recombines with GBA. Over 300 mutations causing GD have been reported. RecTL (c.1342G>C, c.1448T>C, c.1483G>C, and c.1497G>C) and RecNciI (c.1448T>C, c.1483T>G, and c.1497G>C) are the well-known recombinant mutations between GBA and that pseudogene.
The mutations causing GD are significantly associated with patient's ethnicity. N370S (c.1226A>G) is common among Ashkenazi Jewish patients, in which it is found in approximately 70% of cases, whereas in an Asian cohort, this mutant allele has been found only in 12% of cases. The prevalence of F2131 (c.754T>A) and L444P (c.1448T>C) among Japanese patients is about 41% and 11%, respectively, whereas in Ashkenazi Jewish patients, those mutations are relatively rare. Genetic screening for 8 common mutations, including N370S, L444P, F2131, R463C (c.1504C>T), 84GG (c.84dupG), IVS2+1 (c.115+1G>A), D409H (c.1342G>C), and RecNciI, can identify causative mutations in most Ashkenazi Jewish patients. However, this gene screening cannot recognize mutations in 39% of Japanese patients. To detect mutations unidentified by the gene screening, comprehensive resequencing of the GBA gene for all 11 exons is required.
To verify that K157R was responsible for GD in the patient studied, the heterozygous mutations of K157R and RecNciI were confirmed by using DdeI, a restriction enzyme recognizing double stranded deoxyribonucleic acids. However, our case report has a limitation in that it remained unclear whether the mutation was de novo or inherited, as we could not obtain genetic material of the patient's parents or other relatives. Assuming that K157R was inherited from the parents and was also passed to the patient's offspring, there should be a population carrying K157R in Japan. For such population, which could potentially develop GD, further investigation of this gene is needed.
In conclusion, our case demonstrated the utility of 18F-FDG PET/CT for GD diagnosis and suggested the existence of a population carrying K157R allele that causes GD in Japan. For such patients, 18F-FDG PET/CT is valid as the first step of diagnosis.
Data curation: Kaori Adachi, Ryota Nakanishi, Suzuko Moritani, Eiji Nanba.
Writing – original draft: Sakura Hosoba.
Writing – review & editing: Katsuyuki Kito, Yukako Teramoto, Kaori Adachi, Ryota Nakanishi, Ai Asai, Masaki Iwasa, Rie Nishimura, Suzuko Moritani, Masahiro Kawahara, Hitoshi Minamiguchi, Eiji Nanba, Ryoji Kushima, Akira Andoh.
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Keywords:Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
anemia; fluoro-deoxyglucose positron emission tomography; Gaucher disease; mutation; thrombocytopenia