18개월 남아에서 간비장비대, 성장 부진을 동반한 3형 고셔병 증례: 효소 대체 요법 후 임상 경과 A Case of an 18-month-old Boy with Type 3 Gaucher Disease Presenting with Hepatosplenomegaly and Growth Retardation: The Clinical Course after Enzyme Replacement Therapy원문보기
고셔병은 리소좀축적병으로 lysosomal hydrolase glucocerebrosidase 결여로 간비장비대, 골격계 증상, 빈혈, 혈소판 감소증의 증상을 나타내는 드문 상염색체 유전 질환이다. 본 증례에서는 18개월 남아에서 간비장비대, 성장 부진이 관찰되었으며 안구 운동 장애 및 발달 지연이 동반되어 제 3형 고셔병을 의심하였고 효소 분석 및 유전자 검사를 통해 확진하였다. 환아에서 한국인 신경형 고셔병에서 흔하게 관찰되는 c.754T>A(F213I)와 c.887G>A (R257Q)가 이형 접합체 돌연변이로 확인되었고 17개월 간의 효소 대체 요법을 통해 성장, 혈액학적 지표, 간비장비대 및 골증상은 호전되었지만 신경학적 증상의 호전은 없었고, 샤프론 중암브록솔에 유의한 반응이 있다고 알려져 있는 c.754T>A이 확인됨에 따라 환아에서 3개월간 암브록솔 치료를 시도하였지만 뚜렷한 임상적 치료 효과를 확인할 수 없었기에 본 증례를 보고하는 바이다.
고셔병은 리소좀축적병으로 lysosomal hydrolase glucocerebrosidase 결여로 간비장비대, 골격계 증상, 빈혈, 혈소판 감소증의 증상을 나타내는 드문 상염색체 유전 질환이다. 본 증례에서는 18개월 남아에서 간비장비대, 성장 부진이 관찰되었으며 안구 운동 장애 및 발달 지연이 동반되어 제 3형 고셔병을 의심하였고 효소 분석 및 유전자 검사를 통해 확진하였다. 환아에서 한국인 신경형 고셔병에서 흔하게 관찰되는 c.754T>A(F213I)와 c.887G>A (R257Q)가 이형 접합체 돌연변이로 확인되었고 17개월 간의 효소 대체 요법을 통해 성장, 혈액학적 지표, 간비장비대 및 골증상은 호전되었지만 신경학적 증상의 호전은 없었고, 샤프론 중암브록솔에 유의한 반응이 있다고 알려져 있는 c.754T>A이 확인됨에 따라 환아에서 3개월간 암브록솔 치료를 시도하였지만 뚜렷한 임상적 치료 효과를 확인할 수 없었기에 본 증례를 보고하는 바이다.
Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by beta-glucosidase deficiency. An 18 month-old male with hepatosplenomegaly, anemia, thrombocytopenia, and growth retardation referred to our hospital. The patient showed neurological symptoms, such as supranuclear gaz...
Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by beta-glucosidase deficiency. An 18 month-old male with hepatosplenomegaly, anemia, thrombocytopenia, and growth retardation referred to our hospital. The patient showed neurological symptoms, such as supranuclear gaze palsy and developmental delay. Bone marrow biopsy performed to rule out malignancy and the results revealed no malignant cell; however, abnormal histiocytes suggesting storage disease was noted. Based on hepatosplenomegaly, bicytopenia and unexplained neurologic manifestations, enzyme activity and genetic analysis were conducted emergently with a strong suspicion of GD. Beta-glucosidase activity in leukocyte was decreased. GBA sequencing to confirm the diagnosis revealed compound heterozygous pathogenic variants (i.e., c.754T>A, c.887G>A), both previously reported as the cause of neuronopathic GD. Under the diagnosis of type 3 GD, the patient immediately received enzyme replacement therapy (ERT). After 17 months of ERT, the size of spleen decreased, and hemoglobin and platelet count returned to normal. In addition, the activity of chitotriosidase and angiotensin converting enzyme decreased. However, myoclonic movement and generalized seizure occurred at the age of 19 months and antiepileptic drug was started. Other neurological deterioration including supranuclear gaze palsy and developmental delay also persisted. A new therapy to overcome neurologic problems should be developed for patients with type 3 GD.
Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by beta-glucosidase deficiency. An 18 month-old male with hepatosplenomegaly, anemia, thrombocytopenia, and growth retardation referred to our hospital. The patient showed neurological symptoms, such as supranuclear gaze palsy and developmental delay. Bone marrow biopsy performed to rule out malignancy and the results revealed no malignant cell; however, abnormal histiocytes suggesting storage disease was noted. Based on hepatosplenomegaly, bicytopenia and unexplained neurologic manifestations, enzyme activity and genetic analysis were conducted emergently with a strong suspicion of GD. Beta-glucosidase activity in leukocyte was decreased. GBA sequencing to confirm the diagnosis revealed compound heterozygous pathogenic variants (i.e., c.754T>A, c.887G>A), both previously reported as the cause of neuronopathic GD. Under the diagnosis of type 3 GD, the patient immediately received enzyme replacement therapy (ERT). After 17 months of ERT, the size of spleen decreased, and hemoglobin and platelet count returned to normal. In addition, the activity of chitotriosidase and angiotensin converting enzyme decreased. However, myoclonic movement and generalized seizure occurred at the age of 19 months and antiepileptic drug was started. Other neurological deterioration including supranuclear gaze palsy and developmental delay also persisted. A new therapy to overcome neurologic problems should be developed for patients with type 3 GD.
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문제 정의
In conclusion, this study describes the clinical course of type 3 GD patients who underwent prompt initiation of ERT and emphasizes awareness of GD for early diagnosis. Moreover, considering the high proportion of the neuronopathic GD in the Korean population, investigations into new therapeutic strategies targeting the nervous system are required.
환아에서 한국인 신경형 고셔병에서 흔하게 관찰되는 c.754T>A (F213I)와 c.887G>A (R257Q)가 이형 접합체 돌연변이로 확인되었고 17개월 간의 효소 대체 요법을 통해 성장, 혈액학적 지표, 간비장비대 및 골증상은 호전되었지만 신경학적 증상의 호전은 없었고, 샤프론 중 암브록솔에 유의한 반응이 있다고 알려져 있는 c.754T>A이 확인됨에 따라 환아에서 3개월간 암브록솔 치료를 시도하였지만 뚜렷한 임상적 치료 효과를 확인할 수 없었기에 본 증례를 보고하는 바이다.
가설 설정
In general, making a clear distinction between types 2 and 3 is difficult due to the genetic heterogeneity and overlap of the age at onset5). In this study, we classified our patient with type 3 GD rather than type 2, because the onset of neurological symptoms was the age of 1 and older (mean age at onset of the type 2 patient was 7 months10)). Moreover, when considering early manifestation of neurological symptoms including supranuclear gaze palsy and generalized seizure, the patient was finally diagnosed with type 3a GD.
제안 방법
As confirmed by GD, the patient immediately started ERT with imiglucerase, recombinant human GBA with the dose of 60 U/kg every 2 weeks.
The laboratory studies revealed hemoglobin level of 8.8 g/dL, leukocytes count of 11,880/µL with normal differential count, platelet count of 76,000/µL, Prothrombin time (PT) INR of 1.53 (reference range, 0.9-1.2), and ferritin of 2,360.6 ng/mL (reference range, 20-150 ng/mL).
고셔병은 리소좀축적병으로 lysosomal hydrolase glucocerebrosidase 결여로 간비장비대, 골격계 증상, 빈혈, 혈소판 감소증의 증상을 나타내는 드문 상염색체 유전 질환이다. 본 증례에서는 18개월 남아에서 간비 장비대, 성장 부진이 관찰되었으며 안구 운동 장애 및 발달 지연이 동반되어 제 3형 고셔병을 의심하였고 효소 분석 및 유전자 검사를 통해 확진하였다. 환아에서 한국인 신경형 고셔병에서 흔하게 관찰되는 c.
대상 데이터
Chest X-ray showed pneumonic infiltration on the both perihilar regions. As the patient continuously showed high fever and respiratory symptoms over 1 month despite antibiotic therapy for pneumonia, he was transferred to Samsung Medical Center. Based on hepatosplenomegaly, bicytopenia, persistent fever, and severe growth retardation, bone marrow biopsy was performed to rule out malignancy.
Tracheostomy was done because of severe oral secretion and respiratory difficulty at the age of 24 months. At the last follow-up, 39 month-old, the patient was slowly growing except for head circumference. Body measurements at the last follow-up were as follows: height 94 cm (-0.
He started taking antiepileptic drug (levetiracetam). The patient underwent gastrostomy and fundoplication because of frequent vomiting and swallowing difficulty at the age of 22 months. Tracheostomy was done because of severe oral secretion and respiratory difficulty at the age of 24 months.
The patient was the first boy of non-consanguineous Korean parents and was born by a Cesarean section at 39th week of gestation. His birth height was 49 cm (75th-90th percentile), birth weight was 3.
성능/효과
(B) Bone marrow abnormal histiocytes (arrow) with a very low N/C ratio abundant pale blue cytoplasm were observed, but subtle striations, characteristic of Gaucher cells, were not definite (hematoxylin-eosin, original magnification ×1,000).
After 17 months of ERT, chitotriosidase activity decreased from 9,810 nmol/h/mL to 3,813 nmol/h/mL (reference range, 55.21±27.81 nmol/hr/mL), and angiotensinconverting enzyme decreased from 150 U/L to 74 U/L (reference range, 12-78 U/L) (Table 1, Fig 4).
Our results revealed that ERT rapidly reverted the patient’s visceral symptoms and his quality of life improved, even though neurological outcomes had a limited effect.
후속연구
reported that PCT with high-dose oral ambroxol from 6 to 48 months was well tolerated and effective in the treatment of neurological manifestations, particularly in myoclonus and pupillary light reflex dysfunction13). However, in this study, there was no change in neurological symptoms after the treatment of ambroxol, and further analysis of the treatment effect is needed.
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