ADA Deficiency: Evaluation of the Clinical and Laboratory Features and the Outcome
ADA Deficiency: Evaluation of the Clinical and Laboratory Features and the Outcome
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DOI：
10.1007/s10875-018-0496-9
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发表时间：
2018-05-01
影响因子：
9.1
通讯作者：
Tezcan, Ilhan
中科院分区：
文献类型：
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作者：
Cagdas, Deniz;Cetinkaya, Pinar Gur;Tezcan, Ilhan
腺苷脱氨酶（ADA）缺乏症是一种常染色体隐性遗传的原发性免疫缺陷病。它导致有毒代谢物在细胞内积聚，尤其对淋巴细胞和大脑有影响。本研究的目的是评估 13 名 ADA 缺陷患者的结果。我们计划评估他们在酶替代疗法（ERT）、同种异体造血干细胞移植（aHSCT）和造血干细胞基因治疗（HSCGT）前后的临床和实验室检查结果。对大多数ADA缺陷患者进行了ADA酶活性和代谢物的测量以及ADA基因的测序。其中一名迟发性 ADA 缺乏症患者在初级免疫缺陷小组筛查的帮助下被诊断出来。13 名患者中有 10 名被诊断为 SCID，而 13 名患者中有 3 名被诊断为迟发性/迟发性 ADA 缺乏症。晚发 ADA 缺乏症患者有联合免疫缺陷 (CID) 的临床和实验室检查结果。 8 名 ADA-SCID 患者的 ADA 代谢物水平 (dAXP%) (62.1% (34.6-71.9)) 高于 3 名延迟/晚发 ADA 缺陷患者 (6.9% (2.1-8.9))。除一名 SCID 患者外，所有 SCID 患者均具有 T-B-NK- 表型，一名患者具有 T-B-NK+ 表型。11 名患者记录有遗传缺陷。4 11 名患者中有 3 名存在复合杂合缺陷，11 名 SCID 患者中有 7 名存在纯合缺陷。7 名患者中有 5 名具有相同的纯合 indel 移码突变 (c.955-959delGAAGA)，存在两种新的剪接位点缺陷：一种 (IVS10+2T > C)。 13 名患者中的 9 名患者进行了聚乙二醇化 ADA ERT 治疗，其中一名患者进行了 HSCGT 治疗。SCID 患者的基因诊断至关重要。 SCID/CID 存在 ADA 缺陷。尽管 ERT 不足以恢复 ADA-SCID 患者的正常免疫功能，但在治疗性治疗（aHSCT/HSCGT）之前，酶替代治疗对于具有联合免疫缺陷特征的晚发性/迟发性 ADA 缺陷患者来说是有用的，这可能是一种关联或巧合的发现。大多数 ADA 缺陷患者应进行间歇性神经发育评估，特别是针对听力障碍，这可能会减轻随访中可能观察到的言语延迟和认知异常。
Adenosine deaminase (ADA) deficiency is an autosomal recessive primary immunodeficiency. It results in the intracellular accumulation of toxic metabolites which have effects particularly on lymphocytes and the brain. The aim of this study was to evaluate the outcome of 13 ADA-deficient patients. We planned to evaluate their clinical and laboratory findings before and after enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplantation (aHSCT), and hematopoietic stem cell gene therapy (HSCGT).Measurement of ADA enzyme activity and metabolites and sequencing of the ADA gene were performed in most of the patients with ADA deficiency. One of the patients with late-onset ADA deficiency was diagnosed by the help of primary immunodeficiency panel screening.Ten out of 13 patients were diagnosed as SCID, while 3 out of 13 were diagnosed as delayed-/late-onset ADA deficiency. Late-onset ADA deficiency patients had clinical and laboratory findings of combined immunodeficiency (CID). Eight patients with ADA-SCID were found to have higher levels of ADA metabolite (dAXP%) (62.1% (34.6-71.9)) than 3 patients with delayed-/late-onset ADA deficiency (6.9% (2.1-8.9). All but one patient with SCID had T-B-NK- phenotype, one had T-B-NK+ phenotype. Genetic defect was documented in 11 patients. Four out of 11 patients had compound heterozygous defects. Three out of 4 patients with compound heterozygous defects had delayed-onset/late-onset ADA deficiency. Seven out of 11 patients with SCID had homozygous defects. Five out of 7 had the same homozygous indel frameshift mutation (c.955-959delGAAGA) showing a founder effect. There were two novel splice site defects: one (IVS10+2T > C) was heterozygous in a patient with late-onset ADA deficiency, and the other was homozygous (IVS2delT+2) in a SCID patient. Other defects were missense defects. Nine out of 13 patients were put on pegylated ADA ERT. Four out of six patients were transplanted without using a conditioning regimen. HSCGT was performed to one of the patients.The genetic diagnosis of SCID is utmost important. There is a chance to give ERT before the definitive therapy if the patient with SCID/CID has ADA deficiency. Although ERT was insufficient to restore a normal immune function in ADA-SCID patients, it was useful to improve and stabilize the clinical status before curative therapy (aHSCT/HSCGT). Enzyme replacement therapy was successful in patients with late-/delayed-onset ADA deficiency who presented with the features of combined immunodeficiency. Gastrointestinal polyposis in a patient with late-onset ADA deficiency may be an association or a coincidental finding. Intermittent neurodevelopmental evaluation especially for hearing impairment should be performed in most of the ADA-deficient patients. This may alleviate the speech delay and cognitive abnormalities which may be observed in the follow-up.