He Sijia, Chen Hongbo, Guo Xia, Gao Ju
Department of Peadiatrics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, 610041, China.
BMC Med Genomics. 2022 May 4;15(1):102. doi: 10.1186/s12920-022-01248-2.
Adenylate kinase (AK) is a monomolecular enzyme widely found in a variety of organisms. It mainly catalyses the reversible transfer of adenosine nucleotide phosphate groups and plays an important role in maintaining energy metabolism. AK deficiency is a rare genetic disorder that is related to haemolytic anaemia. Chronic haemolytic anaemia associated with AK deficiency is a rare condition, and only 14 unrelated families have been reported thus far. Moreover, only 11 mutations have been identified in the AK1 gene, with only 3 cases of psychomotor impairment.
The patient was a 3-year-old boy with severe haemolytic anaemia and psychomotor retardation. A molecular study of the patient's AK gene revealed 2 different mutations: a heterozygous missense mutation in exon 6 (c.413G > A) and a heterozygous frameshift mutation in exon 5 (c.223dupA). Molecular modelling analyses indicated that AK gene inactivation resulted in a lack of AK activity. The patient recovered after regular blood transfusion therapy.
AK1 deficiency was diagnosed on the basis of low enzymatic activity and the identification of a mutation in the AK1 gene located on chromosome 9q. Here, we report the first case of moderate red cell AK1 deficiency associated with chronic nonspherocytic haemolytic anaemia (CNSHA) in China. The genetic mutations were confirmed by Sanger sequencing. The variants were classified as pathogenic by bioinformatics tools, such as ACMG/AMP guidelines, Mutation Taster, SIFT, MACP, REVEL and PolyPhen2.2. Based on our evidence and previous literature reports, we speculate that the site of the AK1 gene c.413G > A (p.Arg138His) mutation may be a high-frequency mutation site and the other mutation (c.223dupA) might be related to the neuropathogenicity caused by AK1 deficiency. NGS should be a part of newborn to early childhood screening to diagnose rare and poorly diagnosed genetic diseases as early as possible.
腺苷酸激酶（AK）是一种广泛存在于多种生物体中的单分子酶。它主要催化腺苷酸磷酸基团的可逆转移，在维持能量代谢中起重要作用。AK缺乏是一种与溶血性贫血相关的罕见遗传疾病。与AK缺乏相关的慢性溶血性贫血是一种罕见病症，迄今为止仅报道了14个无关家族。此外，在AK1基因中仅鉴定出11种突变，仅有3例精神运动障碍。
该患者是一名3岁男孩，患有严重溶血性贫血和精神运动发育迟缓。对患者AK基因的分子研究发现了2种不同的突变：外显子6中的杂合错义突变（c.413G＞A）和外显子5中的杂合移码突变（c.223dupA）。分子建模分析表明，AK基因失活导致AK活性缺乏。患者经定期输血治疗后康复。
根据低酶活性以及位于9号染色体q上的AK1基因中的突变鉴定，诊断为AK1缺乏。在此，我们报告中国首例与慢性非球形细胞溶血性贫血（CNSHA）相关的中度红细胞AK1缺乏病例。通过Sanger测序确认了基因突变。根据ACMG/AMP指南、Mutation Taster、SIFT、MACP、REVEL和PolyPhen2.2等生物信息学工具，将这些变异分类为致病性变异。基于我们的证据和先前的文献报道，我们推测AK1基因c.413G＞A（p.Arg138His）突变位点可能是高频突变位点，另一个突变（c.223dupA）可能与AK1缺乏引起的神经致病性有关。下一代测序（NGS）应成为新生儿至幼儿筛查的一部分，以便尽早诊断罕见和诊断不佳的遗传疾病。
