Department of Pediatrics, Linyi People's Hospital, Postgrad Training Base Jinzhou Med University, Linyi, People's Republic of China.
Department of Pediatrics, Linyi People's Hospital, Linyi, Shandong, People's Republic of China.
Mol Genet Genomic Med. 2023 May;11(5):e2146. doi: 10.1002/mgg3.2146. Epub 2023 Feb 7.
Pathogenic variants of ATP1A2 (OMIM ID: 182340) are usually associated with familial hemiplegic migraine type 2 (FHM-2), alternating hemiplegia of childhood (AHC), early infantile epileptic encephalopathy (EIEE), transient cytotoxic edema, and so on. Here, we present a novel heterozygous ATP1A2 variant in a girl with alternating hemiplegia, febrile seizures, developmental delay (which subsequently subsided), and MELAS-like syndrome (as indicated by brain MRI). The patient did not experience migraine with aura.
The patient was an 8-year-old girl with normal growth and development. Beginning from the age of 3 years and 8 months, the patient experienced several episodes of alternating limb paralysis. The episodes were accompanied by the appearance of MELAS-like findings on brain MRI, which corresponded to the hemiplegia. There were abnormal linear signals in the cerebral cortex on the opposite side of the hemiplegic limb. Each time the patient recovered from hemiplegia, and each time MRI showed no lesions remained after recovery. No obvious abnormality was found in other examinations. Finally, the patient underwent whole-exome sequencing (WES).
WES revealed a novel and de novo heterozygous variant in the ATP1A2 (NM_000702.3) c.335C>A:p.Ala112Asp (not previously reported). We examined the variant position in the 3D protein structure and found that a missense mutation at this site is a nonconservative substitution. The variation is nonpolymorphic. It occurs at a very low frequency in the population, and its ACMG classification is likely pathogenic.
At present, there are limited reports of mutations in the ATP1A2 gene causing AHC. This is the first case of brain MRI showing MELAS-like imaging in an AHC patient, and more cases are needed for verification. Early genetic testing and family screening can aid in the diagnosis and treatment of genetic diseases. The relationship between ATP1A2 gene mutation genotype and clinical phenotype needs to be further studied.
ATP1A2（OMIM ID：182340）的致病性变异通常与家族性偏瘫性偏头痛 2 型（FHM-2）、儿童交替性偏瘫（AHC）、早发性婴儿癫痫性脑病（EIEE）、短暂性细胞毒性水肿等有关。在此，我们报告了一例新的杂合 ATP1A2 变异，该变异见于一名伴有交替性偏瘫、热性惊厥、发育迟缓（后缓解）和 MELAS 样综合征的女孩（由脑 MRI 提示）。该患者无先兆偏头痛。
患者为 8 岁女孩，生长发育正常。自 3 岁 8 个月起，患者出现数次交替性肢体瘫痪。发作时伴有脑 MRI 上出现 MELAS 样表现，与偏瘫相对应。偏瘫侧对侧大脑皮质出现异常线性信号。每次患者从偏瘫中恢复后，MRI 均显示无病灶残留。其他检查未见明显异常。最终患者行全外显子组测序（WES）。
WES 发现 ATP1A2（NM_000702.3）c.335C>A：p.Ala112Asp 存在一新的、新发的杂合变异（此前未见报道）。我们对该变异在 3D 蛋白质结构中的位置进行了分析，发现该位点的错义突变是一种非保守取代。该变异无多态性，在人群中发生频率极低，ACMG 分类为可能致病性。
目前，ATP1A2 基因突变引起 AHC 的报道有限。本例是 AHC 患者脑 MRI 首次显示出 MELAS 样影像学改变，需要更多病例加以证实。早期进行基因检测和家系筛查有助于遗传疾病的诊断和治疗。ATP1A2 基因突变基因型与临床表型的关系需要进一步研究。
