Vila-Pueyo Marta, Pons Roser, Raspall-Chaure Miquel, Marcé-Grau Anna, Carreño Oriel, Sintas Cèlia, Cormand Bru, Pineda-Marfà Mercè, Macaya Alfons
Grup de Recerca en Neurologia Pediàtrica, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
First Department of Pediatrics, Agia Sofia Hospital, University of Athens, Athens, Greece.
J Neurol Sci. 2014 Sep 15;344(1-2):37-42. doi: 10.1016/j.jns.2014.06.014. Epub 2014 Jun 17.
Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disorder featuring attacks of hemiplegia and other paroxysmal and non-paroxysmal manifestations leading to progressive neurological impairment. De novo mutations in ATP1A3 have been identified in up to 80% of patients. AHC is also associated with rare mutations in other genes involved in episodic neurological disorders. We sought to find mutations in ATP1A3, CACNA1A, ATP1A2, SCN1A and SLC2A1 in a cohort of ten unrelated patients from Spain and Greece. All patients fulfilled AHC diagnostic criteria. All five genes were amplified by PCR and Sanger sequenced. Copy number variation (CNV) analysis of SLC2A1 and CACNA1A was performed using two different approaches. We identified three previously described heterozygous missense ATP1A3 mutations (p.Asp801Asn, p.Glu815Lys and p.Gly947Arg) in five patients. No disease-causing mutations were found in the remaining genes. All mutations occurred de novo; carriers presented on average earlier than non-carriers. Intellectual disability was more severe with the p.Glu815Lys variant. A p.Gly947Arg carrier harbored a maternally-inherited CACNA1A p.Ala454Thr variant. Of note, three of our patients exhibited remarkable clinical responses to the ketogenic diet. We confirmed ATP1A3 mutations in half of our patients. Further AHC genetic studies will need to investigate large rearrangements in ATP1A3 or consider greater genetic heterogeneity than previously suspected.
儿童交替性偏瘫（AHC）是一种罕见的神经发育障碍，其特征为偏瘫发作以及其他阵发性和非阵发性表现，导致进行性神经功能损害。高达80%的患者已被鉴定出ATP1A3基因的新发突变。AHC还与其他参与发作性神经系统疾病的基因中的罕见突变有关。我们试图在一组来自西班牙和希腊的10名无亲缘关系的患者中寻找ATP1A3、CACNA1A、ATP1A2、SCN1A和SLC2A1基因的突变。所有患者均符合AHC诊断标准。通过聚合酶链反应（PCR）扩增所有五个基因并进行桑格测序。使用两种不同方法对SLC2A1和CACNA1A进行拷贝数变异（CNV）分析。我们在5名患者中鉴定出3种先前描述的杂合错义ATP1A3突变（p.Asp801Asn、p.Glu815Lys和p.Gly947Arg）。其余基因未发现致病突变。所有突变均为新发；携带者的发病平均早于非携带者。p.Glu815Lys变异导致的智力残疾更为严重。一名p.Gly947Arg携带者携带母系遗传的CACNA1A p.Ala454Thr变异。值得注意的是，我们的3名患者对生酮饮食表现出显著的临床反应。我们在一半的患者中证实了ATP1A3突变。进一步的AHC基因研究需要调查ATP1A3中的大片段重排，或者考虑比先前怀疑的更大的基因异质性。
