Novel mutations in SLC6A5 with benign course in hyperekplexia
Novel mutations in SLC6A5 with benign course in hyperekplexia
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DOI：
10.1101/mcs.a004465
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发表时间：
2019-12-01
影响因子：
1.8
通讯作者：
Cirak, Sebahattin
中科院分区：
文献类型：
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作者：
Dafsari, Hormos Salimi;Kawalia, Amit;Cirak, Sebahattin
患有危及生命的呼吸暂停、喘鸣、发绀和肌肉张力增加的婴儿经常可能被误诊为婴儿癫痫发作，并且由于缺乏和延迟基因诊断而得到不适当的治疗。在这里，我们报告一个病人出生后肌张力增加和高渗发作与危及生命的呼吸暂停，但没有癫痫样模式的脑电图记录。我们在SLC 6A 5中鉴定了新的复合杂合变体（NM_004211.4：c. [1429T> C];[1430 delC]），其包含由无症状母亲遗传的导致移码的碱基缺失（c.1430delC，p.Ser477PhefsTer9）和导致氨基酸改变的从头碱基交换（c.1429T > C，p.Ser477Pro）。迄今为止，有四个已知的原发性高丛性疾病相关基因，所有这些都参与甘氨酸能突触的功能。SLC 6A 5编码钠和氯依赖性甘氨酸转运蛋白2（GlyT 2），其重新捕获甘氨酸，这是脑干和脊髓中的主要抑制性递质。这一诊断改变了病人的医疗护理，使他受益，因为SLC 6A 5突变与相当良性的过度兴奋过程可能会避免不必要的药物治疗。症状的频率最终下降，直到2岁时约每2个月出现一次。我们提出了第一份报告，停止hyperekplexia发作的母亲安抚在多个实例。我们强调了通过快速下一代测序技术澄清这组婴儿呼吸暂停发作伴过度兴奋的基因诊断的重要性，因为这组婴儿呼吸暂停发作伴过度兴奋的基因诊断具有广泛的鉴别诊断。
Infants suffering from life-threatening apnea, stridor, cyanosis, and increased muscle tone may often be misdiagnosed with infantile seizures and inappropriately treated because of lack and delay in genetic diagnosis. Here, we report a patient with increased muscle tone after birth and hypertonic attacks with life-threatening apnea but no epileptiform patterns in EEG recordings. We identified novel compound heterozygous variants in SLC6A5 (NM_004211.4:c.[1429T> C];[1430delC]) by trio whole-exome sequencing, containing a base deletion inherited by the asymptomatic mother leading to a frameshift (c.1430delC, p.Ser477PhefsTer9) and a de novo base exchange leading to an amino acid change (c.1429T > C, p.Ser477Pro). To date, there are four known disease-associated genes for primary hyperekplexia, all of which are involved in the functioning of glycinergic synapses. SLC6A5 encodes the sodium- and chloride-dependent glycine transporter 2 (GlyT2), which recaptures glycine, a major inhibitory transmitter in the brainstem and spinal cord. The diagnosis altered the patient's medical care to his benefit because SLC6A5 mutations with rather benign courses of hyperekplexia may be spared of needless pharmacotherapy. Symptoms eventually decreased in frequency until about once in 2 mo at 2 yr age. We present the first report of halting hyperekplexia episodes by maternal soothing in multiple instances. We highlight the importance of clarifying the genetic diagnosis by rapid next-generation sequencing techniques in this group of infantile apneic attacks with hyperekplexia due to the broad differential diagnoses.