Phenotypic and genotypic characteristics of fever-induced paroxysmal weakness and encephalopathy caused by ATP1A3 pathogenic variants



Posted: 2019-07-04 19:00:00
Objective: To characterize fever-induced paroxysmal weakness and encephalopathy (FIPWE) caused by ATP1A3 gene pathogenic variant. Methods: Phenotypic and genotypic characteristics of 4 FIPWE patients (3 boys and 1 girl), who were ascertained from October 2016 to March 2018 in Beijing Children's Hospital due to ATP1A3 heterozygous variants, were retrospectively analyzed. The whole exsome sequencing was used for genetic testing. Results: The onset ages of 4 patients were 2 years and 9 months, 2 years and 4 months, 8 months, 2 years and 5 months respectively. The episode ranged from 1 to 3 times, and at 3 months to 2 years and 10 months intervals. All 4 patients had symptoms of limb weakness and encephalopathy, accompanied with mild to severe ataxia or athetosis. The tendon reflex was absent in all patients, and the Babinski's sign was positive. Three patients had dysphagia and 3 patients had slurred speech. Three patients had abnormal eye movements, including strabismus and opsoclonus. None of the 4 patients exhibited visual impairment, auditory impairment or talipes cavus. The duration of acute phase ranged from 1 week to 3 months. In 3 relapsing patients, symptoms became progressively worse, with relapses occurring frequently and recovery being more difficult, and various sequelae were found after the last relapse. All patients carried heterozygous variant in ATP1A3 gene. The missense variants result in the substitution of an arginine residue at position 756. Three variants were identified, including C. 2267G > T (p. R756L) (1 case), C. 2266C > T (p. R756C) (2 cases), and C. 2267G > A (p. R756H) (1 case). Three were de novo and one inherited from his father, but the grandparents did not carry the variant. All variants were reported as pathogenic. Conclusions: FIPWE is one of new clinical phenotypes of ATP1A3 spectrum disease and most cases are sporadic. The missense variants result in the substitution of an arginine residue at position 756. This report provided insights into the phenotype-genotype association in patients with FIPWE caused by pathogenic variants of ATP1A3. 目的: 总结ATP1A3基因变异相关发热诱导阵发性无力及脑病(FIPWE)临床表型和基因型特征。 方法: 对2016年10月至2018年3月,首都医科大学附属北京儿童医院诊治的4例ATP1A3基因变异相关FIPWE患儿(男3例、女1例)的临床表型和基因型进行回顾性分析,基因检测采用全外显子二代测序法。 结果: 4例患儿首发年龄分别为2岁9月龄,2岁4月龄,8月龄及2岁5月龄,发作次数为1至3次,间隔3个月至2年10个月。4例患儿均存在发热后出现肢体无力及脑病表现,并伴有程度不等的共济失调、手足徐动症状。所有患儿腱反射消失,巴氏征阳性。3例患儿吞咽困难。3例患儿口齿不清。3例患儿眼球异常运动,包括斜视及阵挛。4例患儿均无视力及听力损伤,无高弓足。急性期持续时间1周至3个月,3例复发患儿均随发作次数增多,症状严重程度有所加重,且末次发作后,症状恢复较为缓慢,存在程度不等的后遗表现。所有患儿均存在ATP1A3基因杂合变异,基因型为错义变异导致756位精氨酸发生变异。共发现3种变异类型,包括c.2267G>T(p.R756L)(1例),c.2266C>T(p.R756C)(2例),c.2267G>A(p.R756H)(1例)。4例患儿均进行家系验证,结果显示3例患儿为新发变异,1例来源于其父亲,其祖父母不携带此类型变异。3种变异类型均为已报道的致病性变异。 结论: FIPWE是ATP1A3基因变异的表型之一,散发为主,基因型为错义变异导致756位精氨酸发生变异,表型和基因型之间存在关联。. Keywords: Encephalopathy; Fever; Genes, ATP1A3; Sodium-Potassium-exchanging ATPase.

参考サイト PubMed: exsome



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