目的:BRAT1脑病是一种超罕见常染色体隐性遗传性新生儿脑病。我们描述了新生儿临床电表型,并为早期诊断提供见解。
方法:通过跨国合作,我们研究了一组与BRAT1中的双等位基因致病变异相关的脑病的新生儿,神经生理学,和神经影像学信息可从症状的发作。还分析了神经病理变化。
结果:我们纳入了19例新生儿。大多数新生儿在足月(16/19)出生时来自非近亲父母。15/19(79%)出生后不久被送往新生儿ICU,表现出多灶性肌阵鸣,既自发又因刺激而加剧。7/19(37%)出生时患有关节炎,除了一个人之外,所有的人都在生命的第一周逐渐发展为高张力症。多灶性肌阵鸣,除了一个婴儿,是最突出的表现,并且在16/19(84%)中未显示任何脑电图相关。发病时的vEEG在14/19(74%)婴儿中不显著,6例(33%)最初被误诊为中风过度。在14天的中位年龄观察到多灶性癫痫发作(范围:1-29)。在生命的最初几个月里,所有婴儿都出现了进行性脑病,获得性小头畸形,长时间的呼吸暂停,和心动过缓,导致心脏骤停和死亡,中位年龄为3.5个月(范围:20天至30个月)。只有7名婴儿(37%)在死亡前获得了明确的诊断,年龄中位数为34天(范围:25至126),近三分之二(12/19,63%)在死后8天至12年(中位数:6.5年)被诊断.神经病理学检查,在3名患者中进行,发现严重延迟髓鞘形成和弥漫性星形胶质增生,保留上部皮质层。
结论:BRAT1脑病是一种新生儿发病,迅速进展的神经紊乱.新生儿常被误诊为中风过度,许多人死于确诊。关键的表型特征是多灶性肌阵挛性,有组织的脑电图,进步,持久性,弥漫性高张力症,并演变为难治性多灶性癫痫发作,长时间的呼吸暂停,心动过缓,和早逝。BRAT1脑病的早期识别允许及时检查,适当的管理,和遗传咨询。
BRAT1 encephalopathy is an ultra-rare autosomal recessive neonatal encephalopathy. We delineate the neonatal electroclinical phenotype at presentation and provide insights for early diagnosis.
Through a multinational collaborative, we studied a cohort of neonates with encephalopathy associated with biallelic pathogenic variants in BRAT1 for whom detailed clinical, neurophysiologic, and neuroimaging information was available from the onset of symptoms. Neuropathologic changes were also analyzed.
We included 19 neonates. Most neonates were born at term (16/19) from nonconsanguineous parents. 15/19 (79%) were admitted soon after birth to a neonatal intensive care unit, exhibiting multifocal myoclonus, both spontaneous and exacerbated by stimulation. 7/19 (37%) had arthrogryposis at birth, and all except 1 progressively developed hypertonia in the first week of life. Multifocal myoclonus, which was present in all but 1 infant, was the most prominent manifestation and did not show any EEG correlate in 16/19 (84%). Video-EEG at onset was unremarkable in 14/19 (74%) infants, and 6 (33%) had initially been misdiagnosed with
hyperekplexia. Multifocal seizures were observed at a median age of 14 days (range: 1-29). During the first months of life, all infants developed progressive encephalopathy, acquired microcephaly, prolonged bouts of apnea, and bradycardia, leading to cardiac arrest and death at a median age of 3.5 months (range: 20 days to 30 months). Only 7 infants (37%) received a definite diagnosis before death, at a median age of 34 days (range: 25-126), and almost two-thirds (12/19, 63%) were diagnosed 8 days to 12 years postmortem (median: 6.5 years). Neuropathology examination, performed in 3 patients, revealed severely delayed myelination and diffuse astrogliosis, sparing the upper cortical layers.
BRAT1 encephalopathy is a neonatal-onset, rapidly progressive neurologic disorder. Neonates are often misdiagnosed as having
hyperekplexia, and many die undiagnosed. The key phenotypic features are multifocal myoclonus, an organized EEG, progressive, persistent, and diffuse hypertonia, and an evolution into refractory multifocal seizures, prolonged bouts of apnea, bradycardia, and early death. Early recognition of BRAT1 encephalopathy allows for prompt workup, appropriate management, and genetic counseling.