The Neonatal Presentation of BRAT1-Related Neonatal Rigidity and Multifocal Seizure Syndrome

Objectives: A growing variety of genes involved in pathologies causing severe encephalopathy with neonatal-onset epilepsy are being discovered. Recently, autosomal recessive mutations in the BRAT1 gene have been associated with clinical spectrum ranging from lethal neonatal rigidity and multifocal seizures to later onset and less-severe symptoms including developmental delay, dysautonomia, and epilepsy.

Content: We describe the clinical and neurophysiological features at presentation of a newborn for whom the whole exome sequencing revealed compound heterozygosity for two pathogenic variants (c.638dup p. (Val214Glyfs*189) and c.2005C > T p.(Arg669Trp) in the BRAT1 gene. The patient presented with diffuse hypertonia and erratic subcontinuous myoclonic jerks in the first days of life. Early EEG showed a normal pattern and no seizures. The myoclonus was increased by tactile and acoustic stimuli, leading to an initial diagnosis of hyperekplexia. Seizure onset was at 15 days of life. Seizures were initially sporadic and responded to levetiracetam. Seizures progressively increased in frequency, became multifocal, both clinical and subclinical, and refractory to multiple AEDs. Interestingly, the interictal EEG background remained fairly organized during the course of the disease. At 42 days of life, the infant developed central apnea and severe bradycardia leading to cardiac arrest and death at 2 months. By that time, he had developed acquired microcephaly.

Conclusion: Newborns with neonatal-onset BRAT1-related syndrome present with pathognomonic symptoms including diffuse hypertonia and multifocal nonepileptic myoclonic jerks. As the initial EEG may show a normal pattern and no seizure, they may be misdiagnosed with hyperekplexia as a first intention. However, neonates with BRAT1 mutations differ from hyperekplexia by several characteristics, including marked diffuse hypertonia, and rapid progression to encephalopathy, microcephaly, and multifocal epileptic seizures refractory to antiseizures treatments. Given the severe prognosis and the risk of recurrence, an accurate early diagnosis is essential.

Publication History

Article published online:
16 March 2022