Clinical and Neurophysiologic Phenotypes in Neonates With BRAT1 Encephalopathy

Abstract

Background and Objective:BRAT1 encephalopathy is an ultra-rare autosomal recessive neonatal encephalopathy. We delineate the neonatal electroclinical phenotype at presentation and provide insights for early diagnosis.Methods:Through a multinational collaborative, we studied a cohort of neonates with encephalopathy associated with bi-allelic pathogenic variants inBRAT1for whom detailed clinical, neurophysiological, and neuroimaging information was available from the onset of symptoms. Neuropathological changes were also analyzed.Results:We included nineteen neonates. Most neonates were born at term (16/19) from non-consanguineous parents. 15/19 (79%) were admitted soon after birth to a neonatal ICU, exhibiting multifocal myoclonus, both spontaneous and exacerbated by stimulation. 7/19 (37%) had arthrogryposis at birth, and all except one progressively developed hypertonia in the first week of life. Multifocal myoclonus, which was present in all but one infant, was the most prominent manifestation, and did not show any EEG correlate in 16/19 (84%). vEEG 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 seven infants (37%) received a definite diagnosis before death, at a median age of 34 days (range: 25 to 126), and almost two-thirds (12/19, 63%) were diagnosed 8 days to 12 years post mortem (median: 6.5 years). Neuropathology examination, performed in 3 patients, revealed severely delayed myelination and diffuse astrogliosis, sparing the upper cortical layers.Discussion:BRAT1 encephalopathy is a neonatal-onset, rapidly progressive neurological 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 counselling.

Genetic counselling considerations with genetic/genomic testing in Neonatal and Pediatric Intensive Care Units: A scoping review

“…A total of 170 articles were included in the final review (alphabetically ordered based on author in Supplementary Table 2). 1,2,7–50,55,56,68–189 A PRISMA flow diagram is presented to track the process and number of studies included and excluded (Figure 1).…”

“…Studies focusing on rare disorders had specific post‐test genetic counselling considerations. When providing genetic consultation to families with infants or pediatric patients with rare disorders, genetic counselling is recommended to accompany early diagnosis 94 . Different studies emphasized the importance of a rapid diagnosis and timely genetic counselling of families 92,118,128,163 .…”

“…When providing genetic consultation to families with infants or pediatric patients with rare disorders, genetic counselling is recommended to accompany early diagnosis. 94 Different studies emphasized the importance of a rapid diagnosis and timely genetic counselling of families. 92,118,128,163 When a rare disorder has been identified in an ICU setting, it is important to involve highly trained genetic counsellors to provide clinical genomic interpretation 84 and explain potential customized timely treatments.…”

BRAT1-Associated Leukodystrophy Exacerbated by Classic Hodgkin Lymphoma–Directed Therapy

“…There is limited data from previous neonatal and pediatric cases of this mutation, not applicable in our case, given the adult-onset and phenotypic variation. 8 Although it is not possible to completely elucidate, our impression is that the patient's preciptious neurological decline was likely due to BRAT1 leukodystrophy exacerbated by chemotherapy, and his ultimate demise was exacerbated in the setting of sepsis and impaired oxidative function and anaerobic metabolism due to BRAT1 variant.…”

Could Neonatal Electroclinical Syndromes Orchestrate Diagnosis and Treatment?

“…Neonates with BRAT1 encephalopathy develop intractable multifocal tonic seizures, followed by apneas and bradycardia, leading to early death. The accompanying symptoms are pivotal in suspecting a diagnosis (microcephaly and arthrogryposis) [18,47].…”