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.

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Glutamate, the major excitatory neurotransmitter, plays a ubiquitous role in most aspects of normal brain functioning. Its indispensable position is paradoxically doubled by a high excitotoxic potential following disruption of its dynamic equilibrium. Several lines of evidence have suggested the involvement of the glutamatergic N-methyl-D-aspartate receptor (NMDAR) in learning, memory formation, and human cognition. Furthermore, NMDARs play a pivotal role in various neuropsychiatric disorders, recently being identified as an important locus for disease-associated genomic variation. The GRIN2A gene encodes the NMDAR’s GluN2A subunit. Genetic alterations of GRIN2A result in phenotypic pleiotropy, predisposing to a broad range of epilepsy syndromes, with an elusive and unpredictable evolution and response to treatment. The archetypal GRIN2A-related phenotype comprises the idiopathic focal epilepsies (IFEs), with a higher incidence of GRIN2A mutants among entities at the more severe end of the spectrum. We report the case of a patient heterozygous for GRIN2A, c.1081C>T, presenting with febrile convulsions and later superimposed atonic seizures, expressive language delay, and macrocephaly. As the number of reported GRIN2A variants is continuously increasing, the phenotypic boundaries gradually grow faint. Therefore, it is fundamental to maintain an acute critical awareness of the possible genetic etiology of different epilepsy syndromes. So far, therapeutic strategies rely on empirical observations relating genotypes to specific drugs, but the overall success of treatment remains unpredictable. Deciphering the functional consequences of individual GRIN2A variants could lead to the development of precision therapeutic approaches for patients carrying NMDAR mutations.

Congenital cytomegalovirus (cCMV) infection resulting from non-primary maternal infection or reactivation during pregnancy can cause serious fetal-neonatal sequelae. We describe a male newborn born at term, with signs of perinatal asphyxia, and intractable acute provoked seizures, in the context of severe cCMV infection. The newborn was delivered in a referral hospital by emergency caesarean section due to fetal distress. Due to signs of asphyxia at birth and clinical moderate encephalopathy (Sarnat 2), he was transferred to our center for therapeutic hypothermia. Continuous full video-electroencephalography monitoring showed no seizures during the first 72 hours, however, soon after rewarming, he presented refractory status epilepticus. Cranial ultrasonography revealed bilateral ventricular and intraparenchymal hemorrhage. Routine infectious screen-ing on urine, blood, cerebrospinal fluid, and nasopharyngeal secretions revealed positive CMV DNA Polymer-ase Chain Reaction (PCR) on all samples. The CMV DNA performed on the bloodspot (Guthrie) card taken at birth yielded a positive result, confirming the intrauterine transmission and congenital origin of the infection. Maternal non-primary CMV infection in pregnancy is transmitted to the fetus in 0.5-2% of cases. When transmitted, it may cause serious fetal abnormalities, complications in the immediate neonatal period, and se-vere sequelae later in childhood. During pregnancy, it is useful to monitor maternal serology for CMV, even in previously immunized mothers, to identify signs of new infection or viral reactivation and implement measures to prevent neonatal sequelae. The possible advantages of standardized CMV screening of all newborns are a pertinent discussion point, as this may enable us to identify affected neonates timeously and prevent long term disabilities.