Abstracts

Rationale: Lethal neonatal rigidity and multifocal seizure syndrome is an autosomal recessive epileptic encephalopathy caused by mutations in the BRAT1 gene. Reported cases are limited; however, in all but 2 reported cases the infant died before age 2 years. Here we present a case of a neonate born with severe hypertonicity and respiratory compromise. Whole exome sequencing provided the diagnosis. Methods: Single case report Results: The female patient was born at 40 weeks gestational age by cesarean section due to fetal distress. The pregnancy was complicated by oligohydramnios. Following delivery the infant was noted to be severely hypertonic. Respiratory effort was poor and she required intubation. On examination, patient had minor dysmorphic features including low set and rotated ears. The head circumference at birth was 33.5 cm (20%), weight 3.228 kg (25%), and length 48cm (25%). Pupils were round and reactive and face was symmetric. She had minimal spontaneous movements and clonus was present throughout. She began having seizures on day of life 8 which included myoclonic and tonic clonic seizures. Seizures were intractable to multiple medications including pyridoxine and pentobarbital coma. Ketogenic diet was trialed without significant improvement. She was treated for possible autoimmune encephalitis with IVIg, which also did not alter seizure frequency. Throughout her hospitalization she had frequent episodes of apnea and continued to require positive pressure support. A full metabolic evaluation did not reveal a diagnosis. CSF evaluation included neurotransmitters, which were only significant for elevated neopterin level. Chromosomal microarray was abnormal for copy number gains in non-disease associated regions. Her initial brain MRI was normal; however repeat scan 2 months later showed significant volume loss. EEG showed multifocal epileptiform discharges. EMG/NCS was normal. Genetic etiology was highly suspected and whole exome sequencing revealed two heterozygous pathogenic variants in BRAT1 gene at c.1710delG (p.Q5771fs) and c.566dupG (p.D190fs). Her mother was also heterozygous for c.566dupG (p.D190fs), however no paternal sample was submitted. The patient did not attain any developmental milestones in the first few months of life, her head size did not increase and she subsequently died at 9 months of age. Conclusions: BRAT1 encodes BRCA1-associated ATM activator 1 and interacts with BRCA1 and ATM. It has an important function in DNA damage response by modulating the phosphorylation status of multiple kinases. It also regulates mitochondrial function and cell proliferation. Additional functions are still being elucidated. This case illustrates the utility of whole exome sequencing in the neonatal intensive care unit. Early identification of genetic diseases does provide clinicians with information for parental guidance and decision-making Funding: None