BRAT1 mutations

van de Pol LA, Wolf NI, van Weissenbruch MM, Stam CJ, Weiss JM, Waisfisz Q,
Kevelam SH, Bugiani M, van de Kamp JM, van der Knaap MS. Early-Onset Severe
Encephalopathy with Epilepsy: The BRAT1 Gene Should Be Added to the List of
Causes. Neuropediatrics. 2015 Dec;46(6):392-400.

Abstract
A variety of pathologies can underlie early-onset severe encephalopathy with epilepsy. To aid the diagnostic process in such patients we present an overview of causes, including the rapidly expanding list of genes involved. When no explanation is found, whole-exome sequencing (WES) can be used in an attempt to identify gene defects in patients suspected to suffer from a genetic form. We describe three siblings, born to consanguineous parents, with a lethal severe epileptic encephalopathy with early-infantile onset, including their magnetic resonance imaging, electroencephalography and, in one case, neuropathological findings. Using WES a homozygous frameshift mutation in the BRAT1 gene, c.638dup p.(Val214Glyfs*189), was identified. We present our cases in the context of all published cases with mutations in the BRAT1 gene and conclude that BRAT1 should be added to the growing list of genes related to early-onset severe encephalopathy with epilepsy.

Straussberg R, Ganelin-Cohen E, Goldberg-Stern H, Tzur S, Behar DM,
Smirin-Yosef P, Salmon-Divon M, Basel-Vanagaite L. Lethal neonatal rigidity and
multifocal seizure syndrome--report of another family with a BRAT1 mutation. Eur
J Paediatr Neurol. 2015 Mar;19(2):240-2.

Abstract
We describe two siblings born to consanguineous Arab-Muslim parents who presented in early infancy with myoclonic seizures, hypertonia and contractures, arrested head growth, inability to swallow, and bouts of apnea-bradycardia, culminating in cardiac arrest and death. Whole-genome sequencing yielded a c.1173delG mutation in the BRAT1 gene. Three recent reports identified mutations in the same gene in three infants from three Amish sibships, one Mexican neonate and two Japanese siblings with similar clinical manifestations. The authors speculated that the destabilization of the encoded protein may underlie the catastrophic epilepsy and corticobasal neuronal degeneration. We suggest that BRAT1 be added to the growing list of genes that are related to severe early infantile (neonatal) epileptic encephalopathy.

Mundy SA, Krock BL, Mao R, Shen JJ. BRAT1-related disease-identification of a
patient without early lethality. Am J Med Genet A. 2016 Mar;170(3):699-702.

Abstract
We present a patient with neonatal onset of hypertonia and seizures identified through whole exome sequencing to have compound heterozygous variants, c.294dupA (p.Leu99fs) and c.1925C>A (p.Ala642Glu), in the BRCA1-associated protein required for ATM activation-1 (BRAT1) gene. Variants in BRAT1 have been identified to cause lethal neonatal rigidity and multifocal seizure syndrome (OMIM# 614498), which consistently manifests a severe neurological phenotype that includes neonatal presentation of rigidity and hypertonia, microcephaly and arrested head growth, intractable seizures, absence of developmental progress, apneic episodes, and death usually by 6 months of age. Our patient initially had a similarly severe neurological picture but remains alive at 6 years of age, expanding the phenotype to include longer term survival and providing further insights into genotype-phenotype correlations and the natural history of this disease.

Hanes I, Kozenko M, Callen DJ. Lethal Neonatal Rigidity and Multifocal Seizure
Syndrome-A Misnamed Disorder? Pediatr Neurol. 2015 Dec;53(6):535-40.

Abstract
OBJECTIVE:
Lethal neonatal rigidity and multifocal seizure syndrome is a newly recognized genetic disorder associated with early onset of rigidity, multifocal epilepsy, developmental arrest, and early death. It is an autosomal recessive condition resulting from a mutation in the BRAT1 (BRCA1 [breast cancer-1]-associated ataxia telangiectasia mutated activator 1) gene. There are few cases in the literature, and all patients have died before age 2 years, most within the first 6 months of life. The objective of this report is to expand the phenotypic spectrum of BRAT1 disorders and propose new nomenclature for this condition.
RESULTS:
We describe a child with compound heterozygosity for mutations in BRAT1. Her neonatal course was unremarkable. Over the first year of life she was noted to have progressive global developmental delay, visual impairment, microcephaly, hypertonia, hyperreflexia, and seizures. No epileptiform discharges were seen on electroencephalogram. Serial magnetic resonance imaging of the brain showed progressive cerebellar and brainstem atrophy. Unlike previously described patients, our patient has gained a number of developmental skills and, at this time, is 3 years and 8 months old.
CONCLUSION:
Despite the name of this disorder, patients with lethal neonatal rigidity and multifocal seizure syndrome may not present until after the neonatal period and may have a much longer life span than previously reported. We suggest renaming the condition "BRAT1-associated neurodegenerative disorder" to avoid the assumptions associated with the original nomenclature and to encourage clinicians to consider this condition outside the neonatal period.