Thursday, February 25, 2016

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.

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.

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.

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.

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.
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.
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.


  1. My daughter passed away in June 2016. She was almost 6 months old. The Final diagnosis was BRAT1 deficienc. Which we received almost 4 months after her passing. Well that is what the geneticists at the children's hospital of st paul minnesota ultimately decided. I am still trying to learn and understand more. I think maybe if they would have been able to figure it out before she passed there could have been more to help save her.

  2. Hi, I just really want to reach out and firstly say that I'm so sorry for your loss. My daughter was diagnosed with BRAT-1 related genetic disorder last April (2017) after more than a year of genetic tests through children's National Hospital in DC and the genetics team at Walter Reed hospital. The genetics team at WR had no articles and no support groups for us once they discovered her diagnosis and you're the first "comment" from another parent that I've seen in all this time. I'm hoping with our daughter's diagnosis more people become aware of this rare genetic disorder. We were told statistically she's not 1 in a million or 1 in a thousand but that there are only ten's of children with her condition and majority of whom don't survive infancy. Thankfully she is mildly on the spectrum and her brain growth (her cerebellum is smaller than the rest of her brain) and muscle development seem to be most affected so she will be in therapy until her body stops growing and she wears AFO braces to assist with balance and walking. She just turned 4 in November and we have NEVER met or known anyone else with her condition. I've been searching for other families and possible support groups for others like ours. I just want you to know that your daughter is not alone in her diagnosis and I can't imagine the loss you feel. I'm hoping that as my daughter follows up with neurology every 6months and genetics each year that they can use her growth and development to learn more and more about BRAT-1 and that it will help diagnose more children sooner in the future.

    1. Wow I am currently overwhelmed. I just wanna say how happy I am to hear your daughter is well and thriving. I understand the trials you've been through and its not an easy journey but praise the lord you may still hold her in your arms. Please feel free to contact me. And we can share treatments and meds and Drs and try to spread awareness. And try to help each other with all the unanswered questions.

    2. Hi. I am come from Hong Kong.
      My baby girl (8months) had 1 hour seizures after birth 1 hour. The gene report that she had BRAT-1 gene compound heterozygous mutation when She 5months. at the same time, her's head size was stop to growing up. She taken 7 meds per day to control her seizures and still in Hospital now. She not able to cry,smile but will make sound like a normal baby talking when she feel better. Her seizures also is very hard to contorl, our doctor still finding the meds combination,dosage which is suitable for her.
      In Hong Kong, just my baby girl had this gene problem.
      I had find an other parent which her daughter had Brat1 and become 3 years old. I am so happy to find one more parent.
      it's a big encourage on our family. Can we contact in future for share the information? My email address,

    3. kdbug817: My daughter and son in law just found out today that our grand daughter who turned 3 in November has Brac 1. They started genetic testing back in October after she was finally "diagnosed" with Ataxia. She is walking with help of holding a someones hand most of the time. She is is not talking hardly at all. We were told she is one of only 5 kids that has this. I would love to talk to you more about your daughter and what has helped her to progress. My email is We were told that she is on her own path, but knowing what others have tried and what has worked and has not worked certainly would be helpful. Looking forward to hearing from you.

    4. Hi Running Mom and kdbug817,

      My daughter also had Bart1, did your daughter's seizures hard to control too? Any different between Brat1 and Brac1? My email address is Can we contact to get more information?

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