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 Table of Contents  
Year : 2017  |  Volume : 6  |  Issue : 3  |  Page : 200-204

BRCA1-associated ataxia telangiectasia mutated activation-1 mutation: An addition to the early infantile epileptic encephalopathy panel

1 Department of Neurology, Jaslok Hospital and Research Centre, Mumbai, Maharashtra, India
2 Department of Neonatology, Prince Aly Khan Hospital, Prince Aly Khan Hospital, Mumbai, Maharashtra, India
3 Navi Mumbai Institute of Research in Mental and Neurological Handicap, Mumbai, Maharashtra, India

Date of Web Publication11-Jul-2017

Correspondence Address:
Anaita Udwadia Hegde
Department of Neurology, 9th Floor, Research Room, Jaslok Hospital and Research Centre, Dr. G. Deshmukh Marg, Mumbai - 400 026, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcn.JCN_32_17

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We describe a 3-month-old female child born to third degree consanguineous Indian parents with progressive epileptic encephalopathy (EE), microcephaly, and generalized hypertonia. Whole exome sequencing revealed homozygous variant in the BRCA1-associated ataxia telangiectasia mutated activation-1 (BRAT1) gene. Homozygous and compound heterozygous BRAT1 mutations have been described in patients with lethal neonatal rigidity and multifocal seizure syndrome (MIM# 614498). BRAT1 acts as a regulator of cellular proliferation and migration and is required for mitochondrial function. This case highlights the potential of next generation technologies for the diagnosis of rare genetic diseases, including EE of infancy. To our knowledge, this is the first case of BRAT1 mutation from Indian subcontinent.

Keywords: BRCA1-associated ataxia telangiectasia mutated activation-1, lethal neonatal rigidity, progressive epileptic encephalopathy of infancy, whole exome sequencing

How to cite this article:
Hegde AU, Sanghvi KP, Karnavat PK, Jalan AB. BRCA1-associated ataxia telangiectasia mutated activation-1 mutation: An addition to the early infantile epileptic encephalopathy panel. J Clin Neonatol 2017;6:200-4

How to cite this URL:
Hegde AU, Sanghvi KP, Karnavat PK, Jalan AB. BRCA1-associated ataxia telangiectasia mutated activation-1 mutation: An addition to the early infantile epileptic encephalopathy panel. J Clin Neonatol [serial online] 2017 [cited 2022 Aug 9];6:200-4. Available from: https://www.jcnonweb.com/text.asp?2017/6/3/200/210142

  Introduction Top

Lethal neonatal rigidity and multifocal seizure syndrome is severe autosomal recessive epileptic encephalopathy (EE) characterized by onset of rigidity and intractable seizures at or soon after birth. We describe infrequent case of EE caused by BRCA1-associated ataxia telangiectasia mutated activation-1 (BRAT1) mutation presenting as migrating partial epilepsy of infancy (MPEI).

  Case Report Top

We report a 3-month-old female infant, first child of third degree consanguineous parents of Indian-Muslim origin born through normal delivery to young primigravida mother with birth weight of 2420 g and head circumference of 35 cm. She had weak cry at birth; however, Apgar scores were 8/10 at 5 min.

The child showed generalized tightness/rigidity from day 1 of life with feeding difficulties and frequent choking episodes. Her baseline metabolic tests which included liver function test, renal function test, ammonia, lactate, random blood sugar, calcium, magnesium, and septic workup consisting C-reactive protein, complete blood count, erythrocyte sedimentation rate, and blood culture were found to be normal. Lumbar puncture was not successful. She was started on gavage feeds. On day 3 of life, she had two episodes of focal seizures within a period of 24 h. A loading dose of phenobarbitone (20 mg/kg/dose) was given and maintenance doses (4 mg/kg/day) were continued. Electroencephalogram (EEG) on day 7 [Figure 1]a showed occasional generalized bursts of epileptiform activity with relatively well-preserved background activity. Magnetic resonance imaging (MRI) brain [Figure 2]a and [Figure 2]b revealed mild ventriculomegaly with prominent subarachnoid spaces. She was eventually discharged on gavage feeds on day 10 being seizure free but continued to have persistent rigidity.
Figure 1: (a) Day 7 electroencephalogram showing generalized bursts of epileptiform activity with well-preserved background activity. (b) Day 46 electroencephalogram showing burst suppression pattern. (c-e) Day 56 electroencephalogram showing seizure activity from variable foci during the same recording. (f) Electroencephalogram at 3 months showing multifocal epileptiform activity with a very slow poorly organized background activity

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Figure 2: (a and b) Magnetic resonance imaging brain at day 7 - T2 fluid-attenuated inversion recovery axial and sagittal sequences showing mild ventriculomegaly with prominent subarachnoid spaces. (c and d) Magnetic resonance imaging brain at 2 months - T2 fluid-attenuated inversion recovery axial and inversion-recovery sagittal sequences showing cortical atrophy with increase in ventriculomegaly

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Postdischarge, seizures restarted with increasing frequency and she was readmitted at 1 month of life, transferred to a tertiary care setup for further management. Clinical examination showed persistent rigidity, continuous multifocal clonic seizures, eye blinks, and mouth movements. She had soft dysmorphic features - prominent forehead, bulbous nose, thin upper lip, retrognathia, and camptodactyly. Multiple antiepileptic drugs including midazolam, sodium valproate, carbamazepine, phenytoin sodium, and levetiracetam were tried to control convulsions. Repeat septic workup done again was negative. Other tests which included inborn errors of metabolism done by tandem mass spectrophotometry for amino acids, fatty acids, and organic acids along with biotinidase levels was normal. She was treated with high-dose pyridoxine (30 mg/kg/day), biotin (20 mg/day), and folinic acid (8 mg/kg/day) empirically with no benefit. Multiple attempts at cerebrospinal fluid analysis including ultrasound-guided lumbar tap met with failure and a dry tap. Blood was also sent for TORCH titers, glycine levels to rule out nonketotic hyperglycinemia, and serum glutamic acid decarboxylase levels which were all within normal limits. Repeat EEG on day 46 [Figure 1]b showed burst suppression pattern. Repeat MRI brain [Figure 2]c and [Figure 2]d showed cortical and cerebellar atrophy with increased ventriculomegaly. Genetic studies for EE were sent.

Her seizures continued to be refractory with innumerable events per day. EEG on day 56 [Figure 1]c,[Figure 1]d,[Figure 1]e showed clinical and subclinical seizures with migrating variable focus over both hemispheres. We suspected MPEI [1] on basis of this report. Parents were counseled and given guarded prognosis.

She eventually went back to her home at 2½ months of age on gavage feedings and multiple anticonvulsants. Seizures, tone, and feeding showed no improvement. EEG [Figure 1]f at 3 months showed no migrating focus, but multifocal epileptiform activity with very slow poorly organized background activity. There was no head growth since birth or any achievement of milestones.

Whole exome sequencing detected previously unreported homozygous variant in the BRAT1 gene, c.617T>A (p. Leu206*) associated with lethal neonatal rigidity and multifocal seizure syndrome. This was a nonsense substitution that interrupts the reading frame by a premature stop codon. This variant was also detected in both parents of the index patient in a heterozygous state. Therefore, it was confirmed as the homozygous state of the variant in index patient according to recommendations of American College of Medical Genetics.

Parents were counseled and palliative care was provided at home. The infant eventually succumbed at 4 months of age.

  Discussion Top

Lethal neonatal rigidity and multifocal seizure syndrome is a severe autosomal recessive EE characterized by onset of rigidity and intractable seizures at or soon after birth. Affected infants achieve no developmental milestones and die within 1st month or year of life (OMIM#614498). We describe rare case of EE caused by BRAT1 mutation presenting as MPEI. Previously reported patients suffered from severe intractable seizures, but none of them presented as MPEI [Table 1]. The first report described two unrelated Amish infants with lethal, multifocal seizures, hypertonia, microcephaly, apnea, and bradycardia.[2] After this report, few other cases [3],[4],[5] were described. A recently published case of Spanish descent also had microcephaly and hypertonia; however, he was still alive at the age of 4.5 years and no seizures were observed by parents, therapists, or clinicians.[6] van de Pol et al.[7] proposed to add BRAT1 to list of severe infantile epileptic encephalopathies in their case report which described three siblings, born to consanguineous parents, with early infantile onset lethal EE. Our case too presented with rigidity and hypertonia since birth with onset of severe progressive intractable epilepsy at 1 month of age. There were mild dysmorphic features with neither progression of head growth nor any milestones achievement. While the clinical presentation showed persistent intractable seizures, microcephaly, and marked rigidity, the EEG picture varied over months. Baby subsequently succumbed at 4 months of age.
Table 1: Summary of case reports till date

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BRAT1 gene encodes BRAT1 protein.[8] The protein encoded by this ubiquitously expressed gene interacts with the tumor suppressing BRCA1 (breast cancer 1) protein and ATM protein and is thought to play a role in DNA damage pathway regulated by BRCA1 and ATM.[9] It also plays a role in regulating mitochondrial function and cell proliferation [10] and is required for protein stability of mammalian target of rapamycin (mTOR) and mTOR-related proteins and cell cycle progress by growth factors.[11] Loss of BRAT1 expression due to homozygous or compound heterozygous BRAT1 mutations may decrease cell proliferation and migration, affect mitochondrial homeostasis, and cause neuronal atrophy causing lethal EE.

  Conclusion Top

BRAT1 mutation is another entity to be considered in the neonatal/early infantile EE panel. Although rare, it can be identified earlier in view of the marked and obvious generalized rigidity noted since birth. The seizures are progressive from neonatal or early infancy. They have mild dysmorphisms with variable EEG patterns as condition progresses. MRI brain is not characteristic but suggestive of significant brain insult from time of birth. Given that BRAT1 gene is required for mitochondrial function; interventional opportunities at an early stage may be considered in the future. Antenatal diagnosis and counseling can also be provided during pregnancy if there is a history of affected sibling.

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Conflicts of interest

There are no conflicts of interest.

  References Top

McTague A, Appleton R, Avula S, Cross JH, King MD, Jacques TS, et al. Migrating partial seizures of infancy: Expansion of the electroclinical, radiological and pathological disease spectrum. Brain 2013;136(Pt 5):1578-91.  Back to cited text no. 1
Puffenberger EG, Jinks RN, Sougnez C, Cibulskis K, Willert RA, Achilly NP, et al. Genetic mapping and exome sequencing identify variants associated with five novel diseases. PLoS One 2012;7:e28936.  Back to cited text no. 2
Saunders CJ, Miller NA, Soden SE, Dinwiddie DL, Noll A, Alnadi NA, et al. Rapid whole-genome sequencing for genetic disease diagnosis in neonatal Intensive Care Units. Sci Transl Med 2012;4:154ra135.  Back to cited text no. 3
Saitsu H, Yamashita S, Tanaka Y, Tsurusaki Y, Nakashima M, Miyake N, et al. Compound heterozygous BRAT1 mutations cause familial Ohtahara syndrome with hypertonia and microcephaly. J Hum Genet 2014;59:687-90.  Back to cited text no. 4
Straussberg R, Ganelin-Cohen E, Goldberg-Stern H, Tzur S, Behar DM, Smirin-Yosef P, et al. Lethal neonatal rigidity and multifocal seizure syndrome – report of another family with a BRAT1 mutation. Eur J Paediatr Neurol 2015;19:240-2.  Back to cited text no. 5
Fernández-Jaén A, Álvarez S, So EY, Ouchi T, Jiménez de la Peña M, Duat A, et al. Mutations in BRAT1 cause autosomal recessive progressive encephalopathy: Report of a Spanish patient. Eur J Paediatr Neurol 2016;20:421-5.  Back to cited text no. 6
van de Pol LA, Wolf NI, van Weissenbruch MM, Stam CJ, Weiss JM, Waisfisz Q, et al. Early-onset severe encephalopathy with epilepsy: The BRAT1 gene should be added to the list of causes. Neuropediatrics 2015;46:392-400.  Back to cited text no. 7
Aglipay JA, Martin SA, Tawara H, Lee SW, Ouchi T. ATM activation by ionizing radiation requires BRCA1-associated BAAT1. J Biol Chem 2006;281:9710-8.  Back to cited text no. 8
So EY, Ouchi T. Functional interaction of BRCA1/ATM-associated BAAT1 with the DNA-PK catalytic subunit. Exp Ther Med 2011;2:443-7.  Back to cited text no. 9
So EY, Ouchi T. BRAT1 deficiency causes increased glucose metabolism and mitochondrial malfunction. BMC Cancer 2014;14:548.  Back to cited text no. 10
So EY, Ouchi T. The potential role of BRCA1-associated ATM Activator-1 (BRAT1) in regulation of mTOR. J Cancer Biol Res 2013;1. pii: 1001.  Back to cited text no. 11


  [Figure 1], [Figure 2]

  [Table 1]

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