BRAT1 Mutation: the First Reported Case of Chinese Origin and Review of the Literature

J Neuropathol Exp Neurol Vol. 77, No. 12, December 2018, pp. 1071–1078 doi: 10.1093/jnen/nly093

BRIEF REPORT

BRAT1 Mutation: The First Reported Case of Chinese Origin and Review of the Literature

Randy H. Van Ommeren, MD, Andrew F. Gao, MD, Susan I. Blaser, MD, David A. Chitayat, MD, and Lili-Naz Hazrati, MD, PhD Downloaded from https://academic.oup.com/jnen/article/77/12/1071/5139763 by guest on 29 September 2021

been demonstrated to have profound impact on the affected Abstract with rigidity, seizures, and early demise. Postmortem exami- Lethal neonatal rigidity and multifocal seizure syndrome nation consistently demonstrates neuronal loss with back- (RMFSL) (OMIM#614498) is caused by homozygous or compound ground gliosis in various locations throughout the cerebrum heterozygous mutation in the BRAT1 gene (OMIM#614506) on and cerebellum. The pathophysiology of BRAT1 mutation is chromosome 7p22. We report a newborn female infant born to not well understood but is thought to be related to BRAT1 non-consanguineous Chinese parents who presented with hyperto- functions in mitochondrial homeostasis and DNA damage re- nia, dysmorphic features, progressive encephalopathy with sponse. Here, we report a case of Chinese origin with BRAT1 refractory seizures, and worsening episodic apnea, leading to intuba- homozygous mutation and severe phenotype. tion and eventually death at 10 weeks of age. Whole exome sequencing revealed homozygous BRAT1 mutation, c.1395G>C (p.Thr465Thr), predicted to cause splice site disruption. Neuropatho- logical assessment demonstrated microcephaly, severe neuronal Case Report loss, and background gliosis in the dorsal region of the putamen. An infant girl was born to non-consanguineous parents Disruption of BRAT1 function in RMFSL has been proposed to at 39 þ 3 weeks gestation via uncomplicated vaginal delivery cause dysfunction in the DNA damage response pathway and impair following an uncomplicated pregnancy. Parents were mitochondrial homeostasis. To our best knowledge this is the first Mandarin-speaking Chinese, though their ethnic background reported case of Chinese origin. We review all published cases with within the Chinese population is unknown. The infant’s AP- BRAT1 mutation reported in the English literature and known GAR scores were 3, 6, and 8, at 1, 5, and 10 minutes, respec- BRAT1 functions which provide insight into the pathophysiology of tively. The birth weight was 2826 g (15th percentile) and the disease. crown to heel length was 32 cm (3rd percentile). Shortly after birth she was noted to have hypertonia and frequent myoclonic Key Words: BRAT1, DNA damage, Epileptic encephalopathy, seizure activity with left sided twitching and eye rolling. She Hypertonia, Microcephaly, Mitochondrial homeostasis, Multifocal was admitted to the NICU and EEG evaluation demonstrated seizure. diffuse encephalopathy, with frequent ictal activity from mul- tiple cortical areas. TORCH and septic workup were negative and serum quantitative amino acids, urinary organic acids, acylcarnitines, total and free carnitine, lactate, and liver INTRODUCTION enzymes were normal. The patient was treated with phenobar- BRAT1 (BRCA1 [breast-cancer-1]-associated ataxia tel- bital and clonazepam with no effect. She continued to have in- angiectasia mutated activator 1) mutations have been reported tractable seizures with apneic episodes that eventually in 23 infants and children with homozygous or compound het- resulted in intubation and mechanical ventilation. Levetirace- erozygous mutations in 12 publications since 2012 and cause tam was added to the anti-epileptic regimen, with minimal re- lethal neonatal rigidity and multifocal seizure syndrome duction in seizure burden. Measurement of head (RMFSL) (OMIM#614498). Loss of BRAT1 function has circumference at 2 and 11 weeks showed that the OFC dropped to below the 3rd percentile, measuring 33 and 35 cm, respectively. From the Department of Pediatric Laboratory Medicine (RVO, AFG, Brain MR imaging at 3 days of age was unremarkable, L-NH); Division of Neuroimaging (SB); and Division of Clinical and Metabolic Genetics (DC), Hospital for Sick Children, University of To- with no abnormalities beyond small head, small brain, and ronto, Toronto, Ontario, Canada; and The Prenatal Diagnosis and Medi- mild prominence of the pericerebral extraaxial space. Repeat cal Genetics Program, Mount Sinai Hospital, University of Toronto, imaging at 15 days demonstrated small foci of hemorrhage in Toronto, Ontario, Canada (DC). the cerebellum and subdural spaces. A third MRI at 9 weeks Send correspondence to: Lili-Naz Hazrati, MD, PhD, Department of Pediatric Laboratory Medicine, Hospital for Sick Children, 555 University Ave., demonstrated interval increase in pericerebral CSF spaces Toronto, ON M5G 1X8, Canada; E-mail: [email protected] with frontoparietal predominance due to ongoing volume loss. The authors have no duality or conflicts of interest to declare. There was mild thinning of the corpus callous and delayed

VC 2018 American Association of Neuropathologists, Inc. All rights reserved. 1071 Van Ommeren et al J Neuropathol Exp Neurol • Volume 77, Number 12, December 2018 myelination (Fig. 1). Initial genetic investigations performed cerebellar atrophy. Whole exome-sequencing of affected chil- included a hyperekplexia panel, an epilepsy panel and dren demonstrates a wide range of mutations including dupli- SLC2A1 testing, all of which returned negative. Whole cations and insertions (1–3, 6, 7, 9, 12), missense mutations exome-sequencing was performed and demonstrated homozy- disrupting conserved amino acids or protein structure (3, 5, 7– gous c.1395G>C (p.Thr465Thr) mutation in the BRAT1 gene. 9, 11), deletions (4), and splice site disruptions (10). In gen- This mutation is predicted to cause splice-site disruption. eral, homozygous mutations were predictive of severe pheno- Given continued deterioration despite all efforts, a decision type, and compound heterozygosity of milder phenotype. In was made to palliate and the patient died at 10 weeks of age. two sets of siblings with compound heterozygous mutation, The parents consented for autopsy which showed dys- phenotypic divergence was observed, suggestive of variable morphic features including hypertelorism, microcephaly, penetrance between individuals (8, 11). ridges over the cranial sutures, and abnormal lung lobation. Neuropathological assessment has been reported in 4 The brain was small, weighing 349.8 g (normal 503 g 6 51.7 cases to date, all in patients with severe/lethal phenotype (1, 3, Downloaded from https://academic.oup.com/jnen/article/77/12/1071/5139763 by guest on 29 September 2021 g), with no evidence of bleeds, meningeal tears, gyral abnor- 6, 11). The first case, a 4-week-old infant from the original malities, or gross parenchymal or ventricular abnormalities. Amish cohort was described to have focal areas of neuronal Microscopic examination demonstrated delayed and patchy loss with associated gliosis and the presence of Alzheimer myelination throughout the white matter, with absent myelina- type 2 astrocytes throughout the corpus striatum, CA-1 region tion of corpus callosum. The dorso-medial aspect of the puta- of hippocampi, and the frontal, temporal, and occipital lobes men demonstrated marked gliosis, and near complete neuronal (1). The second case, a 3-month-old male infant, was found to loss, with some sparing of large neurons. Karyorrhectic cells have depletion of neurons throughout the cerebral cortex, with were identified in the pons and hippocampus. Immunostaining gliosis throughout the white matter, and absent myelination of for c-H2AX demonstrates DNA double strand breakage in the frontal lobe. Neuronal loss was also identified in the den- glial/astrocytic cells of the affected putaminal region (Fig. 2). tate nucleus, along with depletion of Purkinje cells and den- dritic expansion in the cerebellar cortex (3). The third case, a 3.5-month-old male infant had cortical neuronal loss with in- DISCUSSION tense background gliosis, most prominently in the frontal cor- In 2012, Puffenberger et al reported 3 Amish siblings tex. Neuronal loss and gliosis were also identified in CA1 homozygous for BRAT1 frameshift variant (c.638_639insA) subfield and subiculum, corpus striatum, and intrinsic nuclei (1). All 3 infants presented with episodic jerking beginning in of pons. Severe atrophy of the cerebellum was accompanied utero, microcephaly, overlapping cranial sutures, depressed by loss of granular neurons/Purkinje cells and presence of re- frontal bones, and severe axial and appendicular rigidity. Clin- active Bergmann glia. Cerebral and cerebellar white matter ical course was marked by multifocal seizures minimally re- was found to be gliotic, with numerous interspersed Alzheimer sponsive to therapy, poor head growth, severe developmental type 2 astrocytes, areas of microglial activation, and small cal- delay, and death in first year of life (1). Subsequently, a further cifications. (6). Finally, a 15-month-old male infant was found 20 cases have been published (total 23), and the condition was to have diffuse cerebral and cerebellar atrophy, also with named “Rigidity and multifocal seizure syndrome, Lethal neo- marked cortical neuronal loss and gliotic background (11). natal (RMFSL)” (OMIM#614498) (1–12)(Table). Clinical The homozygous missense mutation of BRAT1 in our features included progressive encephalopathy, hypertonia and patient, predicted to cause splice site disruption, has not been hyperreflexia (sometimes preceded by a period of hypotonia), previously reported in the literature. Of note, this is the first microcephaly, a range of dysmorphic features, and global in- reported Chinese case in homozygote state with non- tellectual disability/developmental delay. A significant subset consanguineous parents, raising the possibility that the fre- of patients had a severe phenotype characterized by prenatal/ quency of this gene in the Chinese population may be high. neonatal onset of refractory myoclonic seizures, episodes of Clinical presentation is similar to other severe phenotype apnea, absence of developmental progression, and demise cases, with findings of dysmorphic features, hypertonia, pro- within weeks to months of birth. However, individuals with gressive encephalopathy, seizures, respiratory failure, and milder phenotype have also been reported with less debilitat- death at 10 weeks. Like all other infants reported, metabolic ing seizures, some progression in developmental milestones and infectious work-up was unremarkable. EEG findings were and survival well into childhood. The oldest patient reported broadly similar to other infants, with multifocal seizure activ- survived to 10 years (10). ity identified on the background of diffuse encephalopathy. Infectious work-up, CSF analysis, and screening serum MRI findings of progressive volume loss, corpus callosum tests for inborn errors of metabolism are uniformly negative. thinning, and delayed myelination have also been noted to Electroencephalography typically shows diffuse slowing con- varying degrees previously (1, 3, 5–8, 10). Findings of micro- sistent with encephalopathy, and (multi)focal sharp wave ac- cephaly, diffuse neuronal loss, corpus callosum thinning, and tivity consistent with ictal activity. Magnetic resonance abnormal myelination in our case are frequent in most pub- imaging findings during neonatal period are variable, and can lished postmortem reports. The specific pattern of cortical, demonstrate focal cerebral and/or cerebellar atrophy/hypopla- hippocampal, and striatal neuronal loss found in our case has sia/encephalomalacia, impaired myelination, thinning of the been reported in 2 others, which also shared findings of Alz- corpus callosum, or no abnormal findings. Scans of patients heimer type II astrocytes (1, 6). The unique neuropathological with milder phenotype who have survived into childhood are feature of this case is that of focal, severe neuronal depletion similarly variable, but generally show some degree of in the dorso-medial aspect of bilateral putamina. The etiology 1072 J Neuropathol Exp Neurol • Volume 77, Number 12, December 2018 BRAT1 Mutation: Case Report and Literature Review Downloaded from https://academic.oup.com/jnen/article/77/12/1071/5139763 by guest on 29 September 2021

FIGURE 1. Brain MRI top row (A–E): GA 39 þ 3, now 3 days of age. Sagittal T1W view (A) at 3 days of age shows a sloping forehead in keeping with microcephaly. The corpus callous (arrow) is thin due to normal lack of myelin at this age. Axial T1W image (B) shows normal bright signal myelin (arrow) in the posterior limb of the internal capsule. Low signal stripe of myelin in the posterior limb of the internal capsule is present on T2W images (C). Normal putaminal (open arrow), caudate and thalamic signal is present. There is prominence of the peri cerebral fluid (white filled arrow). Cerebellar development is normal on T2W axial image (D), although prominent fluid is present in the middle cranial fosse. Intermediate echo single voxel MR spectroscopy (E) shows age appropriate spectra with minimal irregularity at 1.33 in the region of lactate. Middle row (F–J): 15 days old. Sagittal T1W image (F) at 15 days of age shows loss of volume in the corpus callous. The brainstem and cerebellum remain normal in size. There is no progression of PLIC myelin (G) on T1W (arrow) or T2W (H) images. There is very increased signal in the posterior putamen (open arrow). The peri cerebral spaces (filled arrow) are becoming more prominent. Axial MPGR (I) shows several punctate foci of hemosiderin in the interfoliate sulci (arrow). ADC map (J) shows very subtle T2 shine-through in the posterior putamina (open arrow). Bottom row (K–O): Sagittal T1W image (K) at 9 weeks of age shows further volume loss in the corpus callosum (arrow) and overlap of sutures. There has been only minimal myelination of the anterior limb of the internal capsule on T1W image (L), delayed for age. The posterior putamina (open arrow) on T2W image (M) has further increased in signal and lost volume. The caudate heads have also increased in signal. There has been continued increase in pericerebral fluid due to atrophy. The cerebellum remains normal in appearance on T2W axial (N). ADC map (O) shows further T2 shine-through in the posterior putamina (open arrow). of this pattern of neuronal loss is unclear, but we hypothesize phosphorylation site (Ser742) of Akt/cdk/MAPK kinases. Ini- that this may reflect an ischemic or metabolic insult sustained tially identified as a binding partner to the acidic BRCT do- at a neurodevelopmental stage critical for putaminal main of BRCA1, BRAT1 has since been found also to interact development. with ATM (ataxia-telangiectasia mutated), catalytic subunit of Investigation of BRAT1 protein structure, cellular local- DNA-dependent kinase (DNA-PKcs), structural maintenance ization, and binding partners have yielded some insights into of proteins 1 (SMC1), mechanistic target of rapamycin com- its functional roles within the cell. The BRAT1 gene, approxi- plex 1 (mTORC1), and regulatory-associated protein of mately 17 kb in length, is located on chromosome 7p22.3 and mTOR (RPTOR) (14). Interactions with these binding partners encodes an 821 amino acid peptide (13). The protein contains facilitates functions within the DNA damage response path- a CIDE-N (cell death-inducing DFF45-like effector) domain way, and more directly in maintenance of mitochondrial at its N-terminal, and two HEAT (huntingtin, elongation factor homeostasis. 3, a subunit of protein phosphatase 2A, and Tor1) repeat BRAT1 involvement in DNA damage response has domains at its C-terminal, in addition to a putative been proposed to be achieved through support of PI-3 kinase 1073 Van Ommeren et al J Neuropathol Exp Neurol • Volume 77, Number 12, December 2018 Downloaded from https://academic.oup.com/jnen/article/77/12/1071/5139763 by guest on 29 September 2021

FIGURE 2. Histologic features. Gross examination of the brain identifies microcephaly, with no evidence of hemorrhage, meningeal tears, gyral abnormalities, or other developmental anomalies (A). Examination of lentiform nuclei (B), demonstrates gliosis and massive neuronal loss in the dorso-medial aspect of the putamen, with sparing of some large neurons (C). Less severe neuronal loss, similarly associated with gliosis is identified in the CA1 (D), frontal (E), and parietal (F) regions. Alzheimer type II astrocytes are visualized in the parietal region (E). Immunohistochemical staining with antibody to c-H2AX, a biomarker of DNA double-stranded breakage, suggests evidence of DNA damage in glial/astrocytic cells of the putamen (G) and internal capsule (H). like protein kinases (PIKKs) including DNA-PKcs and ATM protein at sites of DSBs, felt to reflect active kinase ATM (3, 9). ATM exists in homodimeric form when inac- functions directly at site of DNA damage. Immunohisto- tive, but undergoes intermolecular autophosphorylation (at chemical analysis demonstrates co-localization of BRAT1 serine 1981), acetylation, and dissociation in response to with ATM and marker of double-stranded DNA breaks DNA damage. ATM, together with ATR and other DNA- (cH2AX), suggesting the possibility of ATM-BRAT1 com- PKcs function to phosphorylate numerous downstream plex formation in the context of DNA damage. Knockdown substrates to mount effective checkpoint responses, allow- of BRAT1 markedly reduces ATM phosphorylation, ing for repair of double-stranded DNA breaks (DSB). Ex- increases levels of p53, and results in higher rates of consti- posure of cells to ionizing radiation leads to enrichment of tutive apoptosis (1). 1074 TABLE. Summary of Cases Published to Date Author Puffenberger Saunders Saitsu et al, Hanes et al, Mundy et al, Straussberg et al, van de Pol et al, Horn et al, 2016 Fernandez- Srivastava Smith et al, Celik et al, et al, 2012 (1) et al, 2014 (3) 2015 (5) 2015 (7) 2015 (4) 2015 (6) (8) Jaen et al, et al, 2016 (10) 2016 (11) 2017 (12) 2012 (2) 2016 (9) n ¼ 3n¼ 1n¼ 2n¼ 1n¼ 1n¼ 2n¼ 3n¼ 2n¼ 1n¼ 4n¼ 2n¼ 1

Mutation described c.638_639insA c.453_454ins c.176T4C disrupts c.294dupA produc- c.294dupA pre- c.1173delG produc- c.638dup predicted c.638_639insA pre- c.1564G>A dis- Infants 1 and 2: c.1857G>A pro- c.2230_2237dup predicted to ATCTTCTC an evolutionarily ing premature dicted to produce ing premature to produce dicted to produce rupts highly con- (sisters): ducing premature AACACTGC pro- produce frame- predicted to pro- conserved amino stop codon frameshift stop codon frameshift frameshift served amino c.638dupA pre- stop codon ducing premature shift mutation duce frameshift acid c.1825C>T pre- mutation mutation mutation acid in HEAT dicted to produce c.2125_2128delTT- stop codon mutation c.962_963del dicted to affect c.1925C>A dis- c.1134 þ 1G>A domain frameshift TG producing (one sibling secondary struc- rupts an evolu- (exon 8) pre- c.638dupA pre- mutation premature stop confirmed) ture of protein tionarily con- dicted to alter dicted to produce c.803Þ1G>C splice codon served amino splice site frameshift site mutation acid Microdeletion (772 mutation Infant 3: c.638dup kb) of chromo- predicted to pro- some 2p13.3 duce frameshift mutation c.419T>C mis- sence variant Infant 4: c.171delG predicted to produce frameshift mutation c.419T>C mis- sence variant Phenotype/outcome Jerking in utero, Infant with Two female infants Female, progres- Microcephalic, Male and female Two males, one fe- Two males, dys- Male, with severe Infants 1/2: Two One male, one fe- Male infant with microcephaly, dysmorphic with dysmor- sive develop- mild dysmor- infant with male, dysmor- morphic facies, psychomotor females, both male, profound myoclonic jerks dysmorphic fea- facies, phic features, mental delay, phic features, marked apnea phic features, and microceph- delay during presenting at 1–2 developmental in utero, hyper- tures, axial, and hypertonia, hypertonia, visual impair- generalized ax- and desaturation early hypotonia aly. Infant 1 de- first years of years of age with delay in early tonia, hyperre- appendicular ri- hyperreflexia, hyperreflexia, ment, micro- ial and periph- at birth, hyper- followed by hy- veloped epi- life, progressive global develop- infancy with flexia, refrac- gidity. Refrac- persistence of and neonatal on- cephaly, hyper- eral hypertonia, tonia, upper pertonia/hyper- sodic jerking in encephalopathy, mental delay, progressive mi- tory seizures, tory seizures, cortical thumbs, set of refractory tonia, hyperre- hyperreflexia. limb contrac- reflexia, pro- utero, neonatal microcephaly, microcephaly, crocephaly and and death from poor head and neonatal myoclonic seiz- flexia, seizures. Development of tures, intractable gressive micro- hypertonia, re- hypertonia, dysmorphic fa- refractory multi- multi-organ fail- growth, severe seizure onset. ures. Both infant Alive at time of seizures at 3 myoclonic seiz- cephaly, refrac- fractory neona- hyperreflexia, cies, and ataxia. focal seizures ure at 10 developmental Succumbed at 1 and infant 2 publication (3 months of age. ures, and death tory seizures, tal seizures, no history of Both alive at onset in first months. delay, and death several weeks succumbed to years, 9 months) Apneic episodes from cardiac ar- and death at be- succumbing at 2 seizures. Alive time reported at year of life. One in first year of of age. pneumonia at 3 developing at rest at 5 and 6 tween 2 and 17 months. Infant 2 at time of publi- 10 and 6 years of child suc- life. months and 1 10 months. 6 months of age. months of age. developed myo- cation (4.5 age. cumbed at 15 year, 9 months years old at time clonic seizures years). Infant 3: Female, months due to of age, of publication. at 5 months, ax- with microceph- respiratory fail- respectively. ial hypotonia aly, dysmorphic ure, the second and appendicu- facies, right eso- alive at 4 years, lar, delayed de- tropica, optic 4 months at velopment and nerve hypopla- time reported. died at 5 years sia, developmen- and 9 months. tal delay, moderate appendicular rigidity and wide-based gait, onset of seizures at 3 years of age. Alive at 4 years 1075

(continued) Downloaded from https://academic.oup.com/jnen/article/77/12/1071/5139763 by guest on 29 September 2021 September 29 on guest by https://academic.oup.com/jnen/article/77/12/1071/5139763 from Downloaded 1076 TABLE. Continued Author Puffenberger Saunders Saitsu et al, Hanes et al, Mundy et al, Straussberg et al, van de Pol et al, Horn et al, 2016 Fernandez- Srivastava Smith et al, Celik et al, et al, 2012 (1) et al, 2014 (3) 2015 (5) 2015 (7) 2015 (4) 2015 (6) (8) Jaen et al, et al, 2016 (10) 2016 (11) 2017 (12) 2012 (2) 2016 (9) n ¼ 3n¼ 1n¼ 2n¼ 1n¼ 1n¼ 2n¼ 3n¼ 2n¼ 1n¼ 4n¼ 2n¼ 1

of age at time reported. Infant 4: Male, hypertonia and microcephaly at birth, dysmorphic facies, appendicular hypertonia and variable rigidity, hyperreflexia, and global developmental delay. Onset of refractory seizures at 4 months of age. Alive at 15 months at time reported. Pertinent neuro- Microcephaly, with n/a Microcephaly, de- n/a n/a n/a Microcephaly, thin- n/a n/a n/a Diffuse cerebral n/a pathological focal lesions of pletion of corti- ning of corpus and cerebellar findings neuronal loss, cal neurons, callosum, atro- atrophy with gliosis, and Purkinje cells, phy of frontal histological con- abundant Alz- and neurons of white matter firmation of heimer type 2 dentate nucleus. with volume widespread cor- astrocytes in the Moderate gliosis loss. Neuronal tical neuronal corpus striatum, throughout loss throughout loss, back- CA-1 region of white matter, frontal cortex, ground gliosis, hippocampi, absent myelina- hippocampi and focal men- and the frontal, tion in frontal (CA1 subfield ingeal calcifica- temporal, and lobe, and subiculum), tion. Also occipital lobes corpus striatum, observed wide- nuclei of pons, spread microve- and cerebellum sicular hepatic (granular, Pur- steatosis.

kinje cells). Downloaded from https://academic.oup.com/jnen/article/77/12/1071/5139763 by guest on 29 September 2021 September 29 on guest by https://academic.oup.com/jnen/article/77/12/1071/5139763 from Downloaded J Neuropathol Exp Neurol • Volume 77, Number 12, December 2018 BRAT1 Mutation: Case Report and Literature Review

In addition to involvement in the DNA damage re- heart, liver, lung, spleen) in young (6- to 7-week-old) mice sponse, BRAT1 has been implicated in maintenance of mito- suggest that BRAT1 is heavily expressed in cortex, lightly chondrial homeostasis. Knockdown of BRAT1 causes expressed in cerebellum, hippocampus, spinal cord, and lung, mitochondria to distribute abnormally in cytoplasm, disrupts and absent in abdominal organs. Interestingly, the pattern the inner transmembrane electrochemical potential gradient, of neuron loss in children with ataxia-telangiectasia (A-T) and drives increased production of mutagenic reactive oxygen diverges markedly from BRAT1 mutated patients despite species (ROS). Furthermore, BRAT1 depleted cells show re- similar functional roles of affected proteins (15). Neuro- duced production of ATP through mitochondrial oxidative pathological assessment in A-T patients demonstrates function, and rely heavily on glycolysis for ATP production. Purkinje, granular, and basket cell depletion, which has The mechanisms by which BRAT1 supports mitochondrial been proposed to result from increased concentrations of health have not been clearly established to date. One possibil- oxidized macromolecules and heme oxygenase in these ity is suggested by findings of BRAT1 interaction with cells (15). Downloaded from https://academic.oup.com/jnen/article/77/12/1071/5139763 by guest on 29 September 2021 mTORC1 (14). mTORC1, as part of the PI3K/Akt/mTOR sig- In conclusion, we present a case of novel homozygous naling cascade, exerts widespread influence over cell pro- BRAT1 mutation with severe clinical phenotype, consistent cesses involved in cellular growth, proliferation, and viability. with rigidity and multifocal seizure syndrome, lethal neonatal. This includes support of mitochondrial function through inter- The pathophysiology of neuronal loss in BRAT1 mutated actions with mitochondrial membrane proteins such as B-cell patients has not been fully resolved, but may be a function of lymphoma-extra-large (Bcl-xl) and by stimulating transcrip- mitochondrial dysfunction and impaired DNA damage re- tion of genes involved in mitochondrial oxidative function sponse. As whole exome sequencing becomes increasingly through interactions with YY1-PGC1a transcriptional com- utilized in cases of suspected genetic anomaly, diagnosis of plex (14). Inhibition of mTOR drives increased reliance on this condition will likely become more frequent (2). To date, glycolysis for energy production, resulting in increased pro- no therapeutic modalities beyond supportive care have been duction of the lactic acid by-product of anaerobic metabolism proposed. However, initiatives to identify therapeutics for (14). Together, these data suggest the possibility of a mecha- treatment of A-T (e.g. antioxidant therapy) may hold some rel- nistic connection between BRAT1, mTOR, and maintenance evance to patients with BRAT1 mutation. In the interim, con- of mitochondrial homeostasis. Interestingly, lymphoblastic tinued genotype-phenotype correlations of novel BRAT1 cells deficient in ATM demonstrate similarities with BRAT1 mutation variants may facilitate more accurate prognostica- knockdown cells including higher numbers of cells with de- tion, and allow for more informed decision-making by clini- creased inner mitochondrial membrane potential, up- cians and parents of affected children. regulation of ROS scavenging genes, and impaired oxidative function. However, specific mechanistic correlation between BRAT1 and ATM functions in mitochondrial support has not REFERENCES 1. Puffenberger EG, Jinks RN, Sougnez C, et al. 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