15q11.2 microdeletions

Inspired by a patient

Basarir G, Erdogan I, Ozyilmaz B, Gencpinar P, Dundar NO. Beyond the Copy Number Differences: The Phenotypic Diversity of Children With 15q11.2 Microdeletions and Microduplications. J Child Neurol. 2025 Oct;40(9):784-793. doi: 10.1177/08830738251366862. Epub 2025 Aug 26. PMID: 40856583.

Abstract

15q11.2 BP1-BP2 copy number variants involving NIPA1, NIPA2, CYFIP1, and TUBGCP5 genes may not warrant a clinical outcome because of the phenotypic variability and low penetrance. The study aims to provide a greater understanding of the phenotypic diversity associated with these copy number variants. We conducted a retrospective analysis of 37 pediatric patients with deletions or duplications in 15q11.2 BP1-BP2 region, and compared the results systemically with the previous literature. Of the 37 patients, 67.6% had microduplications and 32.4% had microdeletions. The mean copy number variant size was 482 ± 157 kb. Patients had a variety of phenotypes including neurodevelopmental delay, hypotonia, speech impairment, intellectual and learning disability, behavioral and psychiatric symptoms, epilepsy and seizures, neuroimaging abnormalities, and dysmorphism. These findings, in combination with previous reports, confirm that copy number variants in this region are linked to phenotypes ranging from normal to severe neurodevelopmental and neuropsychiatric features. Our data also confirm that microcephaly is a particularly prevalent phenotype in patients with microdeletions, rather than in those with microduplications.

Vanlerberghe C, Petit F, Malan V, Vincent-Delorme C, Bouquillon S, Boute O, Holder-Espinasse M, Delobel B, Duban B, Vallee L, Cuisset JM, Lemaitre MP, Vantyghem MC, Pigeyre M, Lanco-Dosen S, Plessis G, Gerard M, Decamp M, Mathieu M, Morin G, Jedraszak G, Bilan F, Gilbert-Dussardier B, Fauvert D, Roume J, Cormier-Daire V, Caumes R, Puechberty J, Genevieve D, Sarda P, Pinson L, Blanchet P, Lemeur N, Sheth F, Manouvrier-Hanu S, Andrieux J. 15q11.2 microdeletion (BP1-BP2) and developmental delay, behaviour issues, epilepsy and congenital heart disease: a series of 52 patients. Eur J Med Genet. 2015 Mar;58(3):140-7. doi: 10.1016/j.ejmg.2015.01.002. Epub 2015 Jan 14. PMID: 25596525.

Abstract

Proximal region of chromosome 15 long arm is rich in duplicons that, define five breakpoints (BP) for 15q rearrangements. 15q11.2 microdeletion between BP1 and BP2 has been previously associated with developmental delay and atypical psychological patterns. This region contains four highly-conserved and non-imprinted genes: NIPA1, NIPA2, CYFIP1, TUBGCP5. Our goal was to investigate the phenotypes associated with this microdeletion in a cohort of 52 patients. This copy number variation (CNV) was prevalent in 0.8% patients presenting with developmental delay, psychological pattern issues and/or multiple congenital malformations. This was studied by array-CGH at six different French Genetic laboratories. We collected data from 52 unrelated patients (including 3 foetuses) after excluding patients with an associated genetic alteration (known CNV, aneuploidy or known monogenic disease). Out of 52 patients, mild or moderate developmental delay was observed in 68.3%, 85.4% had speech impairment and 63.4% had psychological issues such as Attention Deficit and Hyperactivity Disorder, Autistic Spectrum Disorder or Obsessive-Compulsive Disorder. Seizures were noted in 18.7% patients and associated congenital heart disease in 17.3%. Parents were analysed for abnormalities in the region in 65.4% families. Amongst these families, 'de novo' microdeletions were observed in 18.8% and 81.2% were inherited from one of the parents. Incomplete penetrance and variable expressivity were observed amongst the patients. Our results support the hypothesis that 15q11.2 (BP1-BP2) microdeletion is associated with developmental delay, abnormal behaviour, generalized epilepsy and congenital heart disease. The later feature has been rarely described. Incomplete penetrance and variability of expression demands further assessment and studies.

Picinelli C, Lintas C, Piras IS, Gabriele S, Sacco R, Brogna C, Persico AM. Recurrent 15q11.2 BP1-BP2 microdeletions and microduplications in the etiology of neurodevelopmental disorders. Am J Med Genet B Neuropsychiatr Genet. 2016 Dec;171(8):1088-1098. doi: 10.1002/ajmg.b.32480. Epub 2016 Aug 26. PMID: 27566550.

Abstract

Rare and common CNVs can contribute to the etiology of neurodevelopmental disorders. One of the recurrent genomic aberrations associated with these phenotypes and proposed as a susceptibility locus is the 15q11.2 BP1-BP2 CNV encompassing TUBGCP5, CYFIP1, NIPA2, and NIPA1. Characterizing by array-CGH a cohort of 243 families with various neurodevelopmental disorders, we identified five patients carrying the 15q11.2 duplication and one carrying the deletion. All CNVs were confirmed by qPCR and were inherited, except for one duplication where parents were not available. The phenotypic spectrum of CNV carriers was broad but mainly neurodevelopmental, in line with all four genes being implicated in axonal growth and neural connectivity. Phenotypically normal and mildly affected carriers complicate the interpretation of this aberration. This variability may be due to reduced penetrance or altered gene dosage on a particular genetic background. We evaluated the expression levels of the four genes in peripheral blood RNA and found the expected reduction in the deleted case, while duplicated carriers displayed high interindividual variability. These data suggest that differential expression of these genes could partially account for differences in clinical phenotypes, especially among duplication carriers. Furthermore, urinary Mg2+ levels appear negatively correlated with NIPA2 gene copy number, suggesting they could potentially represent a useful biomarker, whose reliability will need replication in larger samples.

Baldwin I, Shafer RL, Hossain WA, Gunewardena S, Veatch OJ, Mosconi MW, Butler MG. Genomic, Clinical, and Behavioral Characterization of 15q11.2 BP1-BP2 Deletion (Burnside-Butler) Syndrome in Five Families. Int J Mol Sci. 2021 Feb 7;22(4):1660. doi: 10.3390/ijms22041660. PMID: 33562221; PMCID: PMC7914695.

Abstract

The 15q11.2 BP1-BP2 deletion (Burnside-Butler) syndrome is emerging as the most common cytogenetic finding in patients with neurodevelopmental or autism spectrum disorders (ASD) presenting for microarray genetic testing. Clinical findings in Burnside-Butler syndrome include developmental and motor delays, congenital abnormalities, learning and behavioral problems, and abnormal brain findings. To better define symptom presentation, we performed comprehensive cognitive and behavioral testing, collected medical and family histories, and conducted clinical genetic evaluations. The 15q11.2 BP1-BP2 region includes the TUBGCP5, CYFIP1, NIPA1, and NIPA2 genes. To determine if additional genomic variation outside of the 15q11.2 region influences expression of symptoms in Burnside-Butler syndrome, whole-exome sequencing was performed on the parents and affected children for the first time in five families with at least one parent and child with the 15q1l.2 BP1-BP2 deletion. In total, there were 453 genes with possibly damaging variants identified across all of the affected children. Of these, 99 genes had exclusively de novo variants and 107 had variants inherited exclusively from the parent without the deletion. There were three genes (APBB1, GOLGA2, and MEOX1) with de novo variants that encode proteins evidenced to interact with CYFIP1. In addition, one other gene of interest (FAT3) had variants inherited from the parent without the deletion and encoded a protein interacting with CYFIP1. The affected individuals commonly displayed a neurodevelopmental phenotype including ASD, speech delay, abnormal reflexes, and coordination issues along with craniofacial findings and orthopedic-related connective tissue problems. Of the 453 genes with variants, 35 were associated with ASD. On average, each affected child had variants in 6 distinct ASD-associated genes (x¯ = 6.33, sd = 3.01). In addition, 32 genes with variants were included on clinical testing panels from Clinical Laboratory Improvement Amendments (CLIA) approved and accredited commercial laboratories reflecting other observed phenotypes. Notably, the dataset analyzed in this study was small and reported results will require validation in larger samples as well as functional follow-up. Regardless, we anticipate that results from our study will inform future research into the genetic factors influencing diverse symptoms in patients with Burnside-Butler syndrome, an emerging disorder with a neurodevelopmental behavioral phenotype.

Intellectual function and psychiatric comorbidities in patients with epilepsy with eyelid myoclonia

Padilla, Hannah, Eva C. Alden , Isha Snehal∙ Jeffrey W. Britton ,Lily C. Wong-Kisiel, Elaine C. Wirrell, Kelsey M. Smith. Intellectual function and psychiatric comorbidities in patients with epilepsy with eyelid myoclonia Epilepsy & Behavior, Volume 176, 110918

Abstract

Background
Epilepsy with Eyelid Myoclonia (EEM) is a rare childhood-onset epilepsy syndrome. There is limited data about cognitive function and psychiatric comorbidities in patients with EEM.

Design/Methods
A database of 134 patients with EEM was reviewed for patients who underwent neuropsychological testing. Psychiatric comorbidities and psychometric test scores were identified. Group comparison was performed between those who underwent neuropsychological testing and those who did not. In addition, we evaluated whether clinical factors were associated with IQ score.

Results
Fourteen patients underwent neuropsychological testing (12 females, 85.7%), with a median age at testing of 17 (range 7–22). Median IQ was 79 (range 56–110); 7 patients had below average IQ. Other median results of neuropsychometric measures were: Verbal Comprehension Index 85.5 (range 66–116), Perceptual Reasoning Index or Visual Spatial Index 81.5 (range 67–100), Working Memory Index 77 (range 54–100), Processing Speed Index 84 (range 53–94), and Reading Standardized Scores 84 (range 64–126). Common psychiatric comorbidities were anxiety (n = 10), depression (n = 7), ADHD (n = 6), and autism (n = 2). Those who underwent neuropsychological testing had a younger age of epilepsy onset, longer follow-up at our institution, and were more likely to have myoclonic seizures or psychosis than those who did not undergo neuropsychological testing. No clinical factors were statistically associated with IQ score.

Conclusions
EEM is associated with a wide range of cognitive abilities, with half of our patients having a below average IQ. Psychiatric comorbidities were common. Identifying cognitive impairment and psychiatric comorbidities is crucial to implement appropriate management strategies.

Superior semicircular canal dehiscence syndrome

Courtesy of a colleague, who wrote: "OK, maybe you all have seen this often, but I haven’t seen this knowingly until the last year and 2 kids with intractable 'dizziness' and headaches were fixed with surgical repair by ENT."

Lazarou I, Sideris G, Papadimitriou N, Delides A, Korres G. Third Window Syndrome: An Up-to-Date Systematic Review of Causes, Diagnosis, and Treatment. J Audiol Otol. 2025 Apr;29(2):86-94. doi: 10.7874/jao.2024.00696. Epub 2025 Apr 18. PMID: 40296471; PMCID: PMC12046203.

Abstract

Third window syndrome (TWS) is an inner ear condition caused by an additional compliant point in the otic capsule that disrupts auditory and vestibular functions. Superior semicircular canal dehiscence is the most common cause, presenting with hearing loss, vertigo, and autophony, significantly impairing quality of life. This study evaluated the pathophysiology, diagnostics, treatments, and recent advancements in TWS while identifying research gaps. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, 70 studies from Embase, MEDLINE, Cochrane, and UpToDate databases were analyzed. TWS affects inner ear mechanics, enhancing bone conduction and reducing air conduction. Diagnosis involves clinical evaluations, high-resolution imaging, and functional tests such as vestibular evoked myogenic potentials, which are known for their high sensitivity and specificity. Management strategies range from vestibular rehabilitation and pharmacotherapy to surgical interventions, including transmastoid and middle cranial fossa approaches, which achieve over 75% success. Emerging minimally invasive techniques, such as underwater endoscopic ear surgery and round window reinforcement, show promise but carry risks like cerebrospinal fluid leakage and inconsistent symptom relief. Advancements in TWS management have improved outcomes, yet gaps remain, particularly in terms of false-positive imaging and long-term efficacy. Future studies should prioritize predictive models and minimally invasive techniques. A multidisciplinary approach is essential to improve patient care.

Suzuki M, Ota Y, Takanami T, Yoshino R, Masuda H. Superior canal dehiscence syndrome: A review. Auris Nasus Larynx. 2024 Feb;51(1):113-119. doi: 10.1016/j.anl.2023.08.004. Epub 2023 Aug 26. PMID: 37640595.

Abstract

Superior canal dehiscence syndrome (SCDS) is a vestibular disorder in which the presence of a pathological third window in the labyrinth causes several vestibular and cochlear symptoms. Herein, we review the diagnostic criteria and treatment of SCDS. The cause of SCDS is considered to be congenital or acquired; however, its etiology is not well known. Symptoms: Vertigo and/or oscillopsia induced by loud sounds (Tullio phenomenon) or stimuli that change the middle ear or intracranial pressure (fistula symptoms) with vestibular symptoms and hyperacusis and aural fullness with cochlear symptoms are characteristic clinical complaints of this syndrome. Neurological tests: Vertical-torsional eye movements can be observed when the Tullio phenomenon or fistula symptoms are induced. Conductive hearing loss with both a decrease in the bone conduction threshold at lower frequencies and an increase in the air conduction threshold at lower frequencies may be present on audiometry. Cervical and/or ocular vestibular evoked myogenic potentials are effective in strongly suspecting the presence of a pathologic third window in the labyrinth. Computed tomography (CT) imaging: High-resolution CT findings with multiplanar reconstruction in the plane of the superior semicircular canal consistent with dehiscence indicate SCDS. The Pöschl view along the plane of the superior semicircular canal and the Stenvers view perpendicular to it are recommended as CT imaging conditions. Findings from all three major diagnostic categories (symptoms, neurological tests, and/or CT imaging) are needed to diagnose SCDS. The surgical approaches for SCDS are as follows: the 1) middle cranial fossa approach, 2) transmastoid approach, and 3) round window and oval window reinforcement. Each technique has advantages and disadvantages.

Kontorinis G, Lenarz T. Superior semicircular canal dehiscence: a narrative review. J Laryngol Otol. 2022 Apr;136(4):284-292. doi: 10.1017/S0022215121002826. Epub 2021 Oct 7. PMID: 34615564.

Abstract

Background: Described just over 20 years ago, superior semicircular canal dehiscence remains a relatively unknown and easily missed cause of dizziness and auditory symptoms.

Objective: This review focused on the origin, presenting symptoms and underlying pathophysiology of superior semicircular canal dehiscence, and the available treatment options.

Main findings and conclusion: The bony dehiscence acts as a 'third window', affecting inner-ear homeostasis, and resulting in hypersensitivity and a vestibular response to lower sound level stimuli. The third window effect explains the pressure- and sound-induced vertigo, oscillopsia, and nystagmus, as well as autophony, conductive hyperacusis and tinnitus. The origin of superior semicircular canal dehiscence is linked to the combination of a congenital or developmental factor, and a 'second event' like head trauma, rapid pressure changes or age-related factors. Computed tomography of the temporal bone and reduced vestibular-evoked myogenic potential thresholds can confirm the diagnosis. Despite only retrospective cohorts, surgery is considered a safe treatment option, targeting mainly vestibular but also auditory symptoms, with transmastoid approaches gaining popularity.

Ward BK, van de Berg R, van Rompaey V, Bisdorff A, Hullar TE, Welgampola MS, Carey JP. Superior semicircular canal dehiscence syndrome: Diagnostic criteria consensus document of the committee for the classification of vestibular disorders of the Bárány Society. J Vestib Res. 2021;31(3):131-141. doi: 10.3233/VES-200004. PMID: 33522990; PMCID: PMC9249274.

Abstract

This paper describes the diagnostic criteria for superior semicircular canal dehiscence syndrome (SCDS) as put forth by the classification committee of the Bárány Society. In addition to the presence of a dehiscence of the superior semicircular canal on high resolution imaging, patients diagnosed with SCDS must also have symptoms and physiological tests that are both consistent with the pathophysiology of a 'third mobile window' syndrome and not better accounted for by another vestibular disease or disorder. The diagnosis of SCDS therefore requires a combination of A) at least one symptom consistent with SCDS and attributable to 'third mobile window' pathophysiology including 1) hyperacusis to bone conducted sound, 2) sound-induced vertigo and/or oscillopsia time-locked to the stimulus, 3) pressure-induced vertigo and/or oscillopsia time-locked to the stimulus, or 4) pulsatile tinnitus; B) at least 1 physiologic test or sign indicating that a 'third mobile window' is transmitting pressure including 1) eye movements in the plane of the affected superior semicircular canal when sound or pressure is applied to the affected ear, 2) low-frequency negative bone conduction thresholds on pure tone audiometry, or 3) enhanced vestibular-evoked myogenic potential (VEMP) responses (low cervical VEMP thresholds or elevated ocular VEMP amplitudes); and C) high resolution computed tomography (CT) scan with multiplanar reconstruction in the plane of the superior semicircular canal consistent with a dehiscence. Thus, patients who meet at least one criterion in each of the three major diagnostic categories (symptoms, physiologic tests, and imaging) are considered to have SCDS.

Misinformation about Tourette Syndrome from major media network

Müller-Vahl KR, Szejko N, Hartmann A, Debes NM, Hedderly T, Parnes M, Abi-Jaoude E, Smilowska K, Nilles C, Coffman K, E Cavanna A, Quezada J, Eccles C, Termine C, Schmitt S, Cramer C, Klages CS, Alvarez-Fischer D, Klansoe SM, Gilbert DL. Call for action: misinformation about tourette syndrome from major media network. Eur Child Adolesc Psychiatry. 2026 Jan 20. doi: 10.1007/s00787-025-02939-8. Epub ahead of print. PMID: 41557034.

No abstract

Excerpt: 

“Stop that! It’s not Tourette’s but a new type of mass sociogenic illness” - this was the title of an article published in BRAIN in August 2021 which received much public interest with a total of 108,647 views as of June 14th 2025. What prompted this commentary? Beginning in 2019, the incidence of adolescents and adults presenting for medical attention with impairing, dramatic, functional tic-like behaviors (FTLB) dramatically increased. As this increase reached global proportions during the COVID-19 pandemic and lockdowns, experts in Tourette Syndrome (TS) and FTLB realized this “outbreak” was a distinct clinical entity that could be confused with chronic tic disorders such as TS. FTLB is not TS, although some individuals may have both conditions FTLB is best conceptualized as a subtype of functional neurological disorder (FND). Subsequent actions by international academic collaborations, individual physicians, and advocacy groups contributed to a better clinical understanding of this disorder and formulation of diagnostic criteria Important factors that helped to raise awareness about this rapidly expanding clinical presentation of FTLB were international collaborations and efforts which provided physicians with assistance in making accurate diagnoses and providing appropriate treatments.

TS is defined as a chronic, childhood-onset disorder with combined motor and vocal tics lasting for at least a year. On average, tics start at the age of five to seven years, most typically with mild simple motor tics such as eye blinking and grimacing, followed by simple vocal tics such as sniffling and coughing, typically about two years later. Tics typically wax and wane and reach their maximum at age 10 to 12 years.

FND usually presents to clinicians as “disease mimics”. For example, individuals may manifest symptoms that resemble seizures, dissociative episodes, paralysis or weakness, tremor, or tics. Prior to 2019, FND presenting as TS was considered a very rare phenotype of FND that primarily presented with movements and sounds that overlapped more closely with standard clinical presentations of TS. Since 2019, however, individuals with FND mimicking TS presented much more commonly with predominantly complex movements and vocalizations such as obscene and socially unaccepted words, phrases and gestures, throwing objects, self-injurious behaviors, and long verbal phrases . The term FTLB has come into wider use as a result of this phenomenon.

In 2023, an international group of Tourette experts, including many of the authors of this commentary, established diagnostic criteria for FTLB based on a Delphi consensus that outlined supportive factors for the diagnosis of FTLB and the differential diagnosis of TS . They proposed that a clinically definite diagnosis of FTLB can be confirmed by an age at first symptom onset of 12 years or older, rapid onset and evolution of symptoms, and at least four of nine further phenomenological features as outlined in Table 2. Although there are clear “positive signs” for the diagnosis of FTLB, a better description of this patient group is needed to exclude circular reasoning due to a lack of clinical benchmarks.

Linked to the rise in FTLBs were two popular influencers, a young German man, who created the YouTube channel “Gewitter im Kopf” (eng. “Thunderstorm in the brain”) and a young English woman, who used the name “This Trippy Hippie” on TikTok. During the COVID-19 pandemic, these videos attracted tens of millions of views. In studies from several different countries and across continents, it could be clearly demonstrated that these presentations on social media directly influenced not only onset, but also clinical presentation of FTLB. In particular, according to an international database including 294 patients from ten tertiary referral centers for tic disorders from eight countries (Canada, United Kingdom, Germany, Australia, United States, Italy, Hungary, and France), FTLB was mainly seen in young female patients with mean age of 15 years (median 14 years; range, 8– 53 years), a demographic profile quite different from TS. In fact, there is about a 4:1 predominance ratio of the male sex in TS, while FND, including FTLB, is mainly seen in females. Furthermore, an overlap could be demonstrated in the type of movements (mainly complex arm and hand movements, head banging and tapping) and vocalizations (often with a large number of swear words, whistles, insults, and comments) as well as socially inappropriate behaviors (including spilling drinks, hitting, and throwing food and objects) between social media influencers and patients. Even more, depending on the place of residence and language of the patient, differences between clinical pattern and sex distribution were found, suggesting that exposure to particular social media content influences clinical presentation.. In this context, it is also important to mention that, while such behaviors are completely atypical for TS, mass use of social media easily creates misconceptions about TS.

SUPT16H-associated neurodevelopmental disorder and neurocristopathy

Lee E, Sim S, Choi HJ, Liang EY, Le C, Bina R, Cohen R, George E, Kim SY, Bhat G, Falsey E, Sidlow R, Clinard K, Ben-Shachar S, England E, Menendez B, Herman I, Nielsen S, Punetha J, Bhola P, Hamm JA, Keeney MA, Sitzman N, Berger S, Mehta L, Conn AJ, Downie L, Ashfaq M, Northrup H, Bruel AL, Odent S, Szot JO, Martinez NN, Park S, Refkin J, Good JM, Maurer F, Le Caignec C, Coman DJ, Anderson E, Richards LJ, Dean RJ, Yang C, Choi C, Hwang BJ, Lee JS, Dobyns WB, Choi M, Sherr EH, Chae JH, Kee Y, Argilli E. SUPT16H-associated neurodevelopmental disorder and neurocristopathy: genetic and phenotypic spectrum. Hum Mol Genet. 2026 Jan 20:ddag003. doi: 10.1093/hmg/ddag003. Epub ahead of print. PMID: 41556401.

Abstract

SUPT16H encodes a subunit of the FACT (FAcilitates Chromatin Transcription) complex, a histone chaperone essential for maintaining chromatin integrity during transcription, replication, and DNA repair. Pathogenic de novo SUPT16H missense variants have previously been linked to neurodevelopmental disorders in eight individuals. Here, we expand the genotypic and phenotypic spectrum by identifying 24 additional individuals harboring ultrarare heterozygous missense or truncating variants, who share overlapping clinical features including intellectual disability, autism spectrum disorder, hypotonia, and characteristic craniofacial dysmorphism. To elucidate the underlying mechanisms, we generated a supt16h knockout zebrafish model using CRISPR/Cas9. The supt16h loss-of-function (LOF) model recapitulated key patient phenotypes such as developmental delay, craniofacial anomalies, and hypotonia. Structural and functional analyses of selected SUPT16H variants demonstrated differential rescue of developmental defects in supt16h-deficient embryos, indicating variant-specific LOF effects in vivo. The presence of non-neural manifestations, including facial and ear anomalies, suggested a role for SUPT16H in neural crest development. Consistently, supt16h loss impaired neural crest cell migration and differentiation and triggered p53-dependent apoptosis in the central nervous system (CNS) and neural crest-derived pharyngeal arches. Notably, supt16h deficiency impaired oligodendrocyte specification in the CNS and perturbed differentiation of neural crest-derived Schwann cells in the peripheral nervous system, providing a plausible basis for hypotonia. These findings uncover a previously unrecognized role of SUPT16H in neural crest development, linking chromatin regulation to neural crest-derived lineage specification and differentiation, thereby defining SUPT16H deficiency as a neurocristopathy that broadens the clinical and mechanistic landscape of SUPT16H-associated disorders.

Oliveira DV, Kato A, Nakamura K, Ikura T, Okada M, Kobayashi J, Yanagihara H, Saito Y, Tauchi H, Komatsu K. Histone chaperone FACT regulates homologous recombination by chromatin remodeling through interaction with RNF20. J Cell Sci. 2014 Feb 15;127(Pt 4):763-72. doi: 10.1242/jcs.135855. Epub 2013 Dec 19. PMID: 24357716.

Abstract

The E3 ubiquitin ligase RNF20 regulates chromatin structure through ubiquitylation of histone H2B, so that early homologous recombination repair (HRR) proteins can access the DNA in eukaryotes during repair. However, it remains unresolved how RNF20 itself approaches the DNA in the presence of chromatin structure. Here, we identified the histone chaperone FACT as a key protein in the early steps of HRR. Depletion of SUPT16H, a component of FACT, caused pronounced defects in accumulations of repair proteins and, consequently, decreased HRR activity. This led to enhanced sensitivity to ionizing radiation (IR) and mitomycin-C in a fashion similar to RNF20-deficient cells, indicating that SUPT16H is essential for RNF20-mediated pathway. Indeed, SUPT16H directly bound to RNF20 in vivo, and mutation at the RING-finger domain in RNF20 abolished its interaction and accumulation, as well as that of RAD51 and BRCA1, at sites of DNA double-strand breaks (DSBs), whereas the localization of SUPT16H remained intact. Interestingly, PAF1, which has been implicated in transcription as a mediator of FACT and RNF20 association, was dispensable for DNA-damage-induced interaction of RNF20 with SUPT16H. Furthermore, depletion of SUPT16H caused pronounced defects in RNF20-mediated H2B ubiquitylation and thereby, impaired accumulation of the chromatin remodeling factor SNF2h. Consistent with this observation, the defective phenotypes of SUPT16H were effectively counteracted by enforced nucleosome relaxation. Taken together, our results indicate a primary role of FACT in RNF20 recruitment and the resulting chromatin remodeling for initiation of HRR.

Unraveling SUDEP: Mechanisms of seizure-induced cardiac and respiratory impairment

Wenker IC, Gehlbach BK, Isom LL, et al. Unraveling SUDEP: Mechanisms of Seizure-Induced Cardiac and Respiratory Impairment. Epilepsy Currents. 2026;0(0). doi:10.1177/15357597261416723

Abstract

People with epilepsy have a markedly increased risk of premature mortality, with sudden unexpected death in epilepsy (SUDEP) accounting for approximately half of epilepsy-related deaths. Although rarely witnessed, converging evidence indicates that SUDEP arises from seizure-triggered cardiorespiratory failure mediated by central and peripheral mechanisms. In this article, we explore mechanisms of SUDEP related to respiratory, cardiac, and autonomic control of vital functions. Specifically, we examine how seizure propagation to a discrete amygdala subregion can induce profound ictal and postictal apnea; how complementary genetic and animal studies reveal that ion channelopathies affecting genes expressed in both brain and heart produce intrinsic neuronal and cardiac electrical dysfunction; and how emerging evidence implicates stress physiology and hypothalamic–pituitary–adrenal axis dysfunction as underrecognized contributors to SUDEP risk. Together, these findings support a multifactorial model in which respiratory suppression, cardiac vulnerability, autonomic dysregulation, and stress-responsive mechanisms converge to produce fatal outcomes.

Where on the receptor the antibodies actually bind in anti-NMDAR encephalitis

Junhoe Kim et al. Cryo-EM of autoantibody-bound NMDA receptors reveals antigenic hotspots in an active immunization model of anti-NMDAR encephalitis.Sci. Adv.12,eaeb4249(2026).DOI:10.1126/sciadv.aeb4249

Abstract

Autoantibodies targeting synaptic membrane proteins are associated with autoimmune encephalitis manifested by seizures, psychosis, and memory dysfunction. Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis, a prototype of these autoimmune synaptic disorders, is unexpectedly common. Unfortunately, how the native repertoire of anti-NMDAR autoantibodies recognizes NMDARs and the precise locations of antigenic epitopes remain poorly understood. Here, we used an active immunization model that closely mimics the human disease to immunize adult mice with intact GluN1/GluN2A receptors, resulting in fulminant autoimmune encephalitis. Serum was collected at 6 weeks postimmunization for single-particle cryo–electron microscopy of GluN1/GluN2A receptors complexed with purified polyclonal anti-NMDAR autoantibody fragments. Native autoantibodies recognized two distinct binding sites on the GluN1 amino-terminal domain, which we confirmed using monoclonal antibodies bound to native NMDARs purified from mouse brain. Structural analysis of autoantibody-bound NMDAR complexes identified antigenic hotspots within the GluN1 amino-terminal domain. These hotspots provide potential targets for therapeutic intervention.
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Some serious brain disorders begin with symptoms that are easy to misinterpret.

A person may become confused, forgetful or paranoid and be treated for mental illness before doctors realize the underlying problem isn’t psychological at all. Instead, the body’s immune system — meant to fight infection — is attacking the brain.

Researchers at Oregon Health & Science University say they have identified, in new detail, how that attack happens. Their findings, published last week in Science Advances, could lead to more precise treatments and earlier diagnosis of an autoimmune condition known as anti-NMDA receptor encephalitis.

The disease affects roughly one in a million people each year and often strikes young adults. It occurs when the immune system produces antibodies — proteins designed to fight disease — that mistakenly latch onto something called an NMDA receptor, which helps brain cells communicate and plays a key role in memory, learning and normal thinking.

Scientists have long known antibodies were involved but did not fully understand where they attached or why current treatments don’t always work.

“What we wanted to understand was where on the receptor the antibodies actually bind,” said co-author Dr. Gary Westbrook, a neurologist and senior scientist at OHSU’s Vollum institute. “That’s important because it provides a clue to how one could design more specific treatments to deal with the disorder.”

To find out, the OHSU team used a mouse model of the disease to examine the entire ensemble of antibodies involved, rather than studying one antibody one at a time.

The researchers also relied on an advanced imaging method called cryo-electron microscopy, which allows scientists to see biological structures at near-atomic detail. OHSU houses one of only three national cryo-electron microscopy centers at its South Waterfront campus.
What they found surprised them.

“We found that the antibodies don’t bind everywhere,” said Eric Gouaux, a senior scientist at OHSU and an investigator with the Howard Hughes Medical Institute. “They don’t coat the receptor like a layer of paint. Instead, they bind to just a few very specific areas.”
The antibodies don’t immediately shut down the receptor. Instead, they act more like glue, causing receptors to clump together and get pulled inside brain cells, where they can’t do their job. That’s when symptoms begin to escalate.

“It can begin in a rather occult way,” Westbrook said. “Someone may be behaving a little funny, and people don’t quite know what’s happening. It may be days or weeks before the full picture becomes clear.”

But Westbrook said diagnosing the disorder early is notoriously difficult because its symptoms can mimic psychiatric illness, viral infections or other neurological disorders. He said many patients are first referred to a psychiatrist before the immune cause is identified — a pattern described in the book and film Brain on Fire, which brought public attention to the disease.

“That delay can be dangerous,” Westbrook said. “By the time the disease is diagnosed, patients may already be very sick.”

If diagnosis is delayed, symptoms can worsen, leading to seizures or extreme states such as catatonia, in which patients may be unable to move or speak, according to researchers.

Westbrook said the mouse model used in the study helps overcome that limitation, by allowing researchers to study the disease from its earliest moments — something that isn’t possible in people.

Gouaux said the findings are especially important for drug development. He said current treatments rely on broadly suppressing the immune system. While many patients improve, recovery can be slow and relapses are common, he said.

“Now that we know exactly how and where the antibodies bind, the most straightforward approach would be to simply block that interaction,” he said.

The research could also improve diagnosis by making antibody tests more specific. Gouaux said current blood tests can detect NMDA receptor antibodies but can’t show where they bind or reliably predict who will develop the disease — something the new findings could help address.

Kristine de Leon

 
https://www.oregonlive.com/health/2026/01/ohsu-researchers-identify-key-trigger-behind-brain-disorder-often-mistaken-for-mental-illness.html