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.
_________________________________________________________________________

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

YIF1B-related neurodevelopmental disorder (Kaya-Barakat-Masson syndrome)

Inspired by a recently diagnosed patient

Medico-Salsench E, Kaya N, Barakat TS. YIF1B-Related Neurodevelopmental Disorder. 2024 Sep 12. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. PMID: 39265055.

Excerpt

Clinical characteristics: YIF1B-related neurodevelopmental disorder (YIF1B-NDD) is characterized by severe-to-profound developmental delay / intellectual disability with variable motor abnormalities including axial hypotonia, peripheral hypertonia, dystonia, and dyskinesia; absence of speech in most individuals or very limited speech subject to regression; feeding difficulties; seizures; postnatal microcephaly with nonspecific brain MRI abnormalities; and ophthalmologic involvement (strabismus, nystagmus, optic atrophy, and cortical blindness). Some individuals have hypoventilation.

Diagnosis/testing: The diagnosis of YIF1B-NDD is established in a proband with suggestive findings and biallelic pathogenic variants in YIF1B identified by molecular genetic testing.

Management: Treatment of manifestations: Developmental and educational support; feeding therapy; gastrostomy tube placement if required for persistent feeding issues; standardized treatments for movement disorder and seizures by an experienced neurologist; treatment per ophthalmologist for refractive errors and strabismus; low vision services as needed; consider ventilation therapy when hypoventilation becomes evident; social work and family support.

Surveillance: Monitor developmental progress, educational needs, growth, nutritional status, safety of oral intake, and changes in seizures at each visit; assess for any new manifestations including seizures, changes in tone, movement disorders, or manifestations of central hypoventilation at each visit; ophthalmology evaluation per treating ophthalmologist; behavioral assessment annually.

Genetic counseling: YIF1B-NDD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a YIF1B pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the YIF1B pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Medico Salsench E, Maroofian R, Deng R, Lanko K, Nikoncuk A, Pérez B, Sánchez-Lijarcio O, Ibáñez-Mico S, Wojcik A, Vargas M, Abbas Al-Sannaa N, Girgis MY, Silveira TRD, Bauer P, Schroeder A, Fong CT, Begtrup A, Babaei M, Toosi MB, Ashrafzadeh F, Imannezhad S, Doosti M, Ahangari N, Najarzadeh Torbati P, Ghayoor Karimiani E, Murphy D, Cali E, Kaya IH, AlMuhaizea M, Colak D, Cardona-Londoño KJ, Arold ST, Houlden H, Bertoli-Avella A, Kaya N, Barakat TS. Expanding the mutational landscape and clinical phenotype of the YIF1B related brain disorder. Brain. 2021 Nov 29;144(10):e85. doi: 10.1093/brain/awab297. PMID: 34373908; PMCID: PMC8634087.

No abstract

Sanri A, Mutlu MB, Sezer O. YIF1B-related Kaya-Barakat-Masson Syndrome: Report of a new patient and literature review. Eur J Med Genet. 2023 Jun;66(6):104751. doi: 10.1016/j.ejmg.2023.104751. Epub 2023 Mar 21. PMID: 36948290.

Abstract

Kaya-Barakat-Masson syndrome (KABAMAS) is a recently identified severe neurodevelopmental disorder characterized by severe global developmental delay, epilepsy, movement disorder, epilepsy, and microcephaly. KABAMAS is caused by bi-allelic variants in the YIF1B gene which encodes a trafficking protein involved in the anterograde traffic from the endoplasmic reticulum to the cell membrane including neural cells in association with other trafficking proteins and also Golgi apparatus morphology. That's why clinical overlapping between KABAMAS and golgipathies isn't surprising. It is a rare condition with only 24 patients reported to date. Here we described a 5.5-year-old boy presenting with severe global developmental delay, epileptic encephalopathy, microcephaly, dystonia, spasticity, blindness, feeding difficulties, respiratory failure, and dysmorphic features. Whole exome sequencing identified homozygous splice site variation (NM_001039672.3: c.297+1G > A) in the YIF1B gene. This splice site variant is rare in the general population (gnomAD Variant allele fraction (VAF): 0.0007%, 2 heterozygotes, 0 homozygotes) and has not previously been associated with the disease. Multiple in silico tools predict a deleterious effect of this splice site change. Considering the points mentioned above, we have considered the detected variant as pathogenic according to guidelines in light of current knowledge. By reporting a new case with the homozygous YIF1B splice site variant we provide further evidence to clinical and molecular data of this recently recognized severe neurodevelopmental disorder. We further emphasize that trafficking errors should be considered as an underlying mechanism in undiagnosed severe neurodevelopmental disorders.

CSNK2A1-related Okur-Chung syndrome

Inspired by a patient

Chung W, Okur V. Okur-Chung Neurodevelopmental Syndrome. 2022 Jun 9. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. PMID: 35679446.

Excerpt

Clinical characteristics: Individuals with Okur-Chung neurodevelopmental syndrome (OCNDS) frequently have nonspecific clinical features, delayed language development, motor delay, intellectual disability (typically in the mild-to-moderate range), generalized hypotonia starting in infancy, difficulty feeding, and nonspecific dysmorphic facial features. Developmental delay affects all areas of development, but language is more impaired than gross motor skills in most individuals. Intellectual disability has been reported in about three quarters of individuals. Less common findings may include kyphoscoliosis, postnatal short stature, disrupted circadian rhythm leading to sleep disturbance, seizures, and poor coordination.

Diagnosis/testing: The diagnosis of OCNDS is established in a proband with suggestive findings and a heterozygous pathogenic variant in CSNK2A1 identified by molecular genetic testing.

Management: Treatment of manifestations: Feeding therapy and consideration of gastrostomy tube placement in those with persistent feeding issues; consideration of growth hormone therapy (as directed by an endocrinologist) in those with short stature and evidence of partial growth hormone deficiency; standard treatment of epilepsy (as directed by a neurologist) with anti-seizure medication; consideration of intravenous immune globulin treatment (as directed by an immunologist) for demonstrated hypogammaglobulinemia; physical therapy / occupational therapy / rehabilitation medicine for those with hypotonia and/or motor coordination issues; standard supportive developmental therapies; standard treatment of scoliosis, constipation, congenital heart defects, renal anomalies / pelviectasis, and sleep disorders.

Surveillance: At each visit: measure growth parameters, growth velocity, and nutritional status; monitor for signs of ongoing feeding issues / safety of oral intake and constipation; assess new neurologic manifestations (seizures, changes in tone, movement disorders, poor coordination); monitor developmental progress, behavior, and educational needs; monitor for evidence of frequent or unusual infections and for signs and symptoms of sleep disturbance. Every one to three years: ophthalmology evaluation.

Genetic counseling: OCNDS disorder is expressed in an autosomal dominant manner and typically caused by a de novo CSNK2A1 pathogenic variant. Therefore, the risk to other family members is presumed to be low. Rarely, individuals diagnosed with OCNDS have the disorder as the result of a CSNK2A1 pathogenic variant inherited from an affected parent or an unaffected parent with low-level mosaicism in the blood. Once a CSNK2A1 pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing are possible.

Owen CI, Bowden R, Parker MJ, Patterson J, Patterson J, Price S, Sarkar A, Castle B, Deshpande C, Splitt M, Ghali N, Dean J, Green AJ, Crosby C; Deciphering Developmental Disorders Study; Tatton-Brown K. Extending the phenotype associated with the CSNK2A1-related Okur-Chung syndrome-A clinical study of 11 individuals. Am J Med Genet A. 2018 May;176(5):1108-1114. doi: 10.1002/ajmg.a.38610. Epub 2018 Jan 31. PMID: 29383814.

Abstract

Variants in the Protein Kinase CK2 alpha subunit, encoding the CSNK2A1 gene, have previously been reported in children with an intellectual disability and dysmorphic facial features syndrome: now termed the Okur-Chung neurodevelopmental syndrome. More recently, through trio-based exome sequencing undertaken by the Deciphering Developmental Disorders Study (DDD study), a further 11 children with de novo CSNK2A1 variants have been identified. We have undertaken detailed phenotyping of these patients. Consistent with previously reported patients, patients in this series had apparent intellectual disability, swallowing difficulties, and hypotonia. While there are some shared facial characteristics, the gestalt is neither consistent nor readily recognized. Congenital heart abnormalities were identified in nearly 30% of the patients, representing a newly recognized CSNK2A1 clinical association. Based upon the clinical findings from this study and the previously reported patients, we suggest an initial approach to the management of patients with this recently described intellectual disability syndrome.

Zhang N, Han M, Zhao T, Tang X, Wang Z, Du Y, Wang L. Identification and functional analysis of a novel CSNK2A1 frameshift variant in stillbirth. Front Genet. 2025 Oct 27;16:1692704. doi: 10.3389/fgene.2025.1692704. PMID: 41216289; PMCID: PMC12597092.

Abstract

Background: Casein Kinase II Subunit Alpha (CK2α), the catalytic subunit of protein kinase CK2, is encoded by CSNK2A1. This kinase catalyzes substrate phosphorylation and regulates diverse cellular processes including cell cycle progression, apoptosis, and transcription. CSNK2A1 is associated with Okur-Chung Neurodevelopmental Syndrome (OCNS, OMIM: 617062). Although CSNK2A1 functional deficiency is implicated in impaired embryonic development, prenatal case reports remain scarce.

Methods: Clinical data and fetal umbilical cord blood samples were collected. Whole-genome sequence (WGS) was used for potential pathogenic variants identification, followed by Sanger sequencing to validate the variant. Bioinformatic tools were employed to predict the 3D structure of the variant. Wild-type and mutant CSNK2A1 overexpression plasmids were constructed to investigate the functional consequences of the variant.

Result: A 33-year-old pregnant woman without adverse obstetric history. At 34+4 weeks, ultrasound showed an intracranial abnormal echoes, multiple cardiovascular anomalies, and stillbirth had occurred at 35 weeks. WGS identified a novel frameshift mutation c.1020_1021delAG (p.Gly342Glnfs*57) in the CSNK2A1 gene. Bioinformatics analysis indicated structural modification in mutant proteins. In vitro kinase assays showed that the variant did not impair kinase activity. Quantitative analysis demonstrated significantly elevated mutant mRNA levels but reduced protein expression compared to wild-type. Elevated ubiquitination in mutants potentially explains diminished CSNK2A1 protein abundance.

Conclusion: We report a novel CSNK2A1 frameshift mutation that significantly reduces protein expression and impairs gene function. These findings expand our understanding of CSNK2A1's genetic diversity and underscore the importance of comprehensive functional analyses to achieve accurate diagnosis. This study facilitates prenatal diagnosis of CSNK2A1-related disorders and informs clinical decision-making for carriers.