Squirmy and Grubs

 "Squirmy and Grubs" is a highly popular YouTube channel run by Shane Burcaw and Hannah Aylward. The couple documents the realities of their "interabled" marriage—Shane has Spinal Muscular Atrophy, a severe muscle-wasting disease, and uses a wheelchair, while Hannah is able-bodied. Their content combines humor and education to confront misconceptions about disability, intimacy, and relationships. 

About the Couple

Shane Burcaw: An award-winning author and disability advocate. He previously founded the nonprofit Laughing At My Nightmare.

Hannah Aylward: A sociology and anthropology graduate who manages the filming and editing for their vlog.T

he Relationship: They began dating in 2016 and were married in September 2020. Because of societal prejudices, their interabled relationship frequently faces scrutiny, with strangers often mistaking Hannah for Shane's nurse.

Books and Advocacy Beyond vlogging, 

Shane and Hannah are active public speakers and authors. They co-authored the book Interabled: True Stories About Love and Disability, which highlights the stories of multiple couples and pushes back against the ableist notion that disabled individuals cannot be equal or romantic partners. 

https://www.youtube.com/c/squirmyandgrubs

We are Hannah and Shane, aka Squirmy and Grubs, and we share our love story with the world in hopes of changing the way society thinks about disability. Far too often, our relationship is perceived by others as remarkable, bizarre, tragic, and unrealistic, but these perceptions originate from a flawed—and extremely damaging—understanding of disability. If one takes the time to look a little deeper, they’ll see that our relationship is really no different than any other. Below is a short recap of our love story, and we’d love nothing more than to bring our story and message to your classroom, workplace, or event!

The Early Days

If anything is exceptionally unique about our story, it’s the unlikely circumstances that brought us together. Shane was living in Pennsylvania working as an author and a nonprofit executive in the disability sector. Hannah was living in Minnesota and studying sociology at Carleton College. One fateful night, Hannah stumbled upon a documentary that had been produced about Shane’s life. She connected with his interests and his humor, so she shot him an email to say hello. To this day, Hannah maintains that her email was a result of late-night exam-cramming delusions. Regardless, we struck up a conversation the next day, and it turned out we DID have a lot in common, from our adoration of traveling to our extreme enjoyment of trying delicious new foods.

In the weeks to follow, we became inseparable, which is ironic considering the 1000+ miles that separated us. We texted and FaceTimed constantly, and very quickly we realized there was a serious spark between us. A few months later, Hannah flew to PA for our first-ever in-person meeting, which Shane inaugurated by arriving an hour late at the airport to pick her up. His lateness did not stop her from saying “Yes” when Shane ~officially~ asked her out the next day.

Over the next two years, we trudged through a long-distance relationship that was both extraordinarily happy and distressingly hard. Thankfully, we had many visits in-person during those two years, and those trips included some unforgettable (and ridiculous) memories. During those years, Hannah learned the nuances of Shane’s daily care. More importantly, we learned that we truly enjoyed each others‘ company, and both of us wanted nothing more than to be together all the time.

The YouTube Channel

After two years of long distance, our desire to be closer became overwhelming. Shane packed up his belongings and made the move to Minneapolis, where we got an apartment together while Hannah finished her senior year of college. Hannah became Shane’s primary caregiver, which often alarms those who are new to our story. So much sacrifice! So much hardship for a young woman! Actually, those ideas can’t be farther from the truth, and one of our favorite speaking topics is how we combine caregiving with intimacy in our relationship.

A few months after moving in together, we had the silly little idea to start a YouTube channel together. We were doing some upcoming travel, and traveling with a disability is always rife with challenges, so we figured we should document it in our humorous tone. We named our channel Squirmy and Grubs, which are the (slightly embarrassing) nicknames that we gave each other early in our relationship. We never expected the channel to take off in the way that it did.

After doing a viral interview with a large YouTuber called Special Books By Special Kids, our channel quickly began to gain hundreds of thousands of followers. We started getting constant calls from talk shows wanting to feature us, national brands wanting us to represent their products, and thousands of emails each week from people connecting with our story. We were thrust into the forefront of disability activism, and although we didn’t expect it, we certainly honored the opportunity. We decided to put everything we had into improving the way society understands disability.

The Future

The rise of Squirmy and Grubs began in January 2019 and so much has happened since then. We got engaged in June of 2019 and bought a house together in November of that same year. Throughout 2019 and 2020 we performed dozens of speaking engagements all over the world, from universities with thousands of audience members to elementary schools via Zoom (thanks, COVID-19). We’ve partnered with many leading businesses to amplify diversity and inclusion in their workplaces. We were even asked to co-author a book about relationships and disability (Interabled: Love Stories - coming to a book store near you in 2022).

In everything that we do, our goal is to normalize the disability experience. We strive to educate while we entertain. Both of us bring boatloads of love and passion to our presentations, and we believe your audience will love laughing and learning with us!

Book us today!

https://www.squirmyandgrubs.com/more-about-squirmy-and-grubs

Diagnostic genetic findings from exome sequencing in a cohort of 1,109 children with epilepsy

Wu F, Ji X, Cheng P, Zhao S, Feng S, Liu W, Chen J, Zhang X, Wang H, Chen Q. Diagnostic Genetic Findings From Exome Sequencing in a Cohort of 1,109 Children With Epilepsy. Neurol Genet. 2026 May 14;12(3):e200387. doi: 10.1212/NXG.0000000000200387. PMID: 42158268; PMCID: PMC13182736.

Abstract

Background and objectives: Genetic testing has emerged as a transformative tool for the diagnosis and treatment of epilepsy. The aim of this study was to characterize the genetic basis of pediatric epilepsy.

Methods: We analyzed a cohort of 1,109 children with epilepsy who underwent whole-exome sequencing. Genetic findings were interpreted based on medical records and genetic testing results.

Results: Genetic diagnostic results were found in 405 of 1,109 patients, with a diagnostic yield of 36.5%. The SCN1A (40/1,109, 3.6%) was the most frequently affected gene, followed by the PRRT2 (26/1,109, 2.3%) and SCN2A (10/1,109, 0.9%). In total, 138 genes were identified with 337 total detections. Gene ontology analysis revealed enrichment in ion channel-related genes (30.0%, 101/337), catalytic activity-related genes (19.6%, 66/337), and pathway-related genes (14.5%, 49/337). Multivariate logistic regression showed that younger age at onset (OR = 0.87, 95% CI 0.81-0.94, p < 0.001), developmental delay or intellectual disability (OR = 2.25, 95% CI 1.62-3.12, p < 0.001), and facial dysmorphisms (OR = 2.30, 95% CI 1.06-5.00, p = 0.036) were associated with a higher likelihood of achieving a genetic diagnosis. Negative results were obtained in 51.4% (570/1,109) of patients.

Discussion: This single-center study provides a comprehensive overview of the genetic landscape of pediatric epilepsy, enhancing our understanding of the genetic basis and offering insights for clinical diagnosis and genetic counseling. These findings underscore the clinical utility of genetic testing in pediatric epilepsy.

HPDL deficiency

Joshua Mould

Joshua Mould, a 21-year-old studying computer science and statistics at Villanova University in Pennsylvania, had suffered from mysterious balance issues and tightness, called spasticity, in his leg muscles since junior high. When Mould was in eighth grade, these symptoms began interfering with his passion for baseball, and eventually sidelined him.

“I wasn't very flexible,” Mould said. “I also wasn't getting stronger, and I wasn’t gaining any velocity on my fastball even though I was lifting weights and working out at least three times a week.”

Pitchers generate power through their legs, with the arm simply following through. “I didn’t have the flexibility to take a very long stride toward the plate, or the leg strength or stability to create much momentum,” Mould said.

After a lackluster sophomore year, Mould trained throughout the offseason, even working with coaches from a top sports performance center in hope of making progress. “But the next spring, we checked the velocity on my fastball, and it had dropped about 10 miles per hour,” he said.

His trainer suggested he see a doctor, and a local neurologist ordered a genetic screening test that identified variations in both copies of his human 4-hydroxyphenylpiruvate dioxygenase-like (HPDL) gene, a gene that had never before been associated with disease. The neurologist connected him with Tyler Pierson, MD, PhD, assistant professor of Pediatrics and Neurology at Cedars-Sinai and lead pediatrician at the center.

Over the years, Pierson had seen a few other patients with symptoms and a genetic variation similar to Mould’s.

“At the time, very little was known about this gene,” Pierson said, “so further research was needed to determine whether the variation was causing Josh’s symptoms.”

Pierson and collaborators put together a study involving nearly 50 institutions in the U.S. and abroad, looking at the cases of Mould and 30 others with the HPDL variation, and were able to describe a new disorder called HPDL deficiency (also called SPG83) and provide Mould and the others with a diagnosis.

Pierson said the diagnosis has value, even though HPDL deficiency doesn’t yet have a cure, because it lets families know the symptoms came from a condition over which they had no control. It also gives the patient the opportunity to pursue genetic counseling before having children, and to seek information within the community of fellow patients.

“It allows them to look for other people with the same diagnosis, whether that’s a family research group or even just a Facebook group,” said Pierson. “They can connect and perhaps gain insight from other families.”

Pierson continues to work to better understand HPDL deficiency in the hope of one day finding a therapy that halts or even reverses the progression of symptoms. And Mould takes medications to reduce the tightness in his legs, which he said is helping improve his balance.

“Early in high school, it was really hard to deal with,” Mould said of his condition. “The diagnosis gives me a reason why my muscles aren’t listening to me, and that it’s not just my failure to work as hard as other people. And it’s been really important to me to know that.”

Pediatric patients referred to the center are diagnosed most often with genetic conditions. Adult patients are more likely to have conditions that arose later in life, and they often have been to multiple specialists who haven't been able to explain their symptoms or test results.

https://www.newswise.com/articles/medical-mysteries-are-their-specialty

Sun Y, Wei X, Fang F, Shen Y, Wei H, Li J, Ye X, Zhan Y, Ye X, Liu X, Yang W, Li Y, Geng X, Huang X, Ruan Y, Qin Z, Yi S, Lyu J, Fang H, Yu Y. HPDL deficiency causes a neuromuscular disease by impairing the mitochondrial respiration. J Genet Genomics. 2021 Aug 20;48(8):727-736. doi: 10.1016/j.jgg.2021.01.009. Epub 2021 Jun 17. PMID: 34334354.

Abstract

Mitochondrial diseases are caused by variants in both mitochondrial and nuclear genomes. A nuclear gene HPDL (4-hydroxyphenylpyruvate dioxygenase-like), which encodes an intermembrane mitochondrial protein, has been recently implicated in causing a neurodegenerative disease characterized by pediatric-onset spastic movement phenotypes. Here, we report six Chinese patients with bi-allelic HPDL pathogenic variants from four unrelated families showing neuropathic symptoms of variable severity, including developmental delay/intellectual disability, spasm, and hypertonia. Seven different pathogenic variants are identified, of which five are novel. Both fibroblasts and immortalized lymphocytes derived from patients show impaired mitochondrial respiratory function, which is also observed in HPDL-knockdown (KD) HeLa cells. In these HeLa cells, overexpression of a wild-type HPDL gene can rescue the respiratory phenotype of oxygen consumption rate. In addition, a decreased activity of the oxidative phosphorylation (OXPHOS) complex II is observed in patient-derived lymphocytes and HPDL-KD HeLa cells, further supporting an essential role of HPDL in the mitochondrial respiratory chain. Collectively, our data expand the clinical and mutational spectra of this mitochondrial neuropathy and further delineate the possible disease mechanism involving the impairment of the OXPHOS complex II activity due to the bi-allelic inactivations of HPDL.

Wiessner M, Maroofian R, Ni MY, Pedroni A, Müller JS, Stucka R, Beetz C, Efthymiou S, Santorelli FM, Alfares AA, Zhu C, Uhrova Meszarosova A, Alehabib E, Bakhtiari S, Janecke AR, Otero MG, Chen JYH, Peterson JT, Strom TM, De Jonghe P, Deconinck T, De Ridder W, De Winter J, Pasquariello R, Ricca I, Alfadhel M, van de Warrenburg BP, Portier R, Bergmann C, Ghasemi Firouzabadi S, Jin SC, Bilguvar K, Hamed S, Abdelhameed M, Haridy NA, Maqbool S, Rahman F, Anwar N, Carmichael J, Pagnamenta A, Wood NW, Tran Mau-Them F, Haack T; Genomics England Research Consortium, PREPARE network; Di Rocco M, Ceccherini I, Iacomino M, Zara F, Salpietro V, Scala M, Rusmini M, Xu Y, Wang Y, Suzuki Y, Koh K, Nan H, Ishiura H, Tsuji S, Lambert L, Schmitt E, Lacaze E, Küpper H, Dredge D, Skraban C, Goldstein A, Willis MJH, Grand K, Graham JM, Lewis RA, Millan F, Duman Ö, Dündar N, Uyanik G, Schöls L, Nürnberg P, Nürnberg G, Catala Bordes A, Seeman P, Kuchar M, Darvish H, Rebelo A, Bouçanova F, Medard JJ, Chrast R, Auer-Grumbach M, Alkuraya FS, Shamseldin H, Al Tala S, Rezazadeh Varaghchi J, Najafi M, Deschner S, Gläser D, Hüttel W, Kruer MC, Kamsteeg EJ, Takiyama Y, Züchner S, Baets J, Synofzik M, Schüle R, Horvath R, Houlden H, Bartesaghi L, Lee HJ, Ampatzis K, Pierson TM, Senderek J. Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia. Brain. 2021 Jun 22;144(5):1422-1434. doi: 10.1093/brain/awab041. Erratum in: Brain. 2021 Sep 4;144(8):e70. doi: 10.1093/brain/awab193. PMID: 33970200; PMCID: PMC8219359.

Abstract

Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays.

Lee EH, Kim-Mcmanus O, Yang JH, Haas R, Zaki MS, Abdel-Salam GMH, Nakamura Y, Abdel-Hamind MS, Ebrahimi-Fakhari D, Alecu JE, Brunetti-Pierri N, Srinivasan VM, Gowda VK, Gross S, Alanay Y, Najarzadeh Totbati P, Yadavilli M, Friedman L, Ojeda NM, Gleeson JG. HPDL Variant Type Correlates With Clinical Disease Onset and Severity. Ann Clin Transl Neurol. 2025 Jul;12(7):1360-1367. doi: 10.1002/acn3.70047. Epub 2025 May 14. Erratum in: Ann Clin Transl Neurol. 2026 Jan;13(1):212. doi: 10.1002/acn3.70084. PMID: 40368591; PMCID: PMC12257120.

Abstract

Objective: Recently, a mitochondrial encephalopathy due to biallelic HPDL variants was described, associated with a broad range of clinical manifestations ranging from severe, infantile-onset neurodegeneration to adolescence-onset hereditary spastic paraplegia. HPDL converts 4-hydroxyphenylpyruvate acid (4-HPPA) into 4-hydroxymandelate (4-HMA), necessary for the synthesis of the mitochondrial electron transporter CoQ10. This suggests a possible bypass of the metabolic block by 4-HMA treatment; however, genotype-phenotype correlations are lacking.

Methods: We established an HPDL Patient Registry to prepare for a future clinical trial. Here we report the clinical features of 13 enrolled participants and compare them with 86 previously reported patients. We establish three major clinical classes: severe, intermediate, and mild, presenting onset in early infancy, childhood, and adolescence, respectively. The biallelic genotypes were classified into truncating/truncating, truncating/missense, and missense/missense variants, mapped onto the predicted 3D protein structure, and correlated with severity.

Results: Patients with biallelic truncating variants presented with severe phenotypes and earlier ages of onset. Missense variants were often associated with milder phenotypes, except those with variants predominantly located in or near the VOC2 domain containing iron-binding sites or the C-terminus, which had more severe phenotypes. In addition, p.Met1? variants were also correlated with more severe phenotypes.

Interpretation: This study demonstrates the correlation of age of onset and disease severity with genotype for HPDL-related conditions. Patients with truncating variants and specific missense variants correlated with severe, early-onset features, whereas the presence of at least one missense variant located outside of the iron-binding sites correlated with milder presentations.

Efficacy of levetiracetam in patients with pediatric epilepsy

Balestrini S, Puliti D, Lombardini M, Bettiol A, Gasparini S, Lomonaco M, Presotto EM, Dalmazio Tarantino EP, De Masi S, Guerrini R. Efficacy of Levetiracetam in Patients With Pediatric Epilepsy: A Systematic Review and Meta-Analysis. Neurology. 2026 Jun 23;106(12):e218080. doi: 10.1212/WNL.0000000000218080. Epub 2026 May 27. PMID: 42202238; PMCID: PMC13225242.

Abstract

Background and objectives: Levetiracetam (LEV) is widely used in pediatric epilepsies because of its favorable pharmacokinetics, ease of administration, and perceived tolerability. However, its comparative efficacy relative to established antiseizure medications (ASMs) in children remains uncertain. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate LEV efficacy in pediatric epilepsies and compare outcomes vs placebo and active comparators.

Methods: We systematically searched PubMed/MEDLINE and Embase (2000-6 August 2025) for RCTs enrolling patients 16 years or younger with epilepsy and reporting seizure freedom and/or ≥50% responder rate. Trials including both pediatric and adult patients were eligible if pediatric participants were represented. Comparisons included LEV vs placebo or active ASMs as monotherapy or adjunctive therapy. Primary outcomes were seizure freedom and responder rate at the trial's primary endpoint or, if not specified, longest reported follow-up. We assessed risk of bias using Cochrane Risk of Bias 2. We pooled risk differences (RDs) with 95% CIs using random-effects models, stratified by comparator and epilepsy subtype.

Results: We included 25 RCTs (4,070 participants): 23 contributed to pooled meta-analyses. Across 25 trials, the mean age ranged from 0.4 to 39.3 years, reflecting pediatric-only and mixed-age RCTs; 43.8% were female. In placebo/no-therapy-controlled trials (mainly add-on studies), LEV was associated with higher seizure freedom (RD 11.0%; 95% CI 5.3%-16.7%) and responder rates (RD 24.3%; 95% CI 19.1%-29.4%). In active-comparator-controlled trials (mainly monotherapy head-to-head studies), LEV showed no overall advantage vs active comparators for seizure freedom (RD -2.4%; 95% CI -5.6% to 0.7%) or responder rate (RD -7.4%; 95% CI -23.0% to 8.1%). Fourteen trials were at high risk of bias. Sensitivity analyses confirmed benefit vs placebo but showed significant disadvantage vs active comparators in low risk-of-bias trials. Findings in pediatric-only trials (16 RCTs; 1,380 participants) were consistent with the overall results.

Discussion: LEV confers benefit vs placebo, mostly as adjunctive therapy, but does not consistently outperform established ASMs in pediatric epilepsies and may be inferior in some subgroups when higher-quality evidence is considered. Limitations include substantial heterogeneity, frequent high risk of bias, variable follow-up durations, publication bias, and limited pediatric-only comparative data.

Child euthanasia in the Netherlands

A terminally ill child under the age of 12 was euthanized in the Netherlands for the first time — two years after a major change to the country’s assisted dying laws came into force.

Dutch Health Minister Sophie Hermans said the “incurably ill” child died last year, but didn’t reveal details about their age or illness during her annual report presentation to the House of Representatives on Monday, according to NOS.

Prosecutors will now decide whether the doctor involved in the case acted legally, Hermans revealed in a letter to the lawmakers.

The Dutch government legalized euthanasia for severely ill children between the ages of 1 and 12 in 2024.

“Euthanasia is only allowed for patients whose unbearable suffering with no prospect of improvement has a medical dimension,” the government says.

“This can be the case with somatic diseases such as cancer or cardiovascular disease, but also with psychiatric disorders, dementia or multiple geriatric syndromes.”

Euthanasia is not permitted “in cases where a person is ‘finished with life’ or deems their life to be ‘completed,'” according to the Dutch government.

Doctors must consult a six point checklist before deciding whether to end a patient’s life under the Termination of Life on Request and Assisted Suicide (Review Procedures) Act.

First, they must rule that the patient is not under duress and decide whether their “suffering is unbearable with no prospect of improvement,” according to the government.

They must have informed the patient about their illness, and conclude there’s “no reasonable alternative.”

Physicians must also consult with an independent doctor, as well as exercise due care and attention throughout the process.

For children under 12, parents must give their consent.

Government ministers said at the time the law change would apply to around five to 10 children, who suffer unbearably from their illnesses.

“The end of life for this group is the only reasonable alternative to the child’s unbearable and hopeless suffering,” the government said.

Euthanasia was already legal for babies under 1 and children over 12, but kids between those ages could only die via palliative sedation or naturally.

For children between the ages of 12 and 15, parents or guardians must consent to the process, but this doesn’t apply in cases involving 16 and 17-year-olds.

They must be consulted, but their consent is not necessary, according to the Dutch government.

Doctors who perform euthanasia unlawfully risk up to 12 years in prison, and could also be slapped with a fine.

In 2002, the Netherlands was the first country in the world to legalise euthanasia under strict conditions. All cases of euthanasia must be reported to medical review boards.

The Netherlands isn’t the first country to allow doctor-assisted death for children of all ages. Belgium has allowed it since 2014.

Last year, 10,341 deaths by assisted suicide or euthanasia were reported in the Netherlands, according to the Regional Euthanasia Review Committees. This was a 3.8% rise compared to 2024. 

Around 85% of cases involved patients battling illnesses such as cancer and lung disease. Three in every four cases involved people over 70.

There was only one teenager – aged between 12 and 18 – who died from euthanasia.

Meanwhile, in the UK, a proposed bill that would’ve allowed terminally ill adults in England and Wales to choose to end their lives failed to clear the House of Lords – even though it was backed by elected parliamentarians.

The bill failed in April after parliamentary time ran out following an effective filibuster by those in the UK’s upper chamber.

Chris Bradford

https://nypost.com/2026/06/24/world-news/netherlands-euthanizes-child-under-12-in-first-case-since-major-law-change-reports/

Low diagnostic yield of presurgical genetic testing in adult patients with epilepsy

Jünemann C, Stuart A, Kaur N, Wiebe S, Jette N, Singh S, Borlot F, Knake S; Calgary Comprehensive Epilepsy Program Collaborators; Billie Au PY, Klein KM. Low diagnostic yield of presurgical genetic testing in adult patients with epilepsy. Epilepsia. 2026 May 20. doi: 10.1002/epi.70291. Epub ahead of print. PMID: 42157695.

Abstract

Objective: To determine the diagnostic yield of genetic testing in patients undergoing presurgical evaluation for epilepsy.

Methods: We conducted a cohort study including 115 adult patients who underwent presurgical evaluation in the Calgary Epilepsy Program between 2019 and 2023 and who had undergone research exome sequencing. A curated epilepsy gene panel comprising 765 Online Mendelian Inheritance in Man (OMIM)-listed epilepsy-associated genes was applied. Variants were classified according to American College of Medical Genetics and Genomics guidelines and assessed for clinical relevance and association with postsurgical outcomes.

Results: Pathogenic or likely pathogenic variants in DEPDC5, NPRL2, KCNT2, and PRRT2 were identified, respectively, in 4 individuals (3.5%, 4/115). All variants met stringent quality criteria with high pathogenicity scores (Combined Annotation Dependent Depletion (CADD) 34-37) and absent or extremely low population frequencies in gnomAD v4.1. None of these patients had intellectual disability, and only one patient (PRRT2) had a positive family history. The patient with the KCNT2 variant underwent epilepsy surgery with good outcome (Engel class ID).

Significance: This presurgical cohort demonstrates a low diagnostic yield of genetic testing in adult epilepsy surgery candidates. However, three of four patients with (likely) pathogenic variants did not have features that would have prompted clinical genetic testing, indicating that their genetic diagnosis would have been missed based on typical clinical genetic testing criteria in many jurisdictions.

DEPDC5-related epilepsy

Inspired by a patient

Rb R, Ajith A, Nayak A, Radhakrishnan A, Thomas B, Kesavadas C. Neuroimaging spectrum of GATOR1-related epilepsy (GATORopathies). Neuroradiology. 2026 May 18. doi: 10.1007/s00234-026-04036-2. Epub ahead of print. PMID: 42149211.

Abstract

Background: The mTOR pathway is important for neurodevelopment. The GATOR1 complex, composed of DEPDC5, NPRL2, and NPRL3, functions as a negative regulator of mTORC1 activity and pathogenic variants in the genes which comprise this complex cause focal epilepsy and malformation of cortical development, all named as GATORopathies. While focal cortical dysplasia is commonly reported, the full spectrum of associated neuroimaging findings remains incompletely defined.

Objective: To characterize the neuroimaging features associated with GATOR1 complex mutations and to explore potential associations between imaging phenotypes and specific genotypes.

Methods: MRI studies were retrospectively reviewed from January 2019 to December 2025 in patients with genetically confirmed GATOR1 mutations. Clinical, radiological, and genetic data were analyzed to identify imaging patterns and genotype-phenotype correlations.

Results: Twenty patients (median age : 6 years; range 1-25 years) were included. DEPDC5 mutations were most frequent (n = 12), followed by NPRL3 (n = 5) and NPRL2 (n = 3). MRI abnormalities were identified in 16 patients (80%). Focal cortical malformations were the most common finding (n = 8), followed by diffuse cortical malformations (n = 5) and generalized neuroparenchymal atrophy (n = 3); four patients had MRI-negative studies. Imaging findings varied considerably across genotypes. DEPDC5 and NPRL2 mutations showed a broad and heterogeneous radiological spectrum, whereas NPRL3 mutations showed a tendency toward cortical malformations, though the small subgroup size limits interpretation. Seizure onset spanned from infancy to adulthood; however, patients with diffuse cortical abnormalities or generalized neuroparenchymal atrophy tended to present earlier and experienced a greater seizure burden.

Conclusion: GATOR1-related epilepsy demonstrates substantial variability in neuroimaging and electroclinical features, extending beyond focal cortical malformations to include diffuse cortical malformations, generalized neuroparenchymal atrophy, and MRI-negative presentations. These findings highlight the value of integrated genetic, imaging, and electroclinical assessment in routine clinical practice.

Yang T, Banerjee R, Scheper M, Jiang M, Dai S, Aronica E, Wang Y. Ectopically overexpressed glycine transporter 2 contributes to epileptogenesis in DEPDC5-related epilepsy. Exp Neurol. 2026 May;399:115668. doi: 10.1016/j.expneurol.2026.115668. Epub 2026 Jan 24. PMID: 41587632.

Abstract

Loss-of-function mutations in DEPDC5 (DEP domain-containing protein 5), a critical negative regulator of mTORC1 (mechanistic Target of Rapamycin Complex 1), are often identified in patients with refractory epilepsy. To understand its underlying pathogenesis and develop novel therapeutics, we used a highly clinically relevant rat model of DEPDC5-related epilepsy and resected human patient tissues to profile the molecular architecture in the dysplastic cortex. We report here that Slc6a5 (solute carrier family 6 member 5 gene), a marker gene for glycinergic inhibitory neurons, is ectopically overexpressed in mutant excitatory neurons in both experimental animal and human tissues. Using CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) in utero electroporation (IUE) to simultaneously knock out Depdc5 and Slc6a5 in forebrain excitatory neurons reduces seizure frequency and duration. These data suggest that SLC6A5 plays an important role in the epileptogenesis of DEPDC5-related epilepsy, although the underlying mechanisms remain unclear.

Samanta D. DEPDC5-related epilepsy: A comprehensive review. Epilepsy Behav. 2022 May;130:108678. doi: 10.1016/j.yebeh.2022.108678. Epub 2022 Apr 14. PMID: 35429726.

Abstract

DEPDC5-related epilepsy, caused by pathogenic germline variants(with or without additional somatic variants in the brain) of DEPDC5 (Dishevelled, Egl-10 and Pleckstrin domain-containing protein 5) gene, is a newly discovered predominantly focal epilepsy linked to enhanced mTORC1 pathway. DEPDC5-related epilepsy includes several familial epilepsy syndromes, including familial focal epilepsy with variable foci (FFEVF) and rare sporadic nonlesional focal epilepsy. DEPDC5 has been identified as one of the more common epilepsy genes linked to infantile spasms and sudden unexpected death (SUDEP). Although intelligence usually is unaffected in DEPDC5-related epilepsy, some people have been diagnosed with intellectual disabilities, autism spectrum disorder, and other psychiatric problems. DEPDC5 variants have also been found in 20% of individuals with various brain abnormalities, challenging the traditional distinction between lesional and nonlesional epilepsies. The most exciting development of DEPDC5 variants is the possibility of precision therapeutics using mTOR inhibitors, as evidenced with phenotypic rescue in many animal models. However, more research is needed to better understand the functional impact of diverse (particularly missense or splice-region) variants, the specific involvement of DEPDC5 in epileptogenesis, and the creation and utilization of precision therapies in humans. Precision treatments for DEPDC5-related epilepsy will benefit not only a small number of people with the condition, but they will also pave the way for new therapeutic approaches in epilepsy (including acquired epilepsies in which mTORC1 activation occurs, for example, post-traumatic epilepsy) and other neurological disorders involving a dysfunctional mTOR pathway.

Gu C, Wei X, Yan D, Cai Y, Li D, Shu J, Cai C. DEPDC5 plays a vital role in epilepsy: Genotypic and phenotypic features in cohort and literature. Epileptic Disord. 2024 Jun;26(3):341-349. doi: 10.1002/epd2.20223. Epub 2024 May 16. PMID: 38752894.

Abstract

Objective: DEPDC5 emerges to play a vital role in focal epilepsy. However, genotype-phenotype correlation in DEPDC5-related focal epilepsies is challenging and controversial. In this study, we aim to investigate the genotypic and phenotypic features in DEPDC5-affected patients.

Methods: Genetic testing combined with criteria published by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), was used to identify pathogenic/likely pathogenic variants in DEPDC5 among the cohort of 479 patients with focal epilepsy. Besides, the literature review was performed to explore the genotype-phenotype correlation and the penetrance in DEPDC5-related focal epilepsies.

Results: Eight unrelated probands were revealed to carry different pathogenic/likely pathogenic variants in DEPDC5 and the total prevalence of DEPDC5-related focal epilepsy was 1.67% in the cohort. Sixty-five variants from 28 studies were included in our review. Combined with the cases reported, null variants accounted for a larger proportion than missense variants and were related to unfavorable prognosis (drug resistance or even sudden unexpected death in epilepsy; χ2 = 5.429, p = .020). And, the prognosis of probands with developmental delay/intellectual disability or focal cortical dysplasia was worse than that of probands with simple epilepsy (χ2 = -, p = .006). Besides, the overall penetrance of variants in DEPDC5 was 68.96% (231/335).

Significance: The study expands the variant spectrum of DEPDC5 and proves that the DEPDC5 variant plays a significant role in focal epilepsy. Due to the characteristics of phenotypic heterogeneity and incomplete penetrance, genetic testing is necessary despite no specific family history. And we propose to adopt the ACMG/AMP criteria refined by ClinGen Sequence Variant Interpretation Working Group, for consistency in usage and transparency in classification rationale. Moreover, we reveal an important message to clinicians that the prognosis of DEPDC5-affected patients is related to the variant type and complications.

Bacq A, Roussel D, Bonduelle T, Zagaglia S, Maletic M, Ribierre T, Adle-Biassette H, Marchal C, Jennesson M, An I; Genomics England Research Consortium; Picard F, Navarro V, Sisodiya SM, Baulac S. Cardiac Investigations in Sudden Unexpected Death in DEPDC5-Related Epilepsy. Ann Neurol. 2022 Jan;91(1):101-116. doi: 10.1002/ana.26256. Epub 2021 Nov 16. PMID: 34693554; PMCID: PMC9299146.

Abstract

Objective: Germline loss-of-function mutations in DEPDC5, and in its binding partners (NPRL2/3) of the mammalian target of rapamycin (mTOR) repressor GATOR1 complex, cause focal epilepsies and increase the risk of sudden unexpected death in epilepsy (SUDEP). Here, we asked whether DEPDC5 haploinsufficiency predisposes to primary cardiac defects that could contribute to SUDEP and therefore impact the clinical management of patients at high risk of SUDEP.

Methods: Clinical cardiac investigations were performed in 16 patients with pathogenic variants in DEPDC5, NPRL2, or NPRL3. Two novel Depdc5 mouse strains, a human HA-tagged Depdc5 strain and a Depdc5 heterozygous knockout with a neuron-specific deletion of the second allele (Depdc5c/- ), were generated to investigate the role of Depdc5 in SUDEP and cardiac activity during seizures.

Results: Holter, echocardiographic, and electrocardiographic (ECG) examinations provided no evidence for altered clinical cardiac function in the patient cohort, of whom 3 DEPDC5 patients succumbed to SUDEP and 6 had a family history of SUDEP. There was no cardiac injury at autopsy in a postmortem DEPDC5 SUDEP case. The HA-tagged Depdc5 mouse revealed expression of Depdc5 in the brain, heart, and lungs. Simultaneous electroencephalographic-ECG records on Depdc5c/- mice showed that spontaneous epileptic seizures resulting in a SUDEP-like event are not preceded by cardiac arrhythmia.

Interpretation: Mouse and human data show neither structural nor functional cardiac damage that might underlie a primary contribution to SUDEP in the spectrum of DEPDC5-related epilepsies. ANN NEUROL 2022;91:101-116.