Neurofibromatosis 1 homozygosity

Alghamdi M, Monies D, Alsohime F, Temsah H, Almodaihsh F, Aldawasri M, Alsultan A, Alkuraya FS. Implications of mosaicism in variant interpretation: A case of a de novo homozygous NF1 variant. Eur J Med Genet. 2021 Jul;64(7):104236. doi: 10.1016/j.ejmg.2021.104236. Epub 2021 May 20. PMID: 33965620.

Abstract

Neurofibromatosis type 1 is a common multisystem autosomal dominant syndrome caused by pathogenic heterozygous variants in the neurofibromin gene (NF1). It is associated with a substantially increased cancer risk. Mosaicism for NF1 has been clinically well-established for "second hit" variants in skin lesions and tumor tissues. Here, we report on a 3-month-old boy with multiple café au lait macules (CAMs) and juvenile myelomonocytic leukemia (JMML) who was found to carry a previously established pathogenic NF1 variant (c.586+5G>A), as revealed by whole-exome sequencing. Surprisingly, however, this variant was detected in the homozygous state in the patient and was absent in the parents and siblings. Deep sequencing of this variant using blood, buccal swabs and skin samples was performed. As expected for an NF1 gene mutation promoting JMML, the variant was detected in 90.6% of the blood DNA reads, in sharp contrast to the mere 5% and 0.74% of reads in the saliva- and skin fibroblast-derived DNA, respectively. Our analysis, therefore, confirmed postzygotic origin of the variant followed by a mitotic event resulting in its homozygosity, although we could not differentiate between the possibilities of a gene conversion and mitotic crossover. Apparently de novo homozygous variants should trigger a careful investigation into mosaicism to achieve accurate interpretation.

Schinzel-Giedion syndrome

Inspired by a patient

Liu WL, He ZX, Li F, Ai R, Ma HW. Schinzel-Giedion syndrome: a novel case, review and revised diagnostic criteria. J Genet. 2018 Mar;97(1):35-46. PMID: 29666323.

Abstract

Schinzel-Giedion syndrome (SGS) is a rare autosomal dominant inheritance disorder. Heterozygous de novo mutations in the SETBP1 gene have been identified as the genetic cause of SGS. Here, we report a novel case with the syndrome with a novel insertion mutation in SETBP1. We also present a review of SGS cases, and first revise diagnostic criteria of SGS based on clinicalfindings and/or SETBP1 mutation worldwide. A revised diagnostic criteria and typing of SGS can be determined. Type I (complex and classic type) SGS patients present a development delay and typical facial features (prominent forehead, midface retraction, and short and upturned nose) associated with hydronephrosis or two of the characteristic skeletal anomalies (a sclerotic skull base, wideoccipital synchondrosis, increased cortical density or thickness, and broad ribs). Type II (middle type) patients show development delay and the distinctive facial phenotype (midface retraction, short and upturned nose), lacking both hydronephrosis and typical skeletal abnormalities, with existence of SETBP1mutation. Type III (simple type) patients with SETBP1 alteration show their major symptom is development delay, in which expressive language delay is the most striking feature. Central nervous system involvement with development delay in which expressive language delay is much more obviously affected is the most prominent feature of SGS. There is another indication that severity of phenotype of SGS may be inversely correlated with degree of SETBP1 alteration, besides gain-of-function or dominant-negative effects in SETBP1 alteration causing SGS.

Duis J, van Bon BWM. Schinzel-Giedion Syndrome. 2024 Mar 7. 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: 38452171.

Excerpt

Clinical characteristics: Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), hypotonia, spasticity, dysautonomia, hearing loss, and cerebral visual impairment. Other findings can include poor weight gain often associated with gastroesophageal reflux disease, chronic vomiting, constipation, gastroparesis, and/or feeding intolerance. Structural malformations can involve the heart, skeleton, kidney and urinary tract, genitalia, and brain. Anomalies of the liver, spleen, and/or pancreas are less common. Other features may include neuroepithelial neoplasia, severely disrupted sleep, choanal stenosis, inguinal hernia, sensitive skin, and increased risk of infection.

To date, more than 50 individuals have been reported with molecularly confirmed classic SGS.

Atypical SGS, reported in five individuals to date, is caused by pathogenic SETBP1 variants in proximity to – but not within – the mutational hot spot. The broad spectrum of clinical features of variable severity partially overlaps with classic SGS; however, this spectrum does not include risk for neuroepithelial neoplasia to date.

Diagnosis/testing: The diagnosis of classic SGS can be established in a proband based on published clinical diagnostic criteria, or the molecular diagnosis can be established in a proband with suggestive findings and a heterozygous SETBP1 pathogenic gain-of-function variant within the mutational hot spot (i.e., a 12-base-pair region in exon 4 encoding a canonical degron). The diagnosis of atypical SGS syndrome is established in a proband with suggestive findings and a heterozygous SETBP1 pathogenic variant adjacent to – but not within – the mutational hot spot.

Management: Treatment of manifestations: There is no cure for classic or atypical SGS. Supportive treatment to improve quality of life, maximize function, and reduce complications can include multidisciplinary care by specialists in pediatrics, neurology, physiatry, occupational and physical therapy, speech-language pathology, psychiatry, ophthalmology, ENT, surgery, pulmonology, oncology, urology, nephrology, audiology, gastroenterology, orthopedics, cardiology, and medical genetics.

Surveillance: At each visit, evaluate for feeding issues (including nutritional status and safety of oral intake), gastrointestinal issues, respiratory issues, neurologic manifestations (including seizures, changes in tone, movement disorders, mood, irritability, and alertness), kidney and urinary tract manifestations, and musculoskeletal manifestations. In individuals with classic SGS, age-related surveillance for occurrence of neoplasia includes liver ultrasound and serum alpha-fetoprotein levels, renal ultrasound examination, pelvic MRI for sacrococcygeal teratoma, and monitoring for clinical signs of leukemia.

Agents/circumstances to avoid: Nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs and vancomycin should be used with caution due to high frequency of chronic renal impairment from recurrent pyelonephritis and structural renal anomalies.

Genetic counseling: Classic and atypical SGS are autosomal dominant disorders typically caused by a de novo SETBP1 pathogenic variant. Rarely, individuals diagnosed with SGS have the disorder as the result of a pathogenic variant inherited from a parent. Sib recurrence of clinically defined classic SGS, presumed to be due to parental germline mosaicism, has been reported in two families. Transmission of a SETBP1 pathogenic missense variant from an unaffected parent to a child with atypical SGS has been reported in one family (of note, the possibility of mosaicism in the unaffected parent was not excluded). Once the SETBP1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Morison LD, Summerfield N, Bradley D, van Bon BW, Morgan AT. Schinzel-Giedion syndrome: communication, feeding and motor skills in 16 individuals. Neurogenetics. 2025 Aug 27;26(1):64. doi: 10.1007/s10048-025-00846-3. PMID: 40859069; PMCID: PMC12380911.

Abstract

Schinzel-Giedion Syndrome (SGS) is a rare neurodevelopmental disorder caused by pathogenic SETBP1 gain-of-function variants. SGS medical features have been well described. Associated skills critical to quality of life have such as communication, feeding, and motor skills are yet to be characterised. Here we used standardised caregiver report tools to characterise these skills as well as the medical features, in 16 children with SGS (median = 5 years, 7 months, range 6 months to 12.5 years). Vineland-3 scores reflected severe impairment in communication, daily living, socialisation and motor skills. Average receptive and expressive language skills were equivalent to a 0-to-1-month-old. Average motor skills were slightly stronger with age equivalents of 2-months-old for gross motor skills and 4-months for fine motor skills. 13/16 (81%) children could attend to someone's voice, and 15/16 (94%) could make happy vocalisations. One individual (6%) could follow basic instructions. Despite a relatively homogenous phenotype, some children presented with relative strengths when compared to the rest of the cohort. Our expanded phenotype of SGS allows better targeted therapies and supports, highlighting the importance of early feeding intervention and augmentative and alternative communication (e.g., assistive technology for communication). Given the severity of the SGS profile, our data highlight the need for sensitive measurement tools for detecting subtle skill changes in SGS in response to precision medicine interventions.

2q13 duplication

Inspired by a colleague's patient

Messina C, Zuccarello M. Parietal Lobe Epilepsy Associated With 2q13 Duplication: Expanding the Neurogenetic Spectrum. Cureus. 2025 Aug 19;17(8):e90456. doi: 10.7759/cureus.90456. PMID: 40979016; PMCID: PMC12444579.

Abstract

Copy number variations (CNVs) involving the 2q13 region have been associated with a wide range of phenotypes, including developmental delay, dysmorphic features, hypotonia, and congenital heart defects. However, parietal lobe epilepsy has not yet been reported in association with 2q13 duplication. We describe the case of a 20-year-old woman with a duplication of the 2q13 region identified during childhood, who later presented with recurrent, brief episodes of right upper limb paresthesia spreading to other limbs, followed by transient pain. Her past medical history included dyspraxia, polycystic ovary syndrome, atrial fibrillation, and intellectual disability. Electroencephalography (EEG) revealed interictal epileptiform discharges, consisting of paroxysmal sharp theta waves in the left parietal and temporal regions, spreading to adjacent and contralateral areas, particularly during hyperventilation. Based on clinical and EEG features, a diagnosis of parietal lobe epilepsy was established. Treatment with levetiracetam resulted in significant clinical improvement, characterized by complete resolution of the previously described episodes of recurrent, brief right upper limb paresthesia spreading to other limbs, followed by transient pain, as well as a reduction of epileptiform abnormalities on EEG. The duplicated region includes several genes involved in neuronal development, synaptic regulation, and myelination, such as MERTK, TMEM87B, and FBLN7. Their altered expression may contribute to cortical excitability and epileptogenesis. This case adds to the phenotypic variability reported in individuals with 2q13 duplication and underscores the importance of further studies to explore possible gene-specific contributions to neurological findings. This is the first report linking 2q13 duplication with parietal epilepsy, underlining the importance of considering CNVs in unexplained focal epilepsy presentations.

Digilio MC, Dentici ML, Loddo S, Laino L, Calcagni G, Genovese S, Capolino R, Bottillo I, Calvieri G, Dallapiccola B, Marino B, Novelli A, Versacci P. Congenital heart defects in the recurrent 2q13 deletion syndrome. Eur J Med Genet. 2022 Jan;65(1):104381. doi: 10.1016/j.ejmg.2021.104381. Epub 2021 Nov 8. PMID: 34763108.

Abstract

The recurrent 2q13 deletion syndrome is a rare genetic disorder associated with developmental delay, cardiac and urogenital malformations, and minor facial anomalies. Congenital heart defects (CHDs) are the most frequent malformations associated with del2q13. Experimental studies in zebrafish suggest that two genes mapping within the 2q13 critical region (FBLN7 and TMEM87B) could confer susceptibility to congenital heart defects in affected individuals. We reviewed the cardiac characteristics in four patients with 2q13 deletion admitted to our hospitals, and in published patients. Two of our patients had congenital heart defects, consisting in partial anomalous pulmonary venous connection, ostium secundum atrial septal defect ostium secundum, and small muscular ventricular septal defect in one of them, and aortic valve insufficiency with partial fusion of two commissures (incomplete bicuspid aortic valve) and mitral valve insufficiency due to trivial mitral valve prolapse in the other. The anatomic types of CHD in del2q13 syndrome are highly variable and distributed widely, including laterality defects, complex atrioventricular septal defect, septal anomalies, and cardiomyopathies. Cardiac evaluation should be part of the clinical workup at diagnosis of 2q13 deletion.

Riley KN, Catalano LM, Bernat JA, Adams SD, Martin DM, Lalani SR, Patel A, Burnside RD, Innis JW, Rudd MK. Recurrent deletions and duplications of chromosome 2q11.2 and 2q13 are associated with variable outcomes. Am J Med Genet A. 2015 Nov;167A(11):2664-73. doi: 10.1002/ajmg.a.37269. Epub 2015 Jul 31. PMID: 26227573.

Abstract

Copy number variation (CNV) in the long arm of chromosome 2 has been implicated in developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD), congenital anomalies, and psychiatric disorders. Here we describe 14 new subjects with recurrent deletions and duplications of chromosome 2q11.2, 2q13, and 2q11.2-2q13. Though diverse phenotypes are associated with these CNVs, some common features have emerged. Subjects with 2q11.2 deletions often exhibit DD, speech delay, and attention deficit hyperactivity disorder (ADHD), whereas those with 2q11.2 duplications have DD, gastroesophageal reflux, and short stature. Congenital heart defects (CHDs), hypotonia, dysmorphic features, and abnormal head size are common in those with 2q13 deletions. In the 2q13 duplication cohort, we report dysmorphic features, DD, and abnormal head size. Two individuals with large duplications spanning 2q11.2-2q13 have dysmorphic features, hypotonia, and DD. This compilation of clinical features associated with 2q CNVs provides information that will be useful for healthcare providers and for families of affected children. However, the reduced penetrance and variable expressivity associated with these recurrent CNVs makes genetic counseling and prediction of outcomes challenging. © 2015 Wiley Periodicals, Inc.

Costain G, Lionel AC, Fu F, Stavropoulos DJ, Gazzellone MJ, Marshall CR, Scherer SW, Bassett AS. Adult neuropsychiatric expression and familial segregation of 2q13 duplications. Am J Med Genet B Neuropsychiatr Genet. 2014 Jun;165B(4):337-44. doi: 10.1002/ajmg.b.32236. Epub 2014 May 8. PMID: 24807792; PMCID: PMC4464821.

Abstract

New genomic disorders associated with large, rare, recurrent copy number variations (CNVs) are being discovered at a rapid pace. Detailed phenotyping and family studies are rare, however, as are data on adult phenotypic expression. Duplications at 2q13 were recently identified as risk factors for developmental delay/autism and reported in the prenatal setting, yet few individuals (all children) have been extensively phenotyped. During a genome-wide CNV study of schizophrenia, we identified two unrelated probands with 2q13 duplications. In this study, detailed phenotyping and genotyping using high-resolution microarrays was performed for 12 individuals across their two families. 2q13 duplications were present in six adults, and co-segregated with clinically significant later-onset neuropsychiatric disorders. Convergent lines of evidence implicated GABAminergic dysfunction. Analysis of the genic content revealed promising candidates for neuropsychiatric disease, including BCL2L11, ANAPC1, and MERTK. Intrafamilial genetic heterogeneity and "second hits" in one family may have been the consequence of assortative mating. Clinical genetic testing for the 2q13 duplication and the associated genetic counseling was well received. In summary, large rare 2q13 duplications appear to be associated with variable adult neuropsychiatric and other expression. The findings represent progress toward clinical translation of research results in schizophrenia. There are implications for other emerging genomic disorders where there is interest in lifelong expression.

Early diagnostic changes in autism spectrum disorder

Yeom JS, Kim YS, Park JS, Park ES, Seo JH, Lim JY, Woo HO. Early Diagnostic Changes in Autism Spectrum Disorder: A Retrospective Study. Ann Child Neurol. 2026;34(2):136-143.

Abstract

Purpose
Autism spectrum disorder (ASD) exhibits heterogeneous developmental trajectories; however, longitudinal studies using the Korean Childhood Autism Rating Scale (K-CARS) are scarce. This study examined diagnostic changes and related developmental characteristics through repeated K-CARS assessments.

Methods
We retrospectively reviewed the medical records of children who underwent repeated K-CARS assessments between May 2021 and December 2024 at Gyeongsang National University Hospital. Based on diagnostic status at the initial (T1) and follow-up (T2) evaluations, participants were classified as having persistent ASD (ASD at T1 and T2), emerging ASD (non-ASD at T1 but ASD at T2), or desisting ASD (ASD at T1 but non-ASD at T2). Developmental profiles were evaluated using the social quotient (SQ), visual-motor integration (VMI), and language quotients.

Results
Forty-three children (32 boys; median age, 2.9 years at T1 and 4.3 years at T2) were included. Twenty-two met ASD criteria at T1, and 15 (68%) retained the diagnosis at T2. Across the cohort, 15 (35%) had persistent ASD, 21 (49%) had emerging ASD, and seven (16%) had desisting ASD. The desisting group showed higher baseline VMI and better outcomes at follow-up. The emerging group initially had higher SQ and VMI than the persistent group, but these differences disappeared over time. Higher baseline VMI was associated with desisting status and higher baseline SQ with emerging ASD (odds ratios, 3.14 and 2.59 per standard deviation increase, respectively; P=0.06 and P=0.07).

Conclusion
Early ASD diagnoses were generally stable yet variable, supporting repeated assessment. Baseline VMI and SQ may relate to later diagnostic changes.

KIF1A associated neurological disorder (KAND)

Father shares daughter’s rare neurological disorder, partnership with Murdoch research center

KIF1A.org founder Luke Rosen discusses his daughter’s battle with a rare neurological disorder and the Murdoch Children’s Research Institute’s work to advance potential treatments on ‘Fox & Friends.’

KIF1A Associated Neurological Disorder (KAND) is a rare, progressive neurodegenerative disorder often described as a form of childhood dementia that currently has no cure, but researchers at the Murdoch Children’s Research Institute (MCRI) in Australia are working to change that.

"[Their research] is helping all of the kids, which is really incredible," said Luke Rosen, founder of KIF1A.org, whose daughter Susannah was diagnosed with the disorder at age 2.

"And the folks at Murdoch, I say they're extended family to us, and they really are."

KAND is a severe and progressive condition. Children can experience seizures and, over time, lose cognitive function, motor skills and vision. The disorder affects each patient differently, often making it difficult to diagnose.

Rosen said what sets MCRI apart is its personal approach — with researchers taking the time to truly know the families they’re trying to help.

"The first thing [a researcher] said to me is, 'How's Susannah? How's she doing?' And he really got to know our family, and he travels and so does their whole team... to our yearly Scientific and Family Conference, so they really get to meet all the families."

A new Fox Nation special spotlights MCRI’s work, as well as families like the Rosens who are working with researchers to treat the debilitating disorder.

Rosen has since dedicated his life to advancing research and finding treatment options. He works closely with MCRI in an effort that is already showing promise.

Susannah was among the first patients to receive antisense oligonucleotide (ASO) therapy, and her family says they’ve seen meaningful improvements in her condition.

While the treatment is not yet approved in Australia, Rosen continues working with doctors to expand access with the hope that, eventually, families won’t have to travel for care.

"Their research is really translational research that helps everybody," Rosen said.

"While we don't have a therapeutic yet from Australia, they're really working hard to develop it, and they're accelerating that entire process. What's special about Murdoch is they work in multimodalities, so there's gene therapy and then traditional drug development, and then they work non-sequentially, and they are just trying to throw as many shots on goal as we can for the kids."

"Hope Starts Here," hosted by Fox News' Benjamin Hall, is available now on Fox Nation.

Taylor Penley

https://www.foxnews.com/media/researchers-race-treat-rare-childhood-dementia-cure-giving-families-new-hope

Lin Q, Verden D, Christodoulou J, Gold WA, Kaur S. KIF1A-associated neurological disorders: therapeutic opportunities and challenges. Eur J Hum Genet. 2025 Nov 27. doi: 10.1038/s41431-025-01978-8. Epub ahead of print. PMID: 41310149.

Abstract

KIF1A-Associated Neurological Disorder (KAND) is a rare, progressive neurodegenerative condition caused by variants in the KIF1A gene, which encodes a kinesin-3 motor protein essential for anterograde axonal transport of synaptic vesicles, dense core vesicles, and organelles in neurons. KAND comprises a broad spectrum of overlapping neurological phenotypes, including hereditary spastic paraplegia, intellectual disability, peripheral neuropathy, optic nerve atrophy, epilepsy, and progressive motor decline. Pathogenic variants in KIF1A disrupt the balance of intracellular transport and neuronal signalling through diverse mechanisms, manifesting with highly variable disease onset, severity, and clinical progression. Although advances in genomic testing have improved diagnosis, reported KAND cases remain concentrated in developed countries, highlighting ongoing global inequities in access to diagnosis and care. At present, no cure exists for KAND; treatment is limited to symptom management. A deeper understanding of KIF1A function, supported by the development of robust cellular and animal models, is critical for therapeutic development. This review summarises the clinical and molecular features of KAND and highlights current and emerging strategies aimed at slowing disease progression or correcting its underlying causes. We emphasise the urgent need for targeted treatment strategies addressing the heterogeneity of KAND.

Chen Z, Chai Y, Guo Z, Fu X, Li W, Zhang J, Ou G, Wang H. Allele-specific conformational rescue of KIF1A T99M by genetic suppressors in a C. elegans model of KIF1A-associated neurological disorder. J Cell Sci. 2025 Oct 1;138(19):jcs264216. doi: 10.1242/jcs.264216. Epub 2025 Oct 14. PMID: 40964787.

Abstract

KIF1A-associated neurological disorder (KAND) arises from mutations in the microtubule motor KIF1A, disrupting synaptic vesicle transport. Here, we investigate the pathogenic T99M substitution in the P-loop of KIF1A, which induces steric hindrance, impairing ATP/ADP coordination and motor activity. Using CRISPR-engineered Caenorhabditis elegans expressing the homologous UNC-104(T95M) mutation, we conducted forward genetic screens and identified recurrent intragenic suppressors (T95V and T95I; T95V/I) that restored animal motility and synaptic vesicle distribution. Molecular dynamics simulations revealed that replacing the methionine residue with valine or isoleucine residues alleviated steric clashes in the nucleotide-binding pocket and stabilized Mg2+-ATP coordination. Biochemical assays showed that T95V/I partially recovered microtubule gliding velocity and processivity, demonstrating that even modest motor reactivation mitigates neuronal dysfunction. Inspired by prior success showing that treatment with the plant flavonol fisetin rescues the effects of the KIF1A R11Q variant, we propose allele-specific conformational stabilization as a therapeutic strategy for KAND. Our findings highlight the structural plasticity of motor domains and provide a framework for precision therapies targeting pathogenic variants through genetic suppressors.

See: https://childnervoussystem.blogspot.com/2020/01/kif1a-mutations.html

Adjunctive cannabidiol in intractable pediatric epilepsy

Shim Y, Yang DH, Byeon JH, Eun BL. Adjunctive cannabidiol in intractable pediatric epilepsy: A retrospective study on tolerability, efficacy, and safety across genetic and nongenetic etiologies. Medicine (Baltimore). 2026 Jan 30;105(5):e47425. doi: 10.1097/MD.0000000000047425. PMID: 41630268; PMCID: PMC12863898.

Abstract

This retrospective cohort study evaluated the tolerability, efficacy, and safety of adjunctive cannabidiol (CBD) therapy in pediatric-onset intractable epilepsy across diverse genetic and nongenetic etiologies. Twenty-nine patients aged 6 to 24 years, treated at Korea University Hospitals between April 2019 and May 2024, were included. The median follow-up duration was 14.3 months. Confirmed genetic etiologies included SCN1A-related epilepsy (6.9%); GABRB3-, SCN2A-, KCNT1-, KIF1A-, and COL4A1-related epilepsies (3.4% each); Angelman syndrome and Down syndrome (3.4% each). Presumed genetic etiologies included hemimegalencephaly (3.4%) and cortical dysplasia (6.9%). Acquired causes included hypoxic brain injury (6.9%) and CNS infection (10.3%). In 41.4% of cases, the etiology was unidentified; among them, 58.3% had a history of infantile spasms. At CBD initiation, patients were receiving a median of 5 antiseizure medications, most commonly valproic acid (93.1%), clobazam (82.8%), and levetiracetam (75.9%). The median maintenance dose of CBD was 14.2 mg/kg/d. The retention rate was above 86% at both 12 and 24 months. At 12 months, 79.3% achieved a ≥50% reduction in seizure frequency, and 34.5% achieved a ≥75% reduction without generalized motor seizures. One patient with a GABRB3 variant achieved seizure freedom. Adverse events occurred in 37.9%, most commonly somnolence and lethargy. These were mild and resolved with antiseizure medication adjustments. CBD was discontinued in 3 patients due to pneumonia, lethargy, or seizure aggravation. CBD therapy demonstrated favorable retention, efficacy, and safety profiles in pediatric-onset intractable epilepsy across a spectrum of etiologies.

González-Alguacil E, García Peñas JJ, Lamagrande Casanova N, Santana Cabrera EM, Duat Rodríguez A, Soto Insuga V. Cannabidiol as Adjunctive Treatment in Drug-Resistant Epilepsy With Epileptic Spasms Beyond Two Years of Age. Pediatr Neurol. 2026 Jan;174:81-85. doi: 10.1016/j.pediatrneurol.2025.10.013. Epub 2025 Oct 24. PMID: 41197417.

Abstract

Background: To assess the efficacy and safety of adjunctive cannabidiol (CBD) in children with drug-resistant epileptic spasms (ES) beyond age 2 years.

Methods: We conducted a retrospective longitudinal study of patients with childhood epileptic spasms (CESs) treated with purified CBD (Epidyolex) at Niño Jesus Hospital in Madrid, Spain, from 2020 to 2024. All patients were older than 2 years and had drug-resistant epilepsy and ES as the primary seizure type. Efficacy was assessed by comparing ES frequency before and after CBD treatment, with a good response defined as a ≥50% reduction in ES. Adverse effects (AEs) were recorded to assess safety and tolerability.

Results: Of the 53 patients included, 58.5% achieved a ≥50% reduction in ES frequency, 15% of whom attained complete freedom from ES. Patients with malformations of cortical development and Down syndrome showed the highest response rates. Clobazam was the most frequently associated medication (77.3%), indicating a potential synergistic effect. AEs were reported in 62.2% of patients, with drowsiness, hyperammonemia, and behavioral disturbances being the most common. CBD was discontinued in 17% due to lack of efficacy and in 11.3% due to AEs.

Conclusions: CBD appears to be an effective and well-tolerated adjunctive treatment for drug-resistant ES in children older than 2 years. Significant response rates were found, particularly in patients with Down syndrome and malformations of cortical development. Future studies with larger cohorts and longer follow-up are needed to validate these findings and explore the potential for earlier use of CBD in treatment-resistant epilepsy.

Herlopian A, Hess EJ, Barnett J, Geffrey AL, Pollack SF, Skirvin L, Bruno P, Sourbron J, Thiele EA. Cannabidiol in treatment of refractory epileptic spasms: An open-label study. Epilepsy Behav. 2020 May;106:106988. doi: 10.1016/j.yebeh.2020.106988. Epub 2020 Mar 10. PMID: 32169600.

Abstract

Objective: This study aimed to evaluate clinical efficacy and safety of purified pharmaceutical cannabidiol (CBD) as an adjunctive therapy in refractory childhood-onset epileptic spasms (ES).

Methods: Nine patients with ES were enrolled in an Institutional Review Board (IRB)- and Food and Drug Administration (FDA)-approved expanded access investigational new drug trial. Patients received plant-derived highly purified CBD in oral solution in addition to their baseline medications at an initial dosage of 5 mg/kg/day, which was increased by 5 mg/kg/day every week to an initial target dosage of 25 mg/kg/day. Seizure frequency, adverse event, and parents' subjective reports of cognitive and behavioral changes were recorded after 2 weeks and 1, 2, 3, 6, 9, and 12 months of CBD treatment. Responder rates (percent of patients with >50% reduction in ES frequency from baseline) were calculated. Electrographic changes were studied in relation to CBD initiation and clinical response.

Results: Overall, the responder rates in 9 patients were 67%, 78%, 67%, 56%, 78%, 78%, and 78% after 2 weeks and 1, 2, 3, 6, 9, and 12 months of CBD treatment, respectively. Three out of nine patients (33%) were ES free after two months of treatment. Parents reported subjective improvements in cognitive and behavioral domains. Side effects, primarily drowsiness, were seen in 89% of patients (n = 8). Eight of the nine (89%) patients had electroencephalographic (EEG) studies prior to and after initiation of CBD. Three out of five patients (60%) had resolution in their hypsarrhythmia pattern.

Significance: Purified pharmaceutical CBD may be an effective and safe adjunctive therapy in refractory ES and may also be associated with improvements in electrographic findings.

Disease-modifying therapies for Rett syndrome

Samanta D. Disease-modifying therapies for Rett syndrome: a review for neurologists. Front Neurol. 2026 Jan 20;17:1766679. doi: 10.3389/fneur.2026.1766679. PMID: 41641323; PMCID: PMC12864443.

Abstract

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder affecting approximately 1 in 10,000-15,000 females, most often caused by loss-of-function mutations in MECP2. Until the recent approval of trofinetide, management relied exclusively on symptomatic treatment and multidisciplinary supportive care. The therapeutic landscape is now undergoing a rapid shift, driven by multiple gene therapy approaches designed to restore functional MeCP2 expression and achieve true disease modification. As these therapies progress toward potential regulatory approval, neurologists will play central roles in identifying eligible patients, counseling families, supporting clinical trial enrollment, delivering treatments, monitoring long-term outcomes, and advocating for equitable access. This review provides neurologists with the essential framework needed to understand and navigate this evolving field. We examine in detail the two most advanced gene replacement therapies currently in clinical trials. TSHA-102 uses an intrathecally delivered miniMECP2 transgene regulated by a microRNA-based autoregulatory system, whereas NGN-401 delivers full-length MECP2 via intracerebroventricular administration using a synthetic expression-feedback circuit. Both approaches have shown encouraging early efficacy, with treated children achieving developmental gains that exceed natural history expectations. However, they differ substantially in molecular design, regulatory control, delivery method, and safety considerations. We also highlight challenges unique to RTT gene therapy, including the narrow therapeutic window between insufficient expression and MeCP2 overexpression toxicity, the impact of X-chromosome inactivation mosaicism, and lessons learned from a fatal hyperinflammatory adverse event. Beyond AAV-mediated gene replacement, we review next-generation strategies in preclinical development-CRISPR-Cas9 genome editing for permanent mutation correction, ADAR-based RNA editing, translation readthrough for nonsense variants, and X-chromosome reactivation to restore endogenous MECP2 expression. Finally, we address key translational considerations such as optimal timing of intervention, dosing constraints, outcome measurement in severely impaired populations, long-term safety surveillance, and barriers to broad and equitable access. The RTT gene therapy experience serves as a model for precision medicine in other monogenic neurodevelopmental disorders, illustrating both the transformative promise and the substantial complexities of translating genetic science into meaningful clinical benefit.

Percy AK, Ananth A, Neul JL. Rett Syndrome: The Emerging Landscape of Treatment Strategies. CNS Drugs. 2024 Nov;38(11):851-867. doi: 10.1007/s40263-024-01106-y. Epub 2024 Sep 9. PMID: 39251501; PMCID: PMC11486803.

Abstract

Rett syndrome (RTT) has enjoyed remarkable progress in achieving specific therapies. RTT, a unique neurodevelopmental disorder first described in 1966, progressed slowly until the landmark paper of Hagberg and colleagues in 1983. Thereafter, rapid advances were achieved including the development of specific diagnostic criteria and the active search for a genetic etiology, resulting 16 years later in identification of variants in the methyl-CpG-binding protein (MECP2) gene located at Xq28. Shortly thereafter, the NIH Office of Rare Diseases funded the RTT Natural History Study (NHS) in 2003, initiating the acquisition of natural history data on clinical features from a large population of individuals with RTT. This information was essential for advancement of clinical trials to provide specific therapies for this disorder. In the process, the International Rett Syndrome Association (IRSA) was formed (now the International Rett Syndrome Foundation-IRSF), which participated directly in encouraging and expanding enrollment in the NHS and, subsequently, in developing the SCOUT program to facilitate testing of potential therapeutic agents in a mouse model of RTT. The overall objective was to review clinical characteristics developed from the NHS and to discuss the status of specific therapies for this progressive neurodevelopmental disorder. The NHS study provided critical information on RTT: growth, anthropometrics, longevity, key comorbidities including epilepsy, breath abnormalities, gastroesophageal dysfunction, scoliosis and other orthopedic issues, puberty, behavior and anxiety, and progressive motor deterioration including the appearance of parkinsonian features. Phenotype-genotype correlations were noted including the role of X chromosome inactivation. Development of clinical severity and quality of life measures also proved critical for subsequent clinical trials. Further, development of biochemical and neurophysiologic biomarkers offered further endpoints for clinical trials. Initial clinical trials prior to the NHS were ineffective, but advances resulting from the NHS and other studies worldwide promoted significant interest from pharmaceutical firms resulting in several clinical trials. While some of these have been unrewarding such as sarizotan, others have been quite promising including the approval of trofinetide by the FDA in 2023 as the first agent available for specific treatment of RTT. Blarcamesine has been trialed in phase 3 trials, 14 agents have been studied in phase 2 trials, and 7 agents are being evaluated in preclinical/translational studies. A landmark study in 2007 by Guy et al. demonstrated that activation of a normal MECP2 gene in a null mouse model resulted in significant improvement. Gene replacement therapy has advanced through translational studies to two current phase 1/2 clinical trials (Taysha102 and Neurogene-401). Additional genetic therapies are also under study including gene editing, RNA editing, and X-chromosome reactivation. Taken together, progress in understanding and treating RTT over the past 40 years has been remarkable. This suggests that further advances can be expected.