RORA encodes the RAR-related orphan receptor-α, playing a pivotal role in cerebellar maturation and function. Here, we report the largest series of individuals with RORA-related-neurodevelopmental disorder. Forty individuals (30 unrelated; 10 siblings from 4 families) carrying RORA pathogenic/likely pathogenic variants were collected through an international collaboration. The 33 variants (29 de novo, 4 inherited, and 1 shared), identified by genome/exome sequencing (n = 21), chromosomal microarray analysis (n = 7), or gene panels (n = 4), included frameshift (n = 18/33), missense (n = 9/33), and stop codon (n = 6/33). Developmental disability (n = 32/37), intellectual disability (n = 22/32), and cerebellar signs (n = 25/34) were the most striking clinical features. Cerebellar symptoms were divided into early-onset, late-onset, and progressive subgroups. Cerebellar hypoplasia, atrophy, or both (n = 16/25) were more frequent in individuals with missense variants in the DNA-binding domain. Epilepsy (n = 18/38), with prominent myoclonic seizure types (n = 11/18), was classified in (1) genetic generalized epilepsy (n = 10/18) with a syndromic diagnosis identifiable for 6: epilepsy with eyelid myoclonia (n = 5/6) and epilepsy with myoclonic absence (n = 1/6); (2) developmental and epileptic encephalopathy (n = 5/18); and (3) unclassified (n = 3/18). A participant with rapid deterioration of visual acuity and cone/rod dystrophy was reported. Missense variants in DNA-binding domain correlate to a more severe cerebellar phenotype. The RORA-related-neurodevelopmental disorder triad comprises developmental disability, cerebellar features, and a spectrum of myoclonic epilepsy.

Doublecortin, encoded by the DCX gene, plays a crucial role in the neuronal migration process during brain development. Pathogenic variants of the DCX gene are the major causes of the “lissencephaly (LIS) spectrum”, which comprehends a milder phenotype like Subcortical Band Heterotopia (SBH) in heterozygous female subjects. We performed targeted sequencing in three unrelated female cases with SBH. We identified three DCX-related variants: a novel missense (c.601A>G: p.Lys201Glu), a novel nonsense (c.210C>G: p.Tyr70*), and a previously identified nonsense (c.907C>T: p.Arg303*) variant. The novel c.601A>G: p.Lys201Glu variant shows a mother–daughter transmission pattern across four generations. The proband exhibits focal epilepsy and achieved seizure freedom with a combination of oxcarbazepine and levetiracetam. All other affected members have no history of epileptic seizures. Brain MRIs of the affected members shows predominant fronto-central SBH with mixed pachygyria on the overlying cortex. The two nonsense variants were identified in two unrelated probands with SBH, severe drug-resistant epilepsy and intellectual disability. These novel DCX variants further expand the genotypic–phenotypic correlations of lissencephaly spectrum disorders. Our documented phenotypic descriptions of three unrelated families provide valuable insights and stimulate further discussions on DCX-SBH cases.

Parkinson’s disease (PD) and essential tremor with resting tremor (rET) show a remarkable symptom overlap that complicates the clinical differentiation and highlights the need for easily assessable diagnostic biomarkers. Neuronally derived extracellular vesicles (NDEVs) have been suggested as a peripheral substrate providing insights on the central nervous system pathology. Here, we assessed the accuracy of NDEV neurofilament light chain (Nf-L) levels in discriminating between PD and rET patients. Thirty-three PD and 13 rET patients and 30 healthy controls (HC) were consecutively enrolled in the study. NDEVs were obtained from serum through size exclusion chromatography followed by immunocapture based on L1CAM expression. NDEV Nf-L levels were quantified by ELISA on Ella Platform. Receiver operator characteristic (ROC) analysis was performed to investigate the NDEV Nf-L classification performance. Associations between NDEV Nf-L and demographical or clinical variables were investigated with Spearman’s method. NDEV Nf-L levels were significantly higher in PD compared to rET patients and HC, and achieved an excellent classification performance in distinguishing PD from both rET and HC (AUC: 0.902 and 0.987, respectively). No differences were observed between rET and HC. A significant negative association between NDEV Nf-L and sex was detected in rET patients. Our pilot study suggests that NDEV Nf-L might be a useful blood-derived biomarker helping the differential diagnosis between PD and rET patients. Future studies are needed to validate these findings in larger independent cohorts.

Objectives: Myotonia is a clinical sign typical of a group of skeletal muscle channelopathies, the non-dystrophic myotonias. These disorders are electrophysiologically characterized by altered membrane excitability, due to specific genetic variants in known causative genes (CLCN1 and SCN4A). Juvenile Myoclonic Epilepsy (JME) is an epileptic syndrome identified as idiopathic generalized epilepsy, its genetics is complex and still unclarified. The co-occurrence of these two phenotypes is rare and the causes likely have a genetic background. In this study, we have genetically investigated an Italian family in which co-segregates myotonia, JME, or abnormal EEG without seizures was observed. Methods: All six individuals of the family, 4 affected and 2 unaffected, were clinically evaluated; EMG and EEG examinations were performed. For genetic testing, Exome Sequencing was performed for the six family members and Sanger sequencing was used to confirm the candidate variant. Results: Four family members, the mother and three siblings, were affected by myotonia. Moreover, EEG recordings revealed interictal generalized sharp-wave discharges in all affected individuals, and two siblings were affected by JME. All four affected members share the same identified variant, c.644 T > C, p.Ile215Thr, in SCN4A gene. Variants that could account for the epileptic phenotype alone, separately from the myotonic one, were not identified. Significance: These results provide supporting evidence that both myotonic and epileptic phenotypes could share a common genetic background, due to variants in SCN4A gene. SCN4A pathogenic variants, already known to be causative of myotonia, likely increase the susceptibility to epilepsy in our family. Plain Language Summary: This study analyzed all members of an Italian family, in which the mother and three siblings had myotonia and epilepsy. Genetic analysis allowed to identify a variant in the SCN4A gene, which appears to be the cause of both clinical signs in this family.

Background: Febrile seizures (FSs) are the most common form of epilepsy in children aged between six months and five years. The exact cause is unknown, but several studies have demonstrated the importance of genetic predisposition, with increasing involvement of receptors and ion channels. The present study aims to identify novel pathogenic variants in Italian patients with FSs. Methods: We performed targeted panel sequencing in a cohort of 21 patients with FSs. In silico analysis was performed to predict the pathogenic role of the resulting variants. Results: We found two novel variants segregating in two families with FSs: c.1021C>G (p.Leu341Val) in the CHRNA2 gene and c.140A>G (p.Glu47Gly) in SCN2A. Conclusions: The c.1021C>G (p.Leu341Val) variant leads to a codon change of highly conserved leucine to valine at position 341 and is located in segments M3 of the subunit, which is important for channel gating. The c.140A>G (p.Glu47Gly) variant causes a substitution of glutamic acid with glycine at position 47 of the protein, which is highly conserved across the species. Moreover, it is located in the N-terminal domain, a region commonly affected in ASD, which impacts the inactivation kinetics and voltage dependence of steady-state activation. Further analyses are needed to better explain the role of CHRNA2 and SCN2A in the development of febrile seizures.

Background: Progressive supranuclear palsy (PSP) is a devastating 4‐repeat tauopathy with no approved disease‐modifying treatments. Recent evidence showed increased transforming growth factor‐β (TGF‐β) levels in PSP patient‐derived ventral midbrain organoids (vMOs) and serum neuronally derived exosomes. Objective: This study investigated whether TGF‐β pharmacological inhibition could mitigate PSP pathology in vMOs. Methods: Ninety‐six vMOs were generated from induced pluripotent stem cells from two PSP‐Richardson's syndrome patients and two healthy control donors (HCs). From day 60 to day 90, PSP organoids were (1) exposed to TGF‐β receptor I inhibitor (SB431542); (2) exposed to recombinant TGF‐β1, TGF‐β2, and TGF‐β3; or (3) untreated. At day 90, several tau species were assessed by immunoblotting; neurodegeneration was evaluated through TUNEL assay and immunofluorescence (tyrosine hydroxylase [TH], neurofilament light chain [NfL]); astrocytic activation (glial fibrillary acidic protein [GFAP]) marker was evaluated by immunofluorescence, and histopathological hallmarks were evaluated by immunohistochemistry. An HC‐derived organoid subgroup was exposed to the treatment conditions to assess potential toxicity. Results: At day 90, untreated PSP‐derived vMOs exhibited increased phosphorylated tau levels (Ser396, Thr181, Ser202/Ser205 [AT8]) compared with HC‐derived vMOs, dopaminergic neuron loss (reduced TH, increased NfL), and astrocytic reactivity (increased GFAP), along with PSP characteristic tau deposition. Tau hyperphosphorylation, neurodegeneration, and astrocytic reactivity were all markedly reduced in PSP‐derived vMOs treated with TGF‐β receptor I inhibitor. Conversely, exposure to TGF‐β exacerbated these features. No toxic effects were observed in HC vMOs exposed to treatment conditions. Conclusions: Pharmacological inhibition of TGF‐β signaling prevented key PSP molecular alterations in patient‐derived organoids. These findings support further research and pave the way for future investigation of TGF‐β–targeting strategies in clinical trials in patients with PSP. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.