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.

Background: Progressive Supranuclear Palsy (PSP) is a rare neurodegenerative disorder characterized by abnormal tau protein aggregation. The MAPT gene encodes for tau protein. The MAPT locus harbors two major haplotypes, H1 and H2, with H1 and its subhaplotypes being associated with an increased risk of PSP. Methods: In this study, we genotyped rs8070723 in a cohort of 73 PSP patients, including 47 PSP Richardson Syndrome (PSP-RS) and 27 PSP variants (vPSP), and 93 age-matched healthy controls (HC) from Southern Italy. Results: Haplotype analysis identified H1 and H2 haplotypes that conferred a risk (OR, 2.620; 95% CI, 1.399–5.140; p = 0.0035) and a protective effect (OR, 0.370; 95% CI, 0.196–0.695; p = 0.0015), respectively. In addition, we genotyped five MAPT variants (rs1467967, rs242557, rs3785883, rs2471738, and rs7521) that, together with rs8070723, defined H1 subhaplotypes. We identified 18 distinct MAPT H1 subhaplotypes, among which H1j displayed a nominally significant reduced risk of PSP (OR, 0.201; 95% CI, 0.044–0.915; p = 0.0265). Conclusions: These findings reinforce the role of MAPT genetic variation in PSP pathogenesis and highlight the potential impact of haplotype diversity on disease susceptibility.

Background: Hereditary transthyretin amyloidosis (ATTRv) is a systemic disorder caused by homozygosity or compound heterozygosity for pathogenic mutations in the TTR gene, leading to destabilization of the transthyretin tetramer, misfolding of monomers, and subsequent amyloid fibril deposition. Among over 150 known TTR variants, p.Val142Ile is particularly associated with late-onset cardiac involvement and is the most prevalent amyloidogenic mutation in individuals of African and, to a lesser extent, European descent. This study reports the identification and familial segregation of the p.Val142Ile mutation in a large multigenerational family from Calabria (Southern Italy). Methods: Genomic DNA was extracted from peripheral blood, and Sanger sequencing of the TTR gene was performed in the proband and extended family. Results: The proband was a 75-year-old man with clinical features suggestive of cardiac amyloidosis. Genetic testing revealed homozygosity for the TTR p.Val142Ile variant. Family screening revealed multiple heterozygous carriers across three generations, most of whom were asymptomatic. Discussion: This is the first report of a native Calabrian family carrying this variant, previously unreported in this region, where p.Phe84Leu was considered the only endemic TTR mutation. Our findings expand the mutational landscape of ATTRv in Southern Italy and highlight the presence of p.Val142Ile in a previously unrecognized geographic area. These results reinforce the importance of including TTR sequencing in the work-up of unexplained cardiomyopathy, particularly in Southern Italy, where atypical variants may be emerging.

Pathogenic KCNQ2 variants are associated with neonatal epilepsies, ranging from self-limited neonatal epilepsy to KCNQ2–developmental and epileptic encephalopathy (DEE). In this study, next-generation sequencing was performed, applying a panel of 142 epilepsy genes on three unrelated individuals and affected family members, showing a wide variability in the epileptic spectrum. The genetic analysis revealed two likely pathogenic missense variants (c.1378G>A and c.2251T>G) and the already-reported pathogenic splice site (c.1631+1G>A) in KCNQ2 (HGNC:6296). The phenotypes observed in the affected members of family 1, which shared the c.2251T>G variant, were epilepsy with auditory features (EAFs), focal epilepsy, and generalized epilepsy, and none of them suffered from neonatal seizures. The gene panel contained further genes related to EAFs (LGI1, RELN, SCN1A, and DEPDC5), which were tested with negative results. The phenotypes observed in family 2 members, sharing the splice site variant, were neonatal seizures and focal epilepsy in childhood. The last unrelated proband, harboring the de novo missense c.1378G>A, presented a clinical phenotype consistent with DEE. In conclusion, we identified two unreported KCNQ2 variants, and report a proband with EAFs and individuals without typical KCNQ2 neonatal seizures. Our study underscores the extreme variability in the phenotypic spectrum of KCNQ2-related epilepsies and unveils the prospect of its inclusion in screening panels for EAFs.

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.

Essential tremor (ET) is a common movement disorder increasingly recognized as a complex syndrome with neurodegenerative features. While mitochondrial dysfunction and cellular aging are implicated in several neurodegenerative diseases, their role in ET remains unexplored. To investigate mitochondrial DNA copy number (mtDNA-CN) and telomere length (TL) in patients with ET and evaluate their potential as biomarkers of mitochondrial dysfunction and biological aging. In this cross-sectional case–control study, 68 ET patients (median age 66 years; 64.7% male) and 62 healthy controls (median age 70 years; 54.8% male) were enrolled. Relative mtDNA-CN and TL were quantified by quantitative PCR, measuring mitochondrial ND1 gene levels and telomere-to-single-copy gene (T/S) ratio, respectively, both normalized to β-actin. Associations with disease status were assessed using age- and sex-adjusted multivariable linear regression on log₂-transformed data, with statistical significance defined as p < 0.05 after false discovery rate (FDR)-corrected Wald tests. Receiver operating characteristic (ROC) and effect size (Cohen’s d) analyses were performed. ET patients showed significantly reduced mtDNA-CN (β = −2.785, 95% CI −3.700 to −1.869; p_FDR = 2.53 × 10⁻⁹) and TL (β = −2.073, 95% CI −2.758 to −1.388; p_FDR = 3.00 × 10⁻⁹), corresponding to ~6.9-fold and ~4.2-fold reductions, respectively. Age- and sex-stratified analyses confirmed consistent reductions, more pronounced in older individuals. Both biomarkers showed good discriminatory performance (mtDNA-CN: AUC = 0.83, 95% CI: 0.75–0.90; TL: AUC = 0.76, 95% CI: 0.68–0.85) and large effect sizes (Cohen’s d = |1.192| and |1.058|), respectively. Reduced mtDNA-CN and TL support the involvement of mitochondrial impairment and accelerated cellular aging in ET and may represent accessible peripheral biomarkers and provide a basis for future longitudinal and mechanistic investigations.