Mario Benvenuto

Background: SCN1A-related genetic epilepsy with febrile seizures plus (GEFS+) is characterized by marked intrafamilial phenotypic variability, ranging from asymptomatic variant carriers to severe, drug-resistant epilepsy. Methods and Results: We present a two-generation family in which two clinically affected sisters inherited a causative heterozygous SCN1A missense variant (c.3824G>A) from the mother, who likely carries the variant in a mosaic state. The proband, a 23-year-old woman, presented with a long-standing drug-resistant febrile and afebrile epilepsy with onset in early infancy, complicated by mild intellectual disability, impulse control disorder, and behavioral comorbidities, leading to a delayed genetic diagnosis in adulthood. Following insufficient control by multiple antiseizure medications, fenfluramine was introduced at age 21, resulting in complete seizure freedom sustained over two years, alongside measurable neuropsychological improvements in cognition, adaptive functioning, socialization and quality of life. Conclusions: This case highlights the importance of systematic family history and targeted genetic workup in patients with drug-resistant epilepsy, adds preliminary evidence for fenfluramine beyond Dravet and Lennox–Gastaut syndromes, and illustrates the potential of precise genetic diagnosis to guide treatment in SCN1A-related GEFS+.

Objectives: Adults with developmental and epileptic encephalopathies (DEEs) often enter adult neurology care without etiologic clarification because of incomplete transition from pediatric services, outdated investigations, and attenuation of childhood electro‐clinical features over time. We aimed to assess the clinical utility and diagnostic yield of a structured, phenotype‐guided etiologic workup in adults meeting study criteria for DEE and to explore associations between electro‐clinical phenotype and etiologic category. Methods: We prospectively enrolled consecutive adults (≥18 years) with drug‐resistant epilepsy and neurodevelopmental impairment temporally related to epileptic activity, consistent with the ILAE operational definition of DEE, referred to a tertiary epilepsy center between May 2022 and December 2025. Patients underwent a 4‐phase reassessment pathway including critical review of prior documentation, detailed clinical and semiologic phenotyping, prolonged video‐EEG monitoring, phenotype‐guided genetic testing (targeted resequencing, chromosomal microarray), high‐resolution neuroimaging, and multidisciplinary case review to support etiologic clarification and treatment planning. Results: Among 144 patients (mean age 28.4 years; 57.6% male), a confirmed etiology was identified in 91 (63.2%). Genetic causes predominated (65 patients, 45.1%), including monogenic (53, 36.8%) and chromosomal (12, 8.3%) disorders, primarily resolved via targeted resequencing gene panels and via chromosomal microarray analysis respectively, while structural‐metabolic etiologies accounted for 26 cases (18.1%). Lennox–Gastaut syndrome was significantly associated with structural‐metabolic and chromosomal etiologies (69.2% and 58.3% vs. 9.4% in monogenic; p < 0.0001), whereas, excluding patients with a broader Lennox–Gastaut syndrome phenotype, absence seizures occurred exclusively in monogenic cases ( p = 0.024). Etiologic clarification changed clinical management in 27.1% of the cohort, including antiseizure medication optimization/precision therapies (25%) and pre‐surgical referral (2.1%). Significance: In adults with suspected DEE, the practical value of this approach lies not only in diagnostic yield, but in showing that structured adult reassessment remains clinically worthwhile. Electro‐clinical phenotype can help prioritize etiologic testing, and etiologic clarification can support more informed treatment planning and counseling even long after transition from pediatric care. Plain Language Summary: Adults with developmental and epileptic encephalopathy (DEE) often reach adult epilepsy services without a clear diagnosis. In this study, we used a structured approach combining clinical review, video‐EEG, MRI, genetic testing, and multidisciplinary discussion in 144 adults with suspected DEE. We identified a confirmed cause in 63.2% of patients. Genetic causes were the most common, but structural and metabolic causes were also important. Some seizure patterns helped guide diagnosis: Lennox–Gastaut syndrome was more common in structural‐metabolic and chromosomal cases, while absence seizures occurred only in monogenic cases. Identifying the cause also helped guide treatment decisions, including medication changes, targeted therapies, surgery referral, and genetic counseling. This study shows that adults with suspected DEE can still benefit from careful diagnostic reassessment, even years after childhood.

Background: Pathogenic variants in the NEXMIF gene have been linked to a broad neurodevelopmental phenotype, encompassing autism spectrum disorder, intellectual disability, and epilepsy. Among epileptic manifestations, Jeavons Syndrome was observed in 24% of affected females in the largest cohort of NEXMIF-related disorders reported to date, but long-term adult outcomes remain poorly documented. Methods and Results: We report a 25-year-old Italian woman with drug-resistant Jeavons syndrome in which the combined approach of next-generation sequencing and chromosomal microarray analysis allowed us to identify, after a 13-year diagnostic odyssey, a de novo ~350 Kb microdeletion at Xq13.2q13.3 encompassing the entire NEXMIF coding region, with no other OMIM genes involved. To our knowledge, this is the first reported case of a patient harboring a deletion restricted to the entire coding sequence of the NEXMIF gene. The patient presented with moderate intellectual disability and seizure onset at age 10 years. Her epilepsy proved refractory to multiple antiseizure medications. Video-EEG/polygraphic monitoring at age 23 years confirmed epilepsy with eyelid myoclonia, demonstrating characteristic eyelid myoclonia with absences triggered by eye closure. Conclutions: This case provides a detailed clinical description of an adult patient useful for genetic counseling regarding adult outcomes and prognostic expectations. Furthermore, this study underscores the diagnostic value of chromosomal microarray analysis alongside next-generation sequencing in individuals with intellectual disability and drug-resistant epilepsy, in order to expedite the diagnostic pathway and enable timelier and more appropriate patient management.

Pathogenic variants in the NEXMIF gene have been linked to a broad neurodevelopmental phenotype, encompassing autism spectrum disorder, intellectual disability, and epilepsy. Among epileptic manifestations, Jeavons Syndrome was observed in 24% of affected females in the largest cohort of NEXMIF-related disorders reported to date, but long-term adult outcomes remain poorly documented. We report a 25-year-old Italian woman with drug-resistant Jeavons syndrome in which the combined approach of next generation sequencing and chromosomal microarray analysis allowed us to identify, after a 13-year diagnostic odyssey, a de novo ~350 Kb microdeletion at Xq13.2q13.3 encompassing the entire NEXMIF coding region, with no other OMIM genes involved. To our knowledge, this is the first reported case of a patient harboring a deletion restricted to the entire coding sequence of the NEXMIF gene. The patient presented with moderate intellectual disability and seizure onset at age 10 years. Her epilepsy proved refractory to multiple antiseizure medications, Video-EEG/polygraphic monitoring at age 23 years confirmed epilepsy with eyelid myoclonia, demonstrating characteristic eyelid myoclonia with absences triggered by eye closure. This case provides a detailed clinical description of an adult patient useful for genetic counseling regarding adult outcomes and prognostic expectations. Furthermore, this study underscores the complementary diagnostic value of chromosomal microarray analysis alongside next-generation sequencing in individuals with intellectual disability and drug-resistant epilepsy, in order to expedite the diagnostic pathway and enable timelier and more appropriate patient management.

Deleterious variants in the CACNA1A gene, encoding the CaV2.1 P/Q‐type voltage‐gated calcium channel, cause a broad spectrum of neurological disorders, including familial hemiplegic migraine, episodic ataxia, and developmental and epileptic encephalopathy (DEE). Information on genotype–phenotype correlations and on the factors influencing clinical variability is still limited, hindering potential applications in precision medicine. We present three adults (aged 26, 27, and 40 years) from two families with heterozygous CACNA1A deleterious variants and DEE, highlighting striking interindividual and intrafamilial variability in adult‐onset presentations. Genetic testing revealed two distinct pathogenic variants [p.(Val1392Met) and p.(Glu1263Lys)], including one instance of germinal/gonosomic mosaicism in unaffected parents. The electroclinical details demonstrated profound differences, notably: a pair of siblings with the same variant showing discordant clinical severity, and an unrelated patient whose complex phenotype, dominated by cerebellar ataxia, required prolonged video‐EEG to accurately diagnose a high burden of subtle absence seizures. These cases significantly expand the phenotypic spectrum and highlight the critical role of comprehensive electroclinical characterization in adults with CACNA1A ‐related DEE for personalized management.

The ADNP syndrome, also known as Helsmoortel‐Van der Aa syndrome (HVDAS), is an autosomal dominant neurodevelopmental disorder caused by heterozygous truncating variants abolishing the homeobox and/or HP1 domains of ADNP. Rare missense changes in the ADNP gene are usually variants of uncertain significance or reclassified as (likely) benign because they are inherited from an unaffected parent, and a causative role was documented for only three of them. We report a 24‐year‐old Italian woman presenting with intellectual disability, visual and severe speech impairment, microcephaly, truncal obesity, and hirsutism. Behavioral disturbance was significant and included fragmented sleep, self‐ and hetero‐aggression, outbursts of anger, and verbal and physical violence crises. Additional unusual findings were hyperandrogenism and secondary amenorrhea. Next‐generation sequencing showed the novel de novo missense variant c.2405C>T, p.(Ser802Phe) affecting the DNA‐binding homeodomain of ADNP . In silico analysis revealed this variant is located in a genomic region highly intolerant to missense changes, and several tools predicted a deleterious effect on protein function. Counterintuitively to the known molecular pathogenesis for ADNP syndrome, calculation of the binding free energy and dissociation constant of the p.(Ser802Phe) missense substitution suggested a stronger ADNP‐DNA interaction, thus opening the path to the hypothesis of a gain‐of‐function effect. This clinical report expands genotype–phenotype variability and correlations in ADNP syndrome.

Background: Lafora disease (LD) is an ultra-rare, autosomal recessive neurodegenerative disorder characterized by the accumulation of Lafora bodies in the brain, leading to drug-resistant epilepsy, myoclonus, progressive dementia, and cerebellar dysfunction. This retrospective study describes the clinical course and management challenges of LD in a cohort of patients from the Apulia region of Southern Italy, where the disease prevalence appears to be higher than in other populations. Methods: We retrospectively analyzed clinical, electroencephalographic, and management data from six unrelated families with a confirmed diagnosis of LD, followed at the Neurology Unit of the Scientific Institute Casa Sollievo della Sofferenza Hospital between 2010 and 2024. Demographic information, clinical presentation, treatment history, disease progression, and outcomes were collected. Results: Our analysis identified three distinct electroclinical stages: an initial Presenting Symptoms Stage with the onset of seizures and subsequent development of myoclonus; a Progressive Neurodegeneration Stage characterized by drug-resistant epilepsy, dementia, and ataxia; and a Terminal Stage marked by severe disability, frequent seizure emergencies, and medical complications. Management in the late stages proved particularly challenging, requiring a multidisciplinary approach to address refractory seizures, status epilepticus, and medical complications such as aspiration pneumonia and respiratory failure. Home-based care, with specialized team support, played a crucial role in minimizing hospitalizations. Discussion: Our findings underscore the importance of early diagnosis and a multidisciplinary approach in the management of LD. The late stages of the disease are characterized by significant clinical challenges necessitating close collaboration among neurologists, epileptologists, and other healthcare professionals, supported by effective home-based care. The apparent higher prevalence in Apulia warrants further investigation into potential genetic or environmental factors. Conclusion: This study highlights the significant clinical burden of LD and emphasizes the importance of multidisciplinary management, particularly in the advanced stages. Home-based care supported by specialized teams and caregivers is essential for optimizing patient well-being. Further research is needed to identify early biomarkers and develop targeted therapies for this devastating condition.

Rare diseases impact ~6%–8% of the population, thus constituting an issue for public health worldwide. The increasing application of genomic technologies in the routine diagnosis of these conditions is documenting the need to integrate multiple techniques in the most complex cases. We describe a 14‐year‐old boy and his 4‐year‐old sister, both presenting with neonatal hypotonia, severe global developmental delay, major feeding difficulties with the need for assisted nutrition, inability to speak and walk autonomously, epilepsy, central sleep apnea, and facial dysmorphism, in whom exome sequencing revealed the novel c.798 + 1G>T variant in the UNC80 gene at the heterozygous state. While reverse phenotyping was compatible with a clinical diagnosis of infantile hypotonia, psychomotor retardation, and characteristic facies type 2 syndrome, chromosomal microarray disclosed a microdeletion involving 5 exons (40–44) in the other allele. Our findings expand the mutational repertoire of UNC80 and demonstrate that infantile hypotonia, psychomotor retardation, and characteristic facies type 2 syndrome may also be caused by intragenic copy number variations. The combination of multiple techniques, also comprising exon‐level resolution array, is a resource in real‐world diagnostics of rare diseases.