The challenge of ultra‐rarity: Dual diagnosis of Lafora disease and developmental encephalopathies linked to TRIO and SHANK3 pathogenic variants

We report two cases of dual genetic diagnoses involving Lafora disease (LD) and co-occurring neurodevelopmental disorders caused by pathogenic variants in TRIO and SHANK3, respectively. LD is an ultra-rare, autosomal recessive, severe form of progressive myoclonus epilepsy affecting previously healthy children or adolescents. In both patients, the presence of developmental delay, intellectual disability, and behavioral abnormalities was consistent with a primary genetic disorder-TRIO-related neurodevelopmental disorder in one, and Phelan-McDermid syndrome in the other. However, the onset of epilepsy with atypical features, coupled with progressive neurological decline in one patient and a positive family history of LD in the other, prompted the additional diagnosis of LD. These cases illustrate how overlapping clinical presentations can obscure the presence of concomitant genetic conditions, potentially delaying diagnosis and appropriate management. Our findings underscore the importance of considering dual diagnoses and show that phenotypical variability in ultra-rare disorders such as LD may be influenced by concurrent genetic conditions.Plain Language Summary This report describes two patients who have both Lafora disease, an ultra-rare, progressive type of epilepsy, and other rare genetic disorders that affect development and behavior. In one case, the patient showed a progressive and unusual neurological deterioration, while the other had atypical epileptic seizures and a family history of Lafora disease. These cases highlight how different genetic conditions can share similar symptoms, making it difficult to identify all the issues a patient may have. Understanding these overlaps is important for proper diagnosis and treatment

Phenotypic Spectrum in Individuals With Pathogenic <i>GABRG2</i> Loss- and Gain-of-Function Variants

Background and Objectives Variants in the GABRG2 gene encoding the gamma 2 subunit of the gamma-aminobutyric acid type A (GABAA) receptor are associated with a spectrum of epilepsy phenotypes. These range from simple febrile seizures to more severe conditions, including developmental and epileptic encephalopathies (DEEs). Despite previous analyses suggesting that pathogenic variants may lead to loss-of-function (LoF) receptors, a correlation between functional analysis and clinical phenotypic diversity remains elusive. We, therefore, aimed to determine why variants in the GABRG2 gene can lead to highly diverse phenotypes.Methods We assembled a cohort of unreported probands carrying presumed pathogenic GABRG2 variants. Electroclinical information was systematically collected, and electrophysiologic measurements were conducted for missense variants to explore potential alterations in receptor function.Results We examined 44 individuals with 35 GABRG2 variants (18 null and 17 missense). Functional assessments of the missense variants revealed that 9 caused LoF and 3 caused gain-of-function (GoF). The remaining 5 did not alter receptor function and are likely not pathogenic. Based on functional analysis and electroclinical data, 37 affected individuals were categorized into 3 groups: null LoF, missense LoF, and GoF variants. Among 19 individuals with null variants, epilepsy was diagnosed in 13, with a median onset of 14 months. The remaining 6 of 19 only had febrile seizures. Developmental delay/intellectual disability (DD/ID) was observed in 1 of 19 and psychiatric features in 4 of 18. By contrast, all 12 individuals with missense LoF variants suffered from epilepsy with a median onset of 15 months. Most common epilepsy diagnoses were febrile seizures plus in 4 of 12 and DEE in 4 of 12. DD/ID affected 9 of 12, and psychiatric features were diagnosed in 8 of 12. Statistical comparisons revealed that null variants were associated with a milder phenotype than missense LoF variants. Finally, 5 of 6 individuals with GoF variants had DEE characterized by early infancy onset at 2 months and severe/profound DD/ID. The sixth individual exhibited mild DD/ID and hypotonia without seizures.Discussion Our findings indicate that the severity of disease associated with pathogenic GABRG2 variants depends on the functional consequences of the variants. Null variants are associated with a mild phenotype and missense LoF variants with an intermediate phenotype while GoF variants can lead to severe phenotypes

Adjunctive Brivaracetam in Focal Epilepsy: Real-World Evidence from the BRIVAracetam add-on First Italian netwoRk STudy (BRIVAFIRST)

Background In randomized controlled trials, add-on brivaracetam (BRV) reduced seizure frequency in patients with drug-resistant focal epilepsy. Studies performed in a naturalistic setting are a useful complement to characterize the drug profile. Objective This multicentre study assessed the effectiveness and tolerability of adjunctive BRV in a large population of patients with focal epilepsy in the context of real-world clinical practice. Methods The BRIVAFIRST (BRIVAracetam add-on First Italian netwoRk STudy) was a retrospective, multicentre study including adult patients prescribed adjunctive BRV. Patients with focal epilepsy and 12-month follow-up were considered. Main outcomes included the rates of seizure-freedom, seizure response (&gt;= 50% reduction in baseline seizure frequency), and treatment discontinuation. The incidence of adverse events (AEs) was also considered. Analyses by levetiracetam (LEV) status and concomitant use of strong enzyme-inducing antiseizure medications (EiASMs) and sodium channel blockers (SCBs) were performed. Results A total of 1029 patients with a median age of 45 years (33-56) was included. At 12 months, 169 (16.4%) patients were seizure-free and 383 (37.2%) were seizure responders. The rate of seizure freedom was 22.3% in LEV-naive patients, 7.1% in patients with prior LEV use and discontinuation due to insufficient efficacy, and 31.2% in patients with prior LEV use and discontinuation due to AEs (p &lt; 0.001); the corresponding values for &gt;= 50% seizure frequency reduction were 47.9%, 29.7%, and 42.8% (p &lt; 0.001). There were no statistically significant differences in seizure freedom and seizure response rates by use of strong EiASMs. The rates of seizure freedom (20.0% vs. 16.6%; p = 0.341) and seizure response (39.7% vs. 26.9%; p = 0.006) were higher in patients receiving SCBs than those not receiving SCBs; 265 (25.8%) patients discontinued BRV. AEs were reported by 30.1% of patients, and were less common in patients treated with BRV and concomitant SCBs than those not treated with SCBs (28.9% vs. 39.8%; p = 0.017). Conclusion The BRIVAFIRST provided real-world evidence on the effectiveness of BRV in patients with focal epilepsy irrespective of LEV history and concomitant ASMs, and suggested favourable therapeutic combinations

The distribution of the transient global amnesia in the province of Ferrara, Italy, a clue to the pathogenesis?

The pathophysiology of transient global amnesia (TGA) is uncertain. In the province of Ferrara (Fe-province) the cases of TGA correspond to the resident outpatients diagnosed as TGA in the ER of the University Hospital of Ferrara. Thanks to this, a retrospective survey identified 35 (14 men, 21 women) first-ever TGA cases in the resident population of the Fe-province in 2018 giving a crude incidence rate of 10.10/100,000 (95% CI 7.00 - 14.00), 8,40 (95% CI 4.60 - 14.10) for men and 11.60 (95% CI 7.20-17.80) for women, a non significant gender difference. The monthly cases of TGA followed the Poisson distribution (goodness-of-fit test: chi-square = 2.557, 5 degrees of freedom , p&gt;0.70). The incidence of TGA in the Fe-province was higher in the highest level of urbanization (21.40/100,000 95% CI 13.10 - 33.00) than in the lowest one (4.20/100,000 95% CI 1.92-8.00). The incident cases of TGA incresed with the level of urbanization (chi-square trend test = 19.940, p &lt; 0.001) and the population density level (chi-square trend test = 46.684, p&lt; 0.001). Since urbanization is likely involved in stress-related disorders, these findings support the hypothesis of the involvement of stress in TGA

Amyotrophic Lateral Sclerosis and Urbanization in the Health District of Ferrara, Italy, in 1964-1998

The relationship between urbanization and Amyotrophic Lateral Sclerosis pathogenesi

The urgent neurological consultation in the population of the province of Ferrara, Italy

In the province of Ferrara, Italy, the urgent neurological consultation (UNC) cases in the population correspond to the resident outpatients who undergo a UNC in the ER of the university hospital of Ferrara (UHFe). Thanks to this health organization a retrospective survey identified 612 UNC cases (range of age 7–102 years, median 67,5 years) in the study period giving a period prevalence rate of 173 per 100,000 (95% CI 159.3–187.3) which increased with age (χ2for trend = 178.4 p 0.70). The prevalence rate decreased with the distance between the patients’ residence and the UHFe (χ2for trend = 82.9, p < 0.001). The commonest clinical conditions requiring UNCs were acute cerebrovascular disorders (28%), headache (14%), and vertigo (9%). The hospital admission rate was 32.5% which increased with age (χ2for trend = 35.8, p < 0.001). The commonest discharge diagnoses of the admitted cases were ischemic stroke (57.3%), epilepsy (7%), TIA (6%), and intraparenchymal hemorrhage (5.5%). Acute cerebrovascular disease accounted for 69% of the discharge diagnoses. The survey showed that the UNCs’ demand was higher than previous Italian data confirming that acute cerebrovascular disease is the most frequent acute neurological condition requiring attention in the ER. It also suggested that the UNCs could be poorly appropriate. These findings would require the healthcare administrators attention

Amyotrophic lateral sclerosis, rural environment and agricultural work in the Local Health District of Ferrara, Italy, in the years 1964-1998.

Previous epidemiological surveys, both analytic and descriptive, in the Local Health District (LHD) of Ferrara, northern Italy, have indicated that rural residence and agricultural work might constitute risk factors for Amyotrophic Lateral Sclerosis (ALS). The present investigation is a demographic survey in the LHD of Ferrara in the years 1964–1998 which aimed to verify whether the level of urbanization and agricultural activities might influence the risk of ALS. Based on the data obtained in a recent incidence study in the LHD of Ferrara which reported a mean annual crude incidence rate of ALS in the years 1964–1998 of 1.63 per 100,000 population (95 % CI 1.31–2.00), it was possible to compare the number of observed ALS cases and the number of expected ALS cases according to the level of urbanization and usual occupation on the basis of the residential and occupational pattern identified in the population of the LHD of Ferrara in the study period under the assumption of a homogeneous distribution of ALS. The present survey identified four different levels of urbanization in the LHD of Ferrara in the study period and for none of them was a difference between the number of observed and expected ALS cases found. Also in the most rural of the four identified levels of urbanization (small villages with an average population in the study period lower than 1,000 inhabitants and scattered houses in the countryside) no difference was found between observed and expected number of ALS cases (observed ALS cases 16, 95% Poisson CI 9.1–25.9, expected ALS cases 18.3). Based on the occupational pattern identified in the population of the LHD of Ferrara in the study period the number of incident cases of ALS whose usual occupation was in agricultural work exceeded the expected number (observed ALS cases 22, 95% Poisson CI 13.8–32.3, expected ALS cases 6.0). The present findings indicate that rural residence itself does not influence the risk of ALS while agricultural activities could influence the risk of ALS, with occupational exposure to agricultural chemicals playing a possible role