Genetic heterogeneity in epilepsy and comorbidities: insights from Pakistani families.

BACKGROUND: Epilepsy, a challenging neurological condition, is often present with comorbidities that significantly impact diagnosis and management. In the Pakistani population, where financial limitations and geographical challenges hinder access to advanced diagnostic methods, understanding the genetic underpinnings of epilepsy and its associated conditions becomes crucial. METHODS: This study investigated four distinct Pakistani families, each presenting with epilepsy and a spectrum of comorbidities, using a combination of whole exome sequencing (WES) and Sanger sequencing. The epileptic patients were prescribed multiple antiseizure medications (ASMs), yet their seizures persist, indicating the challenging nature of ASM-resistant epilepsy. RESULTS: Identified genetic variants contributed to a diverse range of clinical phenotypes. In the family 1, which presented with epilepsy, developmental delay (DD), sleep disturbance, and aggressive behavior, a homozygous splice site variant, c.1339-6 C > T, in the COL18A1 gene was detected. The family 2 exhibited epilepsy, intellectual disability (ID), DD, and anxiety phenotypes, a homozygous missense variant, c.344T > A (p. Val115Glu), in the UFSP2 gene was identified. In family 3, which displayed epilepsy, ataxia, ID, DD, and speech impediment, a novel homozygous frameshift variant, c.1926_1941del (p. Tyr643MetfsX2), in the ZFYVE26 gene was found. Lastly, family 4 was presented with epilepsy, ID, DD, deafness, drooling, speech impediment, hypotonia, and a weak cry. A homozygous missense variant, c.1208 C > A (p. Ala403Glu), in the ATP13A2 gene was identified. CONCLUSION: This study highlights the genetic heterogeneity in ASM-resistant epilepsy and comorbidities among Pakistani families, emphasizing the importance of genotype-phenotype correlation and the necessity for expanded genetic testing in complex clinical cases.

Personality disorders in people with epilepsy: a review.

Epileptologists and psychiatrists have long observed a correlation between epilepsy and personality disorders (PDs) in their clinical practice. We conducted a comprehensive PubMed search looking for evidence on PDs in people with epilepsy (PwE). Out of over 600 results obtained without applying any time restriction, we selected only relevant studies (both analytical and descriptive) limited to English, Italian, French and Spanish languages, with a specific focus on PDs, rather than traits or symptoms, thus narrowing our search down to 23 eligible studies. PDs have been investigated in focal epilepsy (predominantly temporal lobe epilepsy - TLE), juvenile myoclonic epilepsy (JME) and psychogenic non-epileptic seizures (PNES), with heterogeneous methodology. Prevalence rates of PDs in focal epilepsy ranged from 18 to 42% in surgical candidates or post-surgical individuals, with Cluster C personality disorders or related traits and symptoms being most common. In JME, prevalence rates ranged from 8 to 23%, with no strong correlation with any specific PDs subtype. In PNES, prevalence rates ranged from 30 to 60%, with a notable association with Cluster B personality disorders, particularly borderline personality disorder. The presence of a PD in PwE, irrespective of subtype, complicates treatment management. However, substantial gaps of knowledge exist concerning the neurobiological substrate, effects of antiseizure medications and epilepsy surgery on concomitant PDs, all of which are indeed potential paths for future research.

A Male Child with Infantile Epilepsy due to a Mosaic Missense Variant of PCDH19.

Background: Pathogenic variants of PCDH19, located on the X-chromosome (Xq22.1), cause a rare epileptic encephalopathy with speech and development delay, seizures, behavioral and psychiatric problems. The specific underlying pathogenic mechanism is known as "cellular interference" that results in affected heterozygous females, normal hemizygous males and affected mosaic males but its functioning is not yet clear. Objectives: Reporting new cases of affected males is considered useful to a deeper insight. Subject and Method: We present the case of a three-year-old boy with early-onset seizures at 3 months of age, mild cognitive impairment, partial control of seizures with levetiracetam, normal brain imaging. Results: The patient has a mosaic pathogenic variant c.698A>G (p.Asp233Gly) in PCDH19 assessed by Next Generation Sequencing analysis. We have compared his characteristics with the genotypes and phenotypes of 34 PCDH19 mosaic males earlier reported in the literature. Finally, we have summarized today's knowledge about phenotype-genotype correlation and pharmacological response in these patients. Conclusions: Our report confirms that the clinical picture of mosaic affected males, resembling that of females, can show a wide variability in severity of disease and underlines a stringent need to improve therapeutic approaches and to collect data on long-term follow-up.

Management of seizures in patients with primary mitochondrial diseases: consensus statement from the InterERNs Mitochondrial Working Group.

BACKGROUND AND PURPOSE: Primary mitochondrial diseases (PMDs) are common inborn errors of energy metabolism, with an estimated prevalence of one in 4300. These disorders typically affect tissues with high energy requirements, including heart, muscle and brain. Epilepsy may be the presenting feature of PMD, can be difficult to treat and often represents a poor prognostic feature. The aim of this study was to develop guidelines and consensus recommendations on safe medication use and seizure management in mitochondrial epilepsy. METHODS: A panel of 24 experts in mitochondrial medicine, pharmacology and epilepsy management of adults and/or children and two patient representatives from seven countries was established. Experts were members of five different European Reference Networks, known as the Mito InterERN Working Group. A Delphi technique was used to allow the panellists to consider draft recommendations on safe medication use and seizure management in mitochondrial epilepsy, using two rounds with predetermined levels of agreement. RESULTS: A high level of consensus was reached regarding the safety of 14 out of all 25 drugs reviewed, resulting in endorsement of National Institute for Health and Care Excellence guidelines for seizure management, with some modifications. Exceptions including valproic acid in POLG disease, vigabatrin in patients with γ-aminobutyric acid transaminase deficiency and topiramate in patients at risk for renal tubular acidosis were highlighted. CONCLUSIONS: These consensus recommendations describe our intent to improve seizure control and reduce the risk of drug-related adverse events in individuals living with PMD-related epilepsy.

Ictal Bradycardia and Asystole in Sleep-Related Hypermotor Epilepsy: A Study of 200 Patients.

Background: Ictal bradycardia (IB) and asystole (IA) represent a rare but potentially harmful feature of epileptic seizures. The aim of this study was to study IB/IA in patients with sleep-related hypermotor epilepsy (SHE). Methods: We retrospectively included cases with video-EEG-confirmed SHE who attended our Institute up to January 2021. We reviewed the ictal polysomnography recordings focusing on ECG and identified cases with IB (R-R interval ≥ 2 s or a ≥10% decrease of baseline heart rate) and IA (R-R interval ≥ 4 s). Results: We included 200 patients (123 males, 61.5%), with a mean age of 42 ± 16 years. Twenty patients (20%) had focal cortical dysplasia (FCD) on brain MRI. Eighteen (out of 104 tested, 17.3%) carried pathogenic variants (mTOR pathway, n = 10, nAchR subunits, n = 4, KCNT1, n = 4). We identified IB/IA in four cases (2%): three had IA (mean 10 s) and one had IB. Three patients had FCD (left fronto-insular region, left amygdala, right mid-temporal gyrus) and two had pathogenic variants in DEPDC5; both features were more prevalent in patients with IB/IA than those without (p = 0.003 and p = 0.037, respectively). Conclusions: We identified IB/IA in 2% of patients with SHE and showed that this subgroup more frequently had FCD on brain MRI and pathogenic variants in genes related to the mTOR pathway.

Clinical and molecular characterization of patients with YWHAG-related epilepsy.

OBJECTIVE: YWHAG variant alleles have been associated with a rare disease trait whose clinical synopsis includes an early onset epileptic encephalopathy with predominantly myoclonic seizures, developmental delay/intellectual disability, and facial dysmorphisms. Through description of a large cohort, which doubles the number of reported patients, we further delineate the spectrum of YWHAG-related epilepsy. METHODS: We included in this study 24 patients, 21 new and three previously described, with pathogenic/likely pathogenic variants in YWHAG. We extended the analysis of clinical, electroencephalographic, brain magnetic resonance imaging, and molecular genetic information to 24 previously published patients. RESULTS: The phenotypic spectrum of YWHAG-related disorders ranges from mild developmental delay to developmental and epileptic encephalopathy (DEE). Epilepsy onset is in the first 2 years of life. Seizure freedom can be achieved in half of the patients (13/24, 54%). Intellectual disability (23/24, 96%), behavioral disorders (18/24, 75%), neurological signs (13/24, 54%), and dysmorphisms (6/24, 25%) are common. A genotype-phenotype correlation emerged, as DEE is more represented in patients with missense variants located in the ligand-binding domain than in those with truncating or missense variants in other domains (90% vs. 19%, p < .001). SIGNIFICANCE: This study suggests that pathogenic YWHAG variants cause a wide range of clinical presentations with variable severity, ranging from mild developmental delay to DEE. In this allelic series, a genotype-phenotype correlation begins to emerge, potentially providing prognostic information for clinical management and genetic counseling.

Tuberous sclerosis complex in adulthood: focus on epilepsy prognosis.

OBJECTIVE: Typically diagnosed in early childhood or adolescence, TSC is a chronic, multisystemic disorder with age-dependent manifestations posing a challenge for transition and for specific surveillance throughout the lifetime. Data on the clinical features and severity of TSC in adults and on the prognosis of epilepsy are scarce. We analyzed the clinical and genetic features of a cohort of adult patients with TSC, to identify the prognostic predictors of seizure remission after a long follow-up. METHOD: We conducted a retrospective analysis of patients diagnosed with TSC according to the updated international diagnostic criteria. Pearson's chi-square or Fisher's exact test and Mann Whitney U test were used to compare variables among the Remission (R) and Non-Remission (NR) group. Univariate and multivariate logistic regression analyses were performed. RESULTS: We selected 43 patients with TSC and neurological involvement in terms of epilepsy and/or brain lesions, attending the Epilepsy Center of our Institute: of them, 16 (37.2%) were transitioning from the pediatric care and 6 (13.9%) were referred by other specialists. Multiorgan involvement includes cutaneous (86.0%), nephrological (70.7%), hepatic (40.0%), ocular (34.3%), pneumological (28.6%) and cardiac (26.3%) manifestations. Thirty-nine patients (90.7 %) had epilepsy. The mean age at seizure onset was 4 ± 7.3 years: most patients (29, 76.3 %) presented with focal seizures or spasms by age 3 years; only 2 (5.3 %) had seizure onset in adulthood. Twenty-seven patients (69.2 %) experienced multiple seizure types overtime, 23 (59.0 %) had intellectual disability (ID). At last assessment, 14 (35.9 %) were seizure free (R group) and 25 (64.1 %) had drug-resistant seizures (NR group). At logistic regression univariate analysis, ID (OR 7.9, 95 % CI 1.8--34.7), multiple seizure types lifelong (OR 13.2, 95 % CI 2.6- 67.2), spasms/tonic seizures at presentation (OR 6.5, 95 % CI 1.2--35.2), a higher seizure frequency at onset (OR 5.4, 95 % CI 1.2--24.3), abnormal neurological examination (OR 9.8, 95 % CI 1.1--90.6) and pathogenic variants in TSC2 (OR 5.4, 95 % CI 1.2--24.5) were significantly associated with non-remission. In the multivariate analysis, both ID and multiple seizure types lifelong were confirmed as independent predictors of poor seizure outcome. CONCLUSIONS: In our cohort of adult patients with TSC, epilepsy remains one of the main neurological challenges with only 5.3% of cases manifesting in adulthood. Approximately 64% of these patients failed to achieve seizure remission. ID and multiple seizure types were the main predictors of poor outcome. Nephrological manifestations require continuous specific follow-up in adults.

Fingerprick volumetric absorptive microsampling for therapeutic drug monitoring of antiseizure medications: Reliability and real-life feasibility in epilepsy patients.

Volumetric absorptive microsampling (VAMS) is increasingly proposed as a clinically reliable therapeutic drug monitoring (TDM) sampling methodology. The study aimed to establish the reliability and real-life feasibility of patient self-collected capillary VAMS for TDM of antiseizure medication (ASMs), using plasma ASMs concentrations from venous blood as a reference standard. Nurses collected venous and capillary blood samples using VAMS. Afterward, persons with epilepsy (PWE) performed VAMS sampling by themselves. All samples were analyzed by UHPLC-MS/MS. We performed a cross-validation study, comparing ASMs concentrations obtained by VAMS nurses and patients' self-collected versus plasma through Bland-Altman analysis and Passing-Bablok regression. We enrolled 301 PWE (M: F 42.5%:57.5%; mean age 44±16 years), treated with 13 ASMs, providing a total of 464 measurements. Statistical analysis comparing VAMS self-collected versus plasma ASMs concentrations showed a bias close to zero and slope and intercept values indicating a good agreement for CBZ, LCS, LEV, LTG, OXC, PB, and PHT, while a systematic difference between the two methods was found for VPA, PMP, TPM and ZNS. This is the first study showing the reliability and feasibility of the real-world application of PWE self-collected VAMS for most of the ASMs considered, giving a promising basis for at-home VAMS applications.

Biallelic pathogenic variants of PARS2 cause developmental and epileptic encephalopathy with spike-and-wave activation in sleep.

BACKGROUND: Biallelic pathogenic variants in the mitochondrial prolyl-tRNA synthetase 2 gene (PARS2, OMIM * 612036) have been associated with Developmental and Epileptic Encephalopathy-75 (DEE-75, MIM #618437). This condition is typically characterized by early-onset refractory infantile spasms with hypsarrhythmia, intellectual disability, microcephaly, cerebral atrophy with hypomyelination, lactic acidemia, and cardiomyopathy. Most affected individuals do not survive beyond the age of 10 years. METHODS: We describe a patient with early-onset DEE, consistently showing an EEG pattern of Spike-and-Wave Activation in Sleep (SWAS) since childhood. The patient underwent extensive clinical, metabolic and genetic investigations, including whole exome sequencing (WES). RESULTS: WES analysis identified compound heterozygous variants in PARS2 that have been already reported as pathogenic. A literature review of PARS2-associated DEE, focusing mainly on the electroclinical phenotype, did not reveal the association of SWAS with pathogenic variants in PARS2. Notably, unlike previously reported cases with the same genotype, this patient had longer survival without cardiac involvement or lactic acidosis, suggesting potential genetic modifiers contributing to disease variability. CONCLUSION: These findings widen the genetic heterogeneity of DEE-SWAS, including PARS2 as a causative gene in this syndromic entity, and highlight the importance of prolonged sleep EEG recording for the recognition of SWAS as a possible electroclinical evolution of PARS2-related DEE.

Current management of primary mitochondrial disorders in EU countries: the European Reference Networks survey.

BACKGROUND AND PURPOSE: Primary mitochondrial diseases (PMDs) are rare diseases for which diagnosis is challenging, and management and training programs are not well defined in Europe. To capture and assess care needs, five different European Reference Networks have conducted an exploratory survey. METHODS: The survey covering multiple topics relating to PMDs was sent to all ERNs healthcare providers (HCPs) in Europe. RESULTS: We have collected answers from 220 members based in 24/27 European member states and seven non-European member states. Even though most of the responders are aware of neurogenetic diseases, difficulties arise in the ability to deliver comprehensive genetic testing. While single gene analysis is widely available in Europe, whole exome and genome sequencing are not easily accessible, with considerable variation between countries and average waiting time for results frequently above 6 months. Only 12.7% of responders were happy with the ICD-10 codes for classifying patients with PMDs discharged from the hospital, and more than 70% of them consider that PMDs deserve specific ICD codes to improve clinical management, including tailored healthcare, and for reimbursement reasons. Finally, 90% of responders declared that there is a need for further education and training in these diseases. CONCLUSIONS: This survey provides information on the current difficulties in the care of PMDs in Europe. We believe that the results of this survey are important to help rare disease stakeholders in European countries identify key care and research priorities.

Prognostic value of pathogenic variants in Lafora Disease: systematic review and meta-analysis of patient-level data.

BACKGROUND: Lafora disease (LD) is a fatal form of progressive myoclonic epilepsy caused by biallelic pathogenic variants in EPM2A or NHLRC1. With a few exceptions, the influence of genetic factors on disease progression has yet to be confirmed. We present a systematic review and meta-analysis of the known pathogenic variants to identify genotype-phenotype correlations. METHODS: We collected all reported cases with genetically-confirmed LD containing data on disease history. Pathogenic variants were classified into missense (MS) and protein-truncating (PT). Three genotype classes were defined according to the combination of the variants: MS/MS, MS/PT, and PT/PT. Time-to-event analysis was performed to evaluate survival and loss of autonomy. RESULTS: 250 cases described in 70 articles were included. The mutated gene was NHLRC1 in 56% and EPM2A in 44% of cases. 114 pathogenic variants (67 EPM2A; 47 NHLRC1) were identified. The NHLRC1 genotype PT/PT was associated with shorter survival [HR 2.88; 95% CI 1.23-6.78] and a trend of higher probability of loss of autonomy [HR 2.03, 95% CI 0.75-5.56] at the multivariable Cox regression analysis. The population carrying the homozygous p.Asp146Asn variant of NHLRC1 genotype was confirmed to have a more favourable prognosis in terms of disease duration. CONCLUSIONS: This study demonstrates the existence of prognostic genetic factors in LD, namely the genotype defined according to the functional impact of the pathogenic variants. Although the reasons why NHLRC1 genotype PT/PT is associated with a poorer prognosis have yet to be fully elucidated, it may be speculated that malin plays a pivotal role in LD pathogenesis.

Real-world experience with cannabidiol as add-on treatment in drug-resistant epilepsy.

PURPOSE: To evaluate the efficacy and safety of cannabidiol (CBD) for the treatment of epilepsy in a real-world setting. METHODS: In this retrospective observational study, we included PwE with epilepsy who received a prescription for CBD between 01.03.2019 and 30.11.2022 and had a follow-up period ≥ 3 months. Participants were evaluated at baseline and after 3, 6, and 12 months. "Responders" were defined as individuals experiencing a reduction in seizure frequency > 30% but < 80% compared to baseline, while "super responders" were those with a reduction ≥ 80%. Adverse events were recorded to assess safety. RESULTS: Forty-two PwE were included (mean age 36.1 ± 10.9 years; 14 females). In 24 patients CBD was prescribed on-label (Lennox-Gastaut syndrome, n = 18; Dravet syndrome, n = 5; tuberous sclerosis, n = 1), while 18 patients were treated off-label (ring chromosome 20 syndrome, n = 1; ring chromosome 17 syndrome, n = 1; Lafora disease, n = 3; Unverricht-Lundborg disease, n = 1; polymicrogyria, n = 2; febrile infection-related epilepsy syndrome, n = 1; non-lesional focal epilepsy, n = 2; developmental and/or epileptic encephalopathy of unknown etiology n = 6). The mean number of concomitant antiseizure medications was 3.4 (≥2 for all patients). At 3 months, 10 subjects (23%) were "responders" and 12 (29%) were "super-responders". Efficacy was sustained at 6 and 12 months of follow-up. Twenty-two patients (52.3%) developed AEs, with drowsiness (36.5%) and diarrhea (9.8%) being the most common. The retention rate was 85.7%, 78.6%, and 71.4% at 3, 6, and 12 months, respectively. CONCLUSIONS: In this monocentric real-world study, CBD was a safe and effective therapeutic option for highly drug-resistant patients, leading to a dramatic reduction in seizure frequency in over one-fourth of them, including off-label indications.

Pseudohyperkalemia due to cryohydrocytosis in GLUT1 deficiency syndrome. A case report and literature review.

Cryohydrocytosis is a form of stomatocytosis characterized by the leakage of sodium and potassium from red blood cells at low temperatures, characterized by pseudohyperkalemia. Stomatin-deficient cryohydrocytosis is an extremely rare variant that only recently has been related to pathogenic variants in the SLC2A1 gene, encoding the main glucose transporter of the blood-brain barrier and red blood cells, GLUT1. It follows that GLUT1 deficiency syndrome, a rare but significant cause of metabolic epilepsy, may present with stomatin-deficient cryohydrocytosis, although this correlation has only been reported in a few instances. We present the case of a patient carrying a novel de novo SLC2A1 pathogenic variant presenting with GLUT1 deficiency syndrome, pseudohyperkalemia, and splenomegaly consistent with cryohydrocytosis. We also review the previously reported cases of stomatin-deficient cryohydrocytosis in the literature. As highlighted by our case, elevated potassium levels are a cause of concern, and GLUT1 deficiency syndrome patients are thus at risk of being subjected to unnecessary examinations; pseudohyperkalemia may be underrecognized in clinical practice.

Current treatment options for familial adult myoclonus epilepsy.

Familial adult myoclonus epilepsy (FAME) is a genetic condition characterized by the occurrence of cortical tremor, myoclonus, and epilepsy. To date, there is neither a curative nor a preventive treatment for FAME. Clinical management is essentially symptomatic and based on antiseizure medications (ASMs). The choice of the correct therapeutic option is limited to ASMs that have both an antiseizure and an antimyoclonic effect, such as valproate, levetiracetam, benzodiazepines, and perampanel. However, these medications control seizures well while having a limited effect on myoclonus and cortical tremor. In addition, many ASMs, including sodium channel blockers and gabapentin, are contraindicated in this condition. The ideal therapeutic option would be a precision treatment able to revert the genetic defect underlying it. Nevertheless, this does not seem to be an option that will be available soon.

Extended Glasgow Outcome Scale to Evaluate the Functional Impairment of Patients With Subcortical Band Heterotopia: A Multicentric Cross-sectional Study.

BACKGROUND: Subcortical band heterotopia (SBH) is a rare malformation of the cortical development characterized by a heterotopic band of gray matter between cortex and ventricles. The clinical presentation typically includes intellectual disability and epilepsy. PURPOSE: To evaluate if the Extended Glasgow Outcome Scale-pediatric version (EGOS-ped) is a feasible tool for evaluating the functional disability of patients with (SBH). METHOD: Cross-sectional multicenter study of a cohort of 49 patients with SBH (female n = 30, 61%), recruited from 23 Italian centers. RESULTS: Thirty-nine of 49 (80%) cases showed high functional disability at EGOS-ped assessment. In the poor result subgroup (EGOS-ped >3) motor deficit, language impairment, and lower intelligence quotient were more frequent (P < 0.001, P = 0.02, and P = 0.01, respectively); the age at epilepsy onset was remarkably lower (P < 0.001); and the prevalence of epileptic encephalopathy (West syndrome or Lennox-Gastaut-like encephalopathy) was higher (P = 0.04). The thickness and the extension of the heterotopic band were associated with EGOS-ped score (P < 0.01 and P = 0.02). Pachygyria was found exclusively among patients with poor outcome (P < 0.01). CONCLUSIONS: The EGOS-ped proved to be a reliable tool for stratifying the functional disability of patients with SBH. According to this score, patients could be dichotomized: group 1 (80%) is characterized by a poor overall functionality with early epilepsy onset, thick heterotopic band, and pachygyria, whereas group 2 (20%) is characterized by a good overall functionality with later epilepsy onset and thinner heterotopic band.

Clinical characterization of non-ketotic hyperglycemia-related seizures: A systematic review and individual participant data meta-analysis.

New-onset epileptic seizures and status epilepticus (SE) are the most frequent neurological manifestations of non-ketotic hyperglycemia (NKH), an acute complication of diabetes mellitus (DM). Treatment consists of the correction of the underlying metabolic disorder, whereas anti-seizure medications (ASMs) may even worsen seizures. Evidence on NKH-related seizures is currently restricted to case reports and small case-series. We conducted a systematic review of the PubMed, Embase, and Cochrane Library databases to provide a comprehensive description of NKH-related seizures. Statistical analyses were performed to explore possible associations of glycemic and osmolarity levels with clinical variables. We selected 130 publications and 332 patients (186 males, mean age: 61.1 years). DM was newly-diagnosed in 40%. Mean glycemia and osmolarity levels at presentation were 529.7 mg/dL and 309.6 mmol/mol, respectively; 22.6% showed other neurological symptoms besides seizures. Focal motor seizures were the prominent seizure type (49.4%); non-motor focal seizures (23.2%) most commonly manifested as visual symptoms. Reflex seizures occurred in 10.5%. Brain MRI in 48.7% of cases showed focal T2 subcortical hypodensity and/or overlying cortical T2 hyperintensity with DWI restriction. ASMs were administered in 54.2% of cases, achieving seizure control in just 18.3%. Higher osmolarity levels were associated with newly-diagnosed DM (p = 0.002) and other symptoms at presentation (p < 0.001). Glycemic values were higher in patients with focal aware seizures with motor onset compared to those with focal seizures without motor onset (p = 0.0046) or focal seizures with impaired awareness (p = 0.0306). Lower glycemic values were associated with reflex seizures (p = 0.036) and ASM administration (p < 0.001). NKH-related seizures should be suspected in adults with new-onset clustering focal seizures arising from the motor or posterior cortices, even in the absence of a history of DM. Typical focal changes on brain MRI, while not pathognomonic, can drive the clinical diagnosis. Statistical associations suggest a key role of hyperglycemia in the excitability of higher-energy-demanding cortical areas.

A case of clinical worsening after stereo-electroencephalographic-guided radiofrequency thermocoagulation in a patient with polymicrogyria.

Radiofrequency thermocoagulation (RF-TC) is a wide-used procedure for drug-resistant epilepsy. The technique is considered safe with an overall risk of 1.1% of permanent complications, mainly focal neurological deficits. We report the case of a patient with drug-resistant epilepsy who complained of immediate seizure worsening and an unexpected event seven months following RF-TC. A 35-year-old male with drug-resistant epilepsy from the age of 18 years underwent stereoelectroencephalography (SEEG) implantation for a right peri-silvian polymicrogyria. He was excluded from surgery due to extent of the epileptogenic zone and the risk of visual field deficits. RF-TC was attempted to ablate the most epileptogenic zone identified by SEEG. After RF-TC, the patient reported an increase in seizure severity/frequency and experienced episodes of postictal psychosis. Off-label cannabidiol treatment led to improved seizure control and resolution of postictal psychosis. Patients with polymicrogyria (PwP) may present with a disruption of normal anatomy and the co-existence between epileptogenic zone and eloquent cortex within the malformation. RF-TC should be considered in PwP when they are excluded from surgery for prognostic and palliative purposes. However, given the complex interplay between pathological and electrophysiological networks in these patients, the remote possibility of clinical exacerbation after RF-TC should also be taken into account.

Expanding the genetics and phenotypic spectrum of Lysine-specific demethylase 5C (KDM5C): a report of 13 novel variants.

Lysine-specific demethylase 5C (KDM5C) has been identified as an important chromatin remodeling gene, contributing to X-linked neurodevelopmental disorders (NDDs). The KDM5C gene, located in the Xp22 chromosomal region, encodes the H3K4me3-me2 eraser involved in neuronal plasticity and dendritic growth. Here we report 30 individuals carrying 13 novel and one previously identified KDM5C variants. Our cohort includes the first reported case of somatic mosaicism in a male carrying a KDM5C nucleotide substitution, and a dual molecular finding in a female carrying a homozygous truncating FUCA1 alteration together with a de novo KDM5C variant. With the use of next generation sequencing strategies, we detected 1 frameshift, 1 stop codon, 2 splice-site and 10 missense variants, which pathogenic role was carefully investigated by a thorough bioinformatic analysis. The pattern of X-chromosome inactivation was found to have an impact on KDM5C phenotypic expression in females of our cohort. The affected individuals of our case series manifested a neurodevelopmental condition characterized by psychomotor delay, intellectual disability with speech disorders, and behavioral features with particular disturbed sleep pattern; other observed clinical manifestations were short stature, obesity and hypertrichosis. Collectively, these findings expand the current knowledge about the pathogenic mechanisms leading to dysfunction of this important chromatin remodeling gene and contribute to a refinement of the KDM5C phenotypic spectrum.

Neurodevelopmental and Epilepsy Phenotypes in Individuals With Missense Variants in the Voltage-Sensing and Pore Domains of KCNH5.

BACKGROUND AND OBJECTIVES: KCNH5 encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novo KCNH5 variants. METHODS: We screened 893 individuals with developmental and epileptic encephalopathies for KCNH5 variants using targeted or exome sequencing. Additional individuals with KCNH5 variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed; seizure types and epilepsy syndromes were classified. We included 3 previously published individuals including additional phenotypic details. RESULTS: We report a cohort of 17 patients, including 9 with a recurrent de novo missense variant p.Arg327His, 4 with a recurrent missense variant p.Arg333His, and 4 additional novel missense variants. All variants were located in or near the functionally critical voltage-sensing or pore domains, absent in the general population, and classified as pathogenic or likely pathogenic using the American College of Medical Genetics and Genomics criteria. All individuals presented with epilepsy with a median seizure onset at 6 months. They had a wide range of seizure types, including focal and generalized seizures. Cognitive outcomes ranged from normal intellect to profound impairment. Individuals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalized epilepsy and normal intellect, whereas the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two individuals with variants in the pore domain were more severely affected, with a neonatal-onset movement disorder, early-infantile DEE, profound disability, and childhood death. DISCUSSION: We describe a cohort of 17 individuals with pathogenic or likely pathogenic missense variants in the voltage-sensing and pore domains of Kv10.2, including 14 previously unreported individuals. We present evidence for a putative emerging genotype-phenotype correlation with a spectrum of epilepsy and cognitive outcomes. Overall, we expand the role of EAG proteins in human disease and establish KCNH5 as implicated in a spectrum of neurodevelopmental disorders and epilepsy.