MSL2 variants lead to a neurodevelopmental syndrome with lack of coordination, epilepsy, specific dysmorphisms, and a distinct episignature.

Epigenetic dysregulation has emerged as an important etiological mechanism of neurodevelopmental disorders (NDDs). Pathogenic variation in epigenetic regulators can impair deposition of histone post-translational modifications leading to aberrant spatiotemporal gene expression during neurodevelopment. The male-specific lethal (MSL) complex is a prominent multi-subunit epigenetic regulator of gene expression and is responsible for histone 4 lysine 16 acetylation (H4K16ac). Using exome sequencing, here we identify a cohort of 25 individuals with heterozygous de novo variants in MSL complex member MSL2. MSL2 variants were associated with NDD phenotypes including global developmental delay, intellectual disability, hypotonia, and motor issues such as coordination problems, feeding difficulties, and gait disturbance. Dysmorphisms and behavioral and/or psychiatric conditions, including autism spectrum disorder, and to a lesser extent, seizures, connective tissue disease signs, sleep disturbance, vision problems, and other organ anomalies, were observed in affected individuals. As a molecular biomarker, a sensitive and specific DNA methylation episignature has been established. Induced pluripotent stem cells (iPSCs) derived from three members of our cohort exhibited reduced MSL2 levels. Remarkably, while NDD-associated variants in two other members of the MSL complex (MOF and MSL3) result in reduced H4K16ac, global H4K16ac levels are unchanged in iPSCs with MSL2 variants. Regardless, MSL2 variants altered the expression of MSL2 targets in iPSCs and upon their differentiation to early germ layers. Our study defines an MSL2-related disorder as an NDD with distinguishable clinical features, a specific blood DNA episignature, and a distinct, MSL2-specific molecular etiology compared to other MSL complex-related disorders.

Unexpected Neurological Symptoms of Ruxolitinib: A Case Report.

Ruxolitinib is a highly potent JAK2 inhibitor approved for the treatment of myelofibrosis (idiopathic or post-polycythemia vera or post-essential thrombocythemia) and, more recently, for polycythemia vera with an inadequate response to or intolerant of hydroxyurea. The most common adverse events of ruxolitinib include immunosuppression with an increased risk of reactivation of silent infections and increased non-melanoma skin cancer. The known neurological side effects of ruxolitinib are dizziness and headache, but no neurological paroxysmal episodes have been recorded. This report deals with an 80-year-old outpatient woman with polycythemia vera turned into myelofibrosis who experienced neurological episodes of hypoesthesia and weakness of right arm and leg during ruxolitinib treatment.

HLA-G allelic distribution in Sardinian children with Autism spectrum disorders: A replication study.

Recent results show that in mainland Italian children with Autism spectrum disorder (ASD), HLA-G coding alleles distribution is skewed and an association between HLA-G*01:05N and ASD is present. Herein, in an independent cohort of Sardinian ASD (sASD) children and their relatives, we verify whether HLA-G allele association with ASD could be confirmed in this genetically peculiar insular population. One hundred children with a diagnosis of ASD, born in Sardinia and of Sardinian descent, 91 of their mothers, and 40 of their healthy siblings were enrolled. DNA sequencing analysis of HLA-G exon 2, 3 and 4 was used to obtain HLA-G allelic frequencies. Alleles distribution was compared with that of continental ASD children and with a control group of Caucasoid couples of multiparous women and their partners from Brazil and Denmark. Skewing of HLA-G allele distribution was replicated in sASD children; in particular, the HLA-G*01:03 allele, associated with reduced fetal tolerogenicity and development of myeloid leukemia, was more common in both ASD groups compared to controls (pc = 1 × 10-3; OR:3.5, 95%CI: 1.8-6.8). However, given the lack of data on HLA-G*01:03 allelic distribution among Sardinian healthy subjects, we cannot exclude a population effect. These data confirm an association of HLA-G locus with ASD development, particularly with those alleles linked to a lower expression of tolerogenic HLA-G protein, thus warranting further studies on HLA-G polymorphism distribution in different ASD populations.

Preliminary evidence about irritability in patients with epilepsy treated by perampanel as first add-on therapy compared to levetiracetam and valproic acid.

AIMS: Irritability has been described as a frequent adverse event in patients affected by epilepsy and treated with perampanel (PER), levetiracetam (LEV), and less frequently with valproic acid (VPA). Since the questionnaire for irritability (I-EPI) is a validated instrument to measure this psychiatric manifestation in patients affected by epilepsy, in this study we aimed at investigating the effect of PER as first add-on therapy on I-EPI. Moreover, we compared the effectiveness and I-EPI scores obtained at 12-month follow-up visits in patients treated by PER, LEV, or VPA in order to measure irritability as a consequence of these treatments. METHODS: We collected data from 17 patients treated by PER, 16 patients treated by LEV, and 16 patients under VPA treatment followed for 12 months. RESULTS: We did not document significant changes of I-EPI questionnaire between baseline and follow-up in the PER group. As concerning the comparison of I-EPI among PER, LEV, and VPA groups, we documented lower global scores in PER than both LEV (P < 0.05) and VPA (P < 0.05) groups. Moreover, patients under PER treatment showed lower scores than LEV and VPA (P < 0.05) in I-EPI items measuring the gentle personality, anxiety of having epileptic seizures in front of others, and irritability in thinking that they can have an epileptic seizure. CONCLUSIONS: This retrospective study described a stable and possibly lower degree of irritability in patients starting PER than LEV and VPA treatments, although we documented the comparable effectiveness of PER, LEV, and VPA as first add-on treatments in patients affected by uncontrolled epileptic seizures. However, the small sample of patients included in this study and the absence of I-EPI scores obtained at baseline visits in LEV and VPA groups require further investigations to confirm this preliminary evidence.

Defining the electroclinical phenotype and outcome of PCDH19-related epilepsy: A multicenter study.

OBJECTIVE: PCDH19-related epilepsy is an epileptic syndrome with infantile onset, characterized by clustered and fever-induced seizures, often associated with intellectual disability (ID) and autistic features. The aim of this study was to analyze a large cohort of patients with PCDH19-related epilepsy and better define the epileptic phenotype, genotype-phenotype correlations, and related outcome-predicting factors. METHODS: We retrospectively collected genetic, clinical, and electroencephalogram (EEG) data of 61 patients with PCDH19-related epilepsy followed at 15 epilepsy centers. All consecutively performed EEGs were analyzed, totaling 551. We considered as outcome measures the development of ID, autistic spectrum disorder (ASD), and seizure persistence. The analyzed variables were the following: gender, age at onset, age at study, genetic variant, fever sensitivity, seizure type, cluster occurrence, status epilepticus, EEG abnormalities, and cognitive and behavioral disorders. Receiver operating characteristic curve analysis was performed to evaluate the age at which seizures might decrease in frequency. RESULTS: At last follow-up (median = 12 years, range = 1.9-42.1 years), 48 patients (78.7%) had annual seizures/clusters, 13 patients (21.3%) had monthly to weekly seizures, and 12 patients (19.7%) were seizure-free for ≥2 years. Receiver operating characteristic analysis showed a significant decrease of seizure frequency after the age of 10.5 years (sensitivity = 81.0%, specificity = 70.0%). Thirty-six patients (59.0%) had ID and behavioral disturbances. ASD was present in 31 patients. An earlier age at epilepsy onset emerged as the only predictive factor for ID (P = 0.047) and ASD (P = 0.014). Conversely, age at onset was not a predictive factor for seizure outcome (P = 0.124). SIGNIFICANCE: We found that earlier age at epilepsy onset is related to a significant risk for ID and ASD. Furthermore, long-term follow-up showed that after the age of 10 years, seizures decrease in frequency and cognitive and behavioral disturbances remain the primary clinical problems.

Ring chromosome 20.

Ring Chromosome 20 syndrome is a rare chromosomal disorder characterized by refractory epilepsy, with seizures in wakefulness and sleep, behavioral problems and mild to severe cognitive impairment. Facial dysmorphism or other congenital malformations are rarely reported making it difficult to diagnose the syndrome based on clinical findings alone. Therefore, diagnosis requires cytogenetic testing. More than 100 cases have been published since the initial report in 1972. In some patients, the ring (20) is found in all cells analyzed and in these cases, the ring is almost always accompanied by deletions of 20pter and/or 20qter. However, in the majority of cases the ring is present in only a proportion of cells, with two normal 20's in the remaining cells (mosaicism), and in these cases, no deletions of chromosome 20 have been observed. Patients with supernumerary r(20) chromosomes have also been identified, but these individuals do not generally have seizures and are not discussed in this review. Characterization by fluorescence in situ hybridization and array-based analysis has shed insight into the molecular composition and possible mechanisms of ring formation, in both the mosaic and non-mosaic patients. The age of onset of seizures correlates with the percentage of cells with the ring in mosaic patients. While the underlying etiology of the phenotype is still not understood, evidence is accumulating which suggests the deletion of candidate genes on chromosome 20 is not responsible. Cytogenetic analysis, rather than chromosomal microarray analysis is recommended for diagnosis of this syndrome, as the mosaic cases do not have copy number alterations and are therefore not identified by array-based analysis.

A functional polymorphism in the SCN1A gene does not influence antiepileptic drug responsiveness in Italian patients with focal epilepsy.

A splice site variation (c.603-91G>A or rs3812718) in the SCN1A gene has been claimed to influence efficacy and dose requirements of carbamazepine and phenytoin. We investigated the relationship between c.603-91G>A polymorphism and response to antiepileptic drugs (AEDs) in 482 patients with drug-resistant and 401 patients with drug-responsive focal epilepsy. Most commonly used AEDs were carbamazepine and oxcarbazepine. The distribution of c.603-91G>A genotypes was similar among drug-resistant and drug-responsive subjects, both in the entire population and in the groups treated with carbamazepine or oxcarbazepine. There was no association between the c.603-91G>A genotype and dosages of carbamazepine or oxcarbazepine. These findings rule out a major role of the SCN1A polymorphism as a determinant of AED response.

Clinical course and variability of non-Rasmussen, nonstroke motor and sensory epilepsia partialis continua: a European survey and analysis of 65 cases.

PURPOSE: To gain new insights into the clinical presentation, causes, treatment and prognosis of epilepsia partialis continua (EPC), and to develop hypotheses to be tested in a prospective investigation. METHODS: In this retrospective multicenter study, all cases were included that fulfilled these criteria: constantly repeated fragments of epileptic seizures, with preserved consciousness, lasting ≥ 1 h and representing locally restricted motor or sensory epileptic activity. Single episodes were included when they lasted for a minimum of 1 day. EPC with Rasmussen syndrome and acute stroke were excluded. KEY FINDINGS: Three time courses with two subtypes each were distinguished, that is, EPC as a solitary event (de novo or in preexistent epilepsy); chronic repetitive nonprogressive EPC (with frequent or rare episodes); and chronic persistent nonprogressive EPC (primarily or evolving out of an episodic course). These were unrelated to etiologies (morphologic lesions 34%, inflammatory 29%, systemic disorders 9%, idiopathic 5%, unknown 23%). Precipitation and inhibition of seizures is a frequent feature of EPC. Levetiracetam and topiramate have improved the possibilities for pharmacotherapy. Topiramate seems to be particularly effective with dysontogenetic etiologies. SIGNIFICANCE: The existence of several clearly distinct courses of nonprogressive EPC is a new finding. These distinctions will be further investigated in a prospective study with precise protocols for electroencephalography (EEG), imaging, and other studies. This should better establish the relation of motor and somatosensory EPC; further clarify the relations, pathogenesis, and significance of the different types and their etiologies; and possibly identify more semiologic variants. It should also provide more precise knowledge about therapy and modification of ictogenesis by external stimuli.