A registry for Dravet syndrome: The Italian experience.

OBJECTIVES: We describe the Residras registry, dedicated to Dravet syndrome (DS) and to other phenotypes related to SCN1A mutations, as a paradigm of registry for rare and complex epilepsies. Our primary objectives are to present the tools and framework of the integrative platform, the main characteristics emerging from the patient cohort included in the registry, with emphasis on demographic, clinical outcome, and mortality. METHODS: Standardized data of enrolled pediatric and adult patients were collected in 24 Italian expert centers and regularly updated at least on a yearly basis. Patients were prospectively enrolled, at registry starting, but historical retrospective data were also included. RESULTS: At present, 281 individuals with DS and a confirmed SCN1A mutation are included. Most patients have data available on epilepsy (n = 263) and their overall neurological condition (n = 255), based on at least one follow-up update. Median age at first clinical assessment was 2 years (IQR 0-9) while at last follow-up was 11 years (IQR 5-18.5). During the 7-year activity of the registry, five patients died resulting in a mortality rate of 1.84 per 1000-person-years. When analyzing clinical changes over the first 5-year follow-up, we observed a significant difference in cognitive function (P < 0.001), an increased prevalence of behavioral disorders including attention deficit (P < 0.001), a significant worsening of language (P = 0.001), and intellectual disability (P < 0.001). SIGNIFICANCE: The Residras registry represents a large collection of standardized national data for the DS population. The registry platform relies on a shareable and interoperable framework, which promotes multicenter high-quality data collection. In the future, such integrated platform may represent an invaluable asset for easing access to cohorts of patients that may benefit from clinical trials with emerging novel therapies, for drug safety monitoring, and for delineating natural history. Its framework makes it improvable based on growing experience with its use and easily adaptable to other rare and complex epilepsy syndromes.

Efficacy and Safety of Long-Term Treatment with Stiripentol in Children and Adults with Drug-Resistant Epilepsies: A Retrospective Cohort Study of 196 Patients.

BACKGROUND: Stiripentol is an antiseizure medication with multiple potential mechanisms of action, indicated as adjunctive therapy in people with Dravet syndrome, whose seizures are not adequately controlled with clobazam and valproate. However, there are scattered data on its efficacy in other epilepsy aetiologies and types. We previously reported our single-centre experience on the efficacy of adjunctive stiripentol treatment in a cohort of 132 patients with different types of refractory epilepsies. OBJECTIVE: We aimed to expand our analysis to a larger cohort of 196 patients with a long-term follow-up. METHODS: We retrospectively evaluated long-term efficacy, tolerability and predictors of treatment response in 196 patients with a long-term follow-up (range 0.5-232.8 months). RESULTS: After an initial median follow-up of 3 months after stiripentol introduction, we observed a responder rate of 53% including seizure freedom in 9%. At subsequent follow-ups at 12 and 24 months, responder rates were 29% and 22%, respectively. Aetiology was associated with sustained response over time, with Dravet syndrome being the aetiology with the highest responder rate (64%) at 48 months compared with syndromes with other genetic causes (13%) or unknown aetiology (38%). A higher responder rate over time was also observed in patients with generalised (44%) and combined focal and generalised epilepsies (28%) than in patients with focal epilepsies (20%). The highest relapse free-survival was observed when stiripentol was initiated at the youngest age (0-4 years) or in adulthood. The retention rate (i.e. proportion of patients who continued stiripentol with no change in either pharmacological or non-pharmacological therapy) was 53% at 12 months and 33% at 24 months. CONCLUSIONS: Based on our findings, we suggest that stiripentol is an effective and well-tolerated therapeutic option not only in Dravet syndrome but also in other epilepsy syndromes with or without an established genetic aetiology. Response duration was influenced by age at stiripentol initiation across different aetiologies.

Efficacy and safety of Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: A real-world study.

OBJECTIVE: Dravet syndrome (DS) is a drug-resistant, infantile onset epilepsy syndrome with multiple seizure types and developmental delay. In recently published randomized controlled trials, fenfluramine (FFA) proved to be safe and effective in DS. METHODS: DS patients were treated with FFA in the Zogenix Early Access Program at four Italian pediatric epilepsy centers. FFA was administered as add-on, twice daily at an initial dose of 0.2 mg/kg/d up to 0.7 mg/kg/d. Seizures were recorded in a diary. Adverse events and cardiac safety (with Doppler echocardiography) were investigated every 3 to 6 months. RESULTS: Fifty-two patients were enrolled, with a median age of 8.6 years (interquartile range [IQR] = 4.1-13.9). Forty-five (86.5%) patients completed the efficacy analysis. The median follow-up was 9.0 months (IQR = 3.2-9.5). At last follow-up visit, there was a 77.4% median reduction in convulsive seizures. Thirty-two patients (71.1%) had a ≥50% reduction of convulsive seizures, 24 (53.3%) had a ≥75% reduction, and five (11.1%) were seizure-free. The most common adverse event was decreased appetite (n = 7, 13.4%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed. There was no correlation between type of genetic variants and response to FFA. SIGNIFICANCE: In this real-world study, FFA provided a clinically meaningful reduction in convulsive seizure frequency in the majority of patients with DS and was well tolerated.

Long-term efficacy of add-on stiripentol treatment in children, adolescents, and young adults with refractory epilepsies: A single center prospective observational study.

OBJECTIVE: To assess the long-term efficacy and tolerability of stiripentol (STP) as an adjunctive treatment in different forms of refractory epilepsies. METHODS: The medical records of all individuals consecutively treated with STP as add-on therapy for refractory epilepsies, irrespective of their being focal, generalized, or both, and followed at Meyer Children's Hospital between January 2007 and May 2018, were reviewed. The drug scheme administration consisted of a starting dose of STP of 10-15 mg/kg/d with increments every week, up to a maximum of 50 mg/kg/d, based on both age and weight. Etiology of epilepsy was codified as structural, genetic, infectious, immune, metabolic, and unknown. Responders were defined as patients who achieved a seizure frequency reduction of ≥50%. Retention rate was defined as the probability of continuing STP without additional therapy. Tolerability was assessed by reporting adverse events. RESULTS: A total of 132 individuals aged from 5 months to 43 years received add-on STP, including 30 patients with Dravet syndrome (DS). The median follow-up was 14.8 months (range = 4 months-18 years, interquartile range = 25.72). Twenty-nine individuals (22%) received more than two antiepileptic drugs. Benzodiazepines, mainly clobazam, were the most commonly used add-on drugs. Sixty-six patients (50%) were responders, and 13 of them (9.8%) were seizure-free. Responder rate was higher in the genetic etiology group (57%), especially in DS (18/30; 60%), and in patients with refractory focal onset epilepsy without bilateral tonic-clonic seizures (5/15; 33%). The median relapse-free survival was 27 months in the 66 responders. The median time to STP failure was 24.6 months in all 132 individuals. SIGNIFICANCE: This study confirms the long-term efficacy of add-on STP treatment in patients with different types of refractory epilepsies, including focal onset epilepsy without bilateral tonic-clonic seizures. Further confirmations based on prospectively designed studies are required to confirm STP efficacy in focal epilepsy.

Multiple genomic copy number variants associated with periventricular nodular heterotopia indicate extreme genetic heterogeneity.

Periventricular nodular heterotopia (PNH) is a brain malformation in which nodules of neurons are ectopically retained along the lateral ventricles. Genetic causes include FLNA abnormalities (classical X-linked PNH), rare variants in ARFGEF2, DCHS1, ERMARD, FAT4, INTS8, MAP1B, MCPH1, and NEDD4L, as well as several chromosomal abnormalities. We performed array-CGH in 106 patients with different malformations of cortical development (MCD) and looked for common pathways possibly involved in PNH. Forty-two patients, including two parent/proband couples, exhibited PNH associated or not with other brain abnormalities, 44 had polymicrogyria and 20 had rarer MCDs. We found an enrichment of either large rearrangements or cryptic copy number variants (CNVs) in PNH (15/42, 35.7%) vs polymicrogyria (4/44, 9.1%) (i.e., 5.6 times increased risk for PNH of carrying a pathogenic CNV). CNVs in seven genomic regions (2p11.2q12.1, 4p15, 14q11.2q12, 16p13.3, 19q13.33, 20q13.33, 22q11) represented novel, potentially causative, associations with PNH. Through in silico analysis of genes included in imbalances whose breakpoints were clearly detailed, we detected in 9/12 unrelated patients in our series and in 15/24 previously published patients, a significant (P < 0.05) overrepresentation of genes involved in vesicle-mediated transport. Rare genomic imbalances, either small CNVs or large rearrangements, are cumulatively a frequent cause of PNH. Dysregulation of specific cellular mechanisms might play a key pathogenic role in PNH but it remains to be determined whether this is exerted through single genes or the cumulative dosage effect of more genes. Array-CGH should be considered as a first-line diagnostic test in PNH, especially if sporadic and non-classical.

De novo KCNA1 variants in the PVP motif cause infantile epileptic encephalopathy and cognitive impairment similar to recurrent KCNA2 variants.

Derangements in voltage-gated potassium channel function are responsible for a range of paroxysmal neurologic disorders. Pathogenic variants in the KCNA1 gene, which encodes the voltage-gated potassium channel Kv1.1, are responsible for Episodic Ataxia Type 1 (EA1). Patients with EA1 have an increased incidence of epilepsy, but KCNA1 variants have not been described in epileptic encephalopathy. Here, we describe four patients with infantile-onset epilepsy and cognitive impairment who harbor de novo KCNA1 variants located within the Kv-specific Pro-Val-Pro (PVP) motif which is essential for channel gating. The first two patients have KCNA1 variants resulting in (p.Pro405Ser) and (p.Pro405Leu), respectively, and a set of identical twins has a variant affecting a nearby residue (p.Pro403Ser). Notably, recurrent de novo variants in the paralogous PVP motif of KCNA2 have previously been shown to abolish channel function and also cause early-onset epileptic encephalopathy. Importantly, this report extends the range of phenotypes associated with KCNA1 variants to include epileptic encephalopathy when the PVP motif is involved.

Long-term efficacy of add-on lacosamide treatment in children and adolescents with refractory epilepsies: A single-center observational study.

OBJECTIVE: To assess long-term efficacy and tolerability of lacosamide (LCM) as adjunctive treatment through a retrospective study in children and adolescents with refractory epilepsies. METHODS: All patients consecutively treated with LCM as add-on for refractory focal and generalized epilepsy and followed at the Neuroscience Center of Excellence of the Meyer Children's Hospital of Florence between January 2011 and September 2015 were included in the study. Responder rate, relapse-free survival, and retention rate were calculated. Tolerability was assessed by reporting adverse events. RESULTS: A total of 88 individuals (41 female) aged 4 months to 18 years (median 10.5 years; mean ± SD 10.6 ± 4.8 years) received add-on LCM treatment for refractory epilepsy. Thirty-four patients (38.6%) were responders with a median time to relapse of 48 months. Nine (26.4%) of the 34 responders were seizure-free. For all 88 patients, the probability of remaining on LCM without additional therapy was 74.4% at 6 months, 47.7% at 12 months, 27.9% at 24 months, 18.0% at 48 months, and 8.2% at 72 months of follow-up. No statistically significant differences in relapse and retention time were observed with regard to epilepsy and seizure types, duration and course of epilepsy, number and type of antiepileptic drugs (AEDs; sodium channel blockers vs others) used in add-on. The most frequent adverse events were dermatological (4/11) and behavioral (3/11). SIGNIFICANCE: This study documents a real-world progressive and significant loss of LCM efficacy over time in a pediatric population. Further prospective studies on larger populations are required to confirm the remarkable loss of LCM efficacy over time.

Homozygous deletion in TUSC3 causing syndromic intellectual disability: a new patient.

Defects in the TUSC3 gene have been identified in individuals with nonsyndromic autosomal recessive intellectual disability (ARID), due to either point mutations or intragenic deletions. We report on a boy with a homozygous microdeletion 8p22, sizing 203 kb, encompassing the first exon of the TUSC3 gene, detected by SNP-array analysis (Human Gene Chip 6.0; Affymetrix). Both nonconsanguineous parents come from a small Sicilian village and were heterozygous carriers of the microdeletion. The propositus had a few dysmorphic features and a moderate cognitive impairment. Verbal communication was impaired, with an inappropriate phonetic inventory, important phono-articolatory distortions, and bucco-phonatory dyspraxia. Comprehension was possible for simple sentences. Behavior was characterized by motor instability, high tendency to irritability and distraibility, anxiety traits, and an oppositional-defiant disorder. His parents were of normal intelligence. TUSC3 is thought to encode a subunit of the endoplasmic reticulum-bound oligosaccharyltranferase complex that catalyzes a pivotal step in the protein N-glycosylation process. TUSC3 has been recently reported as a member of the plasma membrane Mg(2+) transport system, with a possible involvement in learning abilities, working memory and short- and long-term memory. This is the third family in which a deletion has been described. Although the pathogenic mechanism has not been clarified yet, our report argues for a more prominent role of TUSC3 in the etiology of intellectual disability and that deletions encompassing this gene could be more common than expected.

Confirmation of chromosomal microarray as a first-tier clinical diagnostic test for individuals with developmental delay, intellectual disability, autism spectrum disorders and dysmorphic features.

BACKGROUND AND OBJECTIVES: Submicroscopic chromosomal rearrangements are the most common identifiable causes of intellectual disability and autism spectrum disorders associated with dysmorphic features. Chromosomal microarray (CMA) can detect copy number variants <1 Mb and identifies size and presence of known genes. The aim of this study was to demonstrate the usefulness of CMA, as a first-tier tool in detecting the etiology of unexplained intellectual disability/autism spectrum disorders (ID/ASDs) associated with dysmorphic features in a large cohort of pediatric patients. PATIENTS AND METHODS: We studied 349 individuals; 223 males, 126 females, aged 5 months-19 years. Blood samples were analyzed with CMA at a resolution ranging from 1 Mb to 40 Kb. The imbalance was confirmed by FISH or qPCR. We considered copy number variants (CNVs) causative if the variant was responsible for a known syndrome, encompassed gene/s of known function, occurred de novo or, if inherited, the parent was variably affected, and/or the involved gene/s had been reported in association with ID/ASDs in dedicated databases. RESULTS: 91 CNVs were detected in 77 (22.06%) patients: 5 (6.49%) of those presenting with borderline cognitive impairment, 54 (70.13%) with a variable degree of DD/ID, and 18/77 (23.38%) with ID of variable degree and ASDs. 16/77 (20.8%) patients had two different rearrangements. Deletions exceeded duplications (58 versus 33); 45.05% (41/91) of the detected CNVs were de novo, 45.05% (41/91) inherited, and 9.9% (9/91) unknown. The CNVs caused the phenotype in 57/77 (74%) patients; 12/57 (21.05%) had ASDs/ID, and 45/57 (78.95%) had DD/ID. CONCLUSIONS: Our study provides further evidence of the high diagnostic yield of CMA for genetic testing in children with unexplained ID/ASDs who had dysmorphic features. We confirm the value of CMA as the first-tier tool in the assessment of those conditions in the pediatric setting.

6p25 interstitial deletion in two dizygotic twins with gyral pattern anomaly and speech and language disorder.

Submicroscopic 6p25 deletion is now recognized as a clinically identifiable syndrome, characterized by intellectual disability, language impairment, hearing deficit, craniofacial, ophthalmologic, cardiac, and varying central nervous system anomalies. We report on two dyzogotic twins with a maternal segregating hemizygous interstitial deletion on chromosome 6p25.1, spanning 0.9 kb; the smallest ever reported. Both had dysmorphic features (prominence of the metopic suture, synophrys, hypertelorism, down-slanting palpebral fissures, tented mouth), and a distinct brain MRI, showing a focal significant increase of the right peri-frontal subarachnoid space, with shallow sulci and a mild anomaly of the gyral pattern. Such brain anomaly has never been reported in association with del 6p25. Both propositi had a borderline-mild intellectual disability, speech and language difficulties, and behavior abnormalities. Their mother, formally tested, had a borderline cognitive impairment. Although none of the genes mapping to the deleted region are apparently related to the phenotype, LYRM4 resulted down-regulated in the cerebellar cortex of schizophrenia patients compared with controls, and Lyrm4 was down-regulated in the prefrontal cortex of mice with microdeletions in the locus syntenic to human 22q11.2 patients affected by schizophrenia. These data are in agreement with the emerging concept that similar CNVs are pathogenic in patients affected by distinct neurological diseases, and that these loci are more general risk factors for different disorders. The resemblance of our patients to those with the more extensive 6p25.1p25.3 terminal deletion suggests that the gene/s responsible for the physical phenotype should reside in the 6p25.1 genomic region.