KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum.

Variants in KCNT1, encoding a sodium-gated potassium channel (subfamily T member 1), have been associated with a spectrum of epilepsies and neurodevelopmental disorders. These range from familial autosomal dominant or sporadic sleep-related hypermotor epilepsy to epilepsy of infancy with migrating focal seizures (EIMFS) and include developmental and epileptic encephalopathies. This study aims to provide a comprehensive overview of the phenotypic and genotypic spectrum of KCNT1 mutation-related epileptic disorders in 248 individuals, including 66 previously unpublished and 182 published cases, the largest cohort reported so far. Four phenotypic groups emerged from our analysis: (i) EIMFS (152 individuals, 33 previously unpublished); (ii) developmental and epileptic encephalopathies other than EIMFS (non-EIMFS developmental and epileptic encephalopathies) (37 individuals, 17 unpublished); (iii) autosomal dominant or sporadic sleep-related hypermotor epilepsy (53 patients, 14 unpublished); and (iv) other phenotypes (six individuals, two unpublished). In our cohort of 66 new cases, the most common phenotypic features were: (i) in EIMFS, heterogeneity of seizure types, including epileptic spasms, epilepsy improvement over time, no epilepsy-related deaths; (ii) in non-EIMFS developmental and epileptic encephalopathies, possible onset with West syndrome, occurrence of atypical absences, possible evolution to developmental and epileptic encephalopathies with sleep-related hypermotor epilepsy features; one case of sudden unexplained death in epilepsy; (iii) in autosomal dominant or sporadic sleep-related hypermotor epilepsy, we observed a high prevalence of drug-resistance, although seizure frequency improved with age in some individuals, appearance of cognitive regression after seizure onset in all patients, no reported severe psychiatric disorders, although behavioural/psychiatric comorbidities were reported in ∼50% of the patients, sudden unexplained death in epilepsy in one individual; and (iv) other phenotypes in individuals with mutation of KCNT1 included temporal lobe epilepsy, and epilepsy with tonic-clonic seizures and cognitive regression. Genotypic analysis of the whole cohort of 248 individuals showed only missense mutations and one inframe deletion in KCNT1. Although the KCNT1 mutations in affected individuals were seen to be distributed among the different domains of the KCNT1 protein, genotype-phenotype considerations showed many of the autosomal dominant or sporadic sleep-related hypermotor epilepsy-associated mutations to be clustered around the RCK2 domain in the C terminus, distal to the NADP domain. Mutations associated with EIMFS/non-EIMFS developmental and epileptic encephalopathies did not show a particular pattern of distribution in the KCNT1 protein. Recurrent KCNT1 mutations were seen to be associated with both severe and less severe phenotypes. Our study further defines and broadens the phenotypic and genotypic spectrums of KCNT1-related epileptic conditions and emphasizes the increasingly important role of this gene in the pathogenesis of early onset developmental and epileptic encephalopathies as well as of focal epilepsies, namely autosomal dominant or sporadic sleep-related hypermotor epilepsy.

Mesial Temporal Sclerosis as Late Consequence of Posterior Reversible Encephalopathy Syndrome in Pediatric Hemato-oncologic Patients.

OBJECTIVES: Drug resistant epilepsy has rarely been reported following posterior reversible encephalopathy syndrome (PRES), with few cases of mesial temporal sclerosis (MTS). The aim of this study was to report clinical and neuroimaging features of MTS subsequent to PRES in hemato-oncologic/stem cell transplanted children. MATERIALS AND METHODS: Among 70 children treated in 2 pediatric hemato-oncologic Italian centers between 1994 and 2018 and presenting an episode of PRES, we retrospectively identified and analyzed a subgroup of patients who developed epilepsy and MTS. RESULTS: Nine of 70 patients (12.8%) developed post-PRES persistent seizures with magnetic resonance imaging evidence of MTS. One patient died few months after MTS diagnosis, because of hematologic complications; the remaining 8 patients showed unprovoked seizures over time leading to the diagnosis of epilepsy, focal in all and drug resistant in 4. At PRES diagnosis, all patients with further evidence of epilepsy and MTS suffered of convulsive seizures, evolving into status epilepticus in 3. In 3 patients a borderline cognitive level or intellectual disability were diagnosed after the onset of epilepsy, and 2 had behavioral problems impacting their quality of life. CONCLUSIONS: MTS and long-term focal epilepsy, along with potential cognitive and behavioral disorders, are not uncommon in older pediatric patients following PRES.

Novel CNS malformations and skeletal anomalies in a patient with Beaulieu-boycott-Innes syndrome.

THO/TREX (transcription/export) is a conserved eukaryotic complex that plays a crucial role in gene expression and prevents DNA damage during mitosis and meiosis. In mammals, TREX is essential during embryogenesis, determining stem cell fate specification by regulating posttranscriptional self-renewal and differentiation in several tissues. It is composed of a core called THO, consisting of THOC1, 2, 5, 6, 7, and additional proteins. Bi-allelic mutations in THOC6 have been associated to Beaulieu-Boycott-Innes syndrome (BBIS), a syndromic form of intellectual disability (ID). To date, nine patients harbouring homozygous or compound heterozygous mutations in THOC6 have been reported. Despite the clinical heterogenity and subtle dysmorphic features in some individuals, distinctive facial features are tall forehead, short and upslanting palpebral fissures, deep set eyes, flat philtrum, and malocclusion. Nonlife threatening congenital anomalies are common, including cardiac and renal malformations, anteriorly displaced anus, cryptorchidism in males, submucous cleft palate, and corpus callosum dysgenesis. Affected patients usually have short stature, mild microcephaly, and mild to moderate ID. Here, we describe an Italian patient with BBIS, carrying two compound heterozygous loss-of-function (LoF) variants in THOC6 (c.577C > T, p.R193* and c.792_793delCA, p.V264Vfs*48). In addition to the common phenotype, she displays cerebellar hypoplasia with severe vermian dysgenesis and hydrocephalus due to aqueductal stenosis, multiple skeletal anomalies and hypergonadotropic hypogonadism. Thus, we review the previous cases and discuss the phenotypic spectrum of BBIS, providing further evidence regarding the pivotal role of TREX complex in human development.

Substrate reduction therapy with Miglustat in pediatric patients with GM1 type 2 gangliosidosis delays neurological involvement: A multicenter experience.

BACKGROUND: In GM1 gangliosidosis the lack of function of ß-galactosidase results in an accumulation of GM1 ganglioside and related glycoconjugates in visceral organs, and particularly in the central nervous system, leading to severe disability and premature death. In the type 2 form of the disease, early intervention would be important to avoid precocious complications. To date, there are no effective therapeutic options in preventing progressive neurological deterioration. Substrate reduction therapy with Miglustat, a N-alkylated sugar that inhibits the enzyme glucosylceramide synthase, has been proposed for the treatment of several lysosomal storage disorders such as Gaucher type 1 and Niemann Pick Type C diseases. However, data on Miglustat therapy in patients with GM1 gangliosidosis are still scarce. METHODS: We report here the results of Miglustat administration in four Italian children (average age: 55 months, range 20-125) affected by GM1 gangliosidosis type 2 treated in three different Italian pediatric hospitals specialized in metabolic diseases. CONCLUSION: This treatment was safe and relatively well tolerated by all patients, with stabilization and/or slowing down of the neurological progression in three subjects.

Genotype-phenotype correlations in patients with de novo KCNQ2 pathogenic variants.

OBJECTIVE: Early identification of de novo KCNQ2 variants in patients with epilepsy raises prognostic issues toward optimal management. We analyzed the clinical and genetic information from a cohort of patients with de novo KCNQ2 pathogenic variants to dissect genotype-phenotype correlations. METHODS: Patients with de novo KCNQ2 pathogenic variants were identified from Italy, Denmark, and Belgium. Atomic resolution Kv7.2 structures were also generated using homology modeling to map the variants. RESULTS: We included 34 patients with a mean age of 4.7 years. Median seizure onset was 2 days, mainly with focal seizures with autonomic signs. Twenty-two patients (65%) were seizure free at the mean age of 1.2 years. More than half of the patients (17/32) displayed severe/profound intellectual disability; however, 4 (13%) of them had a normal cognitive outcome.A total of 28 de novo pathogenic variants were identified, most missense (25/28), and clustered in conserved regions of the protein; 6 variants recurred, and 7 were novel. We did not identify a relationship between variant position and seizure offset or cognitive outcome in patients harboring missense variants. Besides, recurrent variants were associated with overlapping epilepsy features but also variable evolution regarding the intellectual outcome. CONCLUSIONS: We highlight the complexity of variant interpretation to assess the impact of a class of de novo KCNQ2 mutations. Genetic modifiers could be implicated, but the study paradigms to successfully address the impact of each single mutation need to be developed.

TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features.

OBJECTIVE: To evaluate the phenotypic spectrum associated with mutations in TBC1D24. METHODS: We acquired new clinical, EEG, and neuroimaging data of 11 previously unreported and 37 published patients. TBC1D24 mutations, identified through various sequencing methods, can be found online (http://lovd.nl/TBC1D24). RESULTS: Forty-eight patients were included (28 men, 20 women, average age 21 years) from 30 independent families. Eighteen patients (38%) had myoclonic epilepsies. The other patients carried diagnoses of focal (25%), multifocal (2%), generalized (4%), and unclassified epilepsy (6%), and early-onset epileptic encephalopathy (25%). Most patients had drug-resistant epilepsy. We detail EEG, neuroimaging, developmental, and cognitive features, treatment responsiveness, and physical examination. In silico evaluation revealed 7 different highly conserved motifs, with the most common pathogenic mutation located in the first. Neuronal outgrowth assays showed that some TBC1D24 mutations, associated with the most severe TBC1D24-associated disorders, are not necessarily the most disruptive to this gene function. CONCLUSIONS: TBC1D24-related epilepsy syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness (not studied here), benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death. There is no distinct correlation with mutation type or location yet, but patterns are emerging. Given the phenotypic breadth observed, TBC1D24 mutation screening is indicated in a wide variety of epilepsies. A TBC1D24 consortium was formed to develop further research on this gene and its associated phenotypes.