Recently, de novo mutations in the gene KCNA2, causing either a dominant-negative loss-of-function or a gain-of-function of the voltage-gated K+ channel Kv1.2, were described to cause a new molecular entity within the epileptic encephalopathies. Here, we report a cohort of 23 patients (eight previously described) with epileptic encephalopathy carrying either novel or known KCNA2 mutations, with the aim to detail the clinical phenotype associated with each of them, to characterize the functional effects of the newly identified mutations, and to assess genotype-phenotype associations. We identified five novel and confirmed six known mutations, three of which recurred in three, five and seven patients, respectively. Ten mutations were missense and one was a truncation mutation; de novo occurrence could be shown in 20 patients. Functional studies using a Xenopus oocyte two-microelectrode voltage clamp system revealed mutations with only loss-of-function effects (mostly dominant-negative current amplitude reduction) in eight patients or only gain-of-function effects (hyperpolarizing shift of voltage-dependent activation, increased amplitude) in nine patients. In six patients, the gain-of-function was diminished by an additional loss-of-function (gain-and loss-of-function) due to a hyperpolarizing shift of voltage-dependent activation combined with either decreased amplitudes or an additional hyperpolarizing shift of the inactivation curve. These electrophysiological findings correlated with distinct phenotypic features. The main differences were (i) predominant focal (loss-of-function) versus generalized (gain-of-function) seizures and corresponding epileptic discharges with prominent sleep activation in most cases with loss-of-function mutations; (ii) more severe epilepsy, developmental problems and ataxia, and atrophy of the cerebellum or even the whole brain in about half of the patients with gain-of-function mutations; and (iii) most severe early-onset phenotypes, occasionally with neonatal onset epilepsy and developmental impairment, as well as generalized and focal seizures and EEG abnormalities for patients with gain- and loss-of-function mutations. Our study thus indicates well represented genotype-phenotype associations between three subgroups of patients with KCNA2 encephalopathy according to the electrophysiological features of the mutations.
The essential micronutrient selenium is found in proteins as selenocysteine (Sec), the only genetically encoded amino acid whose biosynthesis occurs on its cognate tRNA in humans. In the final step of selenocysteine formation, the essential enzyme SepSecS catalyzes the conversion of Sep-tRNA to Sec-tRNA. We demonstrate that SepSecS mutations cause autosomal-recessive progressive cerebellocerebral atrophy (PCCA) in Jews of Iraqi and Moroccan ancestry. Both founder mutations, common in these two populations, disrupt the sole route to the biosynthesis of the 21st amino acid, Sec, and thus to the generation of selenoproteins in humans.
Summary Purpose: Rett syndrome (RTT), an X‐linked, dominant neurodevelopmental disorder caused by mutations in the methyl‐CpG‐binding protein 2 (MECP2) gene, presents with acquired microcephaly, autistic regression, hand usage loss, and stereotypies. Epilepsy is frequent and has been reported to correlate with mutation type, general disease severity, and BDNF polymorphism. Our purpose was a comprehensive description of epilepsy features and course in RTT. Methods: Retrospective review of charts and electroencephalography (EEG) studies in 97 patients with RTT. Results: Seventy‐two percent of patients had epilepsy, appearing at a median age of 3 years. According to age of onset, we divided patients into three groups: 6 with early epileptic variant (0–1 year), 42 with early epilepsy (1–5 years), and 20 with late epilepsy (after 5 years). Early epileptic variant had severe seizure types in the first year of life, followed by a typical RTT picture; all were MECP2 negative. Early epilepsy and late epilepsy groups were similar with respect to Rett‐related symptoms, but seizures were better controlled in the second group (p < 0.05). Epileptiform activity appeared earlier and was more confluent in the early epilepsy group, including nine patients with electrical status epilepticus during sleep (ESES) versus one in the late epilepsy group (p < 0.05). No correlation was found between epilepsy onset or severity and genotype. BDNF val/met polymorphism correlated with earlier onset of seizures (p < 0.05). Discussion: Epilepsy appears earlier than described previously, frequently during the regression stage. Early age of onset predicts a more severe course of seizures. ESES is common among those with early onset epilepsy. BDNF polymorphism was the only genetic correlate with seizure onset, whereas MECP2 mutation type and location did not influence epilepsy.
Summary Purpose: Benign childhood epilepsy with centrotemporal spikes (BCECTS) is the most common epileptic syndrome in childhood. The outcome is usually excellent, but there are some atypical forms of BCECTS with less favorable outcomes. The aim of this study was to delineate the frequency of these atypical features among patients with BCECTS. Methods: We conducted a retrospective chart study by retrieving the medical records of all consecutive patients with BCECTS who were evaluated in four pediatric neurology outpatient clinics in Israel between the years 1991 and 2008. Key Findings: A total of 196 patients with BCECTS were identified (78 female and 118 male; mean age at time of diagnosis 7.64 years, range 1.5–14). The mean duration of follow‐up was 4.43 years (range 2–11). Nine patients (4.6%) developed electrical status epilepticus in slow waves sleep (ESES) during follow‐up, four (2%) had Landau‐Kleffner syndrome, three (1.5%) had BCECTS with frequent refractory seizures, two (1%) had BCECTS with falls at presentation, one (0.5%) had a “classic” atypical variant, and one (0.5%) had oromotor dysfunction. None had rolandic status epilepticus. Sixty‐one patients (31%) had attention deficit hyperactivity disorder (ADHD), 43 (21.9%) had specific cognitive deficits, and 23 (11.7%) had behavioral abnormalities, including aggressiveness, anxiety disorders, depression, and pervasive developmental disorder (PDD). Significance: The prevalence of most atypical forms of BCECTS other than ESES is low. There is, however, a high prevalence of ADHD and specific cognitive deficits among patients with BCECTS.
Rett syndrome (RTT) is a rare genetic disorder within the autistic spectrum. This study compared socio-demographic, clinical and genetic characteristics of the international database, InterRett, and the population based Australian Rett syndrome database (ARSD). It also explored the strengths and limitations of InterRett in comparison with other studies. A literature review compared InterRett with RTT population-based and case-based studies of thirty or more cases that investigated genotype and/or phenotype relationships. Questionnaire data were used to determine case status and to investigate the comparability of InterRett and ARSD. Twenty four case series, five population based studies and a MECP2 mutation database were identified of which twenty one (70%) collected phenotype and genotype data. Only three studies were representative of their underlying case population and many had low numbers. Of one thousand one hundred and fourteen InterRett subjects, nine hundred and thirty five born after 1976 could be verified as Rett cases and compared with the two hundred and ninety five ARSD subjects. Although more InterRett families had higher education and occupation levels and their children were marginally less severe, the distribution of MECP2 mutation types was similar. The InterRett can be used with confidence to investigate genotype phenotype associations and clinical variation in RTT and provides an exemplary international model for other rare disorders.
Background and ObjectivesClinical manifestations in STXBP1 developmental and epileptic encephalopathy (DEE) vary in severity and outcome, and the genotypic spectrum is diverse. We aim to trace the neurodevelopmental trajectories in individuals with STXBP1-DEE and dissect the relationship between neurodevelopment and epilepsy.MethodsRetrospective standardized clinical data were collected through international collaboration. A composite neurodevelopmental score system compared the developmental trajectories in STXBP1-DEE.ResultsForty-eight patients with de novo STXBP1 variants and a history of epilepsy were included (age range at the time of the study: 10 months to 35 years, mean 8.5 years). At the time of inclusion, 65% of individuals (31/48) had active epilepsy, whereas 35% (17/48) were seizure free, and 76% of those (13/17) achieved remission within the first year of life. Twenty-two individuals (46%) showed signs of developmental impairment and/or neurologic abnormalities before epilepsy onset. Age at seizure onset correlated with severity of developmental outcome and the developmental milestones achieved, with a later seizure onset associated with better developmental outcome. In contrast, age at seizure remission and epilepsy duration did not affect neurodevelopmental outcomes. Overall, we did not observe a clear genotype-phenotype correlation, but monozygotic twins with de novo STXBP1 variant showed similar phenotype and parallel disease course.DiscussionThe disease course in STXBP1-DEE presents with 2 main trajectories, with either early seizure remission or drug-resistant epilepsy, and a range of neurodevelopmental outcomes from mild to profound intellectual disability. Age at seizure onset is the only epilepsy-related feature associated with neurodevelopment outcome. These findings can inform future dedicated natural history studies and trial design.
Objectives This study aimed to compare the phenotype of Rett syndrome cases with C-terminal deletions to that of cases with different MECP2 mutations and to examine the phenotypic variation within C-terminal deletions. Methods Cases were selected from InterRett, an international database and from the population-based Australian Rett Syndrome Database. Cases (n=832) were included if they had a pathogenic MECP2 mutation in which the nature of the amino acid change was known. Three severity scale systems were used, and individual aspects of the phenotype were also compared. Results Lower severity was associated with C-terminal deletions (n=79) compared to all other MECP2 mutations (e.g. Pineda scale C-terminals mean 15.0 (95% CI 14.0–16.0) vs 16.2 (15.9–16.5). Cases with C-terminal deletions were more likely to have a normal head circumference (odds ratio 3.22, 95% CI 1.53 – 6.79) and weight (odds ratio 2.97, 95% CI 1.25–5.76). Onset of stereotypies tended to be later (median age 2.5 years vs 2 years, p<0.001 from survival analysis), and age of learning to walk tended to be earlier (median age 1.6 years vs 2 years, p=0.002 from survival analysis). Those with C-terminal deletions occurring later in the region had lower average severity scores than those occurring earlier in the region. Conclusion In terms of overall severity C-terminal deletion cases would appear to be in the middle of the range. In terms of individual aspects of phenotype growth and ability to ambulate appear to be particular strengths. By pooling data internationally this study has achieved the case numbers to provide a phenotypic profile of C-terminal deletions in Rett syndrome.
MTHFR deficiency is a severe disease primarily affecting the central nervous system. Age at presentation and clinical pattern are correlated with residual enzyme activity. Treatment alleviates biochemical abnormalities and clinical symptoms partially.
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