Objective. Mutations in the KCNQ2 gene, encoding the voltage‐gated potassium channel, Kv7.2, cause neonatal epilepsies. The potassium channel opener, retigabine, may improve epilepsy control in cases ...with loss‐of‐function mutations, but exacerbate seizures in cases with gain‐of‐function mutations. Our aim was to describe a patient with a KCNQ2 mutation within the K+‐selectivity fi lter and illustrate how electrophysiological analysis helped us to implement personalized treatment.
Methods. Medical history of a patient with severe neonatal epileptic encephalopathy was recorded. Diagnosis was reached by whole‐exome‐sequencing. The pathogenic variant was expressed in Chinese hamster ovary cells, and patch‐clamp studies were performed, directing therapy.
Results. A seven‐year‐old male presented with neonatal seizures, progressing to hundreds of seizures/day without developmental milestones. Whole‐exome sequencing revealed a pathogenic variant, p.Gly281Arg, in the KCNQ2 gene, located within the ion selectivity fi lter of the pore, predicted to cause loss‐of‐function of Kv7.2, not affected by retigabine. Patch‐clamp analysis revealed no current with the mutant homomer and reduced current with heterotetramer (KCNQ2WT/KCNQ2G281R/KCNQ3WT) channels, consistent with a dominant‐negative effect. Addition of 5 m M retigabine did not produce a current with the mutant homomer, but increased current with the heterotetramer (V50:−30.4 mV vs. −51.3 mV). Following these results, retigabine at 15 mg/kg was administered off‐label, prompting a 90% seizure reduction. Drug withdrawal, imposed by revocation of marketing authorisation for retigabine, caused 50% increase in seizure burden.
Significance. Retigabine may be used for precision therapy in patients with KCNQ2‐related epilepsy due to loss‐of‐function variants. It is imperative to reintroduce safe marketing of retigabine for selected patients as personalized treatment.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The autosomal recessive defect of aromatic L‐amino acid decarboxylase (AADC) leads to a severe neurological disorder with manifestation in infancy due to a pronounced, combined deficiency of ...dopamine, serotonin and catecholamines. The success of conventional drug treatment is very limited, especially in patients with a severe phenotype. The development of an intracerebral AAV2‐based gene delivery targeting the putamen or substantia nigra started more than 10 years ago. Recently, the putaminally‐delivered construct, Eladocagene exuparvovec has been approved by the European Medicines Agency and by the British Medicines and Healthcare products Regulatory Agency. This now available gene therapy provides for the first time also for AADC deficiency (AADCD) a causal therapy, leading this disorder into a new therapeutic era. By using a standardized Delphi approach members of the International Working Group on Neurotransmitter related Disorders (iNTD) developed structural requirements and recommendations for the preparation, management and follow‐up of AADC deficiency patients who undergo gene therapy. This statement underlines the necessity of a framework for a quality‐assured application of AADCD gene therapy including Eladocagene exuparvovec. Treatment requires prehospital, inpatient and posthospital care by a multidisciplinary team in a specialized and qualified therapy center. Due to lack of data on long‐term outcomes and the comparative efficacy of alternative stereotactic procedures and brain target sites, a structured follow‐up plan and systematic documentation of outcomes in a suitable, industry‐independent registry study are necessary.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Summary
Purposes: To describe the clinical spectrum and to evaluate the efficacy of different therapeutic agents in children with electrical status epilepticus in sleep (ESES).
Methods: Clinical ...data of all patients with ESES (not including patients with Landau‐Kleffner syndrome) in four pediatric neurology outpatient clinics were analyzed. Thirty patients with ESES had been treated between 1994 and 2007.
Results: Eleven (37%) children had benign partial epilepsies of childhood, five (17%) had cerebral palsy, five (17%) had hydrocephalus, one (3%) had schizencephaly, one (3%) had prenatal parenchymal bleeding, and the etiology was unclear in seven (23%). The duration of ESES ranged between 2 and 60 months. The antiepileptic drugs that were found to be efficacious were: levetiracetam (41%), clobazam (31%), and sulthiame (17%). Valproic acid, lamotrigine, topiramate, and ethosuximide showed no efficacy. Steroids were efficacious in 65%; immunoglobulins were efficacious in 33%. High‐dose diazepam was efficacious in 37%, but all the children had temporary response. Seventeen patients (57%) had cognitive deterioration, whereas the rest presented with regression in attention, speech, communication, and behavior. Fourteen children had permanent cognitive deficit. There was a significant correlation (p = 0.029) between the duration of ESES and residual intellectual deficit at follow‐up.
Conclusions: ESES reflects an evolution of benign partial epilepsy of childhood in more than one‐third of the patients, whereas there is an underlying structural brain anomaly in another one‐third. The most efficacious antiepileptic drugs (AEDs) are levetiracetam and clobazam. The duration of ESES correlated significantly with residual intellectual deficit at follow‐up.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Mutations in the
gene lead to an incurable rare neurological condition characterized by the onset of seizures in the first weeks of life and severe intellectual disability. Replacement gene or ...protein therapies could represent intriguing options, however, their application may be inhibited by the recent demonstration that
is dosage sensitive. Conversely, correction approaches acting on pre-mRNA splicing would preserve
physiological regulation. Since ~15% of
pathogenic mutations are candidates to affect splicing, we evaluated the capability of variants of the spliceosomal U1 small nuclear RNA (U1snRNA) to correct mutations affecting +1 and +5 nucleotides at the 5' donor splice site and predicted to cause exon skipping. Our results show that
minigene variants expressed in mammalian cells are a valid approach to assess
splicing pattern. The expression of engineered U1snRNA effectively rescued mutations at +5 but not at the +1 nucleotides. Importantly, we proved that U1snRNA-mediated splicing correction fully restores CDKL5 protein synthesis, subcellular distribution and kinase activity. Eventually, by correcting aberrant splicing of an exogenously expressed splicing-competent
transgene, we provided insights on the morphological rescue of
null neurons, reporting the first proof-of-concept of the therapeutic value of U1snRNA-mediated
splicing correction.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Objective:
Rare copy number variants (CNVs)—deletions and duplications—have recently been established as important risk factors for both generalized and focal epilepsies. A systematic assessment of ...the role of CNVs in epileptic encephalopathies, the most devastating and often etiologically obscure group of epilepsies, has not been performed.
Methods:
We evaluated 315 patients with epileptic encephalopathies characterized by epilepsy and progressive cognitive impairment for rare CNVs using a high‐density, exon‐focused, whole‐genome oligonucleotide array.
Results:
We found that 25 of 315 (7.9%) of our patients carried rare CNVs that may contribute to their phenotype, with at least one‐half being clearly or likely pathogenic. We identified 2 patients with overlapping deletions at 7q21 and 2 patients with identical duplications of 16p11.2. In our cohort, large deletions were enriched in affected individuals compared to controls, and 4 patients harbored 2 rare CNVs. We screened 2 novel candidate genes found within the rare CNVs in our cohort but found no mutations in our patients with epileptic encephalopathies. We highlight several additional novel candidate genes located in CNV regions.
Interpretation:
Our data highlight the significance of rare CNVs in the epileptic encephalopathies, and we suggest that CNV analysis should be considered in the genetic evaluation of these patients. Our findings also highlight novel candidate genes for further study. ANN NEUROL 2011;70:974–985
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Summary
Objective
To analyze whether KCNQ2 R201C and R201H variants, which show atypical gain‐of‐function electrophysiologic properties in vitro, have a distinct clinical presentation and outcome.
...Methods
Ten children with heterozygous, de novo KCNQ2 R201C or R201H variants were identified worldwide, using an institutional review board (IRB)–approved KCNQ2 patient registry and database. We reviewed medical records and, where possible, interviewed parents and treating physicians using a structured, detailed phenotype inventory focusing on the neonatal presentation and subsequent course.
Results
Nine patients had encephalopathy from birth and presented with prominent startle‐like myoclonus, which could be triggered by sound or touch. In seven patients, electroencephalography (EEG) was performed in the neonatal period and showed a burst‐suppression pattern. However, myoclonus did not have an EEG correlate. In many patients the paroxysmal movements were misdiagnosed as seizures. Seven patients developed epileptic spasms in infancy. In all patients, EEG showed a slow background and multifocal epileptiform discharges later in life. Other prominent features included respiratory dysfunction (perinatal respiratory failure and/or chronic hypoventilation), hypomyelination, reduced brain volume, and profound developmental delay. One patient had a later onset, and sequencing indicated that a low abundance (~20%) R201C variant had arisen by postzygotic mosaicism.
Significance
Heterozygous KCNQ2 R201C and R201H gain‐of‐function variants present with profound neonatal encephalopathy in the absence of neonatal seizures. Neonates present with nonepileptic myoclonus that is often misdiagnosed and treated as seizures. Prognosis is poor. This clinical presentation is distinct from the phenotype associated with loss‐of‐function variants, supporting the value of in vitro functional screening. These findings suggest that gain‐of‐function and loss‐of‐function variants need different targeted therapeutic approaches.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
At present, there is no internationally accepted set of core outcomes or measurement methods for epilepsy clinical practice. Therefore, the International Consortium for Health Outcomes Measurement ...(ICHOM) convened an international working group of experts in epilepsy, people with epilepsy and their representatives to develop minimum sets of standardized outcomes and outcomes measurement methods for clinical practice that support patient–clinician decision‐making and quality improvement. Consensus methods identified 20 core outcomes. Measurement tools were recommended based on their evidence of strong clinical measurement properties, feasibility, and cross‐cultural applicability. The essential outcomes included many non‐seizure outcomes: anxiety, depression, suicidality, memory and attention, sleep quality, functional status, and the social impact of epilepsy. The proposed set will facilitate the implementation of the use of patient‐centered outcomes in daily practice, ensuring holistic care. They also encourage harmonization of outcome measurement, and if widely implemented should reduce the heterogeneity of outcome measurement, accelerate comparative research, and facilitate quality improvement efforts.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
At present, there is no internationally accepted set of core outcomes or measurement methods for epilepsy clinical practice. The International Consortium for Health Outcomes Measurement (ICHOM) ...convened an international working group of experts in epilepsy, people with epilepsy, and their representatives to develop minimum sets of standardized outcomes and outcome measurement methods for clinical practice. Using modified Delphi consensus methods with consecutive rounds of online voting over 12 months, a core set of outcomes and corresponding measurement tool packages to capture the outcomes were identified for infants, children, and adolescents with epilepsy. Consensus methods identified 20 core outcomes. In addition to the outcomes identified for the ICHOM Epilepsy adult standard set, behavioral, motor, and cognitive/language development outcomes were voted as essential for all infants and children with epilepsy. The proposed set of outcomes and measurement methods will facilitate the implementation of the use of patient‐centered outcomes in daily practice.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
PDF
