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Papers by Sarah Weckhuysen

Neurology, 2015

Epilepsies caused by inborn errors of metabolism consist of a broad range of diseases, typically ... more Epilepsies caused by inborn errors of metabolism consist of a broad range of diseases, typically with early life onset and often associated with progressive encephalopathy. Early recognition and targeted therapy are key to improved outcomes in several metabolic epilepsies, including those related to the pyridoxal vitamer dependencies. Pyridoxine-dependent epilepsy (PDE) is an autosomal recessively inherited metabolic epilepsy characterized by early-onset seizures resistant to traditional antiepileptic drugs. Initially described in 1954, the biochemical basis was elucidated over 50 years later as mutations in ALDH7A1, encoding the protein antiquitin or α-aminoadipic semialdehyde (α-AASA) dehydrogenase and affecting the lysine degradation pathway.1 An elevated concentration of α-AASA in urine or plasma is an excellent biomarker, although this may also be seen in molybdenum cofactor deficiency and isolated sulfite oxidase deficiency.2 On the other hand, recent literature has emphasized the presence of mutations in pyridox(am)ine phosphate oxidase (PNPO) in patients who clinically appear to have the phenotype of PDE including pyridoxine responsiveness, but have negative biomarkers for antiquitin deficiency.3

Clinical Neurophysiology, 2022

OBJECTIVE Epilepsy is a common neurological disease with recurrent seizures. Transcranial direct-... more OBJECTIVE Epilepsy is a common neurological disease with recurrent seizures. Transcranial direct-current stimulation (tDCS) is a safe, non-invasive method used for neuromodulation. The aim of this study was to explore the efficacy of cathodal high-definition tDCS (HD-tDCS) as a noninvasive method for the treatment of patients with drug-resistant focal epilepsy (DRFE). METHODS This study was conducted as a randomized parallel and double-blind clinical trial. Twenty patients with DRFE were randomly selected through the convenience sampling method and then were divided into two groups. Ten patients received 2 mA cathodal HD-tDCS targeting the seizure-onset zone for 30 min for 2 weeks (5 consecutive days in each week and 10 days in total). Ten patients were randomized to the sham group. Seizure frequency and Interictal Epileptiform Discharges (IEDs) frequency were the primary outcome measures of this study. Quality of Life in Epilepsy Inventory (QoLIE-89) and Montreal Cognitive Assessment (MoCA) scores were used as secondary outcome measures. RESULTS Seizure frequency decreased significantly among the patients in the treatment group 2 weeks (P-value ≤ 0.05), 1 month (P-value ≤ 0.05), and 2 months (P-value ≤ 0.05) after the stimulation in comparison to the sham group. Patients in the treatment group showed a decrease in the frequency of IED 2 weeks (P-value ≤ 0.05), 1 month (P-value ≤ 0.05), and 2 months (P-value ≤ 0.05) after stimulation. This cathodal stimulation protocol also improved the overall QoLIE-89 score after the stimulation compared to the sham group. CONCLUSIONS The present study showed that cathodal HD-tDCS had a positive effect on seizure frequency and IED in patients with DRFE. More evidence is required to define the optimal stimulation parameters of HD-tDCS for the treatment of epilepsy. SIGNIFICANCE Cathodal HD-tDCS targeting the seizure-onset zone is a promising treatment modality for patients with drug-resistant focal epilepsy.

Molecular Genetics & Genomic Medicine, 2021

Primary microcephaly (PM) is defined as a significant reduction in occipitofrontal circumference ... more Primary microcephaly (PM) is defined as a significant reduction in occipitofrontal circumference (OFC) of prenatal onset. Clinical and genetic heterogeneity of PM represents a diagnostic challenge.

Journal of Medical Genetics, 2021

BackgroundPathogenic KCNQ2 variants are a frequent cause of developmental and epileptic encephalo... more BackgroundPathogenic KCNQ2 variants are a frequent cause of developmental and epileptic encephalopathy.MethodsWe recruited 13 adults (between 18 years and 45 years of age) with KCNQ2 encephalopathy and reviewed their clinical, EEG, neuroimaging and treatment history.ResultsWhile most patients had daily seizures at seizure onset, seizure frequency declined or remitted during childhood and adulthood. The most common seizure type was tonic seizures (early) infancy, and tonic-clonic and focal impaired awareness seizures later in life. Ten individuals (77%) were seizure-free at last follow-up. In 38% of the individuals, earlier periods of seizure freedom lasting a minimum of 2 years followed by seizure recurrence had occurred. Of the 10 seizure-free patients, 4 were receiving a single antiseizure medication (ASM, carbamazepine, lamotrigine or levetiracetam), and 2 had stopped taking ASM. Intellectual disability (ID) ranged from mild to profound, with the majority (54%) of individuals in ...

Brain, 2020

Cytogenic testing is routinely applied in most neurological centres for severe paediatric epileps... more Cytogenic testing is routinely applied in most neurological centres for severe paediatric epilepsies. However, which characteristics of copy number variants (CNVs) confer most epilepsy risk and which epilepsy subtypes carry the most CNV burden, have not been explored on a genome-wide scale. Here, we present the largest CNV investigation in epilepsy to date with 10 712 European epilepsy cases and 6746 ancestry-matched controls. Patients with genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, and developmental and epileptic encephalopathy were included. All samples were processed with the same technology and analysis pipeline. All investigated epilepsy types, including lesional focal epilepsy patients, showed an increase in CNV burden in at least one tested category compared to controls. However, we observed striking differences in CNV burden across epilepsy types and investigated CNV categories. Genetic generalized epilepsy patients have the highest C...

Brain, 2020

KCNN2 encodes the small conductance calcium-activated potassium channel 2 (SK2). Rodent models wi... more KCNN2 encodes the small conductance calcium-activated potassium channel 2 (SK2). Rodent models with spontaneous Kcnn2 mutations show abnormal gait and locomotor activity, tremor and memory deficits, but human disorders related to KCNN2 variants are largely unknown. Using exome sequencing, we identified a de novo KCNN2 frameshift deletion in a patient with learning disabilities, cerebellar ataxia and white matter abnormalities on brain MRI. This discovery prompted us to collect data from nine additional patients with de novo KCNN2 variants (one nonsense, one splice site, six missense variants and one in-frame deletion) and one family with a missense variant inherited from the affected mother. We investigated the functional impact of six selected variants on SK2 channel function using the patch-clamp technique. All variants tested but one, which was reclassified to uncertain significance, led to a loss-of-function of SK2 channels. Patients with KCNN2 variants had motor and language de...

Annals of Neurology, 2019

Expert Opinion on Therapeutic Targets, 2017

ABSTRACT Introduction: STXBP1 is an essential protein for presynaptic vesicle release. Mutations ... more ABSTRACT Introduction: STXBP1 is an essential protein for presynaptic vesicle release. Mutations in STXBP1 have been associated with a series of (epileptic) neurodevelopmental disorders collectively referred to as STXBP1-encephalopathy (STXBP1-E). In this review we hypothesize about the potential of STXBP1 as a therapeutic target in the field of epileptic encephalopathies. Areas covered: A state of the art overview on current understanding of the pathophysiologic mechanism underlying STXBP1-E is presented. Possibilities of different treatment modalities are discussed including unbiased compound screening, specific protein-protein interaction inhibition and gene therapy, consisting either of gene suppletion or upregulation of gene expression. Expert opinion: Current treatment for STXBP1-E is largely limited to seizure control and future therapies will need to target the developmental aspects of the disease as well. Both in vitro- and animal models used to study the pathophysiology of STXBP1-E could be further optimized as a model for compound screening. They should reflect both the hyper excitable state and the psychomotor delay of STXBP1-E. Specific protein-protein interaction and gene therapy are promising future treatment options that need to be investigated further. We suggest a parallel research strategy on basic pathophysiology and compound development with both fields working in close collaboration with the patient/clinical community.