Anna Jansen

Universitair Ziekenhuis Antwerpen | UZA · Division of Pediatric Neurology

Background Tuberous sclerosis complex (TSC) is associated with a wide range of physical manifestations for which international clinical recommendations for diagnosis and management have been established. TSC is, however, also associated with a wide range of TSC-Associated Neuropsychiatric Disorders (TAND) that are typically under-identified and und...

Background Tuberous sclerosis complex (TSC) is a rare and complex genetic disorder, associated with tumor growth in various organ systems, epilepsy, and a range of neuropsychiatric manifestations including intellectual disability. With improving patient-centered care and targeted therapies, patient-reported outcome measures (PROMs) are needed to me...

Background LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency disease (PID) characterized by a regulatory T cell defect resulting in immune dysregulation and autoimmunity. We present two siblings born to consanguineous parents of North African descent with LRBA deficiency and central nervous system (CNS) manife...

Tuberous sclerosis complex (TSC) is caused by inactivating variants in TSC1 and TSC2. Somatic mosaicism, as well as the size and complexity of the TSC1 and TSC2 loci, makes variant identification challenging. Indeed, in some individuals with a clinical diagnosis of TSC, diagnostic testing fails to identify an inactivating variant. To improve TSC1 a...

Background: Tuberous sclerosis complex-associated neuropsychiatric disorders (TAND) are often present but underidentified and undertreated in individuals with tuberous sclerosis complex (TSC). The clinician-completed TAND-Lifetime Checklist (TAND-L) was developed to address this identification and treatment gap. Stakeholder engagement identified t...

Metachromatic leukodystrophy (MLD) is a neurodegenerative lysosomal storage disorder caused by biallelic pathogenic variants in the gene encoding arylsulfatase A. Disease onset is variable (with late infantile, early and late juvenile, and adult forms) and treatment options depend on age and disease symptoms at onset. In the past, allo-hematopoieti...

Background Environmental exposures have been associated with the juvenile idiopathic inflammatory myopathies (JIIM). We undertook a questionnaire-based study to evaluate patient-reported exposures as possible risk factors for JIIM. Findings One-hundred-seven patients with JIIM were enrolled in a myositis natural history protocol and completed envi...

Background Children with a suspected developmental disability need early diagnostic evaluations and support, to maximize developmental opportunities. Accessibility to diagnostic settings in Flanders, Belgium, is poor, with waiting periods up to two years. Interorganisational coordination of activities using a public health and needs of the populati...

Background Transcriptome profiling of blood cells is an efficient tool to study the gene expression signatures of rheumatic diseases. This study aims to improve the early diagnosis of pediatric rheumatic diseases by investigating patients’ blood gene expression and applying machine learning on the transcriptome data to develop predictive models. M...

Tuberous sclerosis complex (TSC) is a rare multi-system genetic disorder characterized by a high incidence of epilepsy and neuropsychiatric manifestations known as tuberous-sclerosis-associated neuropsychiatric disorders (TANDs), including autism spectrum disorder (ASD) and intellectual disability (ID). MicroRNAs (miRNAs) are small regulatory non-c...

Background Malformations of cortical development (MCDs) have been reported in a subset of patients with pathogenic heterozygous variants in GRIN1 or GRIN2B , genes which encode for subunits of the N-methyl-D-aspartate receptor (NMDAR). The aim of this study was to further define the phenotypic spectrum of NMDAR-related MCDs. Methods We report the...

Sex chromosome trisomies (SCTs) are characterized by an extra X‐ or Y‐chromosome (XXX, XXY, XYY). The present study aims to investigate early signs of social communication and social emotional development in very young children with SCT. Thirty‐four children with SCT (aged 12–24 months) were included in this study, as well as 31 age‐matched control...

Introduction Tuberous Sclerosis Complex (TSC) is a multi-system genetic disorder with various TSC-Associated Neuropsychiatric Disorders (TAND) that significantly impact the mental health and wellbeing of individuals with TSC and their caregivers. TAND represents the number one concern to families worldwide, yet is highly under-identified and under-...

Background Tuberous sclerosis complex (TSC)–associated neuropsychiatric disorders (TAND) is an umbrella term for the behavioural, psychiatric, intellectual, academic, neuropsychological and psychosocial manifestations of TSC. Although TAND affects 90% of individuals with TSC during their lifetime, these manifestations are relatively under-assessed,...

RAC1 is a highly conserved Rho GTPase critical for several cellular and developmental processes. De novo missense RAC1 variants cause a highly variable neurodevelopmental disorder. Some of these variants have been previously shown to have a dominant negative effect. Most previously reported patients with this disorder have either severe microcephal...

Background and objective: Multiple factors have been found to contribute to the high risk of epilepsy in infants with Tuberous Sclerosis Complex (TSC), including evolution of EEG abnormalities, TSC gene mutation and MRI characteristics. The aim of the present prospective multi-center study was to: 1) identify early MRI biomarkers of epilepsy in in...

Free oligosaccharides (fOSs) are soluble oligosaccharide species generated during N-glycosylation of proteins. Although little is known about fOS metabolism, the recent identification of NGLY1 deficiency, a congenital disorder of deglycosylation (CDDG) caused by loss of function of an enzyme involved in fOS metabolism, has elicited increased intere...

Background: The genetic disorder tuberous sclerosis complex (TSC) is frequently accompanied by the development of neuropsychiatric disorders, including autism spectrum disorder and intellectual disability, with varying degrees of impairment. These co-morbidities in TSC have been linked to the structural brain abnormalities, such as cortical tubers...

Background Tuberous Sclerosis Complex (TSC), a multi-system genetic disorder, is associated with a wide range of TSC-Associated Neuropsychiatric Disorders ( TAND). Individuals have apparently unique TAND profiles, challenging diagnosis, psycho-education, and intervention planning. We proposed that identification of natural TAND clusters could lead...

Aim To describe the evolution of electroencephalogram (EEG) characteristics in infants with tuberous sclerosis complex (TSC) and the relationship with neurodevelopmental outcome at 24 months. Method Eighty-three infants were enrolled in the EPISTOP trial and underwent serial EEG follow-up until the age of 24 months (males n=45, females n=37, media...

Background: Epilepsy is the most common neurological manifestation in individuals with tuberous sclerosis complex (TSC). However, real-world evidence on diagnosis and treatment patterns is limited. Here, we present data from TuberOus Sclerosis registry to increase disease Awareness (TOSCA) on changes in patterns of epilepsy diagnosis, treatments, a...

We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups were identified: Group 1, benign familial infantile ep...

Background Tuberous Sclerosis Complex (TSC), a multi-system genetic disorder, is associated with a wide range of TSC-Associated Neuropsychiatric Disorders (TAND). Individuals have apparently unique TAND profiles, challenging diagnosis, psycho-education, and intervention planning. We proposed that identification of natural TAND clusters could lead t...

Background 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. Methods We performed detailed phenotypic and genomic analyses in a large cohort (n = 169) of patients referred for PM and could establish a...

Aim To clarify organizational perspectives on diagnostic evaluations for children with neurodevelopmental disorders (NDD), with the goal to enhance interorganizational collaboration and improve accessibility. Method Focus groups with expert stakeholders in Flanders, Belgium, were organized. Data were analyzed in a continuous, comparative method wi...

Clinical manifestations of malformations of cortical development (MCD) are variable and can range from mild to severe intellectual disability, cerebral palsy and drug-resistant epilepsy. Besides common clinical features, non-specific or more subtle clinical symptoms may be present in association with different types of MCD. Especially in severely a...

Objective The aim of this study is the investigation of early-life EEG background abnormalities or “dysmature” traits in infants with tuberous sclerosis complex (TSC) and their capacity to predict autism spectrum disorder or neurodevelopmental outcome. Methods EEG data were prospectively collected from TSC patients during the EPISTOP trial (NCT020...

Abstract Background Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant disorder caused by pathogenic variants in either the TSC1 or TSC2 gene. Common manifestations of TSC have been grouped into major and minor clinical diagnostic criteria and assessed in clinical routine workup. However, case studies point towards the existe...

Background Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting multiple body systems with wide variability in presentation. In 2013, Pediatric Neurology published articles outlining updated diagnostic criteria and recommendations for surveillance and management of disease manifestations. Advances in knowledge and app...

Introduction Since the end of 2019, measures have been taken to control the spread of COVID-19. The effects of the pandemic-related precautionary measures on children with developmental disorders require specific attention as these children have greater healthcare needs and mental health concerns, and depend on community-based services for support....

Aims Tuberous sclerosis complex (TSC) is a genetic disorder associated with dysregulation of the mechanistic target of rapamycin complex 1 (mTORC1) signalling pathway. Neurodevelopmental disorders, frequently present in TSC, are linked to cortical tubers in the brain. We previously reported microRNA‐34a (miR‐34a) among the most up‐regulated miRs in...

Objective To study the association between timing and characteristics of the first electroencephalography (EEG) with epileptiform discharges (ED‐EEG) and epilepsy and neurodevelopment at 24 months in infants with tuberous sclerosis complex (TSC). Methods Patients enrolled in the prospective Epileptogenesis in a genetic model of epilepsy – Tuberous...

We report detailed functional analyses and genotype-phenotype correlations in 433 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel NaV1.6. Five different clinical subgroups could be identified: 1) Benign familial infantile epilepsy (BFIE) (n=17, normal cognition, treatable seizures), 2) intermediate epi...

This non-interventional post-authorisation safety study (PASS) assessed the long-term safety of everolimus in patients with tuberous sclerosis complex (TSC) who participated in the TuberOus SClerosis registry to increase disease Awareness (TOSCA) clinical study and received everolimus for the licensed indications in the European Union. The rate of...

Background Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant genetic disorder caused by pathogenic mutations in either the TSC1 or TSC2 gene. Common manifestations of TSC have been grouped into major and minor clinical diagnostic criteria and assessed in clinical routine workup. However, case studies point towards the existe...

Aims Malformations of cortical development (MCD) include a heterogeneous spectrum of clinical, imaging, molecular and histopathological entities. While the understanding of genetic causes of MCD has improved with the availability of next‐generation sequencing modalities, genotype‐histopathological correlations remain limited. This is the first syst...

Primary microcephaly (PM) is defined as a significant reduction in occipito-frontal circumference (OFC) of prenatal onset. Clinical and genetic heterogeneity of PM represents a diagnostic challenge. We performed detailed phenotypic and genomic analyses in a large cohort (n=169) of patients referred for PM, and could establish a molecular diagnosis...

Polymicrogyria is a malformation of cortical development characterised by overfolding and abnormal lamination of the cerebral cortex. Manifestations include epilepsy, speech disturbance and motor and cognitive disability. Causes include acquired prenatal insults and inherited and de novo genetic variants. The proportion of patients with polymicrogy...

Pathogenic variants in the RBM10 gene cause a rare X‐linked disorder described as TARP (Talipes equinovarus, Atrial septal defect, Robin sequence and Persistent left vena cava superior) syndrome. We report two novel patients with truncating RBM10 variants in view of the literature, presenting a total of 26 patients from 15 unrelated families. Our r...

Twins have an increased risk for congenital malformations and disruptions, including defects in brain morphogenesis. We analyzed data on brain imaging, zygosity, sex, and fetal demise in 56 proband twins and 7 less affected co‐twins with abnormal brain imaging and compared them to population‐based data and to a literature series. We separated our s...

Background Neurodevelopmental disorders start in early childhood and may restrict personal, scholastic, social and professional development and functioning. Early detection and smooth trajectories of diagnostics, rehabilitation and support affect the child's development and opportunities. A specialized multidisciplinary team must do a diagnostic ev...

Objective Epilepsy develops in 70–90% of children with Tuberous Sclerosis Complex (TSC) and is often resistant to medication. Recently, the concept of preventive antiepileptic treatment to modify the natural history of epilepsy has been proposed. EPISTOP was a clinical trial designed to compare preventive versus conventional antiepileptic treatmen...

Objective A North American registry of JDM patients was examined for frequency of and factors associated with corticosteroid discontinuation, complete clinical response and remission. Methods We evaluated probability of achieving final corticosteroid discontinuation, complete clinical response and remission in 307 JDM patients by Weibull time-to-e...

Chudley-McCullough syndrome, a rare autosomal recessive disorder due to pathogenic variants in the GPSM2 (G-protein signaling modulator 2) gene, is characterized by early-onset sensorineural deafness and a typical combination of brain malformations, including ventriculomegaly, (partial) agenesis of the corpus callosum, cerebellar dysplasia, arachno...

Tuberous sclerosis complex (TSC) is a monogenetic disease that arises due to mutations in either the TSC1 or TSC2 gene and affects multiple organ systems. One of the hallmark manifestations of TSC are cortical malformations referred to as cortical tubers. These tubers are frequently associated with treatment-resistant epilepsy. Some of these patien...

To guide health care professionals in Belgium in selecting the appropriate antiepileptic drugs (AEDs) for their epilepsy patients, a group of Belgian epilepsy experts developed recommendations for AED treatment in adults and children (initial recommendations in 2008, updated in 2012). As new drugs have become available, others have been withdrawn,...

Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder with a high risk of early-onset epilepsy and a high prevalence of neurodevelopmental comorbidities, including intellectual disability and autism spectrum disorder (ASD). Therefore, TSC is an interesting disease model to investigate early biomarkers of neurodevelopmental comorbiditie...

Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imag...

Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imag...

Background: Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) have unique, individual patterns that pose significant challenges for diagnosis, psycho-education, and intervention planning. A recent study suggested that it may be feasible to use TAND Checklist data and data-driven methods to generate natural TAND clusters...

Renal angiomyolipomas are one of the most common renal manifestations in patients with tuberous sclerosis complex (TSC), with potentially life-threatening complications and a poor prognosis. Despite the considerable progress in understanding TSC-associated renal angiomyolipomas, there are no large scale real-world data. The aim of our present study...

Research on tuberous sclerosis complex (TSC) to date has focused mainly on the physical manifestations of the disease. In contrast, the psychosocial impact of TSC has received far less attention. The aim of this study was therefore to examine the impact of TSC on health, quality of life (QoL), and psychosocial well-being of individuals with TSC and...

Objective To evaluate the relationship between age at seizure onset and neurodevelopmental outcome at age 24 months in infants with TSC, as well as the effect on neurodevelopmental outcome of early versus conventional treatment of epileptic seizures with vigabatrin (80–150 mg/kg/day). Methods Infants with TSC, aged ≤4 months and without previous s...

Background: Knowledge is increasing about TSC-Associated Neuropsychiatric Disorders (TAND), but little is known about the potentially confounding effects of intellectual ability (IA) on the rates of TAND across age, sex, and genotype. We evaluated TAND in (a) children vs. adults, (b) males vs. females, and (c) TSC1 vs. TSC2 mutations, after stratif...

Background Variants in genes belonging to the tubulin superfamily account for a heterogeneous spectrum of brain malformations referred to as tubulinopathies. Variants in TUBB2A have been reported in 10 patients with a broad spectrum of brain imaging features, ranging from a normal cortex to polymicrogyria, while one patient has been reported with p...

Objective Pathogenic variants in SCN3A , encoding the voltage‐gated sodium channel subunit Nav1.3, cause severe childhood‐onset epilepsy and malformation of cortical development. Here, we define the spectrum of clinical, genetic, and neuroimaging features of SCN3A ‐related neurodevelopmental disorder. Methods Patients were ascertained via an inter...

To perform comprehensive genotyping of TSC1 and TSC2 in a cohort of 94 infants with tuberous sclerosis complex (TSC) and correlate with clinical manifestations. Infants were enrolled at age <4 months, and subject to intensive clinical monitoring including electroencephalography (EEG), brain magnetic resonance imaging (MRI), and neuropsychological a...

NEDD4L encodes an ubiquitin ligase which is expressed in the cortex and ventricular zone of the fetal brain. Missense variants in NEDD4L have been reported in nine patients with periventricular nodular heterotopia (PNH), polymicrogyria, cleft palate, and syndactyly. All reported variants are located in the HECT domain, causing deregulation of signa...