Mitochondrial diseases are clinically and genetically heterogeneous, often complicating diagnosis. Here, we describe four unrelated individuals with suspected mitochondrial disease who shared similar neuroimaging features, including bilateral symmetrical supra- and infratentorial white-matter abnormalities, together with variable movement disorders and intellectual impairment. Whole-genome sequencing identified the same homozygous MRPS22 variant (c.798_799delinsTA) in all four patients. MRPS22 encodes a component of the mitochondrial small ribosomal subunit (mtSSU). Functional studies in patient-derived fibroblasts showed impaired mitoribosome assembly and reduced de novo mitochondrial translation. Despite largely preserved steady-state levels of OXPHOS proteins, respiratory chain analysis identified a mild, isolated complex I deficiency. Proteomic profiling revealed reduced levels of mitochondrial ribosomal proteins and dysregulation of mitochondrial translation pathways. In line with the proteomic findings, RNA sequencing of fibroblasts from three patients revealed a distinct transcriptional signature compared with controls, with mitochondrial translation emerging as the most affected pathway. Mitochondrial-encoded transcripts were decreased, whereas nuclear-encoded mitochondrial genes were generally increased. Structural modelling suggested that the variant disrupts key interactions important for mitoribosome stability. While previously reported MRPS22 variants have been associated with severe, often prenatal-onset disease, the individuals described here exhibited a milder phenotype, thereby expanding the clinical spectrum of MRPS22-related disorders. Together, these findings support the pathogenicity of this variant and highlight the value of integrated genomic and functional analyses in diagnosing mitochondrial disease.

OBJECTIVE:The aim of this study was to characterize intellectual and motor function, neurological features including epilepsy, treatment response, and adaptive behavior in patients with pyruvate dehydrogenase complex deficiency (PDCD) in Sweden. METHODS:Forty-two individuals with genetically confirmed PDCD (86% PDHA1-related disease) were identified from a nationwide epidemiological study and were included in this cross-sectional study comprising systematic neurological evaluations (n = 41) and caregiver interviews assessing adaptive behavior (n = 35). RESULTS:Intellectual disability was detected in 33/42 (79%) individuals, while 31/35 (89%) demonstrated significant impairments in adaptive functioning. Although 27/39 (69%) were ambulatory, only 8/39 (21%) demonstrated age-appropriate walking ability. Clinical signs of polyneuropathy were observed in 24/41 (59%), bulbar symptoms in 22/41 (54%), spasticity in 19/41 (46%), ataxia in 13/41 (32%), and dystonia in 9/41 (22%). Lifetime epilepsy was present in 16/41 (39%) of individuals. Ketogenic diet treatment, administered to 30 individuals, was effective in both prenatal- and postnatal-onset disease. Seizure frequency decreased in individuals with epilepsy (8/9; 89%) and relapses of dystonia, ataxia, exercise intolerance, and lactic acidosis were prevented in all affected individuals (15/15). Improvements in communication and motor function were also noted. DISCUSSION:Intellectual disability and deficits in adaptive behavior are frequent in PDCD, although cognitive outcomes are more heterogeneous among individuals with postnatal onset. Prenatal onset and epilepsy are associated with severe-profound intellectual disability. Although most are ambulatory, motor deficits are frequent. A ketogenic diet treatment is a safe and effective therapeutic option, contributing to both seizure control and remission of neurological deterioration relapses.

OBJECTIVE:A significant proportion of individuals with suspected genetic developmental and epileptic encephalopathies (DEEs) remain unsolved following whole genome sequencing (WGS). Here we describe biallelic RNU2-2 variants causing a recently reported, severe, recessive DEE. METHODS:We screened individuals who have received WGS analyses at the Genomic Medicine Centre Karolinska for Rare Diseases for biallelic RNU2-2 variants. Deep phenotyping was performed through reviewing entire medical histories and phenotypic traits were transcribed to their corresponding Human Phenotype Ontology (HPO) term. HPO terms were used to generate pairwise phenotypic similarity scores and assess for significantly shared phenotype enrichment in the RNU2-2 sub-cohort. RNA sequencing analyses were performed in fibroblast and blood tissues to compare splicing events between RNU2-2 individuals and two independent control groups. RESULTS:We identified 14 individuals from nine families with 12 ultra-rare biallelic RNU2-2 variants clustering in the conserved 5' domains. Genotype data from 13 of 14 individuals has been reported previously as part of a larger cohort. All individuals presented with a highly concordant, severe DEE, characterized by severe to profound intellectual disability, inability to walk or communicate, hyperkinesia, and refractory seizures. Infantile spasms and tonic seizures were the predominant seizure types and a Lennox-Gastaut syndrome-like phenotype was common. These individuals had a significantly similar phenotypic signature when compared with 703 individuals with complex pediatric epilepsies (two-sided Monte Carlo permutation test, p = .005). RNA sequencing analyses showed aberrant splicing, with the most pronounced effects in fibroblast tissues in mutually exclusive exon and alternate 3' splice-site events, which were not detectable in blood. SIGNIFICANCE:We present deep phenotyping data and transcriptomic analyses that provide support for rare, 5' clustering biallelic RNU2-2 variants causing this novel, severe DEE. We propose an RNA sequencing methodology on fibroblast tissue for future validation of RNU2-2 variants.

Abstract Neurological disorders are a major cause of death and disability worldwide. The brain’s energy metabolism is essential to its proper function, yet the mechanisms driving neuroenergetic dysfunction remain poorly understood. A key challenge is the limited availability of human-relevant models that can reproduce the complexity of brain physiology. An Organ-on-Chip (OoC) system was developed to mimic the neurovascular unit metabolic coupling by incorporating human isogenic iPSC-derived endothelial-like cells, pericyte-like cells, astrocytes, and a cerebral organoid, representing the main cellular components of the NVU. The novel, customized microfluidic platform enables research on neurovascular coupling by interconnecting a blood-brain barrier-on-a-chip model with a 3D brain parenchymal compartment to mimic physiological conditions. Graphical abstract

Abstract Background As clinical genetics evolves towards the broader field of clinical genomics, the diagnostic approach to rare diseases is undergoing a paradigm shift. This transformation has significantly impacted rare disease diagnostics, increasingly done through gene panels, whole exome and whole genome sequencing. To advance beyond genomics into precision medicine and encompass the breadth of relevant clinical scenarios, a true systems shift is required that challenges conventional barriers and enables the formation of cross-disciplinary, integrated environments. Methods The Genomic Medicine Center Karolinska Rare Diseases (GMCK-RD) has, for the past 10 years, brought together healthcare and academia to enable large-scale genome sequencing in a clinical diagnostics context. Within GMCK-RD, experts from various medical disciplines collaborate closely with clinical geneticists, bioinformaticians, and researchers to integrate genome sequencing into healthcare. Results In total, 15 644 individuals with suspected rare diseases were analyzed using clinical genome sequencing, including pediatric (48%), adult (48%) and fetal (4%) samples. The overall diagnostic yield was 22.6%, providing a diagnosis for 3 538 individuals with variants in 1 570 genes. Moreover, a rare disease analysis tool suite developed and validated in house includes a bioinformatic pipeline allowing for comprehensive data analysis covering a wide range of genetic variants including SNVs, INDELs, repeat expansions, uniparental disomies, balanced and unbalanced structural variants as well as insertions of mobile elements. Results are visualized and interpreted in custom-developed decision support systems functioning as an interpretation portal as well as a knowledge-base to capture the interpretation efforts made in a structured format allowing future secondary use. Conclusions Altogether, GMCK-RD has shifted healthcare in our region towards precision diagnostics. We emphasize the need to transition from traditional clinical genetic diagnostics to a broader clinical genomics approach. Beyond this shift, we advocate integrating genomics with specialized clinical and laboratory medicine, a concept pioneered for inborn errors of metabolism (IEM) with stepwise spread to additional disease groups. In this model, a multidisciplinary unit combines screening, targeted diagnostics, individualized treatment, and long-term patient follow-up. Here we provide a road map and guide for inspiration for centers aiming to implement genome sequencing in rare disease diagnostics.

Background and Objectives Pyruvate dehydrogenase complex (PDHc) deficiency is a potentially treatable neurodegenerative genetic disorder. It represents a common cause of mitochondrial disease. Most published reports are limited to single cases, and population-based data are lacking. The objective of this study was to investigate the prevalence, incidence, and life expectancy and to explore genotype-phenotype correlations, clinical onset, and disease course. Methods We conducted a nationwide, population-based epidemiologic cohort study with retrospective, longitudinal, and cross-sectional components. The cohort included all individuals residing in Sweden who were diagnosed between 2003 and 2022. Results A total of 54 patients (35 female patients) were identified, corresponding to a birth prevalence of 2.43 per 100,000 live births (95% CI 1.86-3.17) and a point prevalence of 0.44 per 100,000 population (95% CI 0.40-0.65). Eight patients (15%) died during the study period. The primary causes of death were congenital lactic acidosis (n = 4), stroke (n = 2), and infection (n = 2). We identified 35 pathogenic variants, including 11 not previously reported. X-linked PDHA1-related disease was the most common subtype (n = 44; 30 female patients), accounting for 81% of patients. Prenatal onset occurred in 20 female and 2 male patients. All but 1 affected female survived (97%), whereas more than 40% of affected male patients died (log-rank p < 0.001). Severe frameshift variants were detected in 23% of female patients but were absent in male patients. The clinical presentation was heterogeneous. Facial dysmorphism occurred in 76% of patients, polyneuropathy in 54%, stroke-like episodes or lesions in 15%, and perinatal leukoencephalopathy in 11%. CSF lactate was elevated in all 23 patients who underwent lumbar puncture. Mitochondrial functional studies using polarography or ATP production rate assessment in 34 individuals revealed a reduced pyruvate + malate/glutamate + malate oxidation ratio in all but 1 patient. Discussion This nationwide, population-based study reports on the occurrence and survival of PDHc deficiency. We demonstrate genotype-sex-phenotype differences in PDHA1-related disease and describe a wider spectrum of clinical features than previously recognized. The broader detection likely reflects the study's population-based and cross-sectional design. Furthermore, we show that the discrepancy between pyruvate and glutamate oxidation in muscle mitochondrial investigations may serve as a diagnostic clue.

OBJECTIVE:A large proportion of pediatric epilepsies have an underlying genetic etiology. Limited studies have explored the efficacy of whole genome sequencing (WGS) in a clinical setting. Our academic-clinical center implemented clinical whole exome sequencing (WES) in 2014, then transitioned to WGS from 2015. We report the diagnostic yield, genetic and phenotypic findings, and prognostic factors following WGS/WES in pediatric epilepsy. METHODS:The cohort included 733 families with pediatric epilepsy who received clinical WGS/WES between 2014 and 2022. WGS/WES was performed at the Genomic Medicine Center Karolinska for Rare Diseases and analyzed at the Center for Inherited Metabolic Diseases at Karolinska University Hospital. Phenotypic information was extracted from referrals and medical records. Genetic and phenotypic data were analyzed using descriptive statistics, and univariable and multivariable analyses. RESULTS:The median age at seizure onset was 9 months. Developmental delay and/or intellectual disability (DD/ID) was observed in 61.3% of the cohort; 38.1% of individuals received an International League Against Epilepsy epilepsy syndrome diagnosis. WGS/WES was performed in 640 (87.3%) and 143 (19.5%) families, respectively, totaling 2029 individuals. A molecular diagnosis was identified in 278 of 733 individuals (37.9%), including 51 of 211 individuals analyzed more than once (24.2% of reanalyzed cases). Independent predictors for receiving a genetic diagnosis included female sex (adjusted odds ratio [aOR] = 1.8, 95% confidence interval [CI] = 1.3-2.4, p < .001), neonatal seizure onset (aOR = 2.5, 95% CI = 1.6-4, p < .001), mortality (aOR = 2.2, 95% CI = 1.3-4.0, p = .0048), and an ID/DD/developmental and epileptic encephalopathy (DEE) diagnosis (aOR = 1.8, 95% CI = 1.2-2.5, p = .0019). The strongest independent predictor of ID/DD/DEE was microcephaly (aOR = 7.8, 95% CI = 2-53, p = .0099). In the solved cohort, gene group did not predict cognitive outcome. SIGNIFICANCE:Clinical WGS is an effective diagnostic tool in pediatric epilepsy. We identified female sex as a novel prognostic factor for receiving a genetic diagnosis and highlight the value of reanalyzing previously unsolved cases to improve diagnostic yield.

Pyruvate dehydrogenase complex deficiency (PDCD) is a defect of aerobic carbohydrate metabolism that causes neurological disorders with varying degrees of severity. We report the clinical, biochemical, and molecular findings in patients with primary and secondary PDCD caused by novel atypical genetic variants. Whole-genome sequencing (WGS) identified the synonymous variants c.447A>G, p.(Lys149=) and c.570C>T, p.(Cys190=) in pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1), the deep intronic variants c.1023+2267G>A and c.1023+2302A>G in pyruvate dehydrogenase complex component X (PDHX), and c.185+15054G>A in thiamine pyrophosphokinase (TPK1). Analysis by Sanger and RNA sequencing of cDNA from patient blood and/or cultured fibroblasts showed that the synonymous variants in PDHA1 lead to aberrant splicing and skipping of exons 5 and 5-6 in one of the patients and transcripts lacking exon 6 in the other. The deep intronic variants in PDHX and TPK1 lead to insertion of intronic sequence in the corresponding transcripts. The splice defects in PDHA1 were more pronounced in cultured fibroblasts than in blood. Our findings expand the spectrum of pathogenic variants causing PDCD and highlight the importance of atypical variants leading to aberrant splicing. The severity of the splice defects and resulting biochemical dysfunction varied between tissues, stressing the importance of performing biochemical and transcript analysis in affected tissues. The two males with hemizygous synonymous PDHA1 variants have a mild phenotype and higher PDH enzyme activity than expected, which is consistent with aberrant but leaky splicing with a proportion of the transcripts remaining correctly spliced.

Neurological conditions conquer the world; they are the leading cause of disability and the second leading cause of death worldwide, and they appear all around the world in every age group, gender, nationality, and socioeconomic class. Despite the growing evidence of an immense impact of perturbations in neuroenergetics on overall brain function, only little is known about the underlying mechanisms. Especially human insights are sparse, owing to a shortage of physiologically relevant model systems. With this perspective, we aim to explore the key steps and considerations involved in developing an advanced human in vitro model for studying neuroenergetics. We discuss biological and technological strategies to meet the requirements of a predictive model, aiming at providing a guide and inspiration for future in vitro models of neuroenergetics.

Infectious encephalitis in children is fairly uncommon, but unfavorable outcomes are seen in many survivors. The aim of this study was to prospectively describe the long-term neurocognitive consequences following infectious encephalitis in childhood. Children admitted to a primary and tertiary hospital in Sweden between 2011 and 2016 were asked to participate. Fifty-nine children were assessed at a median time of 18 months (IQR 18-20) after hospitalization. Follow-up included measures of intellectual functioning, attention, working memory, and executive functions. Caregiver ratings of executive functioning and behavioral - emotional symptoms were assessed with standardized questionnaires. Neurocognitive outcome and measures of executive functions and behavioral-emotional symptoms varied greatly among participants. Basic auditory attention, working memory, and mental processing speed were affected and significantly lower compared to a standardized mean. Other domains identified as areas of vulnerability included executive functions, sustained attention, and the exert of self-control. Behavioral-emotional symptoms were less common; however, somatic complaints and behaviors related to conduct problems were seen in about one-third of individuals. This study highlights the importance of a comprehensive neurocognitive examination to identify children with unfavorable outcomes.

The pyruvate dehydrogenase complex (PDC) is responsible for the conversion of pyruvate into acetyl-CoA, which is used for energy conversion in cells. PDC activity is regulated by phosphorylation via kinases and phosphatases (PDK/PDP). Variants in all subunits of the PDC and in PDK3 have been reported, with varying phenotypes including lactic acidosis, neurodevelopmental delay, peripheral neuropathy, or seizures. Here, we report a de novo heterozygous missense variant in PDK1 (c.1139G > A; p.G380D) in a girl with developmental delay and early onset severe epilepsy. To investigate the role of PDK1G380D in energy metabolism and neuronal development, we used a zebrafish model. In zebrafish embryos we show a reduced number of cells with mitochondria with membrane potential, reduced movements, and a delay in neuronal development. Furthermore, we observe a reduction in the phosphorylation of PDH-E1α by PDKG380D, which suggests a disruption in the regulation of PDC activity. Finally, in patient fibroblasts, a mild reduction in the ratio of phosphorylated PDH over total PDH-E1α was detected. In summary, our findings support the notion that this aberrant PDK1 activity is the cause of clinical symptoms in the patient.

We describe two brothers with a truncating variant in EIF2S3 and expand the phenotypic description of MEHMO. Our cases had the previously described facial dysmorphic features, severe microcephaly, hypoglycaemia, hypothyreosis, epilepsy, hypertonus, obesity, micropenis and death due to multiorgan failure. Additionally, we describe hypothermia and reduced umbilical blood flow.

Pyridoxine-dependent epilepsy is a rare autosomal recessive disease usually associated with neonatal seizures that do not respond to common antiseizure medications but are controlled by pyridoxine administration. Because the symptoms can mimic common neonatal disorders, the diagnosis can be initially missed or delayed. We report a fatal case of a boy who was initially diagnosed with respiratory distress, birth asphyxia, and persistent pulmonary hypertension and whose condition rapidly deteriorated during the first day of life.

Here, we present the first two Swedish cases of Conserved Oligomeric Golgi complex subunit 6-congenital disorders of glycosylation (COG6-CDG). Their clinical symptoms include intellectual disability, Attention Deficit/Hyperactivity Disorder (ADHD), delayed brain myelinization, progressive microcephaly, joint laxity, hyperkeratosis, frequent infections, and enamel hypoplasia. In one family, compound heterozygous variants in COG6 were identified, where one (c.785A>G; p.Tyr262Cys) has previously been described in patients of Moroccan descent, whereas the other (c.238G>A; p.Glu80Lys) is undescribed. On the other hand, a previously undescribed homozygous duplication (c.1793_1795dup) was deemed the cause of the disease. To confirm the pathogenicity of the variants, we treated patient and control fibroblasts with the ER-Golgi transport inhibitor Brefeldin-A and show that patient cells manifest a significantly slower anterograde and retrograde ER-Golgi transport.

PPFIBP1 encodes for the liprin-β1 protein, which has been shown to play a role in neuronal outgrowth and synapse formation in Drosophila melanogaster. By exome and genome sequencing, we detected nine ultra-rare homozygous loss-of-function variants in 16 individuals from 12 unrelated families. The individuals presented with moderate to profound developmental delay, often refractory early-onset epilepsy, and progressive microcephaly. Further common clinical findings included muscular hyper- and hypotonia, spasticity, failure to thrive and short stature, feeding difficulties, impaired vision, and congenital heart defects. Neuroimaging revealed abnormalities of brain morphology with leukoencephalopathy, ventriculomegaly, cortical abnormalities, and intracranial periventricular calcifications as major features. In a fetus with intracranial calcifications, we identified a rare homozygous missense variant that by structural analysis was predicted to disturb the topology of the SAM domain region that is essential for protein-protein interaction. For further insight into the effects of PPFIBP1 loss of function, we performed automated behavioral phenotyping of a Caenorhabditis elegans PPFIBP1/hlb-1 knockout model, which revealed defects in spontaneous and light-induced behavior and confirmed resistance to the acetylcholinesterase inhibitor aldicarb, suggesting a defect in the neuronal presynaptic zone. In conclusion, we establish bi-allelic loss-of-function variants in PPFIBP1 as a cause of an autosomal recessive severe neurodevelopmental disorder with early-onset epilepsy, microcephaly, and periventricular calcifications.

Pediatric acute-onset neuropsychiatric syndrome is a clinical concept used to describe a subgroup of children with sudden onset of psychiatric and somatic symptoms. The diagnostic term and especially management of children differs depending on the clinical setting to which they present, and the diagnosis and management is controversial. The aim of this paper is to propose a clinical guidance including homogenous diagnostic work-up and management of paediatric acute onset neuropsychiatric syndrome within the Nordic countries. The guidance is authored by a Nordic-UK working group consisting of paediatric neurologist, child psychiatrists and psychologists from Denmark, Norway, Sweden and Great Britain, and is the result of broad consensus. Consensus was achieved in the collaboration on work-up and treatment of patients with paediatric acute-onset neuropsychiatric syndrome, which we hope will improve and homogenise patient care and enable future collaborative research in the field.

To investigate whether it is possible to predict outcome of post-encephalitic epilepsy based on findings during the acute phase of disease. Children (28 days to 17 years) diagnosed with acute encephalitis at Karolinska University Hospital between 2011 and 2016 were included in this study (n=89). They were examined clinically, with repeated electroencephalographic examinations and analysis of cerebrospinal fluid during the acute illness. Thereafter, patients were followed up to 24 months and evaluated for post-encephalitic epilepsy. Variables determined during the acute illness were used to predict the development of post-encephalitic epilepsy: electroencephalographic parameters, cerebrospinal fluid parameters, aetiology and clinical parameters. Fisher's exact test was used to estimate any predictors of epilepsy among the acutely measured parameters. The prevalence of post-encephalitic epilepsy was 9% (n=8) at 24 months. Of these, 3/8 responded to monotherapy with antiepileptic drugs and 5/8 required two or more and 3/8 were medically refractory at 24 months. Presence of acute seizures during admission, epileptic activity on electroencephalographic recordings and new-onset structural lesions demonstrated a significant association with development of post-encephalitic epilepsy (p<0.03) with an odds ratio greater than 5. Using the three above-mentioned parameters, we designed an algorithm to predict cohorts of patients with increased risk of developing post-encephalitic epilepsy. Moreover, patients who developed post-encephalitic epilepsy had a longer duration of hospital admission and longer care in intensive care units in comparison to those who did not. This study demonstrates that the risk of developing post-encephalitic epilepsy was mainly seen among patients with acute seizures, epileptic encephalographic activity in the acute setting or new-onset structural lesions. A simple algorithm could be used to predict the risk of post-encephalitic epilepsy.

Acta PaediatricaVolume 110, Issue 12 p. 3390-3391 READER'S FORUM Authors' reply regarding “On diagnosing and treating PANS/PANDAS: Questions from a patient support group” Helle Cecilie Viekilde Pfeiffer, Corresponding Author Helle Cecilie Viekilde Pfeiffer helvie@ous-hf.no orcid.org/0000-0001-5136-1883 Department of Child Neurology, Oslo University Hospital, Oslo, Norway Department of Pediatrics and Adolescence Medicine, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark Correspondence Helle Cecilie Viekilde Pfeiffer, Department of Pediatrics and Adolescence Medicine, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark. Email: helvie@ous-hf.noSearch for more papers by this authorCaroline De Visscher, Caroline De Visscher Centre for Psychiatry Research, Department of Clinical Neuroscience, Region Stockholm, Child and Adolescent Psychiatry Research Center, Karolinska Institutet & Stockholm Healthcare Services, Stockholm, SwedenSearch for more papers by this authorInger Helene Gjone, Inger Helene Gjone Division of Pediatric and Adolescent Medicine, Department of Child and Adolescent Mental Health in Hospitals, Oslo University Hospital, Oslo, NorwaySearch for more papers by this authorSofia Ygberg, Sofia Ygberg Neuropediatric Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, SwedenSearch for more papers by this authorLinn Breen Herner, Linn Breen Herner Division of Pediatric and Adolescent Medicine, Department of Child and Adolescent Mental Health in Hospitals, Oslo University Hospital, Oslo, NorwaySearch for more papers by this authorEva Hesselmark, Eva Hesselmark Centre for Psychiatry Research, Department of Clinical Neuroscience, Region Stockholm, Child and Adolescent Psychiatry Research Center, Karolinska Institutet & Stockholm Healthcare Services, Stockholm, SwedenSearch for more papers by this authorSelma Idring Nordstrom, Selma Idring Nordstrom Centre for Psychiatry Research, Department of Clinical Neuroscience, Region Stockholm, Child and Adolescent Psychiatry Research Center, Karolinska Institutet & Stockholm Healthcare Services, Stockholm, SwedenSearch for more papers by this authorInger Sandvig, Inger Sandvig Department of Child Neurology, Oslo University Hospital, Oslo, NorwaySearch for more papers by this authorLiselotte Skov, Liselotte Skov Department of Pediatrics and Adolescence Medicine, Copenhagen University Hospital Herlev, Herlev, DenmarkSearch for more papers by this authorCamilla Birgitte Sørensen, Camilla Birgitte Sørensen Department of Pediatrics and Adolescence Medicine, Copenhagen University Hospital Herlev, Herlev, DenmarkSearch for more papers by this authorMing Lim, Ming Lim Children's Neurosciences, Evelina London Children's Hospital at Guy's and St Thomas' NHS Foundation Trust, King's Health Partners Academic Health Science Centre, London, UKSearch for more papers by this authorRonny Wickstrom, Ronny Wickstrom Neuropediatric Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, SwedenSearch for more papers by this authorTammy Hedderly, Tammy Hedderly Tic and Neurodevelopmental Movements Service (TANDeM), Children's Neurosciences Centre, Evelina London Children's Hospital, Guys and St Thomas' NHS Foundation Trust, London, UKSearch for more papers by this authorNanette Marinette Debes, Nanette Marinette Debes Department of Pediatrics and Adolescence Medicine, Copenhagen University Hospital Herlev, Herlev, DenmarkSearch for more papers by this author Helle Cecilie Viekilde Pfeiffer, Corresponding Author Helle Cecilie Viekilde Pfeiffer helvie@ous-hf.no orcid.org/0000-0001-5136-1883 Department of Child Neurology, Oslo University Hospital, Oslo, Norway Department of Pediatrics and Adolescence Medicine, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark Correspondence Helle Cecilie Viekilde Pfeiffer, Department of Pediatrics and Adolescence Medicine, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark. Email: helvie@ous-hf.noSearch for more papers by this authorCaroline De Visscher, Caroline De Visscher Centre for Psychiatry Research, Department of Clinical Neuroscience, Region Stockholm, Child and Adolescent Psychiatry Research Center, Karolinska Institutet & Stockholm Healthcare Services, Stockholm, SwedenSearch for more papers by this authorInger Helene Gjone, Inger Helene Gjone Division of Pediatric and Adolescent Medicine, Department of Child and Adolescent Mental Health in Hospitals, Oslo University Hospital, Oslo, NorwaySearch for more papers by this authorSofia Ygberg, Sofia Ygberg Neuropediatric Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, SwedenSearch for more papers by this authorLinn Breen Herner, Linn Breen Herner Division of Pediatric and Adolescent Medicine, Department of Child and Adolescent Mental Health in Hospitals, Oslo University Hospital, Oslo, NorwaySearch for more papers by this authorEva Hesselmark, Eva Hesselmark Centre for Psychiatry Research, Department of Clinical Neuroscience, Region Stockholm, Child and Adolescent Psychiatry Research Center, Karolinska Institutet & Stockholm Healthcare Services, Stockholm, SwedenSearch for more papers by this authorSelma Idring Nordstrom, Selma Idring Nordstrom Centre for Psychiatry Research, Department of Clinical Neuroscience, Region Stockholm, Child and Adolescent Psychiatry Research Center, Karolinska Institutet & Stockholm Healthcare Services, Stockholm, SwedenSearch for more papers by this authorInger Sandvig, Inger Sandvig Department of Child Neurology, Oslo University Hospital, Oslo, NorwaySearch for more papers by this authorLiselotte Skov, Liselotte Skov Department of Pediatrics and Adolescence Medicine, Copenhagen University Hospital Herlev, Herlev, DenmarkSearch for more papers by this authorCamilla Birgitte Sørensen, Camilla Birgitte Sørensen Department of Pediatrics and Adolescence Medicine, Copenhagen University Hospital Herlev, Herlev, DenmarkSearch for more papers by this authorMing Lim, Ming Lim Children's Neurosciences, Evelina London Children's Hospital at Guy's and St Thomas' NHS Foundation Trust, King's Health Partners Academic Health Science Centre, London, UKSearch for more papers by this authorRonny Wickstrom, Ronny Wickstrom Neuropediatric Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, SwedenSearch for more papers by this authorTammy Hedderly, Tammy Hedderly Tic and Neurodevelopmental Movements Service (TANDeM), Children's Neurosciences Centre, Evelina London Children's Hospital, Guys and St Thomas' NHS Foundation Trust, London, UKSearch for more papers by this authorNanette Marinette Debes, Nanette Marinette Debes Department of Pediatrics and Adolescence Medicine, Copenhagen University Hospital Herlev, Herlev, DenmarkSearch for more papers by this author First published: 13 October 2021 https://doi.org/10.1111/apa.16149Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume110, Issue12December 2021Pages 3390-3391 RelatedInformation