Article Note: Belen Perez-Duenas and Davide Tonduti are both senior authors of this manuscript. Relevant conflicts of interest/financial disclosures: The authors have no potential conflicts of ...interest to disclose. Funding agencies: For #2genetic diagnosis was performed based on a research project funded by Instituto de Salud Carlos III, grant/award number: PI18/01319. Corrections added on 12 March 2021 after first online publication: Correspondence address updated for Belen Perez-Duenas. CAPTION(S): Figure S1. Xxx APPENDIX S1. Supporting Information Byline: Silvia Masnada, Diego Martinelli, Marta Correa-Vela, Emanuele Agolini, Heidy Baide-Mairena, Anna Marce-Grau, Cecilia Parazzini, Pierangelo Veggiotti, Belen Perez-Duenas, Davide Tonduti
The neurological phenotype of 3‐hydroxyisobutyryl‐CoA hydrolase (HIBCH) and short‐chain enoyl‐CoA hydratase (SCEH) defects is expanding and natural history studies are necessary to improve clinical ...management. From 42 patients with Leigh syndrome studied by massive parallel sequencing, we identified five patients with SCEH and HIBCH deficiency. Fourteen additional patients were recruited through collaborations with other centres. In total, we analysed the neurological features and mutation spectrum in 19 new SCEH/HIBCH patients. For natural history studies and phenotype to genotype associations we also included 70 previously reported patients. The 19 newly identified cases presented with Leigh syndrome (SCEH, n = 11; HIBCH, n = 6) and paroxysmal dystonia (SCEH, n = 2). Basal ganglia lesions (18 patients) were associated with small cysts in the putamen/pallidum in half of the cases, a characteristic hallmark for diagnosis. Eighteen pathogenic variants were identified, 11 were novel. Among all 89 cases, we observed a longer survival in HIBCH compared to SCEH patients, and in HIBCH patients carrying homozygous mutations on the protein surface compared to those with variants inside/near the catalytic region. The SCEH p.(Ala173Val) change was associated with a milder form of paroxysmal dystonia triggered by increased energy demands. In a child harbouring SCEH p.(Ala173Val) and the novel p.(Leu123Phe) change, an 83.6% reduction of the protein was observed in fibroblasts. The SCEH and HIBCH defects in the catabolic valine pathway were a frequent cause of Leigh syndrome in our cohort. We identified phenotype and genotype associations that may help predict outcome and improve clinical management.
Early recognition of SGCE‐myoclonus–dystonia in children Correa‐Vela, Marta; Carvalho, Joao; Ferrero‐Turrion, Julia ...
Developmental medicine and child neurology,
February 2023, 2023-02-00, 20230201, Letnik:
65, Številka:
2
Journal Article
Recenzirano
Aim
To evaluate early dystonic features in children and adolescents with SGCE‐myoclonus–dystonia.
Method
In this cross‐sectional study, 49 patients (26 females and 23 males) with ...SGCE‐myoclonus–dystonia (aged 15y 2mo, SD 12y) with childhood‐onset (2y 10mo, SD 1y 10mo) dystonia were examined using a standardized video recorded protocol. Dystonia was rated using the Writer's Cramp and Gait Dystonia Rating Scales. Disability and impairment for handwriting and walking were also rated.
Results
Dystonia was present at rest (n=1), posture (n=12), and during specific motor tasks (n=45) such as writing (n=35), walking (n=23), and running (n=20). Most children reported disability while performing these tasks. Early dystonic patterns were identified for writer's cramp and gait dystonia, the latter named the ‘circular shaking leg’, ‘dragging leg’, and ‘hobby‐horse gait’ patterns. Sensory tricks were used by five and eight children to improve dystonia and myoclonus during writing and walking respectively. The rating scales accurately measured the severity of action dystonia and correlated with self‐reported disability.
Interpretation
Children with SGCE‐myoclonus–dystonia show recognizable dystonic patterns and sensory tricks that may lead to an early diagnosis and timely therapeutic approach. Isolated writer's cramp is a key feature in childhood and should prompt SCGE analysis. The proposed action dystonia scales could be used to monitor disease course and response to treatment.
What this paper adds
Most children with SGCE‐myoclonus–dystonia got writer's cramp and had walking and running dystonia.
Writer's cramp was a key feature and should prompt SGCE genetic investigation.
‘Circular shaking leg’, ‘dragging leg’, and ‘hobby‐horse gait’ were recognized as early gait patterns.
Children used sensory tricks to improve myoclonus and dystonia, suggesting common pathophysiological mechanisms.
Action dystonia rating scales are valid tools to assess severity in children.
What this paper adds
Most children with SGCE‐myoclonus–dystonia got writer's cramp and had walking and running dystonia.
Writer's cramp was a key feature and should prompt SGCE genetic investigation.
‘Circular shaking leg’, ‘dragging leg’, and ‘hobby‐horse gait’ were recognized as early gait patterns.
Children used sensory tricks to improve myoclonus and dystonia, suggesting common pathophysiological mechanisms.
Action dystonia rating scales are valid tools to assess severity in children.
This study evaluates early dystonic features in a large cohort of children with SGCE‐MDS, describes recognizable dystonic patterns and sensory tricks, and proposes action dystonia scales that could be used to monitor disease course and response to treatment.
This original article is commented on by Roze on pages 151–152 of this issue.
Abstact
FBXO7 is implicated in the ubiquitin–proteasome system and parkin‐mediated mitophagy. FBXO7defects cause a levodopa‐responsive parkinsonian‐pyramidal syndrome(PPS). Methods: We investigated ...the disease molecular bases in a child with PPS and brain iron accumulation. Results: A novel homozygous c.368C>G (p.S123*) FBXO7 mutation was identified in a child with spastic paraplegia, epilepsy, cerebellar degeneration, levodopa nonresponsive parkinsonism, and brain iron deposition. Patient’s fibroblasts assays demonstrated an absence of FBXO7 RNA expression leading to impaired proteasome degradation and accumulation of poly‐ubiquitinated proteins. Conclusion: This novel FBXO7 phenotype associated with impaired proteasome activity overlaps with neurodegeneration with brain iron accumulation disorders.
Premonitory urges are uncomfortable physical sensations preceding tics that occur in most individuals with a chronic tic disorder. The Premonitory Urge for Tics Scale (PUTS) is the most frequently ...used self-report measure to assess the severity of premonitory urges. We aimed to evaluate the psychometric properties of the PUTS in the largest sample size to date (
n
= 656), in children aged 3–16 years, from the baseline measurement of the longitudinal European Multicenter Tics in Children Study (EMTICS). Our psychometric evaluation was done in three age-groups: children aged 3–7 years (
n
= 103), children between 8 and 10 years (
n
= 253), and children aged 11–16 years (
n
= 300). The PUTS exhibited good internal reliability in children and adolescents, also under the age of 10, which is younger than previously thought. We observed significant but small correlations between the severity of urges and severity of tics and obsessive–compulsive symptoms, and between severity of urges and ratings of attention-deficit/hyperactivity disorder and internalizing and externalizing behaviors, however, only in children of 8–10 years. Consistent with previous results, the 10th item of the PUTS correlated less with the rest of the scale compared to the other items and, therefore, should not be used as part of the questionnaire. We found a two-factor structure of the PUTS in children of 11 years and older, distinguishing between sensory phenomena related to tics, and mental phenomena as often found in obsessive–compulsive disorder. The age-related differences observed in this study may indicate the need for the development of an age-specific questionnaire to assess premonitory urges.
•Using IHC only 12% of the cohort showed mild evidence of neuronal antibodies.•8% of the preclinical and onset samples showed hippocampus and/or cerebellum bindings.•Using CBAs two patients had ...antibodies against the NMDAR and none against LGI1/CASPR2.
In Tourette Syndrome (TS) a role for autoantibodies directed against neuronal proteins has long been suspected, but so far results are still inconsistent. The aim of this study was to look for antibodies to specific or undefined neuronal proteins that could be involved in the aetiology of the disease.
Sera from children with Tourette Syndrome or another chronic tic disorder (TS/TD), collected as part of the longitudinal European Multicenter Tics in Children Study, were investigated. Participants included 30 siblings of patients with TS/TD prior to developing tics (preclinical stage) and the same children after the first tic onset (onset), and 158 patients in the chronic phase undergoing an acute relapse (exacerbation). Presence of antibodies binding to rodent brain tissue was assessed by immunohistology on rat brain sections and by immunofluorescent staining of live hippocampal neurons. Live cell-based assays were used to screen for antibodies to NMDAR, CASPR2, LGI1, AMPAR and GABAAR.
Immunohistology indicated evidence of antibodies reactive with brain tissue, binding mainly to the hippocampus, the basal ganglia or the cerebellum in 26/218 (12%), with 8% of the preclinical or onset sera binding to the dentate gyrus/CA3 region or cerebellum. Only two individuals (one pre-clinical, one chronic) had antibodies binding the NMDAR and the binding was only weakly positive. No other specific antibodies were detected.
Despite some immunoreactivity towards neuronal antigens on brain tissue, this was not mirrored by antibodies binding to live neurons, suggesting the presence of non-specific antibodies or those that bind non-pathogenic intracellular epitopes. NMDAR or the other neuronal surface antibodies tested were very infrequent in these patients. The evidence for pathogenic antibodies that could be causative of TS is weak.
Genetic predisposition, autoimmunity and environmental factors e.g. pre- and perinatal difficulties, Group A Streptococcal (GAS) and other infections, stress-inducing events might interact to create ...a neurobiological vulnerability to the development of tics and associated behaviours. However, the existing evidence for this relies primarily on small prospective or larger retrospective population-based studies, and is therefore still inconclusive. This article describes the design and methodology of the EMTICS study, a longitudinal observational European multicentre study involving 16 clinical centres, with the following objectives: (1) to investigate the association of environmental factors (GAS exposure and psychosocial stress, primarily) with the onset and course of tics and/or obsessive–compulsive symptoms through the prospective observation of at-risk individuals (ONSET cohort: 260 children aged 3–10 years who are tic-free at study entry and have a first-degree relative with a chronic tic disorder) and affected individuals (COURSE cohort: 715 youth aged 3–16 years with a tic disorder); (2) to characterise the immune response to microbial antigens and the host’s immune response regulation in association with onset and exacerbations of tics; (3) to increase knowledge of the human gene pathways influencing the pathogenesis of tic disorders; and (4) to develop prediction models for the risk of onset and exacerbations of tic disorders. The EMTICS study is, to our knowledge, the largest prospective cohort assessment of the contribution of different genetic and environmental factors to the risk of developing tics in putatively predisposed individuals and to the risk of exacerbating tics in young individuals with chronic tic disorders.
The human iPSC cell lines, PLANFiPS1-Sv4F-1 (RCPFi004-A), PLANFiPS2-Sv4F-1 (RCPFi005-A), PLANFiPS3-Sv4F-1 RCPFi006-A), derived from dermal fibroblast from three patients suffering PLAN ...(PLA2G6-associated neurodegeneration; MIM 256600) caused by mutations in the PLA2G6 gene, was generated by non-integrative reprogramming technology using OCT3/4, SOX2, CMYC and KLF4 reprogramming factors. The pluripotency was assessed by immunocytochemistry and RT-PCR. Differentiation capacity was verified in vitro. This iPSC line can be further differentiated toward affected cells to better understand molecular mechanisms of disease and pathophysiology.
Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder of complex genetic architecture and is characterized by multiple motor tics and at least one vocal tic persisting for more than ...1 year.
We performed a genome-wide meta-analysis integrating a novel TS cohort with previously published data, resulting in a sample size of 6133 individuals with TS and 13,565 ancestry-matched control participants.
We identified a genome-wide significant locus on chromosome 5q15. Integration of expression quantitative trait locus, Hi-C (high-throughput chromosome conformation capture), and genome-wide association study data implicated the NR2F1 gene and associated long noncoding RNAs within the 5q15 locus. Heritability partitioning identified statistically significant enrichment in brain tissue histone marks, while polygenic risk scoring of brain volume data identified statistically significant associations with right and left thalamus volumes and right putamen volume.
Our work presents novel insights into the neurobiology of TS, thereby opening up new directions for future studies.
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