Pathogenetic Insights into Developmental Coordination Disorder Reveal Substantial Overlap with Movement Disorders.

Developmental Coordination Disorder (DCD) is a neurodevelopmental condition characterized by non-progressive central motor impairments. Mild movement disorder features have been observed in DCD. Until now, the etiology of DCD has been unclear. Recent studies suggested a genetic substrate in some patients with DCD, but comprehensive knowledge about associated genes and underlying pathogenetic mechanisms is still lacking. In this study, we first identified genes described in the literature in patients with a diagnosis of DCD according to the official diagnostic criteria. Second, we exposed the underlying pathogenetic mechanisms of DCD, by investigating tissue- and temporal gene expression patterns and brain-specific biological mechanisms. Third, we explored putative shared pathogenetic mechanisms between DCD and frequent movement disorders with a known genetic component, including ataxia, chorea, dystonia, and myoclonus. We identified 12 genes associated with DCD in the literature, which are ubiquitously expressed in the central nervous system throughout brain development. These genes are involved in cellular processes, neural signaling, and nervous system development. There was a remarkable overlap (62%) in pathogenetic mechanisms between DCD-associated genes and genes linked with movement disorders. Our findings suggest that some patients might have a genetic etiology of DCD, which could be considered part of a pathogenetic movement disorder spectrum.

Instrumented Gait Classification Using Meaningful Features in Patients with Impaired Coordination.

Early onset ataxia (EOA) and developmental coordination disorder (DCD) both affect cerebellar functioning in children, making the clinical distinction challenging. We here aim to derive meaningful features from quantitative SARA-gait data (i.e., the gait test of the scale for the assessment and rating of ataxia (SARA)) to classify EOA and DCD patients and typically developing (CTRL) children with better explainability than previous classification approaches. We collected data from 18 EOA, 14 DCD and 29 CTRL children, while executing both SARA gait tests. Inertial measurement units were used to acquire movement data, and a gait model was employed to derive meaningful features. We used a random forest classifier on 36 extracted features, leave-one-out-cross-validation and a synthetic oversampling technique to distinguish between the three groups. Classification accuracy, probabilities of classification and feature relevance were obtained. The mean classification accuracy was 62.9% for EOA, 85.5% for DCD and 94.5% for CTRL participants. Overall, the random forest algorithm correctly classified 82.0% of the participants, which was slightly better than clinical assessment (73.0%). The classification resulted in a mean precision of 0.78, mean recall of 0.70 and mean F1 score of 0.74. The most relevant features were related to the range of the hip flexion-extension angle for gait, and to movement variability for tandem gait. Our results suggest that classification, employing features representing different aspects of movement during gait and tandem gait, may provide an insightful tool for the differential diagnoses of EOA, DCD and typically developing children.

Early onset ataxia with comorbid myoclonus and epilepsy: A disease spectrum with shared molecular pathways and cortico-thalamo-cerebellar network involvement.

OBJECTIVES: Early onset ataxia (EOA) concerns a heterogeneous disease group, often presenting with other comorbid phenotypes such as myoclonus and epilepsy. Due to genetic and phenotypic heterogeneity, it can be difficult to identify the underlying gene defect from the clinical symptoms. The pathological mechanisms underlying comorbid EOA phenotypes remain largely unknown. The aim of this study is to investigate the key pathological mechanisms in EOA with myoclonus and/or epilepsy. METHODS: For 154 EOA-genes we investigated (1) the associated phenotype (2) reported anatomical neuroimaging abnormalities, and (3) functionally enriched biological pathways through in silico analysis. We assessed the validity of our in silico results by outcome comparison to a clinical EOA-cohort (80 patients, 31 genes). RESULTS: EOA associated gene mutations cause a spectrum of disorders, including myoclonic and epileptic phenotypes. Cerebellar imaging abnormalities were observed in 73-86% (cohort and in silico respectively) of EOA-genes independently of phenotypic comorbidity. EOA phenotypes with comorbid myoclonus and myoclonus/epilepsy were specifically associated with abnormalities in the cerebello-thalamo-cortical network. EOA, myoclonus and epilepsy genes shared enriched pathways involved in neurotransmission and neurodevelopment both in the in silico and clinical genes. EOA gene subgroups with myoclonus and epilepsy showed specific enrichment for lysosomal and lipid processes. CONCLUSIONS: The investigated EOA phenotypes revealed predominantly cerebellar abnormalities, with thalamo-cortical abnormalities in the mixed phenotypes, suggesting anatomical network involvement in EOA pathogenesis. The studied phenotypes exhibit a shared biomolecular pathogenesis, with some specific phenotype-dependent pathways. Mutations in EOA, epilepsy and myoclonus associated genes can all cause heterogeneous ataxia phenotypes, which supports exome sequencing with a movement disorder panel over conventional single gene panel testing in the clinical setting.

A Screening Tool to Quickly Identify Movement Disorders in Patients with Inborn Errors of Metabolism.

BACKGROUND: Movement disorders are frequent in patients with inborn errors of metabolism (IEMs) but poorly recognized, particularly by nonmovement disorder specialists. We propose an easy-to-use clinical screening tool to help recognize movement disorders. OBJECTIVE: The aim is to develop a user-friendly rapid screening tool for nonmovement disorder specialists to detect moderate and severe movement disorders in patients aged ≥4 years with IEMs. METHODS: Videos of 55 patients with different IEMs were scored by experienced movement disorder specialists (n = 12). Inter-rater agreements were determined on the presence and subtype of the movement disorder. Based on ranking and consensus, items were chosen to be incorporated into the screening tool. RESULTS: A movement disorder was rated as present in 80% of the patients, with a moderate inter-rater agreement (κ =0.420, P < 0.001) on the presence of a movement disorder. When considering only moderate and severe movement disorders, the inter-rater agreement increased to almost perfect (κ = 0.900, P < 0.001). Dystonia was most frequently scored (27.3%) as the dominant phenotype. Treatment was mainly suggested for patients with moderate or severe movement disorders. Walking, observations of the arms, and drawing a spiral were found to be the most informative tasks and were included in the screening tool. CONCLUSIONS: We designed a screening tool to recognize movement disorders in patients with IEMs. We propose that this screening tool can contribute to select patients who should be referred to a movement disorder specialist for further evaluation and, if necessary, treatment of the movement disorder. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Neurologic Outcome Comparison between Fetal Open-, Endoscopic- and Neonatal-Intervention Techniques in Spina Bifida Aperta.

INTRODUCTION: In spina bifida aperta (SBA), fetal closure of the myelomeningocele (MMC) can have a neuroprotective effect and improve outcomes. In Europe, surgical MMC closure is offered by fetal-open (OSBAR), fetal-endoscopic (FSBAR), and neonatal (NSBAR) surgical techniques. Pediatric neurologists facing the challenging task of counseling the parents may therefore seek objective outcome comparisons. Until now, such data are hardly available. In SBA, we aimed to compare neurologic outcomes between OSBAR, FSBAR, and NSBAR intervention techniques. METHODS: We determined intervention-related complications, neuromuscular integrity, and neurologic outcome parameters after OSBAR (n = 17) and FSBAR (n = 13) interventions by age- and lesion-matched comparisons with NSBAR-controls. Neurological outcome parameters concerned: shunt dependency, segmental alterations in muscle ultrasound density (reflecting neuromuscular integrity), segmental motor-, sensory- and reflex conditions, and the likelihood of intervention-related gain in ambulation. RESULTS: Compared with NSBAR-controls, fetal intervention is associated with improved neuromuscular tissue integrity, segmental neurological outcomes, reduced shunt dependency, and a higher chance of acquiring ambulation in ≈20% of the operated children. Children with MMC-lesions with a cranial border at L3 revealed the most likely intervention-related motor function gain. The outcome comparison between OSBAR versus FSBAR interventions revealed no significant differences. CONCLUSION: In SBA, OSBAR- and FSBAR-techniques achieved similar neuroprotective results. A randomized controlled trial is helpful in revealing and compare ongoing effects by surgical learning curves.

2D Gait Skeleton Data Normalization for Quantitative Assessment of Movement Disorders from Freehand Single Camera Video Recordings.

Overlapping phenotypic features between Early Onset Ataxia (EOA) and Developmental Coordination Disorder (DCD) can complicate the clinical distinction of these disorders. Clinical rating scales are a common way to quantify movement disorders but in children these scales also rely on the observer's assessment and interpretation. Despite the introduction of inertial measurement units for objective and more precise evaluation, special hardware is still required, restricting their widespread application. Gait video recordings of movement disorder patients are frequently captured in routine clinical settings, but there is presently no suitable quantitative analysis method for these recordings. Owing to advancements in computer vision technology, deep learning pose estimation techniques may soon be ready for convenient and low-cost clinical usage. This study presents a framework based on 2D video recording in the coronal plane and pose estimation for the quantitative assessment of gait in movement disorders. To allow the calculation of distance-based features, seven different methods to normalize 2D skeleton keypoint data derived from pose estimation using deep neural networks applied to freehand video recording of gait were evaluated. In our experiments, 15 children (five EOA, five DCD and five healthy controls) were asked to walk naturally while being videotaped by a single camera in 1280 × 720 resolution at 25 frames per second. The high likelihood of the prediction of keypoint locations (mean = 0.889, standard deviation = 0.02) demonstrates the potential for distance-based features derived from routine video recordings to assist in the clinical evaluation of movement in EOA and DCD. By comparison of mean absolute angle error and mean variance of distance, the normalization methods using the Euclidean (2D) distance of left shoulder and right hip, or the average distance from left shoulder to right hip and from right shoulder to left hip were found to better perform for deriving distance-based features and further quantitative assessment of movement disorders.

Developmental neurobiology of cerebellar and Basal Ganglia connections.

BACKGROUND: The high prevalence of mixed phenotypes of Early Onset Ataxia (EOA) with comorbid dystonia has shifted the pathogenetic concept from the cerebellum towards the interconnected cerebellar motor network. This paper on EOA with comorbid dystonia (EOA-dystonia) explores the conceptual relationship between the motor phenotype and the cortico-basal-ganglia-ponto-cerebellar network. METHODS: In EOA-dystonia, we reviewed anatomic-, genetic- and biochemical-studies on the comorbidity between ataxia and dystonia. RESULTS: In a clinical EOA cohort, the prevalence of dystonia was over 60%. Both human and animal studies converge on the underlying role for the cortico-basal-ganglia-ponto-cerebellar network. Genetic -clinical and -in silico network studies reveal underlying biological pathways for energy production and neural signal transduction. CONCLUSIONS: EOA-dystonia phenotypes are attributable to the cortico-basal-ganglia-ponto-cerebellar network, instead of to the cerebellum, alone. The underlying anatomic and pathogenetic pathways have clinical implications for our understanding of the heterogeneous phenotype, neuro-metabolic and genetic testing and potentially also for new treatment strategies, including neuro-modulation.

Applicability of quantitative oculomotor and SARA assessment in children.

BACKGROUND: In clinical practice, eye movements can provide an early diagnostic marker for early onset ataxia (EOA). However, quantitative oculomotor assessment is not included in the most frequently used and age-validated ataxia rating scale in children, the Scale for the Assessment and Rating of Ataxia (SARA). We aimed to investigate the applicability of semi-quantitative eye movement assessment by the International Cooperative Ataxia Rating Scale (ICARSOCM) and Ocular Motion Score (OMS7-10) complementary to SARA measurements in children. METHODS: In 52 typically developing children (aged 4-16 years; n = 4 per year of age), three independent assessors scored saccadic eye movements and ocular pursuit according to the ICARSOCM and matching parameters from the OMS7-10. For ICARSOCM, we determined 1) construct validity for coordinated eye movements by correlation with OMS7-10, ICARSEYE-HAND-COORDINATION and SARA subscale scores, 2) agreement percentage and inter-rater agreement (Fleiss Kappa) and 3) age-dependency. RESULTS: Spearman's rank correlations of ICARSOCM with OMS7-10 and ICARS- and SARA subscales were moderate to fair (all p < .001). Inter-rater agreement of ICARS-OCM was 80.8%; (Fleiss Kappa: 0.411). ICARSOCM scores revealed a similar exponentially decreasing association with age as the other SARA (sub)scores, reaching a plateau at 10 years of age. INTERPRETATION: ICARSOCM has a valid construct for the measurement of coordinated eye movement performance and is reliably assessable in children. ICARSOCM reveals a similar age-dependent relationship as the other ataxia subscales, reflecting the physiological maturation of the cerebellum. In children, these data may implicate that ICARSOCM can reliably contribute to coordination assessment, complementary to the SARA subscales.

The ARCA Registry: A Collaborative Global Platform for Advancing Trial Readiness in Autosomal Recessive Cerebellar Ataxias.

Autosomal recessive cerebellar ataxias (ARCAs) form an ultrarare yet expanding group of neurodegenerative multisystemic diseases affecting the cerebellum and other neurological or non-neurological systems. With the advent of targeted therapies for ARCAs, disease registries have become a precious source of real-world quantitative and qualitative data complementing knowledge from preclinical studies and clinical trials. Here, we review the ARCA Registry, a global collaborative multicenter platform (>15 countries, >30 sites) with the overarching goal to advance trial readiness in ARCAs. It presents a good clinical practice (GCP)- and general data protection regulation (GDPR)-compliant professional-reported registry for multicenter web-based capture of cross-center standardized longitudinal data. Modular electronic case report forms (eCRFs) with core, extended, and optional datasets allow data capture tailored to the participating site's variable interests and resources. The eCRFs cover all key data elements required by regulatory authorities [European Medicines Agency (EMA)] and the European Rare Disease (ERD) platform. They capture genotype, phenotype, and progression and include demographic data, biomarkers, comorbidity, medication, magnetic resonance imaging (MRI), and longitudinal clinician- or patient-reported ratings of ataxia severity, non-ataxia features, disease stage, activities of daily living, and (mental) health status. Moreover, they are aligned to major autosomal-dominant spinocerebellar ataxia (SCA) and sporadic ataxia (SPORTAX) registries in the field, thus allowing for joint and comparative analyses not only across ARCAs but also with SCAs and sporadic ataxias. The registry is at the core of a systematic multi-component ARCA database cluster with a linked biobank and an evolving study database for digital outcome measures. Currently, the registry contains more than 800 patients with almost 1,500 visits representing all ages and disease stages; 65% of patients with established genetic diagnoses capture all the main ARCA genes, and 35% with unsolved diagnoses are targets for advanced next-generation sequencing. The ARCA Registry serves as the backbone of many major European and transatlantic consortia, such as PREPARE, PROSPAX, and the Ataxia Global Initiative, with additional data input from SPORTAX. It has thus become the largest global trial-readiness registry in the ARCA field.

Clinical phenotypes of infantile onset CACNA1A-related disorder.

BACKGROUND: CACNA1A-related disorders present with persistent progressive and non-progressive cerebellar ataxia and paroxysmal events: epileptic seizures and non-epileptic attacks. These phenotypes overlap and co-exist in the majority of patients. OBJECTIVE: To describe phenotypes in infantile onset CACNA1A-related disorder and to explore intra-familial variations and genotype-phenotype correlations. MATERIAL AND METHODS: This study was a multicenter international collaboration. A retrospective chart review of CACNA1A patients was performed. Clinical, radiological, and genetic data were collected and analyzed in 47 patients with infantile-onset disorder. RESULTS: Paroxysmal non-epileptic events (PNEE) were observed in 68% of infants, with paroxysmal tonic upward gaze (PTU) noticed in 47% of infants. Congenital cerebellar ataxia (CCA) was diagnosed in 51% of patients including four patients with developmental delay and only one neurological sign. PNEEs were found in 63% of patients at follow-up, with episodic ataxia (EA) in 40% of the sample. Cerebellar ataxia was found in 58% of the patients at follow-up. Four patients had epilepsy in infancy and nine in childhood. Seven infants had febrile convulsions, three of which developed epilepsy later; all three patients had CCA. Cognitive difficulties were demonstrated in 70% of the children. Cerebellar atrophy was found in only one infant but was depicted in 64% of MRIs after age two. CONCLUSIONS: Nearly all of the infants had CCA, PNEE or both. Cognitive difficulties were frequent and appeared to be associated with CCA. Epilepsy was more frequent after age two. Febrile convulsions in association with CCA may indicate risk of epilepsy in later childhood. Brain MRI was normal in infancy. There were no genotype-phenotype correlations found.

Early Onset Ataxia with Comorbid Dystonia: Clinical, Anatomical and Biological Pathway Analysis Expose Shared Pathophysiology.

In degenerative adult onset ataxia (AOA), dystonic comorbidity is attributed to one disease continuum. However, in early adult onset ataxia (EOA), the prevalence and pathogenesis of dystonic comorbidity (EOAD+), are still unclear. In 80 EOA-patients, we determined the EOAD+-prevalence in association with MRI-abnormalities. Subsequently, we explored underlying biological pathways by genetic network and functional enrichment analysis. We checked pathway-outcomes in specific EOAD+-genotypes by comparing results with non-specifically (in-silico-determined) shared genes in up-to-date EOA, AOA and dystonia gene panels (that could concurrently cause ataxia and dystonia). In the majority (65%) of EOA-patients, mild EOAD+-features concurred with extra-cerebellar MRI abnormalities (at pons and/or basal-ganglia and/or thalamus (p = 0.001)). Genetic network and functional enrichment analysis in EOAD+-genotypes indicated an association with organelle- and cellular-component organization (important for energy production and signal transduction). In non-specifically, in-silico-determined shared EOA, AOA and dystonia genes, pathways were enriched for Krebs-cycle and fatty acid/lipid-metabolic processes. In frequently occurring EOAD+-phenotypes, clinical, anatomical and biological pathway analyses reveal shared pathophysiology between ataxia and dystonia, associated with cellular energy metabolism and network signal transduction. Insight in the underlying pathophysiology of heterogeneous EOAD+-phenotype-genotype relationships supports the rationale for testing with complete, up-to-date movement disorder gene lists, instead of single EOA gene-panels.

Development of muscle ultrasound density in healthy fetuses and infants.

Muscle ultrasound density (MUD) is a non-invasive parameter to indicate neuromuscular integrity in both children and adults. In healthy fetuses and infants, physiologic MUD values during development are still lacking. We therefore aimed to determine the physiologic, age-related MUD trend of biceps, quadriceps, tibialis anterior, hamstrings, gluteal and calf muscles, from pre- to the first year of postnatal life. To avoid a bias by pregnancy-related signal disturbances, we expressed fetal MUD as a ratio against bone ultrasound density. We used the full-term prenatal MUD ratio and the newborn postnatal MUD value as reference points, so that MUD development could be quantified from early pre- into postnatal life. Results: During the prenatal period, the total muscle group revealed a developmental MUD trend concerning a fetal increase in MUD-ratio from the 2nd trimester up to the end of the 3rd trimester [median increase: 27% (range 16-45), p < .001]. After birth, MUD-values increased up to the sixth month [median increase: 11% (range -7-27), p = 0.025] and stabilized thereafter. Additionally, there were also individual MUD characteristics per muscle group and developmental stage, such as relatively low MUD values of fetal hamstrings and high values of the paediatric gluteus muscles. These MUD trends are likely to concur with analogous developmentally, maturation-related alterations in the muscle water to peptide content ratios.

A detailed description of the phenotypic spectrum of North Sea Progressive Myoclonus Epilepsy in a large cohort of seventeen patients.

INTRODUCTION: In 2011, a homozygous mutation in GOSR2 (c.430G > T; p. Gly144Trp) was reported as a novel cause of Progressive Myoclonus Epilepsy (PME) with early-onset ataxia. Interestingly, the ancestors of patients originate from countries bound to the North Sea, hence the condition was termed North Sea PME (NSPME). Until now, only 20 patients have been reported in literature. Here, we provide a detailed description of clinical and neurophysiological data of seventeen patients. METHODS: We collected clinical and neurophysiological data from the medical records of seventeen NSPME patients (5-46 years). In addition, we conducted an interview focused on factors influencing myoclonus severity. RESULTS: The core clinical features of NSPME are early-onset ataxia, myoclonus and seizures, with additionally areflexia and scoliosis. Factors such as fever, illness, heat, emotions, stress, noise and light (flashes) all exacerbated myoclonic jerks. Epilepsy severity ranged from the absence of or incidental clinical seizures to frequent daily seizures and status epilepticus. Some patients made use of a wheelchair during their first decade, whereas others still walked independently during their third decade. Neurophysiological features suggesting neuromuscular involvement in NSPME were variable, with findings ranging from indicative of sensory neuronopathy and anterior horn cell involvement to an isolated absent H-reflex. CONCLUSION: Although the sequence of symptoms is rather homogeneous, the severity of symptoms and rate of progression varied considerably among individual patients. Common triggers for myoclonus can be identified and myoclonus is difficult to treat; to what extent neuromuscular involvement contributes to the phenotype remains to be further elucidated.

ZMYND11-related syndromic intellectual disability: 16 patients delineating and expanding the phenotypic spectrum.

Pathogenic variants in ZMYND11, which acts as a transcriptional repressor, have been associated with intellectual disability, behavioral abnormalities, and seizures. Only 11 affected individuals have been reported to date, and the phenotype associated with pathogenic variants in this gene have not been fully defined. Here, we present 16 additional patients with predicted pathogenic heterozygous variants in including four individuals from the same family, to further delineate and expand the genotypic and phenotypic spectrum of ZMYND11-related syndromic intellectual disability. The associated phenotype includes developmental delay, particularly affecting speech, mild-moderate intellectual disability, significant behavioral abnormalities, seizures, and hypotonia. There are subtle shared dysmorphic features, including prominent eyelashes and eyebrows, a depressed nasal bridge with bulbous nasal tip, anteverted nares, thin vermilion of the upper lip, and wide mouth. Novel features include brachydactyly and tooth enamel hypoplasia. Most identified variants are likely to result in premature truncation and/or nonsense-mediated decay. Two ZMYND11 variants located in the final exon-p.(Gln586*) (likely escaping nonsense-mediated decay) and p.(Cys574Arg)-are predicted to disrupt the MYND-type zinc-finger motif and likely interfere with binding to its interaction partners. Hence, the homogeneous phenotype likely results from a common mechanism of loss-of-function.

Paediatric motor phenotypes in early-onset ataxia, developmental coordination disorder, and central hypotonia.

AIMS: To investigate the accuracy of phenotypic early-onset ataxia (EOA) recognition among developmental conditions, including developmental coordination disorder (DCD) and hypotonia of central nervous system origin, and the effect of scientifically validated EOA features on changing phenotypic consensus. METHOD: We included 32 children (4-17y) diagnosed with EOA (n=11), DCD (n=10), and central hypotonia (n=11). Three paediatric neurologists independently assessed videotaped motor behaviour phenotypically and quantitatively (using the Scale for Assessment and Rating of Ataxia [SARA]). We determined: (1) phenotypic interobserver agreement and phenotypic homogeneity (percentage of phenotypes with full consensus by all three observers according to the underlying diagnosis); (2) SARA (sub)score profiles; and (3) the effect of three scientifically validated EOA features on phenotypic consensus. RESULTS: Phenotypic homogeneity occurred in 8 out of 11, 2 out of 10, and 1 out of 11 patients with EOA, DCD, and central hypotonia respectively. Homogeneous phenotypic discrimination of EOA from DCD and central hypotonia occurred in 16 out of 21 and 22 out of 22 patients respectively. Inhomogeneously discriminated EOA and DCD phenotypes (5 out of 21) revealed overlapping SARA scores with different SARA subscore profiles. After phenotypic reassessment with scientifically validated EOA features, phenotypic homogeneity changed from 16 to 18 patients. INTERPRETATION: In contrast to complete distinction between EOA and central hypotonia, the paediatric motor phenotype did not reliably distinguish between EOA and DCD. Reassessment with scientifically validated EOA features could contribute to a higher phenotypic consensus. Early-onset ataxia (EOA) and central hypotonia motor phenotypes were reliably distinguished. EOA and developmental coordination disorder (DCD) motor phenotypes were not reliably distinguished. The EOA and DCD phenotypes have different profiles of the Scale for Assessment and Rating of Ataxia.

FENOTIPOS PEDIÁTRICOS MOTORES EN ATAXIA DE INICIO TEMPRANO, TRASTORNO DEL DESARROLLO DE LA COORDINACIÓN E HIPOTONÍA DE ORIGEN CENTRAL: OBJETIVOS: Investigar la precisión del reconocimiento fenotípico de ataxia de inicio temprano (EOA) con respecto a trastornos del desarrollo, incluido el trastorno del desarrollo de la coordinación (TDC) y la hipotonía de origen central. Investigar el efecto de las características científicamente validadas de EOA sobre el consenso fenotípico entre los evaluadores. MÉTODO: Se incluyeron 32 niños (4-17 años) diagnosticados con EOA (n = 11), TDC (n = 10) e hipotonía central (n = 11). Tres neurólogos pediátricos evaluaron de forma independiente el comportamiento motor grabado en video en cuanto a las características fenotípica y cuantitativa (utilizando la Escala de evaluación y calificación de la ataxia [SARA]). Determinamos: (1) coincidencia fenotípica entre los observadores y homogeneidad fenotípica (porcentaje de fenotipos con consenso total de los tres observadores según el diagnóstico subyacente), (2) perfiles de (sub)puntajes en el SARA y (3) el efecto sobre el consenso fenotípico de tres características de EOA validadas científicamente. RESULTADOS: La homogeneidad fenotípica ocurrió en 8 de 11, 2 de 10 y 1 de 11 pacientes con EOA, DCD e hipotonía central, respectivamente. La discriminación fenotípica homogénea de EOA con respecto a TDC e hipotonía central se produjo en 16 de 21 y 22 de 22 pacientes, respectivamente. Los fenotipos EOA y TDC que no fueron discriminados de manera homogénea por los observadores (5 de 21) revelaron superposición en los puntajes del SARA con diferentes perfiles en los subpuntajes del SARA. Después de una reevaluación fenotípica con características EOA científicamente validadas, la homogeneidad fenotípica cambió de 16 a 18 pacientes. INTERPRETACIÓN: En contraste con la distinción completa entre EOA e hipotonía central, el fenotipo motor pediátrico no distinguió confiablemente entre EOA y TDC. La evaluación en base a características EOA científicamente validadas podría contribuir a un mayor consenso fenotípico.

FENÓTIPOS MOTORES PEDIÁTRICOS NA ATAXIA DE INÍCIO PRECOCE, TRANSTORNO DO DESENVOLVIMENTO DA COORDENACÃO, E HIPOTONIA CENTRAL: OBJETIVOS: Investigar a acurácia do reconhecimento fenotípico da ataxia de início precoce (AIP) entre condições desenvolvimentais, incluindo o transtorno do desenvolvimento da coordenação (TDC) e a hipotonia de origem no sistema nervoso central, e o efeito de aspectos cientificamente validados da AIP na modificação do consenso fenotípico. MÉTODO: Incluímos 32 crianças (4-17a) diagnosticadas com AIP (n=11), TDC (n=10), e hipotonia central (n=11). Três neurologistas pediátricos avaliaram de maneira independente por meio de vídeo o comportamento motor tanto por meio do fenótiopo quanto quantitativamente (usando a Escala para Avaliação e Pontuação da Ataxia) [EAPA]). Determinamos: (1) a concordânica fenotípica inter-observadores e a homogeneidade fenotípica (porcentagem de fenótipos com consenso completo pelos três observadores de acordo com o diagnóstico de base, (2) perfis segundo os (sub)escores da EAPA, e (3) o efeito de três aspectos cientificamente validados da AIP sobre o consenso fenotípico. RESULTADOS: A homogeneidade fenotípica ocorreu em 8 entre 12, 2 entre 10, e 1 entre 11 pacientes com AIP, TDC, e hipotonia central, respectivamente. A discriminação fenotípica homogênea da AIP com relação ao TDC e hipotonia central ocorreu em 16 entre 21 e 21 entre 22 pacientes, respectivamente. A discriminação não homogêna dos fenótipos AIP e TDC (5 em 21) revelou escores da EAPA que sobrepõem com diferentes perfis de subescores da EAPA. Após reavaliação fenotípica com aspectos cientificamente validados da AIP, a homogeneidade fenotípica mudou de 16 para 18 pacientes. INTERPRETAÇÃO: Em contraste com a completa distinção entre AIP e hipotonia central, o fenótipo motor pediátrico não distinguiu confiavelmente entre AIP e TDC. A reavaliação com aspectos cientificamente valiaddos da AIP pode contribuir para um maior consenso fenotípica. contrast to complete distinction between EOA and central hypotonia, the paediatric motor phenotype did not reliably distinguish between EOA and DCD. eassessment with scientifically validated EOA features could contribute to a higher phenotypic consensus.

Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction.

PIK3C2A is a class II member of the phosphoinositide 3-kinase (PI3K) family that catalyzes the phosphorylation of phosphatidylinositol (PI) into PI(3)P and the phosphorylation of PI(4)P into PI(3,4)P2. At the cellular level, PIK3C2A is critical for the formation of cilia and for receptor mediated endocytosis, among other biological functions. We identified homozygous loss-of-function mutations in PIK3C2A in children from three independent consanguineous families with short stature, coarse facial features, cataracts with secondary glaucoma, multiple skeletal abnormalities, neurological manifestations, among other findings. Cellular studies of patient-derived fibroblasts found that they lacked PIK3C2A protein, had impaired cilia formation and function, and demonstrated reduced proliferative capacity. Collectively, the genetic and molecular data implicate mutations in PIK3C2A in a new Mendelian disorder of PI metabolism, thereby shedding light on the critical role of a class II PI3K in growth, vision, skeletal formation and neurological development. In particular, the considerable phenotypic overlap, yet distinct features, between this syndrome and Lowe's syndrome, which is caused by mutations in the PI-5-phosphatase OCRL, highlight the key role of PI metabolizing enzymes in specific developmental processes and demonstrate the unique non-redundant functions of each enzyme. This discovery expands what is known about disorders of PI metabolism and helps unravel the role of PIK3C2A and class II PI3Ks in health and disease.

The neurological phenotype of developmental motor patterns during early childhood.

INTRODUCTION: During early childhood, typical human motor behavior reveals a gradual transition from automatic motor patterns to acquired motor skills, by the continuous interplay between nature and nurture. During the wiring and shaping of the underlying motor networks, insight into the neurological phenotype of developmental motor patterns is incomplete. In healthy, typically developing children (0-3 years of age), we therefore aimed to investigate the neurological phenotype of developmental motor patterns. METHODS: In 32 healthy, typically developing children (0-3 years), we video-recorded spontaneous motor behavior, general movements (GMs), and standardized motor tasks. We classified the motor patterns by: (a) the traditional neurodevelopmental approach, by Gestalt perception and (b) the classical neurological approach, by the clinical phenotypic determination of movement disorder features. We associated outcomes by Cramer's V. RESULTS: Developmental motor patterns revealed (a) choreatic-like features (≤3 months; associated with fidgety GMs (r = 0.732) and startles (r = 0.687)), (b) myoclonic-like features (≤3 months; associated with fidgety GMs (r = 0.878) and startles (r = 0.808)), (c) dystonic-like features (0-3 years; associated with asymmetrical tonic neck reflex (r = 0.641) and voluntary movements (r = 0.517)), and (d) ataxic-like features (>3 months; associated with voluntary movements (r = 0.928)). CONCLUSIONS: In healthy infants and toddlers (0-3 years), typical developmental motor patterns reveal choreatic-, myoclonic-, dystonic- and ataxic-like features. The transient character of these neurological phenotypes is placed in perspective of the physiological shaping of the underlying motor centers. Neurological phenotypic insight into developmental motor patterns can contribute to adequate discrimination between ontogenetic and initiating pathological movement features and to adequate interpretation of therapeutic interactions.

Distinguishing Patients With a Coordination Disorder From Healthy Controls Using Local Features of Movement Trajectories During the Finger-to-Nose Test.

Assessment of coordination disorders is valuable for monitoring progression of patients, distinguishing healthy and pathological conditions, and ultimately aiding in clinical decision making, thereby offering the possibility to improve medical care or rehabilitation. A common method to assess movement disorders is by using clinical rating scales. However, rating scales depend on the evaluation and interpretation of an observer, implying that subjective phenotypic assignment precedes the application of the scales. Objective and more accurate methods are under continuous development but gold standards are still scarce. Here, we show how a method we previously developed, originally aimed at assessing dynamic balance by a probabilistic generalized linear model, can be used to assess a broader range of functional movements. In this paper, the method is applied to distinguish patients with coordination disorders from healthy controls. We focused on movements recorded during the finger-to-nose task (FNT), which is commonly used to assess coordination disorders. We also compared clinical FNT scores and model scores. Our method achieved 84% classification accuracy in distinguishing patients and healthy participants, using only two features. Future work could entail testing the reliability of the method by using additional features and other clinical tests such as finger chasing, quiet standing, and/or usage of tracking devices such as depth cameras or force plates.

Motor and non-motor determinants of health-related quality of life in young dystonia patients.

OBJECTIVES: To systematically investigate the relationship between motor and non-motor symptoms, and health-related quality of life (HR-QoL) in children and young adults with dystonia. METHODS: In this prospective observational cross-sectional study, 60 patients (6-25 years) with childhood-onset dystonia underwent a multidisciplinary assessment of dystonia severity (Burke-Fahn-Marsden Dystonia Rating Scale, Global Clinical Impression), motor function (Gross Motor Function Measure, Melbourne Assessment of Unilateral Upper Limb Function), pain (visual analogue scale), intelligence (Wechsler Intelligence Scale), executive functioning (Behavior Rating Inventory of Executive Function) and anxiety/depression (Child/Adult Behavior Checklist). Measures were analyzed using a principal component analysis and subsequent multiple regression to evaluate which components were associated with HR-QoL (Pediatric Quality of life Inventory) for total group, and non-lesional (primary) and lesional (secondary) subgroups. RESULTS: Patients (29 non-lesional, 31 lesional dystonia) had a mean age of 13.6 ±â€¯5.9 years. The principal component analysis revealed three components: 1) motor symptoms; 2) psychiatric and behavioral symptoms; and 3) pain. HR-QoL was associated with motor symptoms and psychiatric and behavioral symptoms (R2 = 0.66) for the total sample and lesional dystonia, but in the non-lesional dystonia subgroup only with psychiatric and behavioral symptoms (R2 = 0.51). CONCLUSIONS: Non-motor symptoms are important for HR-QoL in childhood-onset dystonia. We suggest a multidisciplinary assessment of motor and non-motor symptoms to optimize individual patient management.

Scales for the clinical evaluation of cerebellar disorders.

Clinical scales represent an important tool not only for the initial grading/scoring of disease and assessment of progression, but also for the quantification of therapeutic effects in clinical trials. There are several scales available for the clinical evaluation of cerebellar symptoms. While some scales have been developed and evaluated for specific cerebellar disorders such as Friedreich ataxia, others reliably capture cerebellar symptoms with no respect to the underlying etiology. Each scale has its strengths and weaknesses. Extensive scales are certainly useful for thorough documentation of specific features of certain phenotypes, but this gain of information is not always essential for the purpose of a study. Therefore, compact and manageable scales like the Scale for the Assessment and Rating of Ataxia (SARA) or Brief Ataxia Rating Scale (BARS) are often preferred compared to more complex scales in observational and therapeutic studies.