A Novel Video-Based Methodology for Automated Classification of Dystonia and Choreoathetosis in Dyskinetic Cerebral Palsy During a Lower Extremity Task.

BACKGROUND: Movement disorders in children and adolescents with dyskinetic cerebral palsy (CP) are commonly assessed from video recordings, however scoring is time-consuming and expert knowledge is required for an appropriate assessment. OBJECTIVE: To explore a machine learning approach for automated classification of amplitude and duration of distal leg dystonia and choreoathetosis within short video sequences. METHODS: Available videos of a heel-toe tapping task were preprocessed to optimize key point extraction using markerless motion analysis. Postprocessed key point data were passed to a time series classification ensemble algorithm to classify dystonia and choreoathetosis duration and amplitude classes (scores 0, 1, 2, 3, and 4), respectively. As ground truth clinical scoring of dystonia and choreoathetosis by the Dyskinesia Impairment Scale was used. Multiclass performance metrics as well as metrics for summarized scores: absence (score 0) and presence (score 1-4) were determined. RESULTS: Thirty-three participants were included: 29 with dyskinetic CP and 4 typically developing, age 14 years:6 months ± 5 years:15 months. The multiclass accuracy results for dystonia were 77% for duration and 68% for amplitude; for choreoathetosis 30% for duration and 38% for amplitude. The metrics for score 0 versus score 1 to 4 revealed an accuracy of 81% for dystonia duration, 77% for dystonia amplitude, 53% for choreoathetosis duration and amplitude. CONCLUSIONS: This methodology study yielded encouraging results in distinguishing between presence and absence of dystonia, but not for choreoathetosis. A larger dataset is required for models to accurately represent distinct classes/scores. This study presents a novel methodology of automated assessment of movement disorders solely from video data.

A Novel Missense Variant in the NKX2-1 Homeodomain Prevents Transcriptional Rescue by TAZ.

Background: Brain-lung-thyroid syndrome (BLTS) is caused by NKX2-1 haploinsufficiency, resulting in chorea/choreoathetosis, respiratory problems, and hypothyroidism. Genes interacting with NKX2-1 mutants influence its phenotypic variability. We report a novel NKX2-1 missense variant and the modifier function of TAZ/WWTR1 in BLTS. Methods: A child with BLTS underwent next-generation sequencing panel testing for thyroid disorders. His family was genotyped for NKX2-1 variants and screened for germline mosaicism. Mutant NKX2-1 was generated, and transactivation assays were performed on three NKX2-1 target gene promoters. DNA binding capacity and protein-protein interaction were analyzed. Results: The patient had severe BLTS and carried a novel missense variant c.632A>G (p.N211S) in NKX2-1, which failed to bind to specific DNA promoters, reducing their transactivation. TAZ cotransfection did not significantly increase transcription of these genes, although the variant retained its ability to bind to TAZ. Conclusions: We identify a novel pathogenic NKX2-1 variant that causes severe BLTS and is inherited through germline mosaicism. The mutant lacks DNA-binding capacity, impairing transactivation and suggesting that NKX2-1 binding to DNA is essential for TAZ-mediated transcriptional rescue.

The relationship between manual ability, dystonia and choreoathetosis severity and upper limb movement patterns during reaching and grasping in children and young adults with dyskinetic cerebral palsy.

INTRODUCTION: Impaired upper limb movements are a key feature in dyskinetic cerebral palsy (CP). However, information on how specific movement patterns relate to manual ability, performance and underlying movement disorders is lacking. Insight in these associations may contribute to targeted upper limb management in dyskinetic CP. This study aimed to explore associations between deviant upper limb movement patterns and (1) manual ability, (2) severity of dystonia/choreoathetosis, and (3) movement time/trajectory deviation during reaching and grasping. PARTICIPANTS/METHODS: Participants underwent three-dimensional upper limb analysis during reaching forwards (RF), reaching sideways (RS) and reach-and-grasp vertical (RGV) as well as clinical assessment. Canonical correlation and regression analysis with statistical parametric mapping were used to explore associations between clinical/performance parameters and movement patterns (mean and variability). RESULTS: Thirty individuals with dyskinetic CP participated (mean age 16±5 y; 20 girls). Lower manual ability was related to higher variability in wrist flexion/extension during RF and RS early in the reaching cycle (p < 0.05). Higher dystonia severity was associated with higher mean wrist flexion (40-82 % of the reaching cycle; p = 0.004) and higher variability in wrist flexion/extension (31-75 %; p < 0.001) and deviation (2-14 %; p = 0.007/60-73 %; p = 0.006) during RF. Choreoathetosis severity was associated with higher elbow pro/supination variability (12-19 %; p = 0.009) during RGV. Trajectory deviation was associated with wrist and elbow movement variability (p < 0.05). CONCLUSION: Current novel analysis of upper limb movement patterns and respective timings allows to detect joint angles and periods in the movement cycle wherein associations with clinical parameters occur. These associations are not present at each joint level, nor during the full movement cycle. This knowledge should be considered for individualized treatment strategies.

Catching the Culprit: How Chorea May Signal an Inborn Error of Metabolism.

Background: Movement disorders, particularly chorea, are uncommon in inborn errors of metabolism, but their identification is essential for improved clinical outcomes. In this context, comprehensive descriptions of movement disorders are limited and primarily derived from single cases or small patient series, highlighting the need for increased awareness and additional research in this field. Methods: A systematic review was conducted using the MEDLINE database and GeneReviews. The search included studies on inborn errors of metabolism associated with chorea, athetosis, or ballismus. The review adhered to PRISMA guidelines. Results: The systematic review analyzed 76 studies out of 2350 records, encompassing the period from 1964 to 2022. Chorea was observed in 90.1% of the 173 patients, followed by athetosis in 5.7%. Various inborn errors of metabolism showed an association with chorea, with trace elements and metals being the most frequent. Cognitive and developmental abnormalities were common in the cohort. Frequent neurological features included seizures, dysarthria, and optic atrophy, whereas non-neurological features included, among others, facial dysmorphia and failure to thrive. Neuroimaging and biochemical testing played crucial roles in aiding diagnosis, revealing abnormal findings in 34.1% and 47.9% of patients, respectively. However, symptomatic treatment efficacy for movement disorders was limited. Discussion: This study emphasizes the complexities of chorea in inborn errors of metabolism. A systematic approach with red flags, biochemical testing, and neuroimaging is required for diagnosis. Collaboration between neurologists, geneticists, and metabolic specialists is crucial for improving early detection and individualized treatment. Utilizing genetic testing technologies and potential therapeutic avenues can aid in the improvement of patient outcomes.

Dystonic posturing with athetoid movements in stroke without thalamic lesion.

Complex hyperkinetic movement disorders are a rare complication of stroke, frequently involving posterolateral contralateral thalamic lesions. One of the proposed mechanisms for these presentations is proprioceptive impairment, hence not involving deregulation of the basal ganglia-thalamocortical circuits. We report a patient who presented with dystonic posturing and athetoid movements with onset 2 years after right frontoparietotemporal stroke. Brain MRI showed no thalamic lesion. Based on the phenomenology, a diagnosis of pseudochoreoathetosis was proposed. To our knowledge, this is the first case report of poststroke pseudochoreoathetosis without thalamic involvement.

A case of brain-lung-thyroid syndrome. / 脑-肺-ç”²çŠ¶è ºç»¼åˆå¾1例.

Brain-lung-thyroid syndrome is a rare autosomal dominant disorder. More than 100 cases have been reported worldwide, but few cases have been reported in China. In December 2018, a boy with brain-lung-thyroid syndrome, aged 3 years and 10 months, was admitted to Xiangya Hospital of Central South University due to repeated cough for more than 3 years. In infancy of the boy, psychomotor retardation, repeated cough, and hypothyroidism were found. Gene detection showed that there was c.927delc heterozygous variation in NKX2-1 gene (NM-001079668: exon3: c.927delC). The variation of this gene locus has not been reported in relevant literature so far, which indicates a new mutation. According to the above clinical manifestations and examination results, the boy was diagnosed as brain-lung-thyroid syndrome, which mainly characterized by nervous system disorders, accompanied by respiratory manifestations and hypothyroidism. The boy was treated with oral dopasehydrazine to relieve tremor and levothyroxine sodium tablets to relieve hypothyroidism. Anti-infection, atomization, rehabilitation training and other symptomatic supporting treatment were also administered. The boy's language and movement have improved, the thyroid hormone level is normal, and there are still repeated respiratory tract infections.

Spectrum of Movement Disorders Among Children With Subacute Sclerosing Panencephalitis: A Cross-Sectional Study.

Background: Subacute sclerosing panencephalitis is a progressive devastating condition due to persistence of mutant measles virus, affecting children and adolescents, characterised by myoclonus, seizures, and neuropsychiatric issues. Movement disorders apart from myoclonus are reportedly uncommon. We aimed to describe frequency and proportion of movement disorders among children with subacute sclerosing panencephalitis, hypothesizing that these occur more frequently than previously reported. Methods: In this cross-sectional study, we enrolled children with subacute sclerosing panencephalitis between 1 month and 18 years of age who fulfilled the diagnosis of subacute sclerosing panencephalitis as per modified Dyken criteria, and examined them for movement disorders. We also assessed their clinical profile and disease severity via Jabbour staging and modified Rankin Scale score. We compared demographic, clinical, and laboratory features of children with and without movement disorders. Results: We enrolled 50 children (36 males; 72%) (age range 1.5-14 years). Of these, 28 (56%) had movement disorders. Among movement disorders, the most frequent was myoclonus (92%), followed by ataxia (9; 18%), chorea-athetosis (7; 14%), dystonia (6; 12%), tremor (4; 8%), repetitive behavior (4; 8%), and parkinsonism (3; 6%). Movement disorders were the presenting feature of subacute sclerosing panencephalitis among 7 children. There were no significant differences in clinical or laboratory features among children with and without movement disorders. Conclusions: Movement disorders were frequent in subacute sclerosing panencephalitis. Hyperkinetic disorders were dominant. Dystonia and chorea-athetosis occurred more commonly among nonmyoclonus movement disorders. Movement disorders may manifest even in earlier stages of subacute sclerosing panencephalitis and may be the heralding feature. Recognition of these features is important to plan management and reduce morbidity.

A case of brain-lung-thyroid syndrome / 中南大学学报(医学版)

Brain-lung-thyroid syndrome is a rare autosomal dominant disorder. More than 100 cases have been reported worldwide, but few cases have been reported in China. In December 2018, a boy with brain-lung-thyroid syndrome, aged 3 years and 10 months, was admitted to Xiangya Hospital of Central South University due to repeated cough for more than 3 years. In infancy of the boy, psychomotor retardation, repeated cough, and hypothyroidism were found. Gene detection showed that there was c.927delc heterozygous variation in NKX2-1 gene (NM-001079668: exon3: c.927delC). The variation of this gene locus has not been reported in relevant literature so far, which indicates a new mutation. According to the above clinical manifestations and examination results, the boy was diagnosed as brain-lung-thyroid syndrome, which mainly characterized by nervous system disorders, accompanied by respiratory manifestations and hypothyroidism. The boy was treated with oral dopasehydrazine to relieve tremor and levothyroxine sodium tablets to relieve hypothyroidism. Anti-infection, atomization, rehabilitation training and other symptomatic supporting treatment were also administered. The boy's language and movement have improved, the thyroid hormone level is normal, and there are still repeated respiratory tract infections.

Crossed Choreoathetosis Caused by Unilateral Thalamic Hemorrhage.

In general, involuntary movements after stroke are due to a disturbance in the unilateral cortico-basal ganglia loop and appear contralateral to stroke lesions. Crossed involuntary movements after unilateral stroke are very rare. We observed a case of crossed involuntary movements in the left upper limb and right lower limb after a right thalamic hemorrhage expanded to the right subthalamic nucleus. We considered a possible three-step theory as the basis of crossed choreoathetosis. This case informs our better understanding of the cortico-basal ganglia loop and involuntary movements after stroke.

Improving the objectivity of the current World Para Swimming motor coordination test for swimmers with hypertonia, ataxia and athetosis using measures of movement smoothness, rhythm and accuracy.

The current protocol for classifying Para swimmers with hypertonia, ataxia and athetosis involves a physical assessment where the individual's ability to coordinate their limbs is scored by subjective clinical judgment. The lack of objective measurement renders the current test unsuitable for evidence-based classification. This study evaluated a revised version of the Para swimming assessment for motor coordination, incorporating practical, objective measures of movement smoothness, rhythm error and accuracy. Nineteen Para athletes with hypertonia and 19 non-disabled participants performed 30 s trials of bilateral alternating shoulder flexion-extension at 30 bpm and 120 bpm. Accelerometry was used to quantify movement smoothness; rhythm error and accuracy were obtained from video. Para athletes presented significantly less smooth movement and higher rhythm error than the non-disabled participants (p < 0.05). Random forest algorithm successfully classified 89% of participants with hypertonia during out-of-bag predictions. The most important predictors in classifying participants were movement smoothness at both movement speeds, and rhythm error at 120 bpm. Our results suggest objective measures of movement smoothness and rhythm error included in the current motor coordination test protocols can be used to infer impairment in Para swimmers with hypertonia. Further research is merited to establish the relationship of these measures with swimming performance.

Brain-lung-thyroid syndrome in a neonate with argininosuccinate lyase deficiency.

Argininosuccinate lyase (ASL) deficiency is a rare autosomal recessive urea cycle disorder. The severe neonatal-onset form is characterised by hyperammonaemia in the first days of life and manifests with a variety of severe symptoms. However, an index of suspicion for additional or alternative diagnoses must be maintained when the patient's presentation is out of keeping with expected manifestations and course. We present a case of a neonate with ASL deficiency and concomitant hypotonia, severe respiratory distress, pulmonary hypertension, systemic hypotension and congenital hypothyroidism. The patient was investigated and subsequently diagnosed with brain-lung-thyroid syndrome, caused by a mutation in the NKX2-1 gene.

[Brain-lung-thyroid syndrome in a newborn with deletion 14q12-q21.1]. / Síndrome cerebro-pulmón-tiroides en un recién nacido con deleción 14q12-q21.1.

INTRODUCTION: In newborns with respiratory failure and interstitial lung disease, it should be approached as chILD (Childhood Interstitial Lung Disease) syndrome to rule out alterations in surfactant metabolism and brain-lung-thyroid syndrome caused by pathogenic variants in the NKX2-1 gene. OBJECTIVE: To pre sent a newborn with chILD syndrome and a large deletion in chromosome 14q12-q21.1. CLINICAL CASE: Newborn patient with respiratory distress since birth, chILD syndrome, and hypothyroidism, in which brain-lung-thyroid syndrome was suspected. He also presented seizures, minor and ma jor abnormalities on physical examination. Microarray analysis revealed a 14.7 Mb deletion in the chromosome 14q12-q21.1, which includes the NKX2-1 gene. CONCLUSION: The brain-lung-thyroid syndrome should be considered in newborns with respiratory distress syndrome and diffuse lung disease (chILD syndrome), especially if they present hypotonia, choreoathetosis, or hypothyroidism. Diagnosis confirmation requires genetic analysis, even more, when there are other abnormalities not explained by the suspected syndrome.

Cluster analysis of impairment measures to inform an evidence-based classification structure in RaceRunning, a new World Para Athletics event for athletes with hypertonia, ataxia or athetosis.

RaceRunning enables athletes with limited or no walking ability to propel themselves independently using a three-wheeled frame that has a saddle, handle bars and a chest plate. For RaceRunning to be included as a para athletics event, an evidence-based classification system is required. This study assessed the impact of trunk control and lower limb impairment measures on RaceRunning performance and evaluated whether cluster analysis of these impairment measures produces a valid classification structure for RaceRunning. The Trunk Control Measurement Scale (TCMS), Selective Control Assessment of the Lower Extremity (SCALE), the Australian Spasticity Assessment Scale (ASAS), and knee extension were recorded for 26 RaceRunning athletes. Thirteen male and 13 female athletes aged 24 (SD = 7) years participated. All impairment measures were significantly correlated with performance (rho = 0.55-0.74). Using ASAS, SCALE, TCMS and knee extension as cluster variables in a two-step cluster analysis resulted in two clusters of athletes. Race speed and the impairment measures were significantly different between the clusters (p < 0.001). The findings of this study provide evidence for the utility of the selected impairment measures in an evidence-based classification system for RaceRunning athletes.

Characterization of the GABRB2-Associated Neurodevelopmental Disorders.

OBJECTIVE: We aimed to characterize the phenotypic spectrum and functional consequences associated with variants in the gene GABRB2, coding for the γ-aminobutyric acid type A (GABAA ) receptor subunit ß2. METHODS: We recruited and systematically evaluated 25 individuals with variants in GABRB2, 17 of whom are newly described and 8 previously reported with additional clinical data. Functional analysis was performed using a Xenopus laevis oocyte model system. RESULTS: Our cohort of 25 individuals from 22 families with variants in GABRB2 demonstrated a range of epilepsy phenotypes from genetic generalized epilepsy to developmental and epileptic encephalopathy. Fifty-eight percent of individuals had pharmacoresistant epilepsy; response to medications targeting the GABAergic pathway was inconsistent. Developmental disability (present in 84%) ranged from mild intellectual disability to severe global disability; movement disorders (present in 44%) included choreoathetosis, dystonia, and ataxia. Disease-associated variants cluster in the extracellular N-terminus and transmembrane domains 1-3, with more severe phenotypes seen in association with variants in transmembrane domains 1 and 2 and the allosteric binding site between transmembrane domains 2 and 3. Functional analysis of 4 variants in transmembrane domains 1 or 2 (p.Ile246Thr, p.Pro252Leu, p.Ile288Ser, p.Val282Ala) revealed strongly reduced amplitudes of GABA-evoked anionic currents. INTERPRETATION: GABRB2-related epilepsy ranges broadly in severity from genetic generalized epilepsy to developmental and epileptic encephalopathies. Developmental disability and movement disorder are key features. The phenotypic spectrum is comparable to other GABAA receptor-encoding genes. Phenotypic severity varies by protein domain. Experimental evidence supports loss of GABAergic inhibition as the mechanism underlying GABRB2-associated neurodevelopmental disorders. ANN NEUROL 2021;89:573-586.

Hypoxaemia and interstitial lung disease in an infant with hypothyroidism and hypotonia.

A 7-month-old-term male infant presented with cough, tachypnoea, hypoxaemia and post-tussive emesis. Clinical history was significant for respiratory failure and pulmonary hypertension in the neonatal period requiring assisted ventilation, congenital hypothyroidism, mild hypotonia, recurrent respiratory infections, hypoxaemia requiring supplemental oxygen and nasogastric tube feeds. Physical examination showed tachypnoea, coarse bilateral breath sounds and mild hypotonia. Chest radiograph revealed multifocal pulmonary opacities with coarse interstitial markings and right upper lobe atelectasis. Following antibiotic therapy for suspected aspiration pneumonia, chest CT scan was performed and showed multiple areas of pulmonary consolidation and scattered areas of bilateral ground-glass opacities. Genetic studies showed a large deletion of chromosome 14q13.1-14q21.1, encompassing the NK2 homeobox 1 (NKX2-1) gene consistent with a diagnosis of brain-thyroid-lung (BTL) syndrome. Our case highlights the importance of genetic studies to diagnose BTL syndrome in infants with hypothyroidism, hypotonia and lung disease.