Diagnostic yield of chromosomal microarray and trio whole exome sequencing in cryptogenic cerebral palsy.

OBJECTIVE: To determine the yield of genetic diagnoses using chromosomal microarray (CMA) and trio whole exome sequencing (WES), separately and combined, among patients with cryptogenic cerebral palsy (CP). METHODS: Trio WES of patients with prior CMA analysis for cryptogenic CP, defined as disabling, non-progressive motor symptoms beginning before the age of 3 years without known cause. RESULTS: Given both CMA analysis and trio WES, clinically significant genetic findings were identified for 58% of patients (26 of 45). Diagnoses were eight large CNVs detected by CMA and 18 point mutations detected by trio WES. None had more than one severe mutation. Approximately half of events (14 of 26) were de novo. Yield was significantly higher in patients with CP with comorbidities (69%, 22 of 32) than in those with pure motor CP (31%, 4 of 13; p=0.02). Among patients with genetic diagnoses, CNVs were more frequent than point mutations among patients with congenital anomalies (OR 7.8, 95% CI 1.2 to 52.4) or major dysmorphic features (OR 10.5, 95% CI 1.4 to 73.7). Clinically significant mutations were identified in 18 different genes: 14 with known involvement in CP-related disorders and 4 responsible for other neurodevelopmental conditions. Three possible new candidate genes for CP were ARGEF10, RTF1 and TAOK3. CONCLUSIONS: Cryptogenic CP is genetically highly heterogeneous. Genomic analysis has a high yield and is warranted in all these patients. Trio WES has higher yield than CMA, except in patients with congenital anomalies or major dysmorphic features, but these methods are complementary. Patients with negative results with one approach should also be tested by the other.

Prevalence of cerebral palsy with Gross Motor Function Classification System levels IV and V in children in Israel: a cross-cultural comparison.

PURPOSE: Cerebral palsy is the most common physical disability in childhood. Our aim was to study the prevalence of wheelchair-dependent cerebral palsy (equivalent to gross motor function classification system level IV/V) among Jewish and Arab children in Israel and to investigate differences between the children of the two population groups. METHODS: Children diagnosed with cerebral palsy born in the years 2005-2006 were located through the Israel National Insurance Institute database. Demographic and clinical data were retrieved from children's records. RESULTS: Overall prevalence in Israel was 0.8 (0.7-0.9) per 1000 live births. The prevalence was significantly higher among Arabs (1.2:1000) than Jews (0.6:1000; OR = 1.6, 95% CI 1.2-2.1, p = 0.001) and was highest among Arabs in the South (Bedouins) (2.8:1000). Consanguinity among parents and low socioeconomic status were significantly more common among Arab children with wheelchair- dependent cerebral palsy compared with Jews. Higher rates of children with cerebral palsy following term pregnancy were found in Arabs. Extreme preterm births, very low birth weight, and emergent cesarean section were more common among Jews compared with Arabs. CONCLUSIONS: This study revealed population group differences of cerebral palsy with Gross Motor Function Classification System levels IV and V. Higher rates of cerebral palsy, especially following term pregnancy in the Arab population, may be attributed to consanguinity and genetic factors. There is a need to tailor services to underserved population based on etiology: preterm births and genetic causes for the Jewish and Arab populations, respectively.

Multiple Causes of Pediatric Early Onset Chorea-Clinical and Genetic Approach.

OBJECTIVE: This article elucidates a clinical and genetic approach to pediatric early-onset chorea in patients with normal neuroimaging. METHODS: We retrospectively studied patients with onset hyperkinetic movement disorders. Only children with onset of chorea in the first 3 years of life were included, those with an abnormal magnetic resonance imaging (MRI) or electroencephalogram (EEG) were excluded.We studied the movement disorder phenotype by clinical examination and by interpretation of videos and compared our data to the literature. RESULTS: Four patients, aged 2 to 13 years, were diagnosed. Abnormal involuntary movements appeared between the ages of 6 months to 3 years in association with developmental delay. One patient has a close relative with NKX2.1-related chorea. One patient is from Iraqi-Jewish origin. Facial twitches and nocturnal dyskinetic attacks were observed in one.The unique clinical presentation and family history enabled genetic diagnosis by molecular analysis of a specific mutation in two (NKX2.1, OPA3) and Sanger sequencing of a target gene in one (ADCY5). One patient was diagnosed by whole-exome sequencing (WES) (GNAO1). CONCLUSION: By carefully recording the phenotype and genetic background, a single gene can be suspected in some cases. In the rest, we suggest multigene panels or WES study.

[TELENEUROLOGY CLINIC - HIGH COMPLIANCE AND ADHERENCE].

BACKGROUND: Telemedicine carries the potential of providing healthcare for individuals with limited access to clinics. While in some subspecialties telemedicine has been proved to be effective, its efficacy for replacing standard visits in complex subspecialties, such as pediatric neurology, has not been studied. OBJECTIVES: To determine compliance and adherence to follow-up and medication prescription for online pediatric neurology clinics. METHODS: We reviewed clinical records for follow-up and prescription requests of medication prescribed for children visiting the Maccabi Online Neuropediatric clinic in Ariel. RESULTS: A total of 78 children (aged 10.9±3.2 years; 40 girls, 38 boys) visited the online neuropediatric clinic between October 2015 and November 2017; 78 first visits, 44 follow-up visits. The first visit lasted 50 minutes including technical time. The main diagnoses were ADD/ADHD (41/78, 53%), followed by behavioral/emotional issues (11/78, 14%), headaches/migraines (9/78, 12%), learning disabilities (8/78, 10%) epilepsy (4/78, 5%) and others (5/78, 6%). Follow-up was recommended in most cases (48/78, 62%) mainly for ADD/ADHD and headaches/migraines. Most patients complied with follow-up (55%) with better rates among ADD/ADHD (19/29, 66%). Only a few patients (3/78,4%) continued follow-up in a regular clinic. Medication was recommended for 29/41 (71%) children with ADD/ADHD; all of whom requested medication prescription from the pediatrician (as it could not be prescribed digitally). Adherence was high as most patients (24/29, 83%) continued to request medication prescription. CONCLUSIONS: While adherence and compliance rates are high in tele-neurology clinics, especially for ADHD, further controlled studies are needed to compare services to regular visits and to assess the additional benefits of specialists healthcare delivery to underserved populations.

Pre-hospital stroke monitoring past, present, and future: a perspective.

Integrated brain-machine interface signifies a transformative advancement in neurological monitoring and intervention modalities for events such as stroke, the leading cause of disability. Historically, stroke management relied on clinical evaluation and imaging. While today's stroke landscape integrates artificial intelligence for proactive clinical decision-making, mainly in imaging and stroke detection, it depends on clinical observation for early detection. Cardiovascular monitoring and detection systems, which have become standard throughout healthcare and wellness settings, provide a model for future cerebrovascular monitoring and detection. This commentary reviews the progression of continuous stroke monitoring, spotlighting contemporary innovations and prospective avenues, and emphasizes the influential roles of cutting-edge technologies in shaping stroke care.

Antibodies to surface dopamine-2 receptor in autoimmune movement and psychiatric disorders.

Recent reports of autoantibodies that bind to neuronal surface receptors or synaptic proteins have defined treatable forms of autoimmune encephalitis. Despite these developments, many cases of encephalitis remain unexplained. We have previously described a basal ganglia encephalitis with dominant movement and psychiatric disease, and proposed an autoimmune aetiology. Given the role of dopamine and dopamine receptors in the control of movement and behaviour, we hypothesized that patients with basal ganglia encephalitis and other putative autoimmune basal ganglia disorders harboured serum autoantibodies against important dopamine surface proteins. Basal ganglia encephalitis sera immunolabelled live surface cultured neurons that have high expression of dopamine surface proteins. To detect autoantibodies, we performed flow cytometry cell-based assays using human embryonic kidney cells to express surface antigens. Twelve of 17 children (aged 0.4-15 years, nine males) with basal ganglia encephalitis had elevated immunoglobulin G to extracellular dopamine-2 receptor, compared with 0/67 controls. Immunofluorescence on wild-type mouse brain showed that basal ganglia encephalitis sera immunolabelled microtubule-associated protein 2-positive neurons in striatum and also in cultured striatal neurons, whereas the immunolabelling was significantly decreased in dopamine-2 receptor knock-out brains. Immunocytochemistry confirmed that immunoreactivity localized to the surface of dopamine-2 receptor-transfected cells. Immunoabsorption of basal ganglia encephalitis sera on dopamine-2 receptor-transfected human embryonic kidney cells decreased immunolabelling of dopamine-2 receptor-transfected human embryonic kidney cells, neurons and wild-type mouse brain. Using a similar flow cytometry cell-based assay, we found no elevated immunoglobulin G binding to dopamine 1, 3 or 5 receptor, dopamine transporter or N-methyl-d-aspartate receptor. The 12 dopamine-2 receptor antibody-positive patients with encephalitis had movement disorders characterized by parkinsonism, dystonia and chorea. In addition, the patients had psychiatric disturbance with emotional lability, attention deficit and psychosis. Brain magnetic resonance imaging showed lesions localized to the basal ganglia in 50% of the patients. Elevated dopamine-2 receptor immunoglobulin G was also found in 10/30 patients with Sydenham's chorea, 0/22 patients with paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection and 4/44 patients with Tourette's syndrome. No dopamine-1 receptor immunoglobulin G was detected in any disease or control groups. We conclude that assessment of dopamine-2 receptor antibodies can help define autoimmune movement and psychiatric disorders.

Clinical Phenotype in Individuals With Birk-Landau-Perez Syndrome Associated With Biallelic SLC30A9 Pathogenic Variants.

BACKGROUND AND OBJECTIVES: Birk-Landau-Perez syndrome is a genetic disorder caused by biallelic pathogenic variants in SLC30A9 presenting with a complex movement disorder, developmental regression, oculomotor abnormalities, and renal impairment. It has previously been reported in 2 families. We describe the clinical phenotype of 8 further individuals from 4 unrelated families with SLC30A9-related disease. METHOD: Following detailed clinical phenotyping, 1 family underwent research whole-genome sequencing (WGS), 1 research whole-exome sequencing, and 2 diagnostic WGS. Variants of interest were assessed for pathogenicity using in silico prediction tools, homology modeling, and, where relevant, sequencing of complementary DNA (cDNA) for splicing effect. RESULTS: In 2 unrelated families of Pakistani origin (1 consanguineous and 1 not), the same homozygous missense variant in SLC30A9 (c.1253G>T, p.Gly418Val) was identified. Family 1 included 2 affected brothers, and family 2 one affected boy. In family 3, also consanguineous, there were 4 affected siblings homozygous for the variant c.1049delCAG, pAla350del. The fourth family was nonconsanguineous: the 1 affected individual was compound heterozygous for c.1083dup, p.Val362Cysfs*5, and c.1413A>G, p.Ser471=. Despite phenotypic variability between the 4 families, all affected patients manifested with a progressive hyperkinetic movement disorder, associated with oculomotor apraxia and ptosis. None had evidence of severe renal impairment. For the novel missense variant, the conformation of the loop domain and packing of transmembrane helices are likely to be disrupted based on structure modeling. Its presence in 2 unrelated Pakistani families suggests a possible founder variant. For the synonymous variant p.Ser471=, an effect on splicing was confirmed through cDNA analysis. DISCUSSION: Pathogenic variants in SLC30A9 cause a progressive autosomal recessive neurologic syndrome associated with a complex hyperkinetic movement disorder. Our report highlights the expanding disease phenotype, which can present with a wider spectrum of severity than has previously been recognized.

Transitional Care for Young People with Movement Disorders: Consensus-Based Recommendations from the MDS Task Force on Pediatrics.

Background: The International Parkinson and Movement Disorders Society (MDS) set up a working group on pediatric movement disorders (MDS Task Force on Pediatrics) to generate recommendations to guide the transition process from pediatrics to adult health care systems in patients with childhood-onset movement disorders. Methods: To develop recommendations for transitional care for childhood onset movement disorders, we used a formal consensus development process, using a multi-round, web-based Delphi survey. The Delphi survey was based on the results of the scoping review of the literature and the results of a survey of MDS members on transition practices. Through iterative discussions, we generated the recommendations included in the survey. The MDS Task Force on Pediatrics were the voting members for the Delphi survey. The task force members comprise 23 child and adult neurologists with expertise in the field of movement disorders and from all regions of the world. Results: Fifteen recommendations divided across four different areas were made pertaining to: (1) team composition and structure, (2) planning and readiness, (3) goals of care, and (4) administration and research. All recommendations achieved consensus with a median score of 7 or greater. Conclusion: Recommendations on providing transitional care for patients with childhood onset movement disorders are provided. Nevertheless several challenges remain in the implementation of these recommendations, related to health infrastructure and the distribution of health resources, and the availability of knowledgeable and interested practitioners. Research on the influence of transitional care programs on outcomes in childhood onset movement disorders is much needed.

Cognitive and psychiatric phenotypes of movement disorders in children: a systematic review.

AIM: The cognitive and psychiatric aspects of adult movement disorders are well established, but specific behavioural profiles for paediatric movement disorders have not been delineated. Knowledge of non-motor phenotypes may guide treatment and determine which symptoms are suggestive of a specific movement disorder and which indicate medication effects. METHOD: The goal of this review is to outline the known cognitive and psychiatric symptoms associated with paediatric movement disorders. We used a systematic approach, via PubMed, and reviewed over 400 abstracts of studies of selected disorders, of which 88 papers reporting paediatric non-motor symptoms are summarized. RESULTS: Obsessive-compulsive disorder was manifest in children with paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections and Sydenham chorea. Children with opsoclonus-myoclonus syndrome had, for the most part, cognitive and behavioural problems, and attention-deficit-hyperactivity disorder was reported as a major comorbidity in Tourette syndrome, stereotypies, and restless legs syndrome. Symptoms of depression and anxiety were more frequent in individuals with idiopathic dystonia. Affective disorders were suggestive of Wilson disease. Cognitive decline was common in children with juvenile Huntington disease. A limitation of this review was the lack of systematic assessment in paediatric movement disorders for evaluation and uniform definitions. INTERPRETATION: Although the literature in non-motor phenomena is still emerging, recognition of salient cognitive and psychiatric phenomena may facilitate management of paediatric movement disorders.

Definition and classification of hyperkinetic movements in childhood.

Hyperkinetic movements are unwanted or excess movements that are frequently seen in children with neurologic disorders. They are an important clinical finding with significant implications for diagnosis and treatment. However, the lack of agreement on standard terminology and definitions interferes with clinical treatment and research. We describe definitions of dystonia, chorea, athetosis, myoclonus, tremor, tics, and stereotypies that arose from a consensus meeting in June 2008 of specialists from different clinical and basic science fields. Dystonia is a movement disorder in which involuntary sustained or intermittent muscle contractions cause twisting and repetitive movements, abnormal postures, or both. Chorea is an ongoing random-appearing sequence of one or more discrete involuntary movements or movement fragments. Athetosis is a slow, continuous, involuntary writhing movement that prevents maintenance of a stable posture. Myoclonus is a sequence of repeated, often nonrhythmic, brief shock-like jerks due to sudden involuntary contraction or relaxation of one or more muscles. Tremor is a rhythmic back-and-forth or oscillating involuntary movement about a joint axis. Tics are repeated, individually recognizable, intermittent movements or movement fragments that are almost always briefly suppressible and are usually associated with awareness of an urge to perform the movement. Stereotypies are repetitive, simple movements that can be voluntarily suppressed. We provide recommended techniques for clinical examination and suggestions for differentiating between the different types of hyperkinetic movements, noting that there may be overlap between conditions. These definitions and the diagnostic recommendations are intended to be reliable and useful for clinical practice, communication between clinicians and researchers, and for the design of quantitative tests that will guide and assess the outcome of future clinical trials.

Accelerating Telemedicine for Cerebral Palsy During the COVID-19 Pandemic and Beyond.

The effects of COVID-19 extend beyond the pandemic and are expected to transform healthcare in various ways, many of which remain unknown. With social distancing, telemedicine may become the preferred communication channel between caregivers and patients. Implications for cerebral palsy (CP) children are that this will pose a challenge within this transformation. CP, as a discreet entity, is not considered a risk factor. However, specific comorbidities in individuals with CP, such as chronic lung disease, are known as COVID-19 risk factors. The overall risk for the CP population is probably a factor of age and comorbidities. Staying at home for CP children is both a challenge and an opportunity. Escalation of behavioral conflicts or improved participation and equality within the household may emerge. Interestingly, restricted mobility for the general population narrows existing gaps of ambulation. Telemedicine is the primary way of providing services for chronic conditions during the pandemic and is expected to expand beyond pre-Coronavirus era use. The advantages of telemedicine vary, more so during pandemic times, according to severity, restrictions, and availably of telemedicine. A multidisciplinary therapeutic presence is more accessible with telemedicine, bringing together various specialties and approaches to the child's natural environment. Accessible, continuous care is expected to lower comorbidities, as demonstrated for other chronic conditions. Enhanced monitoring is crucial for younger children as devastating complications, such as hip dysplasia, could be minimized. Last but not least, we will discuss digital health care as an accelerator for participatory medicine, including networked patients and families, as responsible drivers of their health as full partners.

Telemedicine for Hyperkinetic Movement Disorders.

Telemedicine is the use of electronic communication technology to facilitate healthcare between distant providers and patients. In addition to synchronous video conferencing, asynchronous video transfer has been used to support care for neurology patients. There is a growing literature on using telemedicine in movement disorders, with the most common focus on Parkinson's disease. There is accumulating evidence for videoconferencing to diagnose and treat patients with hyperkinetic movement disorders and to support providers in remote underserviced areas. Cognitive testing has been shown to be feasible remotely. Genetic counseling and other counseling-based therapeutic interventions have also successfully performed in hyperkinetic movement disorders. We use a problem-based approach to review the current evidence for the use of telemedicine in various hyperkinetic movement disorders. This Viewpoint attempts to identify possible telemedicine solutions as well as discussing unmet needs and future directions.

Effort Allocation in Children With ADHD: Abnormal Decision-Making or Poor Execution?

Objective: Effort allocation is a multi-faceted process driving both the decision to choose a high effort-high reward alternative over a low effort-low reward alternative, and the execution of this decision by recruiting sufficient effort. The objectives of our study were to examine whether children with ADHD would (a) show different reward-effort cost trade-off, and (b) have difficulty executing their decision. Method: 50 children, aged 9 to 15, with and without ADHD, had to choose between high effort-high reward and low effort-low reward alternatives using a handheld dynamometer and to execute their choice. Results: Children with ADHD and controls made similar number of high-effort choices (p = .806). However, children with ADHD executed their high-effort choices less frequently compared with controls (p = .029). Conclusion: These findings suggest that children with ADHD are not characterized by different effort-reward trade-off but rather by difficulties in recruiting effort for their preferences implementation.

Genetic or Other Causation Should Not Change the Clinical Diagnosis of Cerebral Palsy.

High throughput sequencing is discovering many likely causative genetic variants in individuals with cerebral palsy. Some investigators have suggested that this changes the clinical diagnosis of cerebral palsy and that these individuals should be removed from this diagnostic category. Cerebral palsy is a neurodevelopmental disorder diagnosed on clinical signs, not etiology. All nonprogressive permanent disorders of movement and posture attributed to disturbances that occurred in the developing fetal and infant brain can be described as "cerebral palsy." This definition of cerebral palsy should not be changed, whatever the cause. Reasons include stability, utility and accuracy of cerebral palsy registers, direct access to services, financial and social support specifically offered to families with cerebral palsy, and community understanding of the clinical diagnosis. Other neurodevelopmental disorders, for example, epilepsy, have not changed the diagnosis when genomic causes are found. The clinical diagnosis of cerebral palsy should remain, should prompt appropriate genetic studies and can subsequently be subclassified by etiology.

Intrathecal Baclofen Therapy-Practical Approach: Clinical Benefits and Complication Management.

Intrathecal baclofen is an expanding accepted treatment for children with cerebral palsy and other causes of spasticity and dystonia. The aims of this review are therefore to (1) delineate the clinical benefits of intrathecal baclofen therapy in pediatric spasticity and dystonia and (2) increase awareness of the potential complications and emergency management measures of intrathecal baclofen therapy. A current literature review demonstrates the benefits and complications of this minimally invasive device. Practical guides for recognizing acute conditions and management recommendations are included. Intrathecal baclofen is increasingly being used to help individuals attain realistic functional goals. Therefore, families and health care professionals should be aware of potential complications, symptoms, and emergency management.

Ganglioglioma, Epilepsy, and Intellectual Impairment due to Familial TSC1 Deletion.

BACKGROUND: Tuberous sclerosis complex (TSC) is a multisystem disorder diagnosed by clinical criteria and/or genetic testing. Genetic testing reveals atypical phenotypes that have not met clinical criteria, with practical implications. METHODS: We describe 4 family members with pathogenic partial deletion in TSC1 who individually did not meet tuberous sclerosis complex clinical criteria. RESULTS: Family members had different and atypical findings of tuberous sclerosis complex. Although none of the family members fulfilled the clinical criteria for tuberous sclerosis complex, they all carried the same genomic deletion (9q34.13q34.2) that included part of the TSC1 gene. One member had ganglioglioma and intractable seizures, one sibling presented with seizures, developmental delay, and displayed white matter abnormalities; another sibling had no clinical manifestations but has cortical tuber. Their mother has facial angiofibroma, cortical tuber, and seizures during infancy. CONCLUSIONS: Ganglioglioma may be a phenotypic expression of TSC1. Genetic testing is recommended for infants with brain tumors, especially those with an abnormal familial history.

Auditory stimulation improves motor function and caretaker burden in children with cerebral palsy- A randomized double blind study.

AIM: To investigate the impact of auditory stimulation on motor function in children with cerebral palsy (CP) and disabling hypertonia. METHOD: 9 matched pairs (age: 7y5m, SD 4y1m; 13 boys; gross-motor-functional-classification-scale: median 4; manual-ability-classification-system: median 4) were randomized to receive either auditory stimulation embedded in music (study, n = 9) or music alone (sham, control, n = 9) for at least 10 minutes 4 times a week for 4 weeks. Goal-Attainment-Scale, Care-and-Comfort-Hypertonicity-Questionnaire, Gross-Motor-Function-Measure and Quality-of-Upper-Extremity-Skills-Test (QUEST) were assessed before and 5 months following intervention. RESULT: Children receiving auditory stimulation attained more goals than children who listened to music alone (p = 0.002). Parents reported improved care and comfort in children in the study group compared to a slight deterioration in controls (p = 0.002). Upper extremity skills improved in the study group compared to controls (p = 0.006). Similar gross motor function changes were documented in both groups (p = 0.41). One participant reported increased seizure frequency; no other participants with epilepsy reported increased seizure frequency (n = 6/18) and no other adverse events were reported. INTERPRETATION: Auditory stimulation alleviated hypertonia and improved fine and gross motor functions.

Poor penmanship in children correlates with abnormal rhythmic tapping: a broad functional temporal impairment.

Timing is crucial for proficient motor tasks; temporal impairments may lead to dysfunctional motor activities. Although much research has been dedicated to the study of movement timing, clinical examination often overlooks temporal impairment of motor activity. The authors hypothesize that some children have a global temporal impairment leading to dysfunctional motor skills. This article checks whether temporal abnormalities detected on a simple tapping task correlate with temporal dysfunction during complex motor skills such as handwriting. Twenty-three school-aged children, 8-14 years (11.1 +/- 1.3 years), underwent tests to assess finger tapping and cursive handwriting. Handwriting samples were rated by experienced teachers. Children with abnormal tapping had lower handwriting rating scores. Temporal features were similar in both tasks; variability on the tapping test correlated with handwriting variability. Temporal variability was not significantly higher for children with poor penmanship as a whole but rather specific to the subgroup of children with a tapping abnormality. Poor penmanship could be attributed in certain children to global temporal impairment reflected as variable finger tapping and handwriting. Evaluation of dysfunctional motor performance should include temporal aspects, and further studies are needed to better delineate and address treatment of "dysrhythmia."

Clown-care reduces pain in children with cerebral palsy undergoing recurrent botulinum toxin injections- A quasi-randomized controlled crossover study.

OBJECTIVE: We investigated the impact of clown-care on pain in 45 children with cerebral palsy who underwent recurrent Botulinum-toxin injections (age 7.04± 4.68 years). Participants were randomized to receive either clown (n = 20) or standard (n = 25) -care. METHODS: Pain Visual-Analogue-Scale (range 1-5) was reported before and after procedures. Pain assessment was lower for children undergoing Botulinum-toxin injections with clown-care (2.89± 1.36) compared to standard-care (3.85± 1.39; p = 0.036) even though pain anticipated prior to procedures was similar (~3). FINDINGS: Children who underwent the first procedure with clown-care reported lower pain even after they crossed-over to the following procedure which was standard (p = 0.048). Carryover effect was more prominent in injection-naïve children (p = 0.019) and during multiple procedures (p = 0.009). Prior pain experience correlated with pain in subsequent procedures only when first experience was standard-care (p = 0.001). CONCLUSIONS: Clown-care alleviated pain sensation during Botulinum-toxin injections and initial clown-care experience reduced pain during subsequent injections even though clowns were not present. TRIAL REGISTRATION: clinicaltrials.gov ID # NCT01377883.

Spinocerebellar ataxia type 29 due to mutations in ITPR1: a case series and review of this emerging congenital ataxia.

BACKGROUND: Spinocerebellar ataxia type 29 (SCA29) is an autosomal dominant, non-progressive cerebellar ataxia characterized by infantile-onset hypotonia, gross motor delay and cognitive impairment. Affected individuals exhibit cerebellar dysfunction and often have cerebellar atrophy on neuroimaging. Recently, missense mutations in ITPR1 were determined to be responsible. RESULTS: Clinical information on 21 individuals from 15 unrelated families with ITPR1 mutations was retrospectively collected using standardized questionnaires, including 11 previously unreported singletons and 2 new patients from a previously reported family. We describe the genetic, clinical and neuroimaging features of these patients to further characterize the clinical features of this rare condition and assess for any genotype-phenotype correlation for this disorder. Our cohort consisted of 9 males and 12 females, with ages ranging from 28 months to 49 years. Disease course was non-progressive with infantile-onset hypotonia and delays in motor and speech development. Gait ataxia was present in all individuals and 10 (48%) were not ambulating independently between the ages of 3-12 years of age. Mild-to-moderate cognitive impairment was present in 17 individuals (85%). Cerebellar atrophy developed after initial symptom presentation in 13 individuals (72%) and was not associated with disease progression or worsening functional impairment. We identified 12 different mutations including 6 novel mutations; 10 mutations were missense (with 4 present in >1 individual), 1 a splice site mutation leading to an in-frame insertion and 1 an in-frame deletion. No specific genotype-phenotype correlations were observed within our cohort. CONCLUSIONS: Our findings document significant clinical heterogeneity between individuals with SCA29 in a large cohort of molecularly confirmed cases. Based on the retrospective observed clinical features and disease course, we provide recommendations for management. Further research into the natural history of SCA29 through prospective studies is an important next step in better understanding the condition.