A Network Imaging Biomarker of X-Linked Dystonia-Parkinsonism.

OBJECTIVE: The purpose of this study was to characterize a metabolic brain network associated with X-linked dystonia-parkinsonism (XDP). METHODS: Thirty right-handed Filipino men with XDP (age = 44.4 ± 8.5 years) and 30 XDP-causing mutation negative healthy men from the same population (age = 37.4 ± 10.5 years) underwent [18 F]-fluorodeoxyglucose positron emission tomography. Scans were analyzed using spatial covariance mapping to identify a significant XDP-related metabolic pattern (XDPRP). Patients were rated clinically at the time of imaging according to the XDP-Movement Disorder Society of the Philippines (MDSP) scale. RESULTS: We identified a significant XDPRP topography from 15 randomly selected subjects with XDP and 15 control subjects. This pattern was characterized by bilateral metabolic reductions in caudate/putamen, frontal operculum, and cingulate cortex, with relative increases in the bilateral somatosensory cortex and cerebellar vermis. Age-corrected expression of XDPRP was significantly elevated (p < 0.0001) in XDP compared to controls in the derivation set and in the remaining 15 patients (testing set). We validated the XDPRP topography by identifying a similar pattern in the original testing set (r = 0.90, p < 0.0001; voxel-wise correlation between both patterns). Significant correlations between XDPRP expression and clinical ratings for parkinsonism-but not dystonia-were observed in both XDP groups. Further network analysis revealed abnormalities of information transfer through the XDPRP space, with loss of normal connectivity and gain of abnormal functional connections linking network nodes with outside brain regions. INTERPRETATION: XDP is associated with a characteristic metabolic network associated with abnormal functional connectivity among the basal ganglia, thalamus, motor regions, and cerebellum. Clinical signs may relate to faulty information transfer through the network to outside brain regions. ANN NEUROL 2023;94:684-695.

Advanced MRI techniques for transcranial high intensity focused ultrasound targeting.

Magnetic resonance guided high intensity focused ultrasound is a novel, non-invasive, image-guided procedure that is able to ablate intracranial tissue with submillimetre precision. It is currently FDA approved for essential tremor and tremor dominant Parkinson's disease. The aim of this update is to review the limitations of current landmark-based targeting techniques of the ventral intermediate nucleus and demonstrate the role of emerging imaging techniques that are relevant for both magnetic resonance guided high intensity focused ultrasound and deep brain stimulation. A significant limitation of standard MRI sequences is that the ventral intermediate nucleus, dentatorubrothalamic tract, and other deep brain nuclei cannot be clearly identified. This paper provides original, annotated images demarcating the ventral intermediate nucleus, dentatorubrothalamic tract, and other deep brain nuclei on advanced MRI sequences such as fast grey matter acquisition T1 inversion recovery, quantitative susceptibility mapping, susceptibility weighted imaging, and diffusion tensor imaging tractography. Additionally, the paper reviews clinical efficacy of targeting with these novel MRI techniques when compared to current established landmark-based targeting techniques. The paper has widespread applicability to both deep brain stimulation and magnetic resonance guided high intensity focused ultrasound.

De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability.

Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.

Missense variants in TAF1 and developmental phenotypes: challenges of determining pathogenicity.

We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability syndrome) (MIM# 300966) caused by pathogenic variants involving the X-linked gene TAF1, which participates in RNA polymerase II transcription. The initial study reported eleven families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into intellectual disability (ID) and/or autism spectrum disorder (ASD). We have now identified an additional 27 families through a genotype-first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modelling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology (HPO) terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of TAF1/MRXS33 intellectual disability syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for genes mapping to chromosome X. This article is protected by copyright. All rights reserved.

Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate-binding region.

OBJECTIVE: To characterize the phenotypic spectrum associated with GNAO1 variants and establish genotype-protein structure-phenotype relationships. METHODS: We evaluated the phenotypes of 14 patients with GNAO1 variants, analyzed their variants for potential pathogenicity, and mapped them, along with those in the literature, on a three-dimensional structural protein model. RESULTS: The 14 patients in our cohort, including one sibling pair, had 13 distinct, heterozygous GNAO1 variants classified as pathogenic or likely pathogenic. We attributed the same variant in two siblings to parental mosaicism. Patients initially presented with seizures beginning in the first 3 months of life (8/14), developmental delay (4/14), hypotonia (1/14), or movement disorder (1/14). All patients had hypotonia and developmental delay ranging from mild to severe. Nine had epilepsy, and nine had movement disorders, including dystonia, ataxia, chorea, and dyskinesia. The 13 GNAO1 variants in our patients are predicted to result in amino acid substitutions or deletions in the GNAO1 guanosine triphosphate (GTP)-binding region, analogous to those in previous publications. Patients with variants affecting amino acids 207-221 had only movement disorder and hypotonia. Patients with variants affecting the C-terminal region had the mildest phenotypes. SIGNIFICANCE: GNAO1 encephalopathy most frequently presents with seizures beginning in the first 3 months of life. Concurrent movement disorders are also a prominent feature in the spectrum of GNAO1 encephalopathy. All variants affected the GTP-binding domain of GNAO1, highlighting the importance of this region for G-protein signaling and neurodevelopment.

PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature.

BACKGROUND: De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia. OBJECTIVES: To delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations. METHODS: Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotype-phenotype correlations by analysis of both recurrent mutations as well as mutation classes. RESULTS: We report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes. CONCLUSION: We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity.

Deep brain stimulation for monogenic dystonia.

PURPOSE OF REVIEW: Deep brain stimulation (DBS) has recently emerged as an important management option in children with medically refractory dystonia. DBS is most commonly used, best studied, and thought to be most efficacious for a select group of childhood or adolescent onset monogenic dystonias (designated with a standard 'DYT' prefix). We review how to clinically recognize these types of dystonia and the relative efficacy of DBS for key monogenic dystonias. RECENT FINDINGS: Though used for dystonia in adults for several years, DBS has only lately been used in children. Recent evidence shows that patients with shorter duration of dystonia often experience greater benefit following DBS. This suggests that early recognition of the appropriate dystonic phenotypes and consideration of DBS in these patients may improve the management of dystonia. SUMMARY: DBS should be considered early in patients who have medically refractory dystonia, especially for the monogenic dystonias that have a high response rate to DBS. It is important to differentiate between these monogenic dystonias and dystonias of other causes to properly prognosticate for these patients and to determine whether DBS is an appropriate management option.

Emerging Subspecialties: Pediatric Movement Disorders Neurology.

Pediatric movement disorders (PMD) neurologists care for infants, children, and adolescents with conditions that disrupt typical movement; serving as important subspecialist child neurologists in both academic and private practice settings. In contrast to adult movement disorders neurologists whose "bread and butter" is hypokinetic Parkinson disease, PMD subspecialty practice is often dominated by hyperkinetic movement disorders including tics, dystonia, chorea, tremor, and myoclonus. PMD neurology practice intersects with a variety of subspecialties, including neonatology, developmental pediatrics, rehabilitation medicine, epilepsy, child & adolescent psychiatry, psychology, orthopedics, genetics & metabolism, and neurosurgery. Over the past several decades, significant advancements in the PMD field have included operationalizing definitions for distinct movement disorders, recognizing the spectrum of clinical phenotypes, expanding research on genetic and neuroimmunologic causes of movement disorders, and advancing available treatments. Subspecialty training in PMD provides trainees with advanced clinical, diagnostic, procedural, and management skills that reflect the complexities of contemporary practice. The child neurologist who is fascinated by the intricacies of child motor development, appreciates the power of observation skills coupled with a thoughtful physical examination, and is excited by the challenge of the unknown may be well-suited to a career as a PMD specialist.

Functional Neurological Disorder Among Sexual and Gender Minority People.

Sexual and gender minority (SGM) people can face unique stressors and structural discrimination that result in higher rates of neuropsychiatric symptoms, such as depression, anxiety, and suicidality. Although more rigorous studies are needed, emerging data suggest a possible higher prevalence of functional neurological disorder and other brain-mind-body conditions in SGM people. Representation and iterative feedback from affected community members is critical to the process of developing affirming environments. More research is needed to explore the relevance of functional neurologic disorder in SGM people within a biopsychosocial framework.

A Case Series of Transgender and Gender-Nonconforming Patients in a Pediatric Functional Neurologic Disorder Clinic.

Youth who identify as transgender and gender nonconforming (TGNC) are at increased risk of anxiety, depression, bullying, and loss of social and family support. These factors may increase the risk of developing functional neurologic disorder (FND). If the risk of FND is increased in TGNC youth, then identifying which youth are at increased risk, and the particular times when risk is increased, may allow for earlier diagnosis and treatment of FND. Better awareness of functional symptoms among clinicians who care for TGNC youth may prevent disruption of gender-affirming care if FND symptoms emerge. Patients diagnosed with FND who are TGNC may require different forms of intervention than other youth with FND. We present 4 cases from our multidisciplinary pediatric FND program of TGNC youth who developed FND. In all individuals for whom follow-up information was available, access to gender-affirming health care was associated with marked improvement or resolution of FND symptoms.

In humans, striato-pallido-thalamic projections are largely segregated by their origin in either the striosome-like or matrix-like compartments.

Cortico-striato-thalamo-cortical (CSTC) loops are fundamental organizing units in mammalian brains. CSTCs process limbic, associative, and sensorimotor information in largely separated but interacting networks. CTSC loops pass through paired striatal compartments, striosome (aka patch) and matrix, segregated pools of medium spiny projection neurons with distinct embryologic origins, cortical/subcortical structural connectivity, susceptibility to injury, and roles in behaviors and diseases. Similarly, striatal dopamine modulates activity in striosome and matrix in opposite directions. Routing CSTCs through one compartment may be an anatomical basis for regulating discrete functions. We used differential structural connectivity, identified through probabilistic diffusion tractography, to distinguish the striatal compartments (striosome-like and matrix-like voxels) in living humans. We then mapped compartment-specific projections and quantified structural connectivity between each striatal compartment, the globus pallidus interna (GPi), and 20 thalamic nuclei in 221 healthy adults. We found that striosome-originating and matrix-originating streamlines were segregated within the GPi: striosome-like connectivity was significantly more rostral, ventral, and medial. Striato-pallido-thalamic streamline bundles that were seeded from striosome-like and matrix-like voxels transited spatially distinct portions of the white matter. Matrix-like streamlines were 5.7-fold more likely to reach the GPi, replicating animal tract-tracing studies. Striosome-like connectivity dominated in six thalamic nuclei (anteroventral, central lateral, laterodorsal, lateral posterior, mediodorsal-medial, and medial geniculate). Matrix-like connectivity dominated in seven thalamic nuclei (centromedian, parafascicular, pulvinar-anterior, pulvinar-lateral, ventral lateral-anterior, ventral lateral-posterior, ventral posterolateral). Though we mapped all thalamic nuclei independently, functionally-related nuclei were matched for compartment-level bias. We validated these results with prior thalamostriate tract tracing studies in non-human primates and other species; where reliable data was available, all agreed with our measures of structural connectivity. Matrix-like connectivity was lateralized (left > right hemisphere) in 18 thalamic nuclei, independent of handedness, diffusion protocol, sex, or whether the nucleus was striosome-dominated or matrix-dominated. Compartment-specific biases in striato-pallido-thalamic structural connectivity suggest that routing CSTC loops through striosome-like or matrix-like voxels is a fundamental mechanism for organizing and regulating brain networks. Our MRI-based assessments of striato-thalamic connectivity in humans match and extend the results of prior tract tracing studies in animals. Compartment-level characterization may improve localization of human neuropathologies and improve neurosurgical targeting in the GPi and thalamus.

Cachexia, chorea, and pain in chronic nonbacterial osteitis and inflammatory bowel disease: a case report.

BACKGROUND: Inflammatory bowel disease is an inflammatory disorder that primarily impacts the gastrointestinal tract, leading to malnutrition and chronic microscopic intestinal blood loss. Uncontrolled systemic inflammation can impact other parts of the body, known as extraintestinal manifestations. Up to 25% of patients with inflammatory bowel disease are reported to have these complications in their skin, joints, bones, eyes, liver, lung, and pancreas (Rogler et al. in Gastroenterology 161(4):1118-1132, 2021). Neurologic involvement as extraintestinal manifestations are less common, reported at 3-19%, including neuropathies, demyelination, and cerebrovascular events (Morís in World J Gastroenterol. 20(5):1228-1237, 2014). CASE PRESENTATION: A 13-year-old Caucasian boy presented with 1 month of progressive lower-extremity pain, weakness, and weight loss. His physical examination was notable for cachexia, lower-extremity weakness, and chorea. Labs revealed normocytic anemia and systemic inflammation. Imaging revealed symmetric abnormal marrow signal in the pelvis and upper femurs. Pathologic examination of the bone revealed chronic inflammation consistent with chronic nonbacterial osteitis. Endoscopy revealed colonic inflammation consistent with inflammatory bowel disease. CONCLUSIONS: Children and adolescents with musculoskeletal pain lasting more than 2 weeks with systemic signs or symptoms like weight loss should prompt evaluation for systemic inflammatory disorders such as chronic nonbacterial osteitis, which can occur in isolation or associated with inflammatory bowel disease. This patient also had a nonspecific neurologic abnormality, chorea, which resolved with treatment of underlying inflammatory disorder. These extraintestinal manifestations may be concurrent with or precede intestinal inflammation, requiring a high index of suspicion when investigating nonspecific systemic inflammation.

Sustained activation in basal ganglia and cerebellum after repetitive movement in a non-task-specific dystonia.

We previously observed sustained fMRI BOLD signal in the basal ganglia in focal hand dystonia patients after a repetitive finger tapping task. Since this was observed in a task-specific dystonia, for which excessive task repetition may play a role in pathogenesis, in the current study we asked if this effect would be observed in a focal dystonia (cervical dystonia [CD]) that is not considered task-specific or thought to result from overuse. We evaluated fMRI BOLD signal time courses before, during, and after the finger tapping task in CD patients. We observed patient/control differences in post-tapping BOLD signal in left putamen and left cerebellum during the non-dominant (left) hand tapping condition, reflecting abnormally sustained BOLD signal in CD. BOLD signals in left putamen and cerebellum were also abnormally elevated in CD during tapping itself and escalated as tapping was repeated. There were no cerebellar differences in the previously studied FHD cohort, either during or after tapping. We conclude that some elements of pathogenesis and/or pathophysiology associated with motor task execution/repetition may not be limited to task-specific dystonias, but there may be regional differences in these effects across dystonias, associated with different types of motor control programs.

Chronic striatal cholinergic interneuron excitation induces clinically-relevant dystonic behavior in mice.

Dystonia is common, debilitating, often medically refractory, and difficult to diagnose. The gold standard for both clinical and mouse model dystonia evaluation is subjective assessment, ideally by expert consensus. However, this subjectivity makes translational quantification of clinically-relevant dystonia metrics across species nearly impossible. Many mouse models of genetic dystonias display abnormal striatal cholinergic interneuron excitation, but few display subjectively dystonic features. Therefore, whether striatal cholinergic interneuron pathology causes dystonia remains unknown. To address these critical limitations, we first demonstrate that objectively quantifiable leg adduction variability correlates with leg dystonia severity in people. We then show that chemogenetic excitation of striatal cholinergic interneurons in mice causes comparable leg adduction variability in mice. This clinically-relevant dystonic behavior in mice does not occur with acute excitation, but rather develops after 14 days of ongoing striatal cholinergic interneuron excitation. This requirement for prolonged excitation recapitulates the clinically observed phenomena of a delay between an inciting brain injury and subsequent dystonia manifestation and demonstrates a causative link between chronic striatal cholinergic interneuron excitation and clinically-relevant dystonic behavior in mice. Therefore, these results support targeting striatal ChIs for dystonia drug development and suggests early treatment in the window following injury but prior to dystonia onset. One Sentence Summary: Chronic excitation of dorsal striatal cholinergic interneuron causes clinically-relevant dystonic phenotypes in mice.

Changing the culture of care for children and adolescents with functional neurological disorder.

As members of a multidisciplinary team of professionals who treat children and adolescents with functional neurological (conversion) disorder (FND), we highlight the pressing need to develop an FND-informed culture of care that takes into account recent advances in our understanding of this group of patients. Stories of clinical encounters in health care settings from around the world-told by children and adolescents with FND, their parents, and health professionals-portray an outdated culture of care characterized by iatrogenic stigma, erosion of empathy and compassion within the clinician-patient relationship, and a lack of understanding of FND and its complex neurobiology. After a brief exploration of the outdated culture, we share our counterstories: how we and our colleagues have worked, and continue to work, to create an FND-informed culture in the health systems where we practice. We discuss the therapeutic use of child-friendly language. We also discuss a range of structural, educational, and process interventions that can be used to promote FND-informed beliefs and attitudes, FND-informed clinician-patient encounters, and FND-informed referral processes, treatment pathways, and therapeutic interventions.

Role of child neurologists and neurodevelopmentalists in the diagnosis of cerebral palsy: A survey study.

OBJECTIVE: To contextualize the role of child neurologists and neurodevelopmentalists (CNs/NDDs) in cerebral palsy (CP) care, we review the changing landscape of CP diagnosis and survey stakeholder CNs/NDDs regarding their roles in CP care. METHODS: The optimal roles of the multiple specialties involved in CP care are currently unclear, particularly regarding CP diagnosis. We developed recommendations regarding the role of CNs/NDDs noting (1) increasing complexity of CP diagnosis given a growing number of genetic etiologies and treatable motor disorders that can be misdiagnosed as CP and (2) the views of a group of physician stakeholders (CNs/NDDs from the Child Neurology Society Cerebral Palsy Special Interest Group). RESULTS: CNs/NDDs felt that they were optimally suited to diagnose CP. Many (76%) felt that CNs/NDDs should always be involved in CP diagnosis. However, 42% said that their patients with CP were typically not diagnosed by CNs/NDDs, and 18% did not receive referrals to establish the diagnosis of CP at all. CNs/NDDs identified areas of their expertise critical for CP diagnosis including knowledge of the neurologic examination across development and early identification of features atypical for CP. This contrasts with their views on CP management, where CNs/NDDs felt that they could contribute to the medical team, but were necessary primarily when neurologic coexisting conditions were present. DISCUSSION: Given its increasing complexity, we recommend early referral for CP diagnosis to a CN/NDD or specialist with comparable expertise. This contrasts with current consensus guidelines, which either do not address or do not recommend specific specialist referral for CP diagnosis.

Management of Infantile Spasms During the COVID-19 Pandemic.

Circumstances of the COVID-19 pandemic have mandated a change to standard management of infantile spasms. On April 6, 2020, the Child Neurology Society issued an online statement of immediate recommendations to streamline diagnosis and treatment of infantile spasms with utilization of telemedicine, outpatient studies, and selection of first-line oral therapies as initial treatment. The rationale for the recommendations and specific guidance including follow-up assessment are provided in this manuscript. These recommendations are indicated as enduring if intended to outlast the pandemic, and limited if intended only for the pandemic health care crisis but may be applicable to future disruptions of health care delivery.