Ataxia Syndrome Research Articles

Novel compound heterozygous mutation and phenotype in the tetratricopeptide repeat-like domain of the GEMIN5 gene in two Chinese families.

GEMIN5 is an RNA-binding protein that regulates multiple molecular functions, including splicing, localisation, translation, and mRNA stability. GEMIN5 mutations present a syndrome centred on cerebellar dysplasia, including motor dysfunction, developmental delay, cerebellar atrophy, and hypotonia. We report three patients from two families with novel compound heterozygous mutations in the tetratricopeptide repeat-like domain of the GEMIN5 gene who presented with motor dysfunction, developmental delay, and ataxia syndrome. Novel variants were identified: c.2551_c.2552delCT (Leu851Glufs*30) and c.2911 C > G (Gln971Glu) in Family 1, and c.3287 T > C (Leu1096Pro) and c.2882 G > C (Trp961 Ser) in Family 2, which were inherited from their parents. Moreover, infantile spasms syndrome(ISs) was diagnosed in the family. We report the first case of ISs caused by GEMIN5 gene mutations. Our cases expand on GEMIN5 variants and neurological phenotypes, reinforcing the crucial impact of tetratricopeptide repeat-like domain variants in the GEMIN5 gene.

Vestibular rehabilitation in cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS)- A case report

Background and purposeCerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is a neurodegenerative disease of the cerebellum. The disease progression is slow, with up to 25% of people diagnosed needing to use a wheelchair after 15 years from diagnosis. Vestibular symptoms arise from centrally-mediated ocular movement degradation and the reduced vestibular-ocular reflex functioning bilaterally. To date, no report has shown an improvement in VOR gain or gait outcome measures in someone with CANVAS after a course of vestibular physical therapy. Case descriptionA 65-year-old male, Patient X, first noticed symptoms in his fourth decade of life and was diagnosed with (CANVAS) in his seventh decade. Patient X reported numbness and tingling in his hands and feet, decreased ability to perform daily activities, and several falls. InterventionPatient X completed a four-month course of vestibular physical therapy, including vestibular ocular reflex exercises, balance training, gait training, and the VestAid application for eye gaze compliance monitoring. The Vestaid application uses eyes and facial recognition software to record the percentage of time that the patient kept their eyes on the target. OutcomesAfter vestibular therapy, Patient X had a clinically meaningful improvement in gait speed: from 1.02 m/s to 1.13 m/s and in the Functional Gait Assessment from 20/30 to 27/30. Patient X's eye gaze compliance improved from a median of 43% (range 25–68%) to a median of 67% (58–83%). DiscussionThis case study demonstrates that vestibular rehabilitation improved eye gaze compliance and functional outcomes in a person living with CANVAS.

Normal and pathogenic variation of RFC1 repeat expansions: implications for clinical diagnosis.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is an autosomal recessive neurodegenerative disease, usually caused by biallelic AAGGG repeat expansions in RFC1. In this study, we leveraged whole genome sequencing data from nearly 10 000 individuals recruited within the Genomics England sequencing project to investigate the normal and pathogenic variation of the RFC1 repeat. We identified three novel repeat motifs, AGGGC (n = 6 from five families), AAGGC (n = 2 from one family) and AGAGG (n = 1), associated with CANVAS in the homozygous or compound heterozygous state with the common pathogenic AAGGG expansion. While AAAAG, AAAGGG and AAGAG expansions appear to be benign, we revealed a pathogenic role for large AAAGG repeat configuration expansions (n = 5). Long-read sequencing was used to characterize the entire repeat sequence, and six patients exhibited a pure AGGGC expansion, while the other patients presented complex motifs with AAGGG or AAAGG interruptions. All pathogenic motifs appeared to have arisen from a common haplotype and were predicted to form highly stable G quadruplexes, which have previously been demonstrated to affect gene transcription in other conditions. The assessment of these novel configurations is warranted in CANVAS patients with negative or inconclusive genetic testing. Particular attention should be paid to carriers of compound AAGGG/AAAGG expansions when the AAAGG motif is very large (>500 repeats) or the AAGGG motif is interrupted. Accurate sizing and full sequencing of the satellite repeat with long-read sequencing is recommended in clinically selected cases to enable accurate molecular diagnosis and counsel patients and their families.

RFC1 in an Australasian neurological disease cohort: extending the genetic heterogeneity and implications for diagnostics.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome is a progressive, generally late-onset, neurological disorder associated with biallelic pentanucleotide expansions in Intron 2 of the RFC1 gene. The locus exhibits substantial genetic variability, with multiple pathogenic and benign pentanucleotide repeat alleles previously identified. To determine the contribution of pathogenic RFC1 expansions to neurological disease within an Australasian cohort and further investigate the heterogeneity exhibited at the locus, a combination of flanking and repeat-primed PCR was used to screen a cohort of 242 Australasian patients with neurological disease. Patients whose data indicated large gaps within expanded alleles following repeat-primed PCR, underwent targeted long-read sequencing to identify novel repeat motifs at the locus. To increase diagnostic yield, additional probes at the RFC1 repeat region were incorporated into the PathWest diagnostic laboratory targeted neurological disease gene panel to enable first-pass screening of the locus for all samples tested on the panel. Within the Australasian cohort, we detected known pathogenic biallelic expansions in 15.3% (n = 37) of patients. Thirty indicated biallelic AAGGG expansions, two had biallelic 'Māori alleles' [(AAAGG)exp(AAGGG)exp], two samples were compound heterozygous for the Māori allele and an AAGGG expansion, two samples had biallelic ACAGG expansions and one sample was compound heterozygous for the ACAGG and AAGGG expansions. Forty-five samples tested indicated the presence of biallelic expansions not known to be pathogenic. A large proportion (84%) showed complex interrupted patterns following repeat-primed PCR, suggesting that these expansions are likely to be comprised of more than one repeat motif, including previously unknown repeats. Using targeted long-read sequencing, we identified three novel repeat motifs in expanded alleles. Here, we also show that short-read sequencing can be used to reliably screen for the presence or absence of biallelic RFC1 expansions in all samples tested using the PathWest targeted neurological disease gene panel. Our results show that RFC1 pathogenic expansions make a substantial contribution to neurological disease in the Australasian population and further extend the heterogeneity of the locus. To accommodate the increased complexity, we outline a multi-step workflow utilizing both targeted short- and long-read sequencing to achieve a definitive genotype and provide accurate diagnoses for patients.

Homozygous Mutation in CWF19L1 with Recessive Ataxia Syndrome in a Turkish Child

Homozygous Mutation in CWF19L1 with Recessive Ataxia Syndrome in a Turkish Child

Dissecting the roles of EIF4G homologs reveals DAP5 as a modifier of CGG repeat-associated toxicity in a Drosophila model of FXTAS

Neurodegeneration in Fragile X-associated tremor/ataxia syndrome (FXTAS) is caused by a CGG trinucleotide repeat expansion in the 5′ UTR of FMR1. Expanded CGG repeat RNAs form stable secondary structures, which in turn support repeat-associated non-AUG (RAN) translation to produce toxic peptides. The parameters that impact RAN translation initiation efficiency are not well understood. Here we used a Drosophila melanogaster model of FXTAS to evaluate the role of the eIF4G family of eukaryotic translation initiation factors (EIF4G1, EIF4GII and EIF4G2/DAP5) in modulating RAN translation and CGG repeat-associated toxicity. DAP5 knockdown robustly suppressed CGG repeat-associated toxicity and inhibited RAN translation. Furthermore, knockdown of initiation factors that preferentially associate with DAP5 (such as EIF2β, EIF3F and EIF3G) also selectively suppressed CGG repeat-induced eye degeneration. In mammalian cellular reporter assays, DAP5 knockdown exhibited modest and cell-type specific effects on RAN translation. Taken together, these data support a role for DAP5 in CGG repeat associated toxicity possibly through modulation of RAN translation.

Atypical vocal quality in women with the FMR1 premutation: an indicator of impaired sensorimotor control.

Women with the FMR1 premutation are susceptible to motor involvement related to atypical cerebellar function, including risk for developing fragile X tremor ataxia syndrome. Vocal quality analyses are sensitive to subtle differences in motor skills but have not yet been applied to the FMR1 premutation. This study examined whether women with the FMR1 premutation demonstrate differences in vocal quality, and whether such differences relate to FMR1 genetic, executive, motor, or health features of the FMR1 premutation. Participants included 35 women with the FMR1 premutation and 45 age-matched women without the FMR1 premutation who served as a comparison group. Three sustained/a/vowels were analyzed for pitch (mean F0), variability of pitch (standard deviation of F0), and overall vocal quality (jitter, shimmer, and harmonics-to-noise ratio). Executive, motor, and health indices were obtained from direct and self-report measures and genetic samples were analyzed for FMR1 CGG repeat length and activation ratio. Women with the FMR1 premutation had a lower pitch, larger pitch variability, and poorer vocal quality than the comparison group. Working memory was related to harmonics-to-noise ratio and shimmer in women with the FMR1 premutation. Vocal quality abnormalities differentiated women with the FMR1 premutation from the comparison group and were evident even in the absence of other clinically evident motor deficits. This study supports vocal quality analyses as a tool that may prove useful in the detection of early signs of motor involvement in this population.

Phenotypic and genetic aspects of hereditary ataxia in dogs.

Hereditary ataxias are a large group of neurodegenerative diseases that have cerebellar or spinocerebellar dysfunction as core feature, occurring as an isolated sign or as part of a syndrome. Based on neuropathology, this group of diseases has so far been classified into cerebellar cortical degenerations, spinocerebellar degenerations, cerebellar ataxias without substantial neurodegeneration, canine multiple system degeneration, and episodic ataxia. Several new hereditary ataxia syndromes are described, but most of these diseases have similar clinical signs and unspecific diagnostic findings, wherefore achieving a definitive diagnosis in these dogs is challenging. Eighteen new genetic variants associated with these diseases have been discovered in the last decade, allowing clinicians to reach a definitive diagnosis for most of these conditions, and allowing breeding schemes to adapt to prevent breeding of affected puppies. This review summarizes the current knowledge about hereditary ataxias in dogs, and proposes to add a "multifocal degenerations with predominant (spino)cerebellar component" category regrouping canine multiple system degeneration, new hereditary ataxia syndromes that do not fit in 1 of the previous categories, as well as specific neuroaxonal dystrophies and lysosomal storage diseases that cause major (spino)cerebellar dysfunction.

Glial dysregulation in the human brain in fragile X-associated tremor/ataxia syndrome

Short trinucleotide expansions at the FMR1 locus are associated with the late-onset condition fragile X-associated tremor/ataxia syndrome (FXTAS), which shows very different clinical and pathological features from fragile X syndrome (associated with longer expansions), with no clear molecular explanation for these marked differences. One prevailing theory posits that the shorter, premutation expansion uniquely causes extreme neurotoxic increases in FMR1 mRNA (i.e., four to eightfold increases), but evidence to support this hypothesis is largely derived from analysis of peripheral blood. We applied single-nucleus RNA sequencing to postmortem frontal cortex and cerebellum from 7 individuals with premutation and matched controls (n = 6) to assess cell type-specific molecular neuropathology. We found only modest upregulation (~1.3-fold) of FMR1 in some glial populations associated with premutation expansions. In premutation cases, we also identified decreased astrocyte proportions in the cortex. Differential expression and gene ontology analysis demonstrated altered neuroregulatory roles of glia. Using network analyses, we identified cell type-specific and region-specific patterns of FMR1 protein target gene dysregulation unique to premutation cases, with notable network dysregulation in the cortical oligodendrocyte lineage. We used pseudotime trajectory analysis to determine how oligodendrocyte development was altered and identified differences in early gene expression in oligodendrocyte trajectories in premutation cases specifically, implicating early cortical glial developmental perturbations. These findings challenge dogma regarding extremely elevated FMR1 increases in FXTAS and implicate glial dysregulation as a critical facet of premutation pathophysiology, representing potential unique therapeutic targets directly derived from the human condition.

Síndrome de temblor y ataxia asociado a frágil X (FXTAS): revisión de la literatura

El síndrome de temblor y ataxia asociado al síndrome del cromosoma X frágil (FXTAS) es un desorden neurodegenerativo progresivo (1), de inicio tardío, que ocurre entre los portadores de la premutación del gen FMR1 (Fragile X Mental Retardation 1), el cual está estrechamente asociado con el síndrome del cromosoma X frágil (FXS). El FXTAS se caracteriza por déficits neurológicos que incluyen temblor de intención progresivo, ataxia cerebelosa, parkinsonismo, neuropatía periférica, déficits cognitivos y disfunción autonómica (2-4).
 El FXTAS surge como una importante opción diagnóstica en hombres con temblor, alteraciones en la marcha y síntomas neurodegenerativos. En general existe subregistro de esta patología dado que es un síndrome recientemente descrito y falta conocimiento de los profesionales de salud al respecto, los cuales, debido a la similitud de su presentación clínica con otros desórdenes neurológicos, generalmente suelen confundir el diagnóstico (5).
 En Colombia no se ha documentado la prevalencia de SXF o de FXTAS. Sin embargo, se ha descrito un corregimiento en el Valle del Cauca que tiene una prevalencia de más de cien veces lo reportado en la literatura de SFX, lo que nos sugiere que en Colombia existe subregistro del SFX y de FXTAS.
 Esta revisión tiene por objeto difundir los avances del conocimiento de las manifestaciones clínicas, la neurofisiopatología y las posibilidades de tratamiento de los pacientes con FXTAS, y así aumentar diagnóstico y aportar a mejorar la calidad de vida de los afectados y de sus familias.

Reactive Bergmann glia play a central role in spinocerebellar ataxia inflammation via the JNK pathway

The spinocerebellar ataxias (SCAs) are devastating neurological diseases characterized by progressive cerebellar incoordination. While neurons bear the brunt of the pathology, a growing body of evidence suggests that glial cells are also affected. It has, however, been difficult to understand the role of glia, given the diversity of subtypes, each with their individual contributions to neuronal health. Using human SCA autopsy samples we have discovered that Bergmann glia—the radial glia of the cerebellum, which form intimate functional connections with cerebellar Purkinje neurons—display inflammatory JNK-dependent c-Jun phosphorylation. This phosphorylation defines a signaling pathway not observed in other activated glial populations, providing an opportunity to isolate the role of Bergmann glia in SCA inflammation. Turning to an SCA1 mouse model as a paradigmatic SCA, we demonstrate that inhibiting the JNK pathway reduces Bergmann glia inflammation accompanied by improvements in the SCA1 phenotype both behaviorally and pathologically. These findings demonstrate the causal role for Bergmann glia inflammation in SCA1 and point to a novel therapeutic strategy that could span several ataxic syndromes where Bergmann glia inflammation is a major feature.

An escalating continuum of learning and attention difficulties from premutation to full mutation in female carriers of FMR1 expansion.

Carriers of Fragile X premutation may have associated medical comorbidities, such as Fragile X-associated tremor and ataxia (FXTAS) and Fragile X-associated premature ovarian insufficiency (FXPOI). We examined the Fragile X premutation effect on cognition, and we assumed that there is a direct correlation between the continuous spectrum of specific learning and attention deficits to the number of CGG repeats on the FMR1 gene. A total of 108 women were referred to our center due to a related Fragile X syndrome (FXS) patient, 79 women carried a premutation of 56-199 repeats, and 19 women carried a full mutation of more than 200 CGG repeats on FMR1 gene. Genetic results of CGG repeats, demographic information, structured questionnaires for ADHD, learning disabilities of language and mathematics, and independence level were analyzed in women carrying the FMR1 premutation and compared to the group carrying the full mutation. Women with FXS and FXTAS were excluded. When analyzed as a continuum, there was a significant increase in the following complaints which were associated with a higher number of repeats: specific daily function skills such as driving a car, writing checks, disorientation in directions, and also specific learning difficulties such as spelling and math difficulties. Additionally, when tested as a categorical independent variable, we observe that women with the full mutation were more likely to have ADHD or other learning disability diagnoses in the past than during premutation (<200 CGG repetitions). Specific learning and attention difficulties and resulting daily function difficulties correlate with an increased number of CGG repeats and are more likely to be associated as a common feature of premutation and full mutation in a female premutation carrier. Despite evidence of learning and attention difficulties, it is encouraging that most female carriers of the premutation and full mutation function well in most areas. Nevertheless, they face significant difficulties in specific areas of functioning such as driving, and confusion in times and schedules. Those daily function skills are mostly impacted by dyscalculia, right and left disorientation, and attention difficulties. This may aid to design specific interventions to address specific learning deficits in order to improve daily function skills and quality of life.

Clinical implications of somatic allele expansion in female FMR1 premutation carriers

Carriers of a premutation allele (PM) in the FMR1 gene are at risk of developing a number of Fragile X premutation asssociated disorders (FXPAC), including Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), Fragile X-associated Primary Ovarian Insufficiency (FXPOI), and Fragile X-associated neuropsychiatric disorders (FXAND). We have recently reported somatic CGG allele expansion in female PM; however, its clinical significance remains unclear. The aim of this study was to examine the potential clinical association between somatic FMR1 allele instability and PM associated disorders. Participants comprised of 424 female PM carriers age 0.3– 90 years. FMR1 molecular measures and clinical information on the presence of medical conditions, were determined for all subjects for primary analysis. Two sub-groups of participants (age ≥ 25, N = 377 and age ≥ 50, N = 134) were used in the analysis related to presence of FXPOI and FXTAS, respectively. Among all participants (N = 424), the degree of instability (expansion) was significantly higher (median 2.5 vs 2.0, P = 0.026) in participants with a diagnosis of attention deficit hyperactivity disorder (ADHD) compared to those without. FMR1 mRNA expression was significantly higher in subjects with any psychiatric disorder diagnosis (P = 0.0017); specifically, in those with ADHD (P = 0.009), and with depression (P = 0.025). Somatic FMR1 expansion was associated with the presence of ADHD in female PM and FMR1 mRNA levels were associated with the presence of mental health disorders. The findings of our research are innovative as they suggest a potential role of the CGG expansion in the clinical phenotype of PM and may potentially guide clinical prognosis and management.

Fragile-X-associated Tremor/Ataxia Syndrome in a Woman with Full Mutation: A Case Report (P5-11.009)

<h3>Objective:</h3> To describe the first case of FXTAS in a full mutation woman without Fragile X syndrome. <h3>Background:</h3> Fragile-X-associated tremor/ataxia syndrome (FXTAS) is caused by expanded trinucleotide (CGG) repeats between 55–199 (premutation) in the <i>Fragile X Mental Retardation 1 (FMR1) gene</i>. Core clinical features of FXTAS include cerebellar ataxia, intention tremor and Parkinsonism. In contrast, a full mutation of CGG repeats&gt;200 repeats with methylation of the gene leads to fragile X syndrome, which is characterized by early intellectual disability, autistic features, and seizures. <i>FMR1</i> premutation carrier women presenting as FXTAS have been reported. This is the first report of a woman with a full mutation presenting with FXTAS. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> A 65-year-old woman presented with problems with dexterity and shuffling gait. The patient also complained of urinary urgency, constipation, anxiety, depression, and mild cognitive complaints. The patient’s son was diagnosed with fragile X syndrome at 14 months. Neurological exam of the patient showed parkinsonism, action tremor and limb ataxia. MRI brain demonstrated chronic ischemic small vessel disease and mildly reduced brain volume. <i>FMR1 CGG</i> repeat sizes were 20 and &gt;200. The 20 repeat allele was seen on the active X chromosome (representing non-random X-inactivation), while the &gt;200 repeat allele was fully methylated on Southern blot. Testing for Parkinson’s disease-associated genes were negative. <h3>Conclusions:</h3> This is the first report of a woman with a <i>FMR1</i> full mutation presenting with signs and symptoms of FXTAS. Several cases of FXTAS have been reported in <i>FMR1</i> full mutation men with fragile X syndrome due to mosaicism of repeat sizes and the presence of a premutation allele. Full mutation adults with complete methylation have not been reported to have FXTAS. The clinical presentation of this case might be due to size or methylation mosaicism in brain. Alternatively, one could also consider a different disease mimicking FXTAS. <b>Disclosure:</b> Dr. Kazanci has nothing to disclose. The institution of Dr. Berry-Kravis has received research support from NIH. The institution of Dr. Berry-Kravis has received research support from Ovid. The institution of Dr. Berry-Kravis has received research support from Zynerba. The institution of Dr. Berry-Kravis has received research support from Roche. The institution of Dr. Berry-Kravis has received research support from CDC. The institution of Dr. Berry-Kravis has received research support from FRAXA Research Foundation. The institution of Dr. Berry-Kravis has received research support from GeneTx. The institution of Dr. Berry-Kravis has received research support from Angelman Syndrome Foundation. The institution of Dr. Berry-Kravis has received research support from Acadia. The institution of Dr. Berry-Kravis has received research support from GW. The institution of Dr. Berry-Kravis has received research support from Anavex. The institution of Dr. Berry-Kravis has received research support from Rett Syndrome Research Trust. The institution of Dr. Berry-Kravis has received research support from Ultragenyx. The institution of Dr. Berry-Kravis has received research support from Mallinckrodt. The institution of Dr. Berry-Kravis has received research support from Together Strong Foundation. The institution of Dr. Berry-Kravis has received research support from Orphazyme. The institution of Dr. Berry-Kravis has received research support from Ionis. The institution of Dr. Berry-Kravis has received research support from Taysha. The institution of Dr. Berry-Kravis has received research support from Erydel. The institution of Dr. Berry-Kravis has received research support from Tetra. The institution of Dr. Berry-Kravis has received research support from Neuren. The institution of Dr. Berry-Kravis has received research support from FRAXA Research Foundation. Dr. Hall has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for American Academy of Neurology. Dr. Hall has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier - Parkinsonism and Related Disorders. Dr. Hall has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Annals of Neurology. The institution of Dr. Hall has received research support from Parkinson’s Foundation. The institution of Dr. Hall has received research support from CHDI. The institution of Dr. Hall has received research support from Biohaven. The institution of Dr. Hall has received research support from Neurocrine. The institution of Dr. Hall has received research support from Uniqure. Dr. Hall has received personal compensation in the range of $500-$4,999 for serving as a Study section with NIH.

Case Series of Patients with Brainstem Inflammation Causing Paroxysmal Movement Disorders (P4-5.016)

<h3>Objective:</h3> We describe five patients with various neuroinflammatory diseases who developed Paroxysmal Movement Disorders (PMD). <h3>Background:</h3> PMD are a rare phenomenon that has been described in patients with multiple sclerosis since the 1940s. PMD are typically responsive to carbamazepine. One subtype of PMD is paroxysmal dysarthria and ataxia syndrome (PDA), characterized by stereotyped episodes of dysarthria and ataxia, lasting seconds and recurring several times per day. This is thought to be due to transverse ephaptic transmission between demyelinated axons in the brainstem. Recently, cases of PDA in other neuroinflammatory diseases such as Behcet’s disease, MOG-antibody disease (MOGAD), Bickerstaff encephalitis, and anti-NMDA encephalitis have been described but the spectrum of PMD in neuroinflammatory diseases has not been sufficiently studied. <h3>Design/Methods:</h3> Case report series. <h3>Results:</h3> We describe in detail five patients with CNS inflammatory diseases who developed PMD. Underlying diseases were chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS), MS, MOGAD, and post-infectious encephalitis (COVID and LaCrosse virus). Four patients developed PDA, while one presented with paroxysmal esophageal contractions. Paroxysms were brief (less than 10 seconds) and frequent (up to hundreds of times a day). On MRI, four patients had lesions in the medial midbrain and one had a lesion in a cerebellar peduncle. In four cases paroxysms were treated successfully with carbamazepine. All patients had complete or near-complete remission of their PMD. <h3>Conclusions:</h3> This series highlights that different neuroinflammatory disorders can cause PMD. This is the first report of PDA in CLIPPERS or post-COVID encephalitis, and the second report in MOGAD. Most patients had lesions in the dorsal midbrain below the red nucleus, a site commonly reported to cause PDA. Treatment with carbamazepine was successful. PMD in neuroinflammatory disease is important to recognize as symptoms can be debilitating but successfully treated. This case series can help improve awareness of this rare condition. <b>Disclosure:</b> Dr. Luxenberg has nothing to disclose. The institution of Dr. Wang has received research support from Genentech. The institution of Dr. Wundes has received research support from Benaroya Research Institute . The institution of Dr. Von Geldern has received research support from Novartis. The institution of Dr. Von Geldern has received research support from National MS Society. Dr. Von Geldern has received personal compensation in the range of $0-$499 for serving as a DSMB member with NIH, NINDS. Dr. Von Geldern has a non-compensated relationship as a editorial board member with MS and Related Disorders Journal that is relevant to AAN interests or activities.

Pediatric opsoclonus myoclonus ataxia syndrome in the setting of COVID-19 (P5-9.010)

<h3>Objective:</h3> To describe peri-infectious opsoclonus myoclonus ataxia syndrome (OMAS) in the setting of COVID-19 infection in children. <h3>Background:</h3> OMAS is well described in pediatric patients with peripheral neuroblastic tumors and less defined in the setting of peri-infectious etiologies such as SARS-CoV-19 which is better appreciated in adults. <h3>Design/Methods:</h3> We describe two separate cases of peri-infectious COVID-19 OMAS in pediatric patients at a tertiary Children’s Hospital in 2022, both previously healthy female patients, 2 years and 18 months of age. <h3>Results:</h3> Patient A is a two year-old female who initially presented with ataxia in context of acute COVID-19 infection at 16 months of age and later developed abnormal eye movements, myoclonus and irritability with multiple relapses over a nine month period. Patient B is a 18 month-old female presenting with acute onset abnormal eye movements and ataxia at age 14 months and later developed myoclonic jerks and irritability with sleep disturbance, subsequently found to have COVID-19 antibodies, now with remission of symptoms. Both patients had comprehensive work up for malignancy, toxic-metabolic encephalopathy, structural central nervous system disease, infectious meningoencephalitis and genetic ataxia syndromes. Both were treated with IVIG and high dose steroids. Patient A had subsequent relapses and required escalation of treatment to ACTH. Patient A had a more complicated course which included treatment with acetazolamide and levetiracetam for myoclonus. Her myoclonic jerks demonstrated intermittent electrographic correlates on EEG. <h3>Conclusions:</h3> While OMAS associated with neuroblastic tumors is well described in the pediatric literature, it is less well known in relation to peri-infectious phenomena, particularly SARS-CoV-2 infection in children. Prior published reports of OMAS related to COVID-19 infection in adults indicated a favorable prognosis after initial treatment. However, we present a case with repeated relapses and the need for more aggressive treatment. The present report broadens the phenotypic spectrum for OMAS outside of paraneoplastic etiologies. <b>Disclosure:</b> Dr. Yakir has nothing to disclose. Dr. Most has nothing to disclose. Dr. Hermel has nothing to disclose. Dr. Zimbric has received personal compensation in the range of $0-$499 for serving as a Survey volunteer with Opinionsite. An immediate family member of Dr. Friedman has received personal compensation in the range of $0-$499 for serving as a Consultant for Sinopia Biosciences. An immediate family member of Dr. Friedman has received personal compensation in the range of $0-$499 for serving as an officer or member of the Board of Directors for Pet Dx. Dr. Friedman has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for MedLink Neurology. Dr. Friedman has stock in Friedman Bioventure . Dr. Rho has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Eisai. Dr. Rho has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Nutricia. Dr. Rho has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cerecin. Dr. Rho has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mallinckrodt. Dr. Rho has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biocodex. Dr. Rho has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Zogenix. Dr. Rho has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Aquestive. The institution of Dr. Rho has received research support from National Institutes of Health. Dr. Rho has received publishing royalties from a publication relating to health care.

Clinical, Electroencephalographic and Neuroimage Findings of Patients with Cerebellar Ataxia and Epilepsy (P9-11.003)

<h3>Objective:</h3> To describe phenotypical, imaging and neurophysiological features of patients affected by cerebellar ataxia and epilepsy. <h3>Background:</h3> The association of epilepsy with hereditary cerebellar ataxia is an emerging issue that has raised interest among researchers in the fields of movement disorders, epilepsy and neurogenetics, particularly the characterization of clinical and neurophysiological findings of affected patients. Although there are thorough descriptions of clinical and electroencephalographic findings of some diseases (such as SCA10 and progressive myoclonic epilepsies), there are no studies that accomplish a systematic correlation of clinical features, EEG and neuroimaging findings as a group of diseases. <h3>Design/Methods:</h3> 30 patients from southern Brazil diagnosed with both cerebellar ataxia and epilepsy were retrospectively assessed regarding specific diagnosis, clinical characteristics (severity, disease duration, seizure type and frequency), EEG and neuroimaging findings. Patients were also divided in 3 groups: autosomal dominant ataxias (SCAs), recessive ataxias and progressive myoclonic epilepsies and the findings were compared between those groups. <h3>Results:</h3> The most common diagnosis in each group was SCA10, undefined recessive ataxia and Unverricht Lundborg disease, respectively. A higher severity of ataxia symptoms (SARA rating scale) and worse seizure frequency control was found in patients with progressive myoclonic epilepsies. In 62%, seizure onset was determined to be generalized, with a higher frequency of tonic-clonic seizures. EEG analysis showed higher prevalence of epileptiform activity in the recessive ataxia group (57%, p&lt;0.005). 80% of patients presented cerebellar atrophy on brain MRI, being the isolated abnormal finding in 56%. <h3>Conclusions:</h3> The heterogeneity of the diseases that present cerebellar ataxia and epilepsy can be challenging. Higher frequency of SCA 10 was expected in the AD group, although in the southern Brazilian cohort this is the exception. PME ataxia was more severe and seizure control was poorer, compared to other groups. The results highlight the need for better characterization of epileptic ataxic patients and syndromes. <b>Disclosure:</b> Dr. Cassou has nothing to disclose. Luciano De Paola has nothing to disclose. Salmo Raskin has nothing to disclose. Paula Marques has nothing to disclose. Ms. Zulfiqar Ali has nothing to disclose. Ms. Qaiser has nothing to disclose. Dr. Andrade has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai. Dr. Andrade has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biocodex. Dr. Andrade has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Zodiac. Dr. Andrade has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Stoke therapeutics. Dr. Andrade has received publishing royalties from a publication relating to health care. Dr. Andrade has a non-compensated relationship as a Chair of task force on Transition with International League Against Epilepsy that is relevant to AAN interests or activities. Dr. Teive has nothing to disclose.

Recurrent GRAF1 Antibody Encephalitis in Woman with History of Cancer and Powassan Encephalitis (P4-5.012)

<h3>Objective:</h3> To review details of a rare presentation of autoimmune encephalitis with antibody to GRAF1, which is rare and with little information about its origin or associated clinical syndrome, and educate clinicians to identify similar presentations early to allow effective treatment and prognostic counseling for patients and their family. <h3>Background:</h3> This case details presentation of a rare cause of autoimmune encephalitis with antibodies to GTPase regulator associated with focal adhesion kinase-1 (GRAF1). Reports in the literature may group this with other anti-Ca channel antibodies, and often associate it with an ataxic clinical syndrome. Little is known about the origin of these antibodies, as it is not always associated with malignancy or specific systemic conditions. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> A 68 year old woman with a history of breast and cervical cancer, as well as Powassan encephalitis had recurrent episodes of encephalitis with prominent confusion, and was found to have a high titer of antibody to GRAF1 in her CSF with each clinical episode. She unfortunately did not respond well to immunosuppressive medications or IVIG, and passed away on hospice. The details of this case report highlight the clinical features associated with this case of GRAF1 antibody encephalitis and poses questions about whether cancer or prior CNS infection may be the origin of these antibodies, as our patient had a history or Powassan encephalitis. It is also not clear whether serial CSF testing can be used as maintenance to guide management. <h3>Conclusions:</h3> GRAF1 antibody encephalitis is a poorly understood cause of autoimmune encephalitis, without a consistent associated clinical syndrome, or associated condition that may be a source of the increased antibody titer. We pose the question whether this can be a post-infectious entity, and highlight a case of encephalitis which had recurrent episodes before becoming progressive and refractory to treatment. <b>Disclosure:</b> Dr. Dobson has nothing to disclose. Dr. Crissinger has nothing to disclose.

Neurodegeneration, Ataxia, Dystonia, and Gaze Palsy (NADGP) Syndrome with Nocturnal Paroxysmal Head Tremor.

Video 1: Showing rhythmic oscillatory movements on the patient's head during sleep. Video 2: Showing gait ataxia during tandem walking, dystonic posture of hands during walking and holding arms outstretched, which superimposed with choreiform movements on his hands. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Five Years Follow-up of Opsoclonus-Myoclonus-Ataxia Syndrome-Associated Neurogenic Tumors in Children.

Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare autoimmune disorder. Approximately half of the cases are associated with neuroblastoma in children. This study's aim is to review management of our cases with OMAS-associated neuroblastoma for treatment approach as well as long-term follow-up. Age at onset of symptoms and tumor diagnosis, tumor location, histopathology, stage, chemotherapy, OMAS protocol, surgery, and follow-up period were evaluated retrospectively in six patients between 2007 and 2022. Mean age of onset of OMAS findings was 13.5 months and mean age at tumor diagnosis was 15.1 months. Tumor was located at thorax in three patients and surrenal in others. Four patients underwent primary surgery. Histopathological diagnosis was ganglioneuroblastoma in three, neuroblastoma in two, and undifferentiated neuroblastoma in one. One patient was considered as stage 1 and rest of them as stage 2. Chemotherapy was provided in five cases. The OMAS protocol was applied to five patients. Our protocol is intravenous immunoglobulin (IVIG) 1 g/kg/d for 2 consecutive days once a month and dexamethasone for 5 days (20 mg/m2/d for 1-2 days, 10 mg/m2/d for 3-4 days, and 5 mg/m2/d for the fifth day) once a month, alternatively by 2-week intervals. Patients were followed up for a mean of 8.1 years. Neuropsychiatric sequelae were detected in two patients. In tumor-related cases, alternating use of corticosteroid and IVIG for suppression of autoimmunity as the OMAS protocol, total excision of the tumor as soon as possible, and chemotherapeutics in selected patients seem to be related to resolution of acute problems, long-term sequelae, and severity.