Cerebellar Ataxia Research Articles

Cross-Sectional Analysis of Exome Sequencing Diagnosis in Patients With Neurologic Phenotypes Facing Barriers to Clinical Testing.

Exome sequencing (ES) demonstrates a 20-50 percent diagnostic yield for patients with a suspected monogenic neurologic disease. Despite the proven efficacy in achieving a diagnosis for such patients, multiple barriers for obtaining exome sequencing remain. This study set out to assess the efficacy of ES in patients with primary neurologic phenotypes who were appropriate candidates for testing but had been unable to pursue clinical testing. A total of 297 patients were identified from the UCLA Clinical Neurogenomics Research Center Biobank, and ES was performed, including bioinformatic assessment of copy number variation and repeat expansions. Information regarding demographics, clinical indication for ES, and reason for not pursuing ES clinically were recorded. To assess diagnostic efficacy, variants were interpreted by a multidisciplinary team of clinicians, bioinformaticians, and genetic counselors in accordance with the American College of Medical Genetics and Genomics variant classification guidelines. We next examined the specific barriers to testing for these patients, including how frequently insurance-related barriers such as coverage denials and inadequate coverage of cost were obstacles to pursuing exome sequencing. The cohort primarily consisted of patients with sporadic conditions (n = 126, 42.4%) of adult-onset (n = 239, 80.5%). Cerebellar ataxia (n = 225, 75.8%) was the most common presenting neurologic phenotype. Our study found that in this population of mostly adult patients with primary neurologic phenotypes that were unable to pursue exome sequencing clinically, 47 (15.8%) had diagnostic results while an additional 24 patients (8.1%) had uncertain results. Of the 297 patients, 206 were initially recommended for clinical exome but 88 (42.7%) could not pursue ES because of insurance barriers, of whom 14 (15.9%) had diagnostic findings, representing 29.8% of all patients with diagnostic findings. In addition, the incorporation of bioinformatic repeat expansion testing was valuable, identifying a total of 8 pathogenic repeat expansions (17.0% of all diagnostic findings) including 3 of the common spinocerebellar ataxias and 2 patients with Huntington disease. These findings underscore the importance and value of clinical ES as a diagnostic tool for neurogenetic disease and highlight key barriers that prevent patients from receiving important clinical information with potential treatment and psychosocial implications for patients and family members.

Clinical and Genetic Characterization of a Cohort of Brazilian Patients With Congenital Ataxia.

Congenital ataxias are rare hereditary disorders characterized by hypotonia and developmental motor delay in the first few months of life, followed by cerebellar ataxia in early childhood. The course of the disease is predominantly nonprogressive, and many patients are incorrectly diagnosed with cerebral palsy. Despite significant advancements in next-generation sequencing in the past few decades, a specific genetic diagnosis is seldom obtained in cases of congenital ataxia. The aim of the study was to analyze the clinical, radiologic, and genetic features of a cohort of Brazilian patients with congenital ataxia. Thirty patients with a clinical diagnosis of congenital ataxia were enrolled in this study. Clinical and demographic features and neuroimaging studies were analyzed. Genetic testing (whole-exome sequencing) was also performed. A heterogeneous pattern of genetic variants was detected. Eighteen genes were involved: ALDH5A1, BRF1, CACNA1A CACNA1G, CC2D2A, CWF19L1, EXOSC3, ITPR1, KIF1A, MME, PEX10, SCN2A, SNX14, SPTBN2, STXBP1, TMEM240, THG1L, and TUBB4A. Pathogenic/likely pathogenic variants involving 11 genes (ALDH5A1, CACNA1A, EXOSC3, MME, ITPR1, KIF1A, STXBP1, SNX14, SPTBN2, TMEM240, and TUBB4A) were identified in 46.7% of patients. Variants of uncertain significance involving 8 genes were detected in 33.3% of patients. Congenital ataxias were characterized by a broad phenotype. A genetic diagnosis was more often obtained in patients with cerebellar-plus syndrome than in patients with a pure cerebellar syndrome. This study re-emphasizes the genetic heterogeneity of congenital ataxias and the absence of a clear phenotype-genotype relationship. A specific genetic diagnosis was established in 46.7% of patients. Autosomal dominant, associated with sporadic cases, was recognized as an important genetic inheritance. The results of this analysis highlight the value of whole-exome sequencing as an efficient screening tool in patients with congenital ataxia.

RFC1 Repeat Distribution in the Cypriot Population: Study of a Large Cohort of Patients With Undiagnosed Ataxia and Non-Disease Controls.

The intronic biallelic AAGGG expansion in the replication factor C subunit 1 (RFC1) gene was recently associated with a phenotype combining cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, as well as with late-onset ataxia. Following this discovery, studies in multiple populations extended the phenotypic and genotypic spectrum of this locus. Multiple benign and additional pathogenic configurations are currently known. Our main objectives were to study the prevalence of the pathogenic AAGGG expansion in the Cypriot population, to further characterize the RFC1 repeat locus allele distribution, and to search for possible novel repeat configurations. Cypriot undiagnosed patients, in the majority presenting at least with cerebellar ataxia and non-neurologic disease controls, were included in this study. A combination of conventional methods was used, including standard PCR flanking the repeat region, repeat-primed PCR, long-range PCR, and Sanger sequencing. Bioinformatics analysis of already available in-house short-read whole-genome sequencing data was also performed. A large group of undiagnosed patients (n = 194), mainly presenting with pure ataxia or with ataxia accompanied by neuropathy or additional symptoms, as well as a group of non-disease controls (n = 100), were investigated in the current study. Our findings include the diagnosis of 10 patients homozygous for the pathogenic AAGGG expansion and a high percentage of heterozygous AAGGG carriers in both groups. The benign AAAAGn, AAAGGn, and AAGAGn configurations were also identified in our cohorts. We also report and discuss the identification of 2 recently reported novel and possibly benign repeat configurations, AAAGGGn and AAGACn, thus confirming their existence in another distinct population, and we highlight an increased frequency of the AAAGGGn in the patient group, including a single case of homozygosity. Our findings indicate the existence of genetic heterogeneity regarding the RFC1 repeat configurations and that the AAGGG pathogenic expansion is a frequent cause of ataxia in the Cypriot population.

ATP1A3 Disease Spectrum Includes Paroxysmal Weakness and Encephalopathy Not Triggered by Fever.

Heterozygous pathogenic variants in ATP1A3, which encodes the catalytic alpha subunit of neuronal Na+/K+-ATPase, cause primarily neurologic disorders with widely variable features that can include episodic movement deficits. One distinctive presentation of ATP1A3-related disease is recurrent fever-triggered encephalopathy. This can occur with generalized weakness and/or ataxia and is described in the literature as relapsing encephalopathy with cerebellar ataxia. This syndrome displays genotype-phenotype correlation with variants at p.R756 causing temperature sensitivity of ATP1A3. We report clinical and in vitro functional evidence for a similar phenotype not triggered by fever but associated with protein loss-of-function. We describe the phenotype of an individual with de novo occurrence of a novel heterozygous ATP1A3 variant, NM_152296.5:c.388_390delGTG; p.(V130del). We confirmed the pathogenicity of p.V130del by cell survival complementation assay in HEK293 cells and then characterized its functional impact on enzymatic ion transport and extracellular sodium binding by two-electrode voltage clamp electrophysiology in Xenopus oocytes. To determine whether variant enzymes reach the cell surface, we surface-biotinylated oocytes expressing N-tagged ATP1A3. The proband is a 7-year-old boy who has had 2 lifetime episodes of paroxysmal weakness, encephalopathy, and ataxia not triggered by fever. He had speech regression and intermittent hand tremors after the second episode but otherwise spontaneously recovered after episodes and is at present developmentally appropriate. The p.V130del variant was identified on clinical trio exome sequencing, which did not reveal any other variants possibly associated with the phenotype. p.V130del eliminated ATP1A3 function in cell survival complementation assay. In Xenopus oocytes, p.V130del variant Na+/K+-ATPases showed complete loss of ion transport activity and marked abnormalities of extracellular Na+ binding at room temperature. Despite this clear loss-of-function effect, surface biotinylation under the same conditions revealed that p.V130del variant enzymes were still present at the oocyte's cell membrane. This individual's phenotype expands the clinical spectrum of ATP1A3-related recurrent encephalopathy to include presentations without fever-triggered events. The total loss of ion transport function with p.V130del, despite enzyme presence at the cell membrane, indicates that haploinsufficiency can cause relatively mild phenotypes in ATP1A3-related disease.

Potential Clinical Benefit of Very Long Chain Fatty Acid Supplementation in Spinocerebellar Ataxia Type 34.

Spinocerebellar ataxia type 34 (SCA34) is a dominantly inherited disease that causes late-onset ataxia, in association with skin lesions in the form of erythrokeratodermia variabilis. It is caused by mutations in the ELOVL4 gene, which encodes for the ELOVL4 protein and has the function of lengthening very long chain (VLC) fatty acids (FA), which are important components of central myelin. The aim of this work was to review the medical literature on the biochemical abnormalities of SCA34, and based on the obtained information, to propose supplementation of deficient FAs. A review of the ad hoc medical literature was performed. Plasma levels of the ELOVL4 products C32, C34 and C36 FA have not been reported in SCA34 yet. However, pathogenic variants of ELOVL4 revealed deficient biosynthesis of C28, C30, C32, C34 and C36 FA compared to WT in cell cultures, and the levels of ceramides and phosphatidylcholines containing ≥ 34C FA were decreased compared to WT in HeLa cells expressing mutant SCA34 proteins. Besides, a pathological study of SCA34 revealed myelin destruction and loss of oligodendrocytes in cerebral and cerebellar white matter. Levels of VLC-FA should be determined, to identify specifically deficient FAs in SCA34. Cerebellar ataxia could possibly be improved by administration of the deficient FAs, as found in SCA38 with supplementation of docosahexaenoic acid. The authors suggest investigators with access to SCA34, to take into consideration this therapeutic hypothesis, and try to verify the potential efficacy of administration of VLCFA in this disease.

Item performance of the scale for the assessment and rating of ataxia in rare and ultra-rare genetic ataxias.

The Scale for the Assessment and Rating of Ataxia (SARA) is widely used for assessing the severity and progression of genetic cerebellar ataxias. SARA is now considered a primary end point in several ataxia treatment trials, but its underlying composite item measurement model has not yet been tested. This work aimed to evaluate the composite properties of SARA and its items using item response theory (IRT) and to demonstrate its applicability across even ultra-rare genetic ataxias. Leveraging SARA subscores data from 1932 visits from 990 patients of the Autosomal Recessive Cerebellar Ataxias (ARCA) registry, we assessed the performance of SARA using IRT methodology. The item characteristics were evaluated over the ataxia severity range of the entire ataxia population as well as the assessment validity across 115 genetic ARCA subpopulations. A unidimensional IRT model was able to describe SARA item data, indicating that SARA captures one single latent variable. All items had high discrimination values (1.5-2.9) indicating the effectiveness of the SARA in differentiating between subjects with different disease statuses. Each item contributed between 7% and 28% of the total assessment informativeness. There was no evidence for differences between the 115 genetic ARCA subpopulations in SARA applicability. These results show the good discrimination ability of SARA with all of its items adding informational value. The IRT framework provides a thorough description of SARA on the item level, and facilitates its utilization as a clinical outcome assessment in upcoming longitudinal natural history or treatment trials, across a large number of ataxias, including ultra-rare ones.

HISTOSTRUCTURAL ALTERATIONS IN THE CEREBRAL ARCHITECTURE ASSOCIATED WITH THE PROGRESSION OF ALCOHOL INTOXICATION: AN EXPERIMENTAL ANALYSIS

The aim of this study is to evaluate the histological changes in the cerebellum of rat brains following chronic alcohol intoxication. Materials and Methods. We employed a classical approach for modeling chronic alcohol intoxication by administering 40% ethanol to rats (n=55) in a dosage of 2 ml per 100 g of body weight daily for three months. The cerebellar structure was then analyzed. Results. This study investigates the impact of chronic alcohol intoxication on the histological structures of the cerebellar cortex. The cerebellum, like the nervous system overall, possesses a significant cellular and functional reserve. However, teratogenic factors, including ethanol, notably influence the activity of cerebellar neurons, increasing it. Ethanol exposure during early pregnancy can lead to prenatal growth retardation, stillbirth, cleft palate, hydrocephaly, and reductions in fetal body size. There is evidence suggesting a correlation between blood ethanol levels and a reduction in the number of Purkinje cells. Chronic alcohol consumption results in cerebellar ataxia, alterations in upper limb movements, decreased reaction speeds, reduced attention concentration, impaired coordination accuracy, and disturbances in postural stability and balance. Conclusion. The cerebellum, especially during development, is particularly vulnerable to the toxic effects of alcohol. Recent research suggests that changes in the neurotransmission of gamma-aminobutyric acid (GABA)-dependent receptors may contribute to cerebellar dysfunction induced by ethanol. Ethanol exposure increases the release of GABA not only in Purkinje cells but also in the interneurons of the molecular layer and granule cells.

An Update on the Adult-Onset Hereditary Cerebellar Ataxias: Novel Genetic Causes and New Diagnostic Approaches.

The hereditary cerebellar ataxias (HCAs) are rare, progressive neurologic disorders caused by variants in many different genes. Inheritance may follow autosomal dominant, autosomal recessive, X-linked or mitochondrial patterns. The list of genes associated with adult-onset cerebellar ataxia is continuously growing, with several new genes discovered in the last few years. This includes short-tandem repeat (STR) expansions in RFC1, causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS), FGF14-GAA causing spinocerebellar ataxia type 27B (SCA27B), and THAP11. In addition, the genetic basis for SCA4, has recently been identified as a STR expansion in ZFHX3. Given the large and growing number of genes, and different gene variant types, the approach to diagnostic testing for adult-onset HCA can be complex. Testing methods include targeted evaluation of STR expansions (e.g. SCAs, Friedreich ataxia, fragile X-associated tremor/ataxia syndrome, dentatorubral-pallidoluysian atrophy), next generation sequencing for conventional variants, which may include targeted gene panels, whole exome, or whole genome sequencing, followed by various potential additional tests. This review proposes a diagnostic approach for clinical testing, highlights the challenges with current testing technologies, and discusses future advances which may overcome these limitations. Implementing long-read sequencing has the potential to transform the diagnostic approach in HCA, with the overall aim to improve the diagnostic yield.

A novel MT-ATP6 variant associated with complicated ataxia in two unrelated Italian patients: case report and functional studies

BackgroundMT-ATP6 is a mitochondrial gene which encodes for the intramembrane subunit 6 (or A) of the mitochondrial ATP synthase, also known asl complex V, which is involved in the last step of oxidative phosphorylation to produce cellular ATP through aerobic metabolism. Although classically associated with the NARP syndrome, recent evidence highlights an important role of MT-ATP6 pathogenic variants in complicated adult-onset ataxias.MethodsWe describe two unrelated patients with adult-onset cerebellar ataxia associated with severe optic atrophy and mild cognitive impairment. Whole mitochondrial DNA sequencing was performed in both patients. We employed patients’ primary fibroblasts and cytoplasmic hybrids (cybrids), generated from patients-derived cells, to assess the activity of respiratory chain complexes, oxygen consumption rate (OCR), ATP production and mitochondrial membrane potential.ResultsIn both patients, we identified the same novel m.8777 T > C variant in MT-ATP6 with variable heteroplasmy level in different tissues. We identifed an additional heteroplasmic novel variant in MT-ATP6, m.8879G > T, in the patients with the most severe phenotype. A significant reduction in complex V activity, OCR and ATP production was observed in cybrid clones homoplasmic for the m.8777 T > C variant, while no functional defect was detected in m.8879G > T homoplasmic clones. In addition, fibroblasts with high heteroplasmic levelsof m.8777 T > C variant showed hyperpolarization of mitochondrial membranes.ConclusionsWe describe a novel pathogenic mtDNA variant in MT-ATP6 associated with adult-onset ataxia, reinforcing the value of mtDNA screening within the diagnostic workflow of selected patients with late onset ataxias.

Cerebellar Heterogeneity and Selective vulnerability in Spinocerebellar Ataxia Type 1 (SCA1)

Heterogeneity is one of the key features of the healthy brain and selective vulnerability characterizes many, if not all, neurodegenerative diseases. While cerebellum contains majority of brain cells, neither its heterogeneity nor selective vulnerability in disease are well understood. Here we describe molecular, cellular and functional heterogeneity in the context of healthy cerebellum as well as in cerebellar disease Spinocerebellar Ataxia Type 1 (SCA1). We first compared disease pathology in cerebellar vermis and hemispheres across anterior to posterior axis in a knock-in SCA1 mouse model. Using immunohistochemistry, we demonstrated earlier and more severe pathology of PCs and glia in the posterior cerebellar vermis of SCA1 mice. We also demonstrate heterogeneity of Bergmann glia in the unaffected, wild-type mice. Then, using RNA sequencing, we found both shared, as well as, posterior cerebellum-specific molecular mechanisms of pathogenesis that include exacerbated gene dysregulation, increased number of altered signaling pathways, and decreased pathway activity scores in the posterior cerebellum of SCA1 mice. We demonstrated unexpectedly large differences in the gene expression between posterior and anterior cerebellar vermis of wild-type mice, indicative of robust intraregional heterogeneity of gene expression in the healthy cerebellum. Additionally, we found that SCA1 disease profoundly reduces intracerebellar heterogeneity of gene expression. Further, using fiber photometry, we found that population level PC calcium activity was altered in the posterior lobules in SCA1 mice during walking. We also identified regional differences in the population level activity of Purkinje cells (PCs) in unrestrained wild-type mice that were diminished in SCA1 mice.

A combination of chlorzoxazone and folic acid improves recognition memory, anxiety and depression in SCA3-84Q mice.

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is reported to be the most common type of autosomal dominant cerebellar ataxia (ADCA). SCA3 patients suffer from a progressive decline in motor coordination and other disease-associated symptoms. Moreover, recent studies have reported that SCA3 patients also exhibit symptoms of cerebellar cognitive affective syndrome (CCAS). We previously observed signs of CCAS in mouse model of SCA3. Particularly, SCA3-84Q mice suffer from anxiety, recognition memory decline, and also exhibit signs of low mood and aversion to activity. Here we studied the effect of long-term injections of SK channels activator chlorzoxazone (CHZ) together and separately with the folic acid (FA) on the cerebellar Purkinje cell (PC) firing and histology, and also on the motor and cognitive functions as well as mood alterations in SCA3-84Q hemizygous transgenic mice. We realized that both CHZ and CHZ-FA combination had similar positive effect on pure cerebellum impairments including PC firing precision, PC histology, and motor performance in SCA3-84Q mice. However, only the CHZ-FA combination, but not CHZ, had significantly ameliorated the signs of anxiety and depression, and also noticeably improved recognition memory in SCA3-84Q mice. Our results suggest that the combination therapy for both ataxia and non-motor symptoms is required for the complex treatment of ADCA.

The vestibular symptomatology of Machado-Joseph Disease.

Machado Joseph Disease (MJD) is an autosomal dominant neurodegenerative disease. In previous studies, we described significant bilateral horizontal Vestibulo-Ocular Reflex (VOR) deficit within this population without any reference to the presence of vestibular symptomatology. To evaluate whether, beyond cerebellar ataxia complaints, MJD patients have typical vestibular symptomatology corresponding to the accepted diagnostic criteria of Bilateral Vestibulopathy (BVP) according to the definition of the International Barany Society of Neuro-Otology. Twenty-one MJD, 12 clinically stable chronic Unilateral Vestibulopathy (UVP), 15 clinically stable chronic BVP, and 22 healthy Controls underwent the video Head Impulse Test (vHIT) evaluating VOR gain and filled out the following questionnaires related to vestibular symptomatology: The Dizziness Handicap Inventory (DHI), the Activities-specific Balance Confidence Scale (ABC), the Vertigo Visual Scale (VVS) and the Beck Anxiety Inventory (BAI). The MJD group demonstrated significant bilateral vestibular impairment with horizontal gain less than 0.6 in 71% of patients (0.54±0.17). Similar to UVP and BVP, MJD patients reported a significantly higher level of symptoms than Controls in the DHI, ABC, VVS, and BAI questionnaires. MJD demonstrated significant VOR impairment and clinical symptoms typical of BVP. We suggest that in a future version of the International Classification of Vestibular Disorders (ICVD), MJD should be categorized under a separate section of central vestibulopathy with the heading of bilateral vestibulopathy. The present findings are of importance regarding the clinical diagnosis process and possible treatment based on vestibular rehabilitation.

Late-onset cerebellar ataxia and a new frameshift L2HGDH mutation in a Chinese adult with L-2-hydroxyglutaric aciduria: a case report.

L-2-Hydroxyglutaric aciduria (L2HGA) is a rare, autosomal recessive neurometabolic disease, which presents with elevated L-2-hydroxyglutarate acid. Generally, L2HGA appear as slowly progressing central nervous system function deterioration during infancy, and a rapid progression in adulthood is uncommon for the syndrome's classic phenotype.

External laryngeal tremor in adult-onset Alexander disease

Introduction. Alexander disease is caused by mutations in GFAP, the glial fibrillary acidic protein gene. External laryngeal tremor has not been reported in adult-onset Alexander disease (AOAxD). The aims of this work were to report one such case, and to review the literature on palatolaryngeal tremor and AOAxD. Case presentation. A 43-year-old man experienced involuntary movements at the front of his neck. Continuous, rhythmic vertical movements of the laryngeal skeleton, soft palate and tongue, and lower-limb dysmetria, were observed. The pathogenic GFAP variant, c.994G>A; p.(Glu332Lys) was found. MRI demonstrated spinal cord and medulla oblongata atrophy, and hyperintensities at the cerebellum and cerebral white matter. Conclusion. External laryngeal and palatopharyngeal tremor, and cerebellar ataxia, constituted a mild phenotype as expected from this variant, herein reported in isolation for the third time. Imaging was consistent with AOAxD, including the so-called tadpole sign. Additional studies are necessary to define this infrequent disease.

Single-Session Cerebellar Transcranial Direct Current Stimulation Improves Postural Stability and Reduces Ataxia Symptoms in Spinocerebellar Ataxia.

Spinocerebellar ataxia (SCA) results in balance and coordination impairment, and current treatments have limited efficacy. Recent evidence suggests that combining postural training with cerebellar transcranial direct current stimulation (ctDCS) can improve these symptoms. However, the combined effects of ctDCS and postural training on individuals with spinocerebellar ataxia remain underexplored. Ten volunteers with (SCA type 3) participated in a triple-blind, randomized, crossover study to receive a single session of ctDCS (2mA for 20min) and a sham ctDCS session separated by at least one week. The Biodex Balance System was used to assess balance at each session, measuring overall stability index, anteroposterior stability index, and medial-lateral stability index. As secondary outcomes, cerebellar ataxia symptoms were evaluated using the 8-item Scale for Assessment and Rating of Ataxia. The assessments were conducted before and after each session. The results indicated that ctDCS enhanced the overall stability index when compared to sham ctDCS (Z = -2.10, p = 0.03), although it did not significantly affect the anteroposterior or medial-lateral stability indices. Compared to the baseline, a single session of ctDCS reduced appendicular symptoms related to cerebellar ataxia, as evidenced by improvements in the nose-finger test (Z = -2.07, p = 0.04), fast alternating hand movements (Z = -2.15, p = 0.03), and heel-to-shin slide (Z = -1.91, p = 0.05). In conclusion, our study suggests that a single session of ctDCS, in combination with postural training, can enhance balance and alleviate ataxia symptoms in individuals with cerebellar ataxia. This study was approved by the local research ethics committee (No. 2.877.813) and registered on clinicaltrials.org (NCT04039048 - https://www.clinicaltrials.gov/study/NCT04039048 ) on 2019-07-28.

Abstract PO5-20-06: Paraneoplastic cerebellar degeneration in anti-Yo antibody and HER2-positive metastatic breast carcinoma

Abstract Paraneoplastic cerebellar degeneration (PCD) in the context of breast carcinoma affects less than 1% of patients. In most cases, breast cancer diagnosis follows several months or even years after the onset of neurological symptoms. The first association between PCD and occult gynecologic cancers (breast or ovarian) was identified in 1938 with the discovery of antibodies directed against cytoplasmic antigens of Purkinje cells (“anti-Yo antibodies”). Since then, evidence has grown significantly to support anti-Yo antibodies as excellent diagnostic markers of PCD with underlying gynecologic and breast carcinoma. This case study evaluates a 57-year-old female who initially presented with headache and subacute cerebellar ataxia. Her symptoms progressed over a period of three months with multiple falls, onset of speech difficulties, and diplopia. She also reported 30-pound weight loss, which she attributed to dieting and starting semaglutide. Magnetic resonance imaging (MRI) of the brain and spine were unremarkable and autoimmune workup was normal. Cerebral spinal fluid (CSF) and serum studies demonstrated positive anti-Yo antibodies. Computed tomography (CT) of the abdomen and pelvis showed an enlarged left axillary lymph node concerning for metastatic disease with a 1.2cm focus of asymmetric density in the central inferior left breast parenchyma. Diagnostic mammogram one year prior was reportedly normal. Ataxia symptoms improved after a course of empiric intravenous immunoglobulins and steroids. Ultrasound-guided biopsy of the left axillary lymph node revealed metastatic mammary carcinoma: estrogen and progesterone receptor negative and human epidermal growth factor receptor 2 (HER2)-positive, cT0N2aM0, ypTxN1aM0, stage IIIa (AJCC 8th edition). She underwent further metastatic workup, including repeat CSF studies and MRI. MRI of the spine was remarkable for multiple hemangiomas throughout the cervical, thoracic, and lumbar spine, with subsequent unremarkable bone scan. MRI of the abdomen was remarkable for right hepatic lobe hemangioma and a right adrenal nodule. CSF studies showed no sign of metastases. After multidisciplinary discussion, TCHP (docetaxel, carboplatin, trastuzumab, and pertuzumab) neoadjuvant therapy was initiated and repeat imaging demonstrated favorable treatment response with a shrinking axillary mass; no primary breast mass was identified. The patient underwent left sentinel lymph node biopsy with a positive frozen section intraoperative for invasive cancer, therefore proceeded with left axillary lymph node dissection. She was offered a mastectomy but elected for only axillary surgery. Pathology revealed 1 of 14 lymph nodes were positive for metastatic ductal carcinoma. She remains in a rehabilitation center and her ataxia is improving, but her functional status remains below baseline. She is undergoing radiation to whole breast and regional lymph nodes. With this case, we aim to continue to build upon the limited base of the exceedingly rare presentation of breast cancer-associated paraneoplastic syndrome. In addition, several studies and case reports have demonstrated a strong correlation between HER2 overexpression and anti-Yo associated PCD. As we continue to diagnose and monitor breast cancer patients, we could consider starting to screen for anti-Yo antibodies in HER2-positive patients to gain insight into a patient’s prognosis and development of PCD. Citation Format: You Kim, Alison Coogan, Andrea Madrigrano. Paraneoplastic cerebellar degeneration in anti-Yo antibody and HER2-positive metastatic breast carcinoma [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-20-06.

Cerebellar Ataxia, Parkinsonism and Peripheral Neuropathy in an Indian Family with MME Mutation

Cerebellar Ataxia, Parkinsonism and Peripheral Neuropathy in an Indian Family with MME Mutation

Chronic Cough and Cerebellar Ataxia With Neuropathy and Bilateral Vestibular Areflexia Syndrome (CANVAS): Screening for Mutations in Replication Factor C Subunit 1 (RFC1)

IntroductionA common complaint in patients is chronic cough (CC), which may be refractory (RCC) or unexplained (UCC). Recent studies point, as a possible cause of CC, to the hereditary cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS), with an estimated carrier prevalence of 1 in 20000. AimIn patients with CC, determine the prevalence of the biallelic (AAGGG)exp mutation in replication factor C subunit 1 (RFC1) responsible for CANVAS, test the usefulness of the Rydel-Seiffer fork test, and evaluate patient quality of life (QoL). MethodsClinical and functional data were collected for the 33 included patients undergoing CC studies in our specialized unit. Performed were an etiological study of CC following European Respiratory Society recommendations, a genetic study of RFC1 mutations, and Rydel-Seiffer fork testing to detect possible peripheral vibratory sensitivity impairment. Administered to evaluate QoL were 4 questionnaires. ResultsPrevalence of biallelic (AAGGG)exp in RFC1 was 6.1% (n=2) overall, increasing to 7.1% in the RCC subgroup, and to 33.3% in the Rydel-Seiffer fork altered results subgroup. Prevalence of monoallelic (AAGGG)exp in RFC1 was 18.2% (n=6) overall, rising to 50.0% (n=2) in the UCC subgroup. ConclusionGenetic screening for (AAGGG)exp in RFC1, and also use of the Rydel-Seiffer fork test, should be considered in specialized CC consultations for patients with RCC and UCC. Detecting possible CANVAS symptoms in CC studies would identify candidates for early genetic screening, of interest in reducing the disease burden for patients and health systems alike.

Genome sequence analyses identify novel risk loci for multiple system atrophy.

Multiple system atrophy (MSA) is an adult-onset, sporadic synucleinopathy characterized by parkinsonism, cerebellar ataxia, and dysautonomia. The genetic architecture of MSA is poorly understood, and treatments are limited to supportive measures. Here, we performed a comprehensive analysis of whole genome sequence data from 888 European-ancestry MSA cases and 7,128 controls to systematically investigate the genetic underpinnings of this understudied neurodegenerative disease. We identified four significantly associated risk loci using a genome-wide association study approach. Transcriptome-wide association analyses prioritized USP38-DT, KCTD7, and lnc-KCTD7-2 as novel susceptibility genes for MSA within these loci, and single-nucleus RNA sequence analysis found that the associated variants acted as cis-expression quantitative trait loci for multiple genes across neuronal and glial cell types. In conclusion, this study highlights the role of genetic determinants in the pathogenesis of MSA, and the publicly available data from this study represent a valuable resource for investigating synucleinopathies.

Clinical Presentation, Management, and Diagnostic Performance of 2021 Criteria for Paraneoplastic Neurologic Syndromes in Childhood.

Paraneoplastic neurologic syndromes (PNSs) are remote neurologic immune-related effects of tumors. The clinical characteristics of pediatric PNSs remain unclear. We retrospectively examined the clinical characteristics of cases of pediatric PNSs and assessed the performance of the 2021 diagnostic criteria in children. Patients hospitalized in the Beijing Children's Hospital between June 2015 and June 2023 and fulfilling the description of definite by 2004 diagnostic criteria of PNSs were included. A retrospective analysis of clinical characteristics was conducted, and the 2021 diagnostic criteria were applied to rediagnostic stratification. Among the 42 patients included, the most common neurologic syndrome was opsoclonus-myoclonus syndrome (OMS) (62%), followed by rapidly progressive cerebellar syndrome (26%). Most tumors were neuroblastomas (88%), with few being ovarian teratomas (10%). Approximately 71% (30/42) of patients were classified as definite and 24% (10/42) as probable according to the 2021 criteria. All cases judged as probable exhibited rapidly progressive cerebellar ataxia with neuroblastoma. For OMS, chemotherapy was administered based on the tumor's risk stage, accompanied by regular infusion of IV gamma globulin and oral steroids following tumor diagnosis. Twenty-one patients underwent regular follow-ups over 4.92 (0.58-7.58) years. The initial hospitalization recorded a median score of 12 (7-14) on the Mitchell and Pike OMS rating scale, decreasing to 0 (0-5) at the final follow-up. In cases of rapidly progressive cerebellar syndrome, a similar therapeutic regimen was used. Nine patients underwent regular follow-ups over 4.42 (1.17-7.50) years. The mean modified Rankin scale score at first hospitalization was 4 (3-4), reducing to 1 (0-4) at the final follow-up. Only 17% (5/30) of patients across both groups exhibited poor response to this regimen. Among these 5 patients, 4 belonged to the low-risk group (without chemotherapy). OMS followed by rapidly progressive cerebellar ataxia are the most common forms of PNSs in children and are associated with neuroblastoma. An aggressive approach with multiple immunotherapies may improve the prognosis of neuroblastoma-associated PNSs. The 2021 criteria perform well in pediatric PNSs. However, we propose upgrading the classification of antibody-negative rapidly progressive cerebellar ataxia with neuroblastoma to definite diagnosis. This adjustment aims to further improve the diagnostic efficacy of this diagnostic criterion in childhood.