[Clinical features of CAPOS syndrome caused by maternal ATP1A3 gene variation: a case report].

CAPOS syndrome is an autosomal dominant neurological disorder caused by mutations in the ATP1A3 gene. Initial symptoms, often fever-induced, include recurrent acute ataxic encephalopathy in childhood, featuring cerebellar ataxia, optic atrophy, areflflexia, sensorineural hearing loss, and in some cases, pes cavus. This report details a case of CAPOS syndrome resulting from a maternal ATP1A3 gene mutation. Both the child and her mother exhibited symptoms post-febrile induction,including severe sensorineural hearing loss in both ears, ataxia, areflexia, and decreased vision. Additionally, the patient's mother presented with pes cavus. Genetic testing revealed a c. 2452G>A（Glu818Lys） heterozygous mutation in theATP1A3 gene in the patient . This article aims to enhance clinicians' understanding of CAPOS syndrome, emphasizing the case's clinical characteristics, diagnostic process, treatment, and its correlation with genotypeic findings.

The FGF14 GAA repeat expansion in Greek patients with late-onset cerebellar ataxia and an overview of the SCA27B phenotype across populations.

A pathogenic GAA repeat expansion in the first intron of the fibroblast growth factor 14 gene (FGF14) has been recently identified as the cause of spinocerebellar ataxia 27B (SCA27B). We herein screened 160 Greek index cases with late-onset cerebellar ataxia (LOCA) for FGF14 repeat expansions using a combination of long-range PCR and bidirectional repeat-primed PCRs. We identified 19 index cases (12%) carrying a pathogenic FGF14 GAA expansion, a diagnostic yield higher than that of previously screened repeat-expansion ataxias in Greek LOCA patients. The age at onset of SCA27B patients was 60.5 ± 12.3 years (range, 34-80). Episodic onset (37%), downbeat nystagmus (32%) and vertigo (26%) were significantly more frequent in FGF14 expansion-positive cases compared to expansion-negative cases. Beyond typical cerebellar signs, SCA27B patients often displayed hyperreflexia (47%) and reduced vibration sense in the lower extremities (42%). The frequency and phenotypic profile of SCA27B in Greek patients was similar to most other previously studied populations. We conclude that FGF14 GAA repeat expansions are the commonest known genetic cause of LOCA in the Greek population and recommend prioritizing testing for FGF14 expansions in the diagnostic algorithm of patients with LOCA.

Atezolizumab-induced cerebellar ataxia in a patient with metastatic small cell lung cancer: A case report and literature review.

INTRODUCTION: The use of immune checkpoint inhibitors, which have an important role in the treatment of malignant tumors, is increasing. Although rarely observed, neurological immune-related adverse events associated with immune checkpoint inhibitors result in high morbidity and mortality. Small cell lung cancer is a common cause of neurological paraneoplastic syndromes. The differentiation between paraneoplastic syndromes and neurological immune-related adverse events is important in patients using immune checkpoint inhibitors. Cerebellar ataxia caused by atezolizumab is a rare immune-related adverse event. CASE REPORT: In this context, we present a 66-year-old man with small cell lung cancer who developed immune-mediated cerebellar ataxia after three cycles of atezolizumab, a programmed cell death ligand-1 inhibitor. The admission of brain and spinal gadolinium-based contrast-enhanced magnetic resonance imaging supported the preliminary diagnosis and indicated leptomeningeal involvement. However, the blood tests and a lumbar puncture did not reveal any structural, biochemical, paraneoplastic, or infectious cause. MANAGEMENT AND OUTCOME: High-dose steroid treatment resulted in an improvement in the radiological involvement, as evidenced both clinically and on follow-up whole spine magnetic resonance imaging. Therefore, the immunotherapy was discontinued. The patient was discharged on day 20 without neurological sequelae. DISCUSSION: In light of this, we present this case to emphasize the differential diagnosis of neurological immune-related adverse events originating from immune checkpoint inhibitors, which require rapid diagnosis and treatment, and clinically similar paraneoplastic syndromes and radiologically similar leptomeningeal involvement, in a case of small cell lung cancer.

Intronic FGF14 GAA repeat expansions are a common cause of ataxia syndromes with neuropathy and bilateral vestibulopathy.

BACKGROUND: Intronic GAA repeat expansions in the fibroblast growth factor 14 gene (FGF14) have recently been identified as a common cause of ataxia with potential phenotypic overlap with RFC1-related cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS). Our objective was to report on the frequency of intronic FGF14 GAA repeat expansions in patients with an unexplained CANVAS-like phenotype. METHODS: We recruited 45 patients negative for biallelic RFC1 repeat expansions with a combination of cerebellar ataxia plus peripheral neuropathy and/or bilateral vestibulopathy (BVP), and genotyped the FGF14 repeat locus. Phenotypic features of GAA-FGF14-positive versus GAA-FGF14-negative patients were compared. RESULTS: Frequency of FGF14 GAA repeat expansions was 38% (17/45) in the entire cohort, 38% (5/13) in the subgroup with cerebellar ataxia plus polyneuropathy, 43% (9/21) in the subgroup with cerebellar ataxia plus BVP and 27% (3/11) in patients with all three features. BVP was observed in 75% (12/16) of GAA-FGF14-positive patients. Polyneuropathy was at most mild and of mixed sensorimotor type in six of eight GAA-FGF14-positive patients. Family history of ataxia (59% vs 15%; p=0.007) was significantly more frequent and permanent cerebellar dysarthria (12% vs 54%; p=0.009) significantly less frequent in GAA-FGF14-positive than in GAA-FGF14-negative patients. Age at onset was inversely correlated to the size of the repeat expansion (Pearson's r, -0.67; R2=0.45; p=0.0031). CONCLUSIONS: GAA-FGF14-related disease is a common cause of cerebellar ataxia with polyneuropathy and/or BVP, and should be included in the differential diagnosis of RFC1 CANVAS and disease spectrum.

Etiologies and clinical characteristics of acute ataxia in a single national children's medical center.

OBJECTIVE: To analyze etiologic factors of pediatric acute ataxia and to identify the severity of its underlying causes for urgent medical intervention. METHODS: Clinical data of children diagnosed with acute ataxia between December 2015 and December 2021 from one national medical center were analyzed retrospectively. RESULTS: A total of 99 children (59 boys, 40 girls), median age at disease onset 55 (range: 12-168) months, were enrolled. The median follow period was 46 (range 6-78) months. Eighty-six (86.9 %) children were diagnosed with immune-associated acute ataxia, among which acute post-infectious cerebellar ataxia (APCA) was the most common diagnosis (50.5 %), followed by demyelinating diseases of the central nervous system (18.2 %) and Guillain-Barré syndrome (9.1 %). On cerebrospinal fluid (CSF) examination, 35/73 (47.9 %) patients had pleocytosis (>5 cells/mm3), and 18/73 (24.7 %) had elevated protein levels. Thirty-one patients (31.3 %) had an abnormal cerebral MRI. Children with other immune-associated acute cerebellar ataxia had more extracerebellar symptoms, intracranial MRI lesions, abnormal CSF results, longer hospital stay, higher recurrence rates and incidence of neurological sequelae than children with APCA. CONCLUSION: Immune-associated acute ataxia is the main cause of pediatric acute ataxia, among which APCA is the most common phenotype. However, some immune-associated diseases, especially autoantibody-mediated disease, which has a higher recurrence rate and neurological sequelae account for an increasing proportion of pediatric acute ataxia. When children present with extracerebellar symptoms, abnormal cranial MRI or CSF results, and without prodromal infection, prudent differential diagnosis is recommended.

Clinical and functional characteristics, possible causes, and impact of chronic cough in patients with cerebellar ataxia, neuropathy, and bilateral vestibular areflexia syndrome (CANVAS).

Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is an hereditary autosomal recessive disease. Recent studies propose including chronic cough (CC) as a symptom of CANVAS. For 10 patients with CANVAS as genetically confirmed by biallelic expansion of the AAGG repeat motif (AAGGGexp) in intron 2 of replication factor C subunit 1 (RFC1), our aim was, as a multidisciplinary team, to describe clinical and functional characteristics and possible causes of CC following European Respiratory Society (ERS) recommendations, and to evaluate CC impact on quality of life (QoL) using self-administered questionnaires (Cough Severity Diary, Leicester Cough Questionnaire, Discrete Emotions Questionnaire, and EQ-5D-5L). In all 10 patients, the CC was a dry cough that developed several years prior to the neurological symptoms (mean 14.2 years); 7 patients had symptoms compatible with gastroesophageal reflux (GER), 5 with pathological GER diagnosed by 24-h esophageal pH testing, and 6 patients had impaired esophageal motility diagnosed by high-resolution esophageal manometry, most frequently ineffective peristalsis. Although further studies are required for confirmation, we conclude that CC may be a characteristic prodrome of CANVAS and may be related to GER and esophageal disorders. Furthermore, CC affects patients' QoL, especially in the psychosocial sphere.

Investigation of RFC1 tandem nucleotide repeat locus in diverse neurodegenerative outcomes in an Indian cohort.

An intronic bi-allelic pentanucleotide repeat expansion mutation, (AAGGG)400-2000, at AAAAG repeat locus in RFC1 gene, is known as underlying genetic cause in cases with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) and late-onset sporadic ataxia. Biallelic positive cases carry a common recessive risk haplotype, "AAGA," spanning RFC1 gene. In this study, our aim is to find prevalence of bi-allelic (AAGGG)exp in Indian ataxia and other neurological disorders and investigate the complexity of RFC1 repeat locus and its potential association with neurodegenerative diseases in Indian population-based cohorts. We carried out repeat number and repeat type estimation using flanking PCR and repeat primed PCR (AAAAG/AAAGG/AAGGG) in four Indian disease cohorts and healthy controls. Haplotype assessment of suspected cases was done by genotyping and confirmed by Sanger sequencing. Blood samples and consent of all the cases and detailed clinical details of positive cases were collected in collaboration with A.I.I.M.S. Furthermore, comprehension of RFC1 repeat locus and risk haplotype analysis in Indian background was performed on the NGS data of Indian healthy controls by ExpansionHunter, ExpansionHunter Denovo, and PHASE analysis, respectively. Genetic screening of RFC1-TNR locus in 1998 uncharacterized cases (SCA12: 87; uncharacterized ataxia: 1818, CMT: 93) and 564 heterogenous controls showed that the frequency of subjects with bi-allelic (AAGGG)exp are 1.15%, < 0.05%, 2.15%, and 0% respectively. Two RFC1 positive sporadic late-onset ataxia cases, one bi-allelic (AAGGG)exp and another, (AAAGG)~700/(AAGGG)exp, had recessive risk haplotype and CANVAS symptoms. Long normal alleles, 15-27, are significantly rare in ataxia cohort. In IndiGen control population (IndiGen; N = 1029), long normal repeat range, 15-27, is significantly associated with A3G3 and some rare repeat motifs, AGAGG, AACGG, AAGAG, and AAGGC. Risk-associated "AAGA" haplotype of the original pathogenic expansion of A2G3 was found associated with the A3G3 representing alleles in background population. Apart from bi-allelic (AAGGG)exp, we report cases with a new pathogenic expansion of (AAAGG)exp/(AAGGG)exp in RFC1 and recessive risk haplotype. We found different repeat motifs at RFC1 TNR locus, like AAAAG, AAAGG, AAAGGG, AAAAGG, AAGAG, AACGG, AAGGC, AGAGG, and AAGGG, in Indian background population except ACAGG and (AAAGG)n/(AAGGG)n. Our findings will help in further understanding the role of long normal repeat size and different repeat motifs, specifically AAAGG, AAAGGG, and other rare repeat motifs, at the RFC1 locus.

A retrospective study of autoimmune cerebellar ataxia over a 20-year period in a single institution.

BACKGROUND: It is important to differentiate autoimmune cerebellar ataxia (ACA) from neurodegenerative CA, but this is sometimes difficult. We performed a retrospective study in a single institution in Japan over a 20-year period to reveal the clinical features of ACA. METHODS: Patients with CA as the primary neurological symptom were enrolled from those admitted to the Department of Neurology, Hokkaido University Hospital between April 2002 and March 2022. ACA was diagnosed retrospectively according to the following criteria: (1) CA being the predominant symptom; (2) identification of cancer within 2 years of onset; (3) improvement in cerebellar symptoms following immunotherapy; and (4) ruling out alternative causes of CA. Patients fulfilling criteria (1), (2), and (4) were classified as paraneoplastic cerebellar degeneration (PCD), while those fulfilling (1), (3), and (4) were classified as non-PCD and enrolled as patients with ACA. Neurodegenerative diseases, e.g., multiple system atrophy (MSA), were confirmed retrospectively based on generally used diagnostic criteria and enrolled. Furthermore, the ACA diagnostic criteria proposed by Dalmau and Graus were applied retrospectively to the ACA patients to examine the validity of the diagnoses. RESULTS: Among the 243 patients with CA, 13 were enrolled as ACA; five were PCD and eight were non-PCD. Eight of these cases met the proposed diagnostic criteria by Dalmau and Graus. MSA was the most prevalent disease among CA patients, with 93 cases. The incidence of cerebellar atrophy was significantly lower in ACA (3/13) than in MSA (92/92). Cerebrospinal fluid (CSF) pleocytosis was significantly more frequent in ACA than in MSA (4/13 vs. 2/55, respectively). However, there was no significant difference in the presence of oligoclonal bands, increased protein in CSF, and laterality differences in ataxia. CONCLUSION: ACA was present in ~ 5% of Japanese CA patients. The absence of cerebellar atrophy, despite the presence of CA, strongly supports ACA over MSA. While CSF pleocytosis was observed more often in ACA, the positivity rate was only ~ 30%. Since ACA is treatable, further studies are needed to identify additional clinical features and accurate diagnostic biomarkers.

Pseudo-eye-of-the-tiger sign in cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS).

The well-known eye-of-the-tiger sign features bilateral and symmetrical changes in the globus pallidus, with a central area of high signal and peripheral low signal on T2-weighted MRI. Although formally considered pathognomonic of pantothenate kinase-associated neurodegeneration (PKAN), there are other neurodegenerative or genetic diseases showing similar findings. Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a late-onset ataxia, that was recently associated with biallelic AAGGG repeat expansion in the RFC1 gene. Although its predominant MRI finding is cerebellar atrophy, there may be other less common associated findings. Our aim is to present two cases of CANVAS with associated (pseudo-)eye-of-the-tiger sign, highlighting the possibility of yet another differential diagnosis for this imaging sign.

Clinical and genetic analyses of a Swedish patient series diagnosed with ataxia.

Hereditary ataxia is a heterogeneous group of complex neurological disorders. Next-generation sequencing methods have become a great help in clinical diagnostics, but it may remain challenging to determine if a genetic variant is the cause of the patient's disease. We compiled a consecutive single-center series of 87 patients from 76 families with progressive ataxia of known or unknown etiology. We investigated them clinically and genetically using whole exome or whole genome sequencing. Test methods were selected depending on family history, clinical phenotype, and availability. Genetic results were interpreted based on the American College of Medical Genetics criteria. For high-suspicion variants of uncertain significance, renewed bioinformatical and clinical evaluation was performed to assess the level of pathogenicity. Thirty (39.5%) of the 76 families had received a genetic diagnosis at the end of our study. We present the predominant etiologies of hereditary ataxia in a Swedish patient series. In two families, we established a clinical diagnosis, although the genetic variant was classified as "of uncertain significance" only, and in an additional three families, results are pending. We found a pathogenic variant in one family, but we suspect that it does not explain the complete clinical picture. We conclude that correctly interpreting genetic variants in complex neurogenetic diseases requires genetics and clinical expertise. The neurologist's careful phenotyping remains essential to confirm or reject a diagnosis, also by reassessing clinical findings after a candidate genetic variant is suggested. Collaboration between neurology and clinical genetics and combining clinical and research approaches optimizes diagnostic yield.

Can CANVAS due to RFC1 biallelic expansions present with pure ataxia?

BACKGROUND: Biallelic expansion of AAGGG in the replication factor complex subunit 1 (RFC1) was identified as a major cause of cerebellar ataxia, neuropathy (sensory ganglionopathy, or SG) and vestibular areflexia syndrome (CANVAS). We wanted to clarify if RFC1 expansions can present with pure ataxia and if such expansions could be responsible for some cases where an alternative diagnosis had been made. METHODS: We identified patients with a combination of ataxia and SG and no other cause found, patients where an alternative diagnosis had been made, and patients with pure ataxia. Testing for RFC1 expansions was done using established methodology. RESULTS: Among 54 patients with otherwise idiopathic sporadic ataxia without SG, none was found to have RFC1 expansions. Among 38 patients with cerebellar ataxia and SG in which all other causes were excluded, 71% had RFC1 expansions. Among 27 patients with cerebellar ataxia and SG diagnosed with coeliac disease or gluten sensitivity, 15% had RFC1 expansions. CONCLUSIONS: Isolated cerebellar ataxia without SG makes the diagnosis of CANVAS due to RFC1 expansions highly improbable, but CANVAS is frequently the cause of the combination of idiopathic cerebellar ataxia with SG. It is important to screen patients diagnosed with other causes of acquired ataxia and SG as a small percentage were found to have RFC1 expansions.

Prognostic and relapsing factors of primary autoimmune cerebellar ataxia: a prospective cohort study.

OBJECTIVE: The objective of this study was to investigate the factors influencing relapse and prognosis in patients with primary autoimmune cerebellar ataxia (PACA), an area previously not well understood. METHODS: This prospective cohort study included patients who satisfied the modified diagnostic criteria of PACA. A modified Rankin scale score ≤ 2 at the last follow-up was defined as a favorable prognosis. Cox and Logistic regression were utilized to identify relapsing and prognostic factors, respectively. RESULTS: A total of 68 patients were included and 35.3% were male. The median onset age was 42.9 years (IQR 22.1-54.0). Neuronal autoantibodies were detected in 33 (50.8%) patients. Of the 65 patients who received first-line immunotherapy, 55 (84.6%) were responsive and 10 (15.4%) were not. Responsiveness to first-line immunotherapy emerged as an independent factor for favorable prognosis (HR 16.762; 95% CI 2.877-97.655; p = 0.002), as did the absence of peripheral neuropathy/radiculopathy (HR 14.286; 95% CI 2.41-83.333; p = 0.003). Relapses occurred in 19 (27.9%) patients. Onset age ≤ 43 years (HR 5.245; 95% CI 1.499-18.35; p = 0.009), presence of peripheral neuropathy/radiculopathy (HR 4.280; 95% CI 1.622-11.298; p = 0.003) and elevated cerebrospinal fluid (CSF) protein concentration (HR 3.443; 95% CI 1.083-10.951; p = 0.036) were statistically significant relapsing factors. CONCLUSION: This study identified younger onset age, presence of peripheral neuropathy/radiculopathy and elevated CSF protein concentration as relapsing factors, and absence of peripheral neuropathy/radiculopathy and responsiveness to first-line immunotherapy as independent factors for favorable prognosis in PACA patients. These findings may guide individualized treatment strategies and potentially improve patient outcomes.

Unraveling the genetic landscape of undiagnosed cerebellar ataxia in Brazilian patients.

INTRODUCTION: Hereditary ataxias (HAs) encompass a diverse and genetically intricate group of rare neurodegenerative disorders, presenting diagnostic challenges. Whole-exome sequencing (WES) has significantly improved diagnostic success. This study aimed to elucidate genetic causes of cerebellar ataxia within a diverse Brazilian cohort. METHODS: Biological samples were collected from individuals with sporadic or familial cerebellar ataxia, spanning various ages and phenotypes, excluding common SCAs and Friedreich ataxia. RFC1 biallelic AAGGG repeat expansion was screened in all patients. For AAGGG-negative cases, WES targeting 441 ataxia-related genes was performed, followed by ExpansionHunter analysis for repeat expansions, including the recently described GGC-ZFHX3. Variant classification adhered to ClinGen guidelines, yielding definitive or probable diagnoses. RESULTS: The study involved 76 diverse Brazilian families. 16 % received definitive diagnoses, and another 16 % received probable ones. RFC1-related ataxia was predominant, with two definitive cases, followed by KIF1A (one definitive and one probable) and SYNE-1 (two probable). Early-onset cases exhibited higher diagnostic rates. ExpansionHunter improved diagnosis by 4 %.We did not detected GGC-ZFHX3 repeat expansion in this cohort. CONCLUSION: This study highlights diagnostic complexities in cerebellar ataxia, even with advanced genetic methods. RFC1, KIF1A, and SYNE1 emerged as prevalent mutations. ZFHX3 repeat expansion seem to be rare in Brazilian population. Early-onset cases showed higher diagnostic success. WES coupled with ExpansionHunter holds promise as a primary diagnostic tool, emphasizing the need for broader NGS accessibility in Brazil.

Clinical and genetic keys to cerebellar ataxia due to FGF14 GAA expansions.

BACKGROUND: SCA27B caused by FGF14 intronic heterozygous GAA expansions with at least 250 repeats accounts for 10-60% of cases with unresolved cerebellar ataxia. We aimed to assess the size and frequency of FGF14 expanded alleles in individuals with cerebellar ataxia as compared with controls and to characterize genetic and clinical variability. METHODS: We sized this repeat in 1876 individuals from France sampled for research purposes in this cross-sectional study: 845 index cases with cerebellar ataxia and 324 affected relatives, 475 controls, as well as 119 cases with spastic paraplegia, and 113 with familial essential tremor. FINDINGS: A higher frequency of expanded allele carriers in index cases with ataxia was significant only above 300 GAA repeats (10.1%, n = 85) compared with controls (1.1%, n = 5) (p < 0.0001) whereas GAA250-299 alleles were detected in 1.7% of both groups. Eight of 14 index cases with GAA250-299 repeats had other causal pathogenic variants (4/14) and/or discordance of co-segregation (5/14), arguing against GAA causality. We compared the clinical signs in 127 GAA≥300 carriers to cases with non-expanded GAA ataxia resulting in defining a key phenotype triad: onset after 45 years, downbeat nystagmus, episodic ataxic features including diplopia; and a frequent absence of dysarthria. All maternally transmitted alleles above 100 GAA were unstable with a median expansion of +18 repeats per generation (r2 = 0.44; p < 0.0001). In comparison, paternally transmitted alleles above 100 GAA mostly decreased in size (-15 GAA (r2 = 0.63; p < 0.0001)), resulting in the transmission bias observed in SCA27B pedigrees. INTERPRETATION: SCA27B diagnosis must consider both the phenotype and GAA expansion size. In carriers of GAA250-299 repeats, the absence of documented familial transmission and a presentation deviating from the key SCA27B phenotype, should prompt the search for an alternative cause. Affected fathers have a reduced risk of having affected children, which has potential implications for genetic counseling. FUNDING: This work was supported by the Fondation pour la Recherche Médicale, grant number 13338 to JLM, the Association Connaître les Syndrome Cérébelleux - France (to GS) and by the European Union's Horizon 2020 research and innovation program under grant agreement No 779257 ("SOLVE-RD" to GS). DP holds a Fellowship award from the Canadian Institutes of Health Research (CIHR). SK received a grant (01GM1905C) from the Federal Ministry of Education and Research, Germany, through the TreatHSP network. This work was supported by the Australian Government National Health and Medical Research Council grants (GNT2001513 and MRFF2007677) to MB and PJL.

Modified Recurrence Quantification Analysis for Objective Assessment of Cerebellar Ataxia.

Cerebellar Ataxia (CA) is a neurological condition that affects coordination, balance and speech. Assessing its severity is important for developing effective treatment and rehabilitation plans. Traditional assessment methods involve a clinician instructing a person with ataxia to perform tests and assigning a severity score based on their performance. However, this approach is subjective as it relies on the clinician's experience, and can vary between clinicians. To address this subjectivity, some researchers have developed automated assessment methods using signal processing and data-driven approaches, such as supervised machine learning. These methods still rely on subjective ground truth and can perform poorly in real-world scenarios. This research proposed an alternative approach that uses signal processing to modify recurrence plots and compare the severity of ataxia in a person with CA to a control cohort. The highest correlation score obtained was 0.782 on the back sensor with the feet-apart and eyes-open test. The contributions of the research include modifying the recurrence plot as a measurement tool for assessing CA severity, proposing a new approach to assess severity by comparing kinematic data between people with CA and a control reference group, and identifying the best subtest and sensor position for practical use in CA assessments.

A Study of Upper-Limb Motion using Kinematic Measures for Clinical Assessment of Cerebellar Ataxia.

Cerebellar Ataxia (CA) is a group of diseases affecting the cerebellum, which is responsible for movement coordination. It causes uncoordinated movements and can also impact balance, speech, and eye movements. There are no approved disease-modifying medications for CA, so clinical studies to assess potential treatments are crucial. These studies require robust, objective measurements of CA severity to reflect changes in the progression of the disease due to medication. In recent years, studies have used kinematic measures to evaluate CA severity, but the current method relies on subjective clinical observations and is insufficient for telehealth. There is a need for a non-intrusive system that can monitor people with CA regularly to better understand the disease and develop an automated assessment system. In this study, we analyzed kinematic measures of upper-limb movements during a ballistic tracking test, which primarily involves movements at the shoulder joint. We aimed to understand the challenges of identifying CA and evaluating its severity when measuring such movements. Statistical features of the kinematic signals were used to develop machine learning models for classification and regression. The Gradient Boosting Classifier model had a maximum accuracy of 74%, but the models had low specificity and performed poorly in regression, suggesting that kinematic measures from shoulder-dominated movements during ballistic tracking are not as viable for CA assessment as other measures.

A Case Report of SYNE1 Deficiency-Mimicking Mitochondrial Disease and the Value of Pangenomic Investigations.

Mitochondrial disorders are characterized by a huge clinical, biochemical, and genetic heterogeneity, which poses significant diagnostic challenges. Several studies report that more than 50% of patients with suspected mitochondrial disease could have a non-mitochondrial disorder. Thus, only the identification of the causative pathogenic variant can confirm the diagnosis. Herein, we describe the diagnostic journey of a family suspected of having a mitochondrial disorder who were referred to our Genetics Department. The proband presented with the association of cerebellar ataxia, COX-negative fibers on muscle histology, and mtDNA deletions. Whole exome sequencing (WES), supplemented by a high-resolution array, comparative genomic hybridization (array-CGH), allowed us to identify two pathogenic variants in the non-mitochondrial SYNE1 gene. The proband and her affected sister were found to be compound heterozygous for a known nonsense variant (c.13258C>T, p.(Arg4420Ter)), and a large intragenic deletion that was predicted to result in a loss of function. To our knowledge, this is the first report of a large intragenic deletion of SYNE1 in patients with cerebellar ataxia (ARCA1). This report highlights the interest in a pangenomic approach to identify the genetic basis in heterogeneous neuromuscular patients with the possible cause of mitochondrial disease. Moreover, even rare copy number variations should be considered in patients with a phenotype suggestive of SYNE1 deficiency.