Ataxia Syndrome Research Articles

A Rare Case of Paroxysmal Kinesigenic Dyskinesia with Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

Abstract Paroxysmal kinesigenic dyskinesia (PKD) represents a rare subset of movement disorders characterized by involuntary movements triggered by sudden voluntary actions, without loss of consciousness. Typically manifesting in the first or second decade of life, PKD can present as either familial or sporadic, with the most common mutation identified in familial cases being in the proline-rich transmembrane protein 2 gene. This abstract presents a unique case of PKD accompanied by a progressive spastic ataxic syndrome in a 17-year-old male with a history of consanguinity. The patient exhibited a constellation of symptoms including delayed motor milestones, unsteady gait, slurred speech, and dystonic movements, alongside neurological findings consistent with cerebellar dysfunction and peripheral neuropathy. Genetic testing revealed pathogenic variants in the SACS gene, confirming the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay. This case underscores the importance of thorough neurological evaluation, including consideration of atypical presentations, in patients with PKD. In addition, it sheds light on the association between SACS gene mutations and an autosomal recessive variant of PKD, emphasizing the need for awareness and recognition of such rare manifestations in clinical practice.

A rare case of peripheral facial paralysis associated with meningococcal meningitis - case report

Introduction. Meningococcal meningitis is a severe form of bacterial meningitis caused by the bacterium Neisseria meningitidis (N. meningitidis). It is a medical emergency and requires prompt treatment to prevent severe complications or death. Peripheral facial paralysis is one of the rare complications that can occur in this condition. Aim. This paper aimed to draw attention to the possibility of an unexpected complication in a child with meningococcal meningitis, which requires prompt clinical and paraclinical management. Materials and methods. We present the case of a 2-year and 8-month-old female patient who, in the context of meningococcal meningitis, develops peripheral facial paralysis, a very rare complication, especially in the pediatric population. Results. The patient initially presented with clinical and paraclinical signs of a respiratory viral infection. However, in a febrile context, she has two generalized tonic-clonic paroxysmal episodes, characterized by gaze fixation, each lasting 2-3 minutes, followed by spontaneous recovery. Laboratory tests revealed neutrophilia, anemia, and elevated inflammatory markers, while the cranio-cerebral CT scan showed no structural changes. Blood cultures were also collected, and treatment was initiated with third-generation cephalosporin antibiotics, along with supportive and symptomatic therapy. The following day, the patient exhibited signs of right-sided peripheral facial paralysis, and intravenous corticosteroid therapy was added to the treatment. Approximately 24 hours after admission, the blood culture tested positive for gram-negative cocci, suggesting meningococcal meningitis. A cerebral MRI was performed, revealing changes indicative of acute meningoencephalitis. The clinical and paraclinical course was slowly favorable, with a slight persistence of facial asymmetry and intermittent ataxic syndrome. Conclusions. Meningococcal meningitis remains a relevant pathology in the pediatric population, able of causing severe complications that can result in long-term disability for the patient. Prompt treatment is crucial when this condition is suspected.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS): a family with five affected sibs from Turkey

BackgroundCerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS), a relatively common cause of late-onset progressive ataxia, is a genetic disease characterised by biallelic pentanucleotide AAGGG repeat expansion in intron 2 of the replication factor complex subunit 1 gene. Herein, we describe the first molecularly confirmed CANVAS family with five affected siblings from Turkey.Case presentationThe family comprised seven siblings born from healthy non-consanguineous parents. CANVAS phenotype was present in five of them; two were healthy and asymptomatic. Chronic cough was the first symptom reported in all five siblings, followed by the development of sensory symptoms, oscillopsia and imbalance. Clinical head impulse test (HIT) was positive in all cases and video HIT performed on three patients revealed very low vestibulo-ocular reflex gains bilaterally. Magnetic resonance imaging and nerve conduction studies revealed cerebellar atrophy and sensory neuronopathy, respectively. RP-PCR confirmed the homozygous presence of the AAGGG repeat expansion in all five cases.ConclusionGenetic screening for CANVAS should be considered in all patients with late-onset ataxia, sensory disturbances and vestibular involvement, especially in the presence of chronic cough.

From dynamic FMR1 mutation to variable phenotypes: A case series from a large Tunisian family

AbstractBackgroundFragile X messenger ribonucleoprotein 1 gene (FMR1) disorders result from a mutation in the FMR1 gene, leading to a deficiency or absence of the FMRP. Full mutations and premutations of the FMR1 gene are known to cause completely different symptoms.AimTo determine the clinical phenotype of individuals with a full mutation or premutation of the FMR1 gene.MethodsWe report 6 patients of the same Tunisian family with different clinical phenotypes. We gathered recent findings on the clinical spectrum of FMR1 mutations from 2020 to 2024 using PubMed, Google Scholar, ScienceDirect, and Web of Science.ResultsOur observations revealed two first cousins, aged 4 and 13 years, respectively, with a medical history of recurrent infections. They exhibited developmental delay, hyperactivity, concentration difficulties, and autistic traits, with characteristic facial dysmorphia. Family investigation revealed a history of early menopause and primary ovary insufficiency diagnosis in their mothers and one aunt. The 79‐year‐old grandfather presented with recent memory and sleep disturbances, with signs suggestive of fragile X‐associated tremor/ataxia syndrome (FXTAS) on brain MRI. The genetic assessment confirmed the fragile X syndrome (FXS) in children and the fragile X‐associated primary ovarian insufficiency (FXPOI) in their mothers. Our search in literature uncovered a genetically diverse disorder exhibiting clinical variability influenced by factors such as gene size, methylation mosaicism, and the presence of premutations or full mutations, alongside various pathophysiological mechanisms.ConclusionClinical signs highlighted in our family report should alert clinicians to consider FXS, particularly facial dysmorphia and intellectual disability or language developmental delay, FXPOI for early menopause, and FXTAS for tremor and ataxia within the family context of FXS.

Language use predicts symptoms of fragile X-associated tremor/ataxia syndrome in men and women with the FMR1 premutation

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an age-related neurodegenerative disorder caused by a premutation of the FMR1 gene on the X chromosome. Despite the pervasive physical and cognitive effects of FXTAS, no studies have examined language in symptomatic males and females, limiting utility as an outcome measure in clinical trials of FXTAS. The goal of this work is to determine (a) the extent to which male and female FMR1 premutation carriers with FXTAS symptoms differ in their language use and (b) whether language production predicts FXTAS symptoms. Thirty-one individuals with the FMR1 premutation (21M, 10F), ages 58–85 years with some symptoms of FXTAS, were recruited from a larger cross-sectional study. Participants completed a five-minute monologic language sample. Language transcripts were assessed for rate of dysfluencies, lexical-semantics, syntax, and speech rate. Multivariable linear and ordinal regressions were used to predict FXTAS-associated symptoms, cognitive functioning, and executive functioning. Males and females did not differ in their language use. Language production predicted FXTAS symptom severity, cognitive functioning, and executive functioning. Language production difficulties may co-occur with FXTAS-associated symptoms and may be a viable outcome measure in future clinical trials, with future research needed.

Nerve ultrasound in CANVAS-spectrum disease: Reduced nerve size distinguishes genetically confirmed CANVAS from other axonal polyneuropathies.

Ultrasound nerve cross-sectional area (CSA) of patients affected with axonal neuropathy usually shows normal value. Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) seems to represent an exception, showing smaller CSA, but previous reports did not test for biallelic RFC1 gene repeat expansions. We compared nerve CSA from CANVAS patients (tested positive for biallelic RFC1 gene repeat expansions) with the CSA from a group of patients with chronic idiopathic axonal polyneuropathy (CIAP) who tested negative for RFC1 gene repeat expansions, hereditary axonal neuropathy (Charcot-Marie-Tooth type 2, CMT2), and Friedreich ataxia (FRDA). We enrolled 15 CANVAS patients (eight men, mean age 66.3 ± 11.5 years, mean disease duration 9.3 ± 4.1 years), affected with sensory axonal neuronopathy. Controls consisted of 13 CIAP (mean age 68.5 ± 12.8 years, seven men), seven CMT2 (mean age 47.9 ± 18.1 years, four men), 12 FRDA (mean age 33.7 ± 8.8, five men). Nerve ultrasound was performed at median, ulnar, sciatic, sural, and tibial nerves and brachial plexus, bilaterally. The nerve CSA from CANVAS patients was significantly smaller than the one from the other cohorts at several sites with significant and high accuracy at Receiver-operating characteristic (ROC) curve analyses. RFC1 AAGGG pentanucleotide expansion, disease duration, and disability did not correlate with CSA at any site, after Bonferroni correction. Decreased sonographic nerve sizes, in arms and legs, in patients with sensory neuropathy and normal motor conduction studies could point to CANVAS-spectrum disease and help guide appropriate genetic testing.

Phenotypic variability related to dominant UCHL1 mutations: about three families with optic atrophy and ataxia.

Ubiquitin C-terminal hydrolase L1 (UCHL1) has been associated with a severe, complex autosomal recessive spastic paraplegia (HSP79) [1] [2] [3][4]. More recently, UCHL1 loss of function (LoF) variants have been associated to an autosomal dominant disease characterized by late-onset spastic ataxia, neuropathy, and frequent optic atrophy [5]. Routine clinical care whole-genome (WGS) and exome (ES) sequencing. We present three families with autosomal dominant UCHL1-related disorder. The clinical phenotype mainly associated optic atrophy, mixed cerebellar and sensory ataxia, and possible hearing loss. We delineated two major phenotypes, even within the same family: (1) juvenile severe optic atrophy followed by a later-onset ataxia, or (2) late-onset ataxia with asymptomatic or mild optic atrophy. The families harboured three novel heterozygous variants in UCHL1: two loss of function (p.Lys115AsnfsTer40; c.171_174 + 7del11), and one missense (p.Asp176Asn) involving the catalytic site of the protein and potentially altering the adjacent splice site. We confirm the existence of dominantly inherited UCHL1 pathogenic variants. We describe a considerable intrafamilial phenotypic variability, with two main phenotypes. Optic atrophy was consistently present, but with varying degrees of severity. Neither delayed motor or intellectual development, nor dysmorphic features were part of the dominant phenotype in comparison with the autosomal recessive form. The molecular mechanism appears to be haploinsufficiency. UCHL1 monoallelic variants should therefore be considered in any case of early-onset optic atrophy or in late-onset complex ataxic syndrome with asymptomatic optic atrophy.

Efficacy and safety of riluzole for treating motor function in rare dyskinesia syndromes: a systematic review with meta-analysis.

We conducted a systematic review and meta-analysis to evaluate the clinical effectiveness and safety of riluzole to treat neurodegenerative dyskinesia in patients, using the Cochrane collaboration guidelines. We searched databases including Medline, Embase, and Cochrane without any language filters. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was used as a guideline, and the study protocol was registered in PROSPERO (CRD42022354627). Eleven studies involving 1376 patients were included. There was a significant overall effect of riluzole on changes in motor function scores. However, the level of heterogeneity was I2 = 74%. In the subgroup analyses, there were no significant effects of riluzole on motor scores in hereditary ataxia, Parkinson's disease, or Huntington's disease. In the sensitivity analysis, there were no significant effects of riluzole on motor function scores. Furthermore, there were no significant differences in adverse events between the riluzole and placebo groups. Although riluzole may not have significant efficacy for improving motor function in neurodegenerative dyskinesia syndromes compared with placebo, it seems to have an acceptable safety profile. Moreover, it may be effective for hereditary ataxia syndromes, although there was a relatively small effect size and limited quality of evidence.

Patterns of the Health and Economic Burden of 33 Rare Diseases in China: Nationwide Web-Based Study.

Rare diseases (RDs) affect millions of individuals collectively worldwide, contributing to significant burdens on patients and families in various aspects. However, there is a lack of evidence on the underlying patterns of burdens among diverse RDs for informing targeted social and health policies to address the unmet needs of this vulnerable population. This study aimed to examine the underlying patterns of the health and economic burden of 33 different RDs in China and identify the potential determinants. A nationwide internet-based cross-sectional survey was conducted in China between 2019 and 2020. Physical and mental health burden was measured by health-related quality of life. Economic burden was evaluated based on the proportions of direct medical, direct nonmedical, and indirect costs relative to household income. We used cluster analysis to identify patterns of health and economic burdens and conducted multinomial logistic regression to explore potential predictors of cluster membership. The study included 8454 adults and 8491 children affected by 33 RDs. The following 3 clusters were identified: "extremely high burden" (representing 92/8454, 1.1% and 19/8491, 0.2% of adult and pediatric patients, respectively), "overall high burden" (5933/8454, 70.2% and 4864/8491, 57.3%, respectively), and "overall low burden" (2429/8454, 28.7% and 3608/8491, 42.5%, respectively). Wilson disease, Marfan syndrome, and Langerhans cell histiocytosis more likely resulted in an "extremely high burden" than others. Poverty was significantly associated with being in this extremely high burden group. Diseases causing neuromuscular symptoms and requiring long-term treatment (eg, amyotrophic lateral sclerosis, spinocerebellar ataxia, and Dravet syndrome) were prevalent in the "overall high burden" group. Key predictors of this group included older age, lower socioeconomic status, diagnostic delay, and comorbidity. This study provides novel and valuable evidence on the burden of RDs in developing regions like China. The findings reveal significant disparities in the impact of RDs, emphasizing the need for targeted health care interventions and policies.

Pathological Role of High Sugar in Mitochondrial Respiratory Chain Defect-Augmented Mitochondrial Stress.

According to many research groups, high glucose induces the overproduction of superoxide anions, with reactive oxygen species (ROS) generally being considered the link between high glucose levels and the toxicity seen at cellular levels. Respiratory complex anomalies can lead to the production of ROS. Calcium [Ca2+] at physiological levels serves as a second messenger in many physiological functions. Accordingly, mitochondrial calcium [Ca2+]m overload leads to ROS production, which can be lethal to the mitochondria through various mechanisms. F1F0-ATPase (ATP synthase or complex V) is the enzyme responsible for catalyzing the final step of oxidative phosphorylation. This is achieved by F1F0-ATPase coupling the translocation of protons in the mitochondrial intermembrane space and shuttling them to the mitochondrial matrix for ATP synthesis to take place. Mitochondrial complex V T8993G mutation specifically blocks the translocation of protons across the intermembrane space, thereby blocking ATP synthesis and, in turn, leading to Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP) syndrome. This study seeks to explore the possibility of [Ca2+]m overload mediating the pathological roles of high glucose in defective respiratory chain-mediated mitochondrial stress. NARP cybrids are the in vitro experimental models of cells with F1FO-ATPase defects, with these cells harboring 98% of mtDNA T8993G mutations. Their counterparts, 143B osteosarcoma cell lines, are the parental cell lines used for comparison. We observed that NARP cells mediated and enhanced the death of cells (apoptosis) when incubated with hydrogen peroxide (H2O2) and high glucose, as depicted using the MTT assay of cell viability. Furthermore, using fluorescence probe-coupled laser scanning confocal imaging microscopy, NARP cells were found to significantly enable mitochondrial reactive oxygen species (mROS) formation and enhance the depolarization of the mitochondrial membrane potential (ΔΨm). Elucidating the mechanisms of sugar-enhanced toxicity on the mitochondria may, in the future, help to alleviate the symptoms of patients with NARP syndromes and other neurodegenerative diseases.

Psychiatric Manifestations in Early to Middle Stages of Fragile X-Associated Tremor-Ataxia Syndrome (FXTAS).

The purpose of the present study was to assess the psychiatric manifestations of early to middle stages of fragile X-associated tremor-ataxia syndrome (FXTAS) and their relationship with executive function and FMR1 cytosine-guanine-guanine (CGG) repeat numbers across genders. Cross-sectional data from 100 participants (62 men, 38 women; mean±SD age=67.11±7.90 years) with FXTAS stage 1, 2, or 3 were analyzed, including demographic information, cognitive measures, psychiatric assessments (Symptom Checklist-90-Revised and Behavioral Dyscontrol Scale-II [BDS-II]), and CGG repeat number. Participants with FXTAS stage 3 exhibited significantly worse psychiatric outcomes compared with participants with either stage 1 or 2, with distinct gender-related differences. Men showed differences in anxiety and hostility between stage 3 and combined stages 1 and 2, whereas women exhibited differences in anxiety, depression, interpersonal sensitivity, obsessive-compulsive symptoms, and somatization, as well as in the Global Severity Index, the Positive Symptom Distress Index, and the Positive Symptom Total. Among male participants, negative correlations were observed between BDS-II total scores and obsessive-compulsive symptoms, as well as between anxiety and CGG repeat number. These findings suggest that even at early FXTAS stages, patients have significant cognitive and other psychiatric symptoms, with notable gender-specific differences. This study underscores the clinical and prognostic relevance of comorbid psychiatric conditions in FXTAS, highlighting the need for early intervention and targeted support for individuals with relatively mild motor deficits.

Expanding the genetic and phenotypic landscape of replication factor C complex-related disorders: RFC4 deficiency is linked to a multisystemic disorder

The precise regulation of DNA replication is vital for cellular division and genomic integrity. Central to this process is the replication factor C (RFC) complex, encompassing five subunits, which loads proliferating cell nuclear antigen onto DNA to facilitate the recruitment of replication and repair proteins and enhance DNA polymerase processivity. While RFC1's role in cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is known, the contributions of RFC2-5 subunits on human Mendelian disorders is largely unexplored. Our research links bi-allelic variants in RFC4, encoding a core RFC complex subunit, to an undiagnosed disorder characterized by incoordination and muscle weakness, hearing impairment, and decreased body weight. We discovered across nine affected individuals rare, conserved, predicted pathogenic variants in RFC4, all likely to disrupt the C-terminal domain indispensable for RFC complex formation. Analysis of a previously determined cryo-EM structure of RFC bound to proliferating cell nuclear antigen suggested that the variants disrupt interactions within RFC4 and/or destabilize the RFC complex. Cellular studies using RFC4-deficient HeLa cells and primary fibroblasts demonstrated decreased RFC4 protein, compromised stability of the other RFC complex subunits, and perturbed RFC complex formation. Additionally, functional studies of the RFC4 variants affirmed diminished RFC complex formation, and cell cycle studies suggested perturbation of DNA replication and cell cycle progression. Our integrated approach of combining in silico, structural, cellular, and functional analyses establishes compelling evidence that bi-allelic loss-of-function RFC4 variants contribute to the pathogenesis of this multisystemic disorder. These insights broaden our understanding of the RFC complex and its role in human health and disease.

Comprehensive Analysis of a Japanese Pedigree with Biallelic ACAGG Expansions in RFC1 Manifesting Motor Neuronopathy with Painful Muscle Cramps.

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is an autosomal recessive multisystem neurologic disorder caused by biallelic intronic repeats in RFC1. Although the phenotype of CANVAS has been expanding via diagnostic case accumulation, there are scant pedigree analyses to reveal disease penetrance, intergenerational fluctuations in repeat length, or clinical phenomena (including heterozygous carriers). We identified biallelic RFC1 ACAGG expansions of 1000 ~ repeats in three affected siblings having sensorimotor neuronopathy with spinocerebellar atrophy initially presenting with painful muscle cramps and paroxysmal dry cough. They exhibit almost homogeneous clinical and histopathological features, indicating motor neuronopathy. Over 10years of follow-up, painful intractable muscle cramps ascended from legs to trunks and hands, followed by amyotrophy and subsequent leg pyramidal signs. The disease course combined with the electrophysical and imagery data suggest initial and prolonged hyperexcitability and the ensuing spinal motor neuron loss, which may progress from the lumbar to the rostral anterior horns and later expand to the corticospinal tract. Genetically, heterozygous ACAGG expansions of similar length were transmitted in unaffected family members of three successive generations, and some of them experienced muscle cramps. Leukocyte telomere length assays revealed comparatively shorter telomeres in affected individuals. This comprehensive pedigree analysis demonstrated a non-anticipating ACAGG transmission and high penetrance of manifestations with a biallelic state, especially motor neuronopathy in which muscle cramps serve as a prodromal and disease progress marker. CANVAS and RFC1 spectrum disorder should be considered when diagnosing lower dominant motor neuron disease, idiopathic muscle cramps, or neuromuscular hyperexcitability syndromes.

Apolipoproteine and KLOTHO Gene Variants Do Not Affect the Penetrance of Fragile X-Associated Tremor/Ataxia Syndrome.

In this study, the potential role and interaction of the APOε and KLOTHO genes on the penetrance of fragile X-associated tremor/ataxia syndrome (FXTAS) and on the IQ trajectory were investigated. FXTAS was diagnosed based on molecular, clinical and radiological criteria. Males with the premutation (PM) over 50 years, 165 with and 34 without an FXTAS diagnosis, were included in this study and were compared based on their APO (ε2-ε3-ε4) and KLOTHO variant (KL-VS) genotypes. The effect of APOε4 on FXTAS stage and on diagnosis did not differ significantly by KL-VS genotype with interaction effect p = 0.662 and p = 0.91, respectively. In the FXTAS individuals with an APOε2 allele, a marginal significance was observed towards a larger decline in verbal IQ (VIQ) in individuals with an APOε4 allele compared to those without an APOε4 allele (p = 0.071). In conclusion, our findings suggest that the APOε4 and KL-VS genotypes alone or through their interaction effect do not appear to predispose to either FXTAS diagnosis or stage in male carriers of the PM allele. A further study is needed to establish the trend of IQ decline in the FXTAS individuals who carry APOε4 with APOε2 compared to those without APOε4.

Whole genome joint analysis reveals ATM:C.1564_1565del variant segregating with Ataxia-Telangiectasia and breast cancer

ATM gene is implicated in the development of breast cancer in the heterozygous state, and Ataxia-telangiectasia (A-T) in a homozygous or compound heterozygous state. Ataxia-telangiectasia (A-T) is a rare cerebellar ataxia syndrome presenting with progressive neurologic impairment, telangiectasia, and an increased risk of leukemia and lymphoma.Although the role of ATM, separately, in association with A-T and breast cancer is well documented, there is a limited number of studies investigating ATM variants when segregating with both phenotypes in the same family. Here, using joint analysis and whole genome sequencing, we investigated ATM c.1564_1565del in a family with one homozygous member presenting with A-T (OMIM # 208900) and three heterozygous members, of whom one had breast cancer (OMIM #114480). To our knowledge, this is the first study of ATM c.1564_1565del segregation with both A-T and breast cancer phenotypes within the same kindred. This study highlights the need for a comprehensive genomic approach in the appropriate cancer risk management of heterozygote carriers of ATM in families with A-T.

Fragile X Syndrome and FMR1 premutation: results from a survey on associated conditions and treatment priorities in Italy

Background and objectivesFragile X Syndrome (FXS) is the most common cause of inherited intellectual disability, caused by CGG-repeat expansions (> 200) in the FMR1 gene leading to lack of expression. Espansion between 55 and 200 triplets fall within the premutation range (PM) and can lead to different clinical conditions, including fragile X- primary ovarian insufficiency (FXPOI), fragile X-associated neuropsychiatric disorders (FXAND) and fragile X-associated tremor/ataxia syndrome (FXTAS). Although there is not a current cure for FXS and for the Fragile X-PM associated conditions (FXPAC), timely diagnosis as well as the implementation of treatment strategies, psychoeducation and behavioral intervention may improve the quality of life (QoL) of people with FXS or FXPAC. With the aim to investigate the main areas of concerns and the priorities of treatment in these populations, the Italian National Fragile X Association in collaboration with Bambino Gesù Children’s Hospital, conducted a survey among Italian participants.MethodHere, we present a survey based on the previous study that Weber and colleagues conducted in 2019 and that aimed to investigate the main symptoms and challenges in American individuals with FXS. The survey has been translated into Italian language to explore FXS needs of treatment also among Italian individuals affected by FXS, family members, caretakers, and professionals. Furthermore, we added a section designated only to people with PM, to investigate the main symptoms, daily living challenges and treatment priorities.ResultsAnxiety, challenging behaviors, language difficulties and learning disabilities were considered the major areas of concern in FXS, while PM was reported as strongly associated to cognitive problems, social anxiety, and overthinking. Anxiety was reported as a treatment priority in both FXS and PM.ConclusionFXS and PM can be associated with a range of cognitive, affective, and physical health complications. Taking a patient-first perspective may help clinicians to better characterize the cognitive-behavioral phenotype associated to these conditions, and eventually to implement tailored therapeutic approaches.

Streamlined two-step fragment analysis PCR and exome sequencing of RFC1 for diagnostic testing of suspected CANVAS patients.

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is caused by biallelic pathogenic expansions, or compound heterozygosity with other pathogenic variants in the RFC1 gene. CANVAS is estimated to be underdiagnosed, both because of the lack of formal diagnostic criteria and molecular challenges that translate to lesser access and high cost of routine testing. Our aim was to address the need for making CANVAS genetic testing routine, by designing a streamlined two-step PCR consisting of a short-allele screening PCR and a confirmatory PCR with fragment capillary electrophoresis detection. Exome sequencing of RFC1 was additionally foreseen to resolve potential compound heterozygosity cases. Specificity of our approach was evaluated using ataxia patients with known non-CANVAS diagnoses, and optimized using Southern blot confirmed CANVAS patients. We evaluated our approach by testing patients consecutively referred for clinically suspected CANVAS using first the two-step PCR, followed by exome sequencing. Our approach was able to accurately identify negative and confirm positive cases in prospectively collected suspected CANVAS patients presenting with at least three typical clinical signs. The proposed testing approach provides an alternative method able to clearly distinguish between CANVAS negative and positive cases and can be easily incorporated into the genetic diagnostic laboratory workflow.

Infectious Cerebellitis Rare Entity About Two Cases

Introduction: Cerebellitis is an inflammatory pathology of cerebellar structures more common in children, frequently of post-infectious origin or following vaccination, seldom during a viral or bacterial infection. Ataxia is most frequently caused by dysfunction of the complex circuitry connecting the cerebellum, basal ganglia and cerebral cortex. Results: We report the case of 2 patients aged 3 and 10 years presenting acute cerebellitis of infectious origin: Ataxic syndrome associated with balance disorders and speech disorders and fever. The evolution was quickly favorable with corticosteroid therapy and proprioceptive physiotherapy. The absence of fatalities in our case report suggests early diagnosis, and steroid treatment can increase the chance of recovery. Discussion: Clinical presentations are deceptive and variable with cerebellar symptoms of acute kinetic and static ataxia with inflammatory signs. The treatment is based on steroids when symptoms are moderate to severe. Antimicrobial therapy should always be considered, because ataxia can be a presenting sign of both viral encephalitis and bacterial meningitis. The prognosis for acute cerebellitis is generally favorable. The courses vary from what is commonly a benign and self-limiting disease to what occasionally is fulminant disease resulting in several cerebellar damage or even sudden death. Conclusion: Recognizing ataxia in children can be difficult, which is why a lumbar punction should be considered if infectious cerebellitis is suspected. Most people fully recover, however there is a risk of lasting disability.

Saccade and pupil changes in children recovering from opsoclonus‐myoclonus ataxia syndrome reveal midbrain alterations in oculomotor circuits

Saccade and pupil changes in children recovering from opsoclonus‐myoclonus ataxia syndrome reveal midbrain alterations in oculomotor circuits

An Updated Canvas of the RFC1-mediated CANVAS (Cerebellar Ataxia, Neuropathy and Vestibular Areflexia Syndrome).

Proliferation of specific nucleotide sequences within the coding and non-coding regions of numerous genes has been implicated in approximately 40 neurodegenerative disorders. Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS), a neurodegenerative disorder, is distinguished by a pathological triad of sensory neuropathy, bilateral vestibular areflexia and cerebellar impairments. It manifests in adults gradually and is autosomal recessive and multi-system ataxia. Predominantly, CANVAS is associated with biallelic AAGGG repeat expansions in intron 2 of the RFC1 gene. Although various motifs have been identified, only a subset induces pathological consequences, by forming stable secondary structures that disrupt gene functions both in vitro and in vivo. The pathogenesis of CANVAS remains a subject of intensive research, yet its precise mechanisms remain elusive. Herein, we aim to comprehensively review the epidemiology, clinical ramifications, molecular mechanisms, genetics, and potential therapeutics in light of the current findings, extending an overview of the most significant research on CANVAS.