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![Frequency of the main genotypes of patients with autosomal recessive cerebellar ataxia (ARCA) in South America, including both molecularly defined ARCA and genetically still undetermined ARCA. The figure also depicts the main Ataxia Centers in South America that participated in this epidemiological investigation. FRDA, Friedreich's ataxia; AT, ataxia telangiectasia; ARSACS, autosomal recessive spastic ataxia of Charlevoix-Saguenay; NPC, Niemann-Pick type C; AOA, ataxia with oculomotor apraxia. [Color figure can be viewed at wileyonlinelibrary.com]](profile/Sergio-Rodriguez-Quiroga/publication/360378334/figure/fig1/AS:1169012100734977@1655725612853/Frequency-of-the-main-genotypes-of-patients-with-autosomal-recessive-cerebellar-ataxia.png)
Frequency of the main genotypes of patients with autosomal recessive cerebellar ataxia (ARCA) in South America, including both molecularly defined ARCA and genetically still undetermined ARCA. The figure also depicts the main Ataxia Centers in South America that participated in this epidemiological investigation. FRDA, Friedreich's ataxia; AT, ataxia telangiectasia; ARSACS, autosomal recessive spastic ataxia of Charlevoix-Saguenay; NPC, Niemann-Pick type C; AOA, ataxia with oculomotor apraxia. [Color figure can be viewed at wileyonlinelibrary.com]
Contexts in source publication
Context 1
... particular when now preparing for large-scale natural history and treatment trials in ARCAs. 1 This multicenter study aimed to retrospectively capture the frequency of the most common forms of ARCA across South America, combining data from 11 large ataxia centers in South America: one in Argentina, one in Chile, one in Peru, and eight in Brazil (Fig. ...
Context 2
... from each ataxia center were captured via a standardized questionnaire that included the following questions (see also the list in Fig. 1): (A) number of ARCA patients, defined as an ataxia patient with (i) a molecularly confirmed ARCA diagnosis or (ii) ataxia onset before age 40 years and negative but informative family history; (B) number of ARCA patients with genetic diagnosis versus no genetic diagnosis as of yet; and (C) number of patients of each genetic ARCA ...
Context 3
... (ii) ataxia onset before age 40 years and negative but informative family history; (B) number of ARCA patients with genetic diagnosis versus no genetic diagnosis as of yet; and (C) number of patients of each genetic ARCA subtype. The frequency of patients with specific genotypes was analyzed. A total of 1338 patients were included in this study ( Fig. 1) making it the largest ARCA frequency study to ...
Similar publications
Introduction. Autosomal recessive cerebellar ataxias (ARCAs) are inherited neurological disorders that can affect both thecentral and peripheral nervous systems. To assess the effects of interventions according to the perception of people affected, patient-reported outcome measures (PROMs) must be available.
Objective. This paper presents the deve...
Autosomal recessive cerebellar ataxias (ARCAs) are inherited neurological disorders that can affect both the central and peripheral nervous systems. To assess the effects of interventions according to the perception of people affected, patient-reported outcome measures (PROMs) must be available. This paper presents the development process of the Pe...
Citations
... Initial reports found RFC1 biallelic expansion in 33/150 (22%) of CANVAS or late-onset ataxia patients [1]. Later studies on late-onset, non-dominant cerebellar ataxia (CA) showed diagnostic yields of 1.5-15%, with differences across studies explained by factors like multiple system atrophy (MSA) patients' inclusion, prior genetic testing, family history, and ethnicity [7,15,39,57,69,70,[73][74][75][76][77]. In a study of 205 sporadic late-onset ataxia patients, expansions in the RFC1 gene were the second most common cause after SPG7 mutations, with 3/205 (1.5%) biallelic carriers [78]. ...
Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is a late-onset, autosomal recessive
neurodegenerative disorder characterised by the triad of cerebellar ataxia, bilateral vestibular areflexia, and sensory neuropathy.
First identified more than 30 years ago, its clinical phenotype has since expanded to include chronic cough, dysautonomia, and
pain, with isolated neuronopathy reported in some cases. The discovery of biallelic AAGGG repeat expansions in intron 2 of
the RFC1 gene in 2019 established the genetic basis for CANVAS, with the pathogenic expansions disrupting gene function via
secondary structures such as G-quadruplexes. Despite this breakthrough, the precise pathophysiological mechanisms behind
CANVAS remain elusive, necessitating further research into the molecular, clinical, and genetic aspects of this disease. This
review consolidates the current understanding of CANVAS, encompassing the expanding spectrum of RFC1-related disorders,
clinical manifestations, molecular underpinnings, and epidemiology, while exploring future directions for diagnostics and therapeutic advancements.
Keywords: cerebellar ataxia, sensory neuropathy, bilateral vestibular areflexia, RFC1 gene, AAGGG repeat expansion
... Autosomal recessive ataxias are a group of heterogeneous disorders which are different in terms of genetics and clinical features. Uncoordinated movements, peripheral neuropathy, gait imbalance, dysarthria, pyramidal tract dysfunction, and eye movement abnormalities can be seen in these patients [6,146,147]. In this section, the clinical presentation of most common autosomal recessive ataxias is briefly discussed focusing on the oculomotor alterations in each disease. ...
Cerebellar ataxias are a wide heterogeneous group of disorders that may present with fine motor deficits as well as gait and balance disturbances that have a significant influence on everyday activities. To review the ocular movements in cerebellar ataxias in order to improve the clinical knowledge of cerebellar ataxias and related subtypes. English papers published from January 1990 to May 2022 were selected by searching PubMed services. The main search keywords were ocular motor, oculomotor, eye movement, eye motility, and ocular motility, along with each ataxia subtype. The eligible papers were analyzed for clinical presentation, involved mutations, the underlying pathology, and ocular movement alterations. Forty-three subtypes of spinocerebellar ataxias and a number of autosomal dominant and autosomal recessive ataxias were discussed in terms of pathology, clinical manifestations, involved mutations, and with a focus on the ocular abnormalities. A flowchart has been made using ocular movement manifestations to differentiate different ataxia subtypes. And underlying pathology of each subtype is reviewed in form of illustrated models to reach a better understanding of each disorder.
... 65 % eine klare monogenetische Ursache [9]. Bei dieser Gruppe der genetisch gelösten früh beginnenden/autosomal-rezessiven Ataxien bleibt die häufigste genetische Ursache mit 50 % die Friedreich-Ataxie, mit deutlichem Abstand (alle jeweils < 10 %) gefolgt von RFC1, SPG7, autosomalrezessive Ataxie Charlevoix Saguenay (ARSACS) und Ataxia teleangiectasia (AT) [10]. ...
ZUSAMMENFASSUNG
Hereditäre Ataxien werden aufgrund ihrer genetischen Grundlage zu Vorreitern einer zielgerichteten molekularen Präzisionsmedizin in der Neurologie. Neben diversen Small-molecule-Ansätzen werden erste Antisense-Oligonukleotid (ASO)-Therapiestudien erwartet. Dabei gestaltet sich jedoch die vorausgehende klinisch-genetische Aufarbeitung degenerativer Ataxie-Erkrankungen schwierig, angesichts einer zunehmenden, selbst für Experten oftmals kaum überschaubaren Anzahl neuer – teils häufiger, teils extremst seltener – genetischer Ataxie-Erkrankungen. Die vorliegende Arbeit gibt eine pragmatische Orientierung für Nichtataxie-Experten für die klinisch-genetische Aufarbeitung von Patienten mit degenerativer Ataxie. Nach einer allgemeinen Einführung zu besonderen Aspekten bei der Untersuchung und Anamnese bei Ataxie-Patienten werden vor allem Häufigkeit und Therapierelevanz der jeweiligen Ataxie-Typen berücksichtigt und ein praktisch orientierter genetischer diagnostischer Algorithmus vorgestellt.
... Recently, Algahtani et al 8 described a missense variant, c.395A > G,that changes Asp to Gly and is associated with a milder presentation of the phenotype. Although the existing findings cannot sufficiently explain the molecular mechanism of ARCA, they could be used as scientific evidence for the diagnosis.Reviewing the literatures, most ARCAs have heterogeneous age at onset, severity of disease progression, and frequency of extracerebellar and systemic signs.[15][16][17][18][19] These novel variants are likely to reduce the severity of the phenotype compared with that in patients with homozygous or compound heterozygous nonsense variants.This conclusion provides a reasonable explanation for the clinical severity of this case. ...
Background
CWF19L1 is responsible for spinocerebellar ataxia, autosomal recessive 17, which presents with cerebellar ataxia, and atrophy. Here, we report novel compound heterozygous variants of CWF19L1 in a Chinese family with progressive ataxia and mental retardation of unknown etiology by analyzing clinical characteristics and genetic variations.
Methods
Clinical profiles and genomic DNA extracts of family members were collected. Whole‐exome and Sanger sequencing were performed to detect associated genetic variants. Pathogenicity prediction and conservation analysis of the identified variants were performed using bioinformatics tools.
Results
We identified heterozygous variants at the invariant +2 position (c.1555_c.1557delGAG in exon 14 and c.1070G > T in exon 11) of the CWF19L1 gene. Two novel heterozygous variants of the CWF19L1 gene were identified in the CWF19L1 gene associated with autosomal recessive cerebellar ataxia.
Conclusion
Our results suggest that CWF19L1 variants may be a novel cause of recessive ataxia with developmental delay. Whole‐exome sequencing is an efficient tool for screening variants associated with the disease. This case report may help diagnose and identify the causes of other ataxias, leading to novel therapies, especially in China. This finding enriches the variant spectrum of the CWF19L1 gene and lays the foundation for future studies on the correlation between genotype and phenotype.
... And it is relevant to emphasize that our data is preliminar. These results should be seen as exploratory and associated with recent reports on recessive ataxias [23] and on founder effects, the latter also from the PAHAN group [24]. More reliable data should be collected in a standardized manner in the following investigations. ...
Little is known about access of rare disease carriers to health care. To increase this knowledge, the Pan American Hereditary Ataxia Network (PAHAN) conducted an exploratory survey about care for hereditary ataxias in American continents and the Caribbean. A questionnaire was sent to health professionals about the hereditary ataxias identified; access to care; and local teaching and research. The number of ataxics under current care per 100,000 inhabitants was subtracted from the expected overall prevalence of 6/100,000, to estimate the prevalence of uncovered ataxic patients. Local Human Development Indexes (HDI) were used to measure socio-economic factors. Twenty-six sites participated. Twelve sites had very high, 13 had high, and one site had medium HDI. Participants reported on 2239 and 602 patients with spinocerebellar ataxias and recessive forms under current care. The number of patients under current care per inhabitants varied between 0.14 and 12/100,000. The estimated prevalence of uncovered ataxic patients was inversely proportional to HDIs (rho = 0.665, p = 0.003). Access to diagnosis, pre-symptomatic tests, and rehabilitation were associated with HDIs. More and better molecular diagnostic tools, protocols and guidelines, and professional training for ataxia care were the top priorities common to all respondents. Evidence of inequalities was confirmed. Lower HDIs were associated with high potential numbers of uncovered ataxic subjects, and with lack of molecular diagnosis, pre-symptomatic testing, and rehabilitation. More and better diagnostic tools, guidelines, and professional training were priorities to all sites. PAHAN consortium might help with the last two tasks.
Background. Chronic ataxias, a complex group of over 300 diseases, pose significant diagnostic challenges because of their clinical and genetic heterogeneity. Here, we propose that artificial intelligence (AI) can aid in the identification and understanding of these disorders through the utilization of a smart virtual assistant.
Objectives. The aim is to develop and validate an AI-powered virtual assistant for diagnosing chronic ataxias.
Methods. A non-commercial virtual assistant was developed using advanced algorithms, decision trees, and large language models. In the validation process, 453 clinical cases from the literature were selected from 151 causes of chronic ataxia. The diagnostic accuracy was compared with that of 21 neurologists specializing in movement disorders and GPT-4. Usability regarding time and number of questions needed were also evaluated.
Results. The virtual assistant accuracy was 90.9%, higher than neurologists (18.3%), and GPT-4 (19.4%). It also significantly outperformed in causes of ataxia distributed by age, inheritance, frequency, associated clinical manifestations, and treatment availability. Neurologists and GPT-4 mentioned 110 incorrect diagnoses, 83.6% of which were made by GPT-4, which also generated seven data hallucinations. The virtual assistant required an average of 14 questions and 1.5 minutes to generate a list of differential diagnoses, significantly faster than the neurologists (mean, 19.4 minutes).
Conclusions. The virtual assistant proved to be accurate and easy fast-use for the diagnosis of chronic ataxias, potentially serving as a support tool in neurological consultation. This diagnostic approach could also be expanded to other neurological and non-neurological diseases. © 2025 International Parkinson and Movement Disorder Society.
Hereditary cerebellar ataxias are a diverse group of neurodegenerative disorders characterized by progressive cerebellar dysfunction and possible multisystemic involvement. While significant advancements have been made in understanding autosomal dominant cerebellar ataxias (ADCAs), autosomal recessive cerebellar ataxias (ARCAs) remain less extensively investigated than autosomal dominant ataxias, particularly in regions with high consanguinity. This study aimed to characterize 57 patients with ARCAs in Ceará, northeast Brazil. We analyzed 57 patients diagnosed with ARCAs caused by biallelic variants in ARCA-associated genes. Patients underwent clinical evaluations, including neurological examinations and functional assessments. Results: Friedreich’s ataxia (FRDA) was the most prevalent diagnosis, accounting for 12 cases (21%), followed by Ataxia-Telangiectasia (A-T) with (N = 9; 15.8%) and Niemann-Pick Disease Type C (NPC) (N = 9; 15.8%). Metabolic disorders, including Cerebrotendinous Xanthomatosis (N = 6;10.5%) were also common causes. The cohort demonstrated a broad age distribution, with childhood-onset conditions such as A-T predominantly affecting younger patients. In contrast, adult-onset conditions like FRDA and NPC were more common in those aged 18 years and older. Discussion: This study highlights the heterogeneity of ARCAs in a region with high consanguinity, reflecting these disorders’ diverse genetic and clinical spectrum. Conclusion: The clinical and genetic characterization of ARCAs presented in this case series emphasizes the importance of early diagnosis, genetic confirmation, and targeted management strategies. Our findings highlight the need for continued research and expanded diagnostic programs, particularly in regions with high consanguinity, to improve patient outcomes and advance therapeutic development.
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.
Biallelic intronic expansions (AAGGG)exp in intron 2 of the RFC1 gene have been shown to be a common cause of late-onset ataxia. Since their first description, the phenotypes, neurological damage, and pathogenic variants associated with the RFC1 gene have been frequently updated. Here, we review the various motifs, genetic variants, and phenotypes associated with the RFC1 gene. We searched PubMed for scientific articles published between March 1st, 2019, and January 15th, 2024. The motifs and phenotypes associated with the RFC1 gene are highly heterogeneous, making molecular diagnosis and clinical screening and investigation challenging. In this review we will provide clues to give a better understanding of RFC1 disease. We briefly discuss new methods for molecular diagnosis, the origin of cough in RFC1 disease, and research perspectives.
