Ataxias in Brazil: 17 years of experience in an ataxia center

Abstract Background  Cerebellar ataxias comprise sporadic and genetic etiologies. Ataxia may also be a presenting feature in hereditary spastic paraplegias (HSPs). Objective  To report a descriptive analysis of the frequency of different forms of cerebellar ataxia evaluated over 17 years in the Ataxia Unit of Universidade Federal de São Paulo, Brazil. Methods  Charts of patients who were being followed from January 2007 to December 2023 were reviewed. We used descriptive statistics to present our results as frequencies and percentages of the overall analysis. Diagnosed patients were classified according to the following 9 groups: sporadic ataxia, spinocerebellar ataxias (SCAs), other autosomal dominant cerebellar ataxias, autosomal recessive cerebellar ataxias (ARCAs), mitochondrial ataxias, congenital ataxias, X-linked ataxias, HSPs, and others. Results  There were 1,332 patients with ataxias or spastic paraplegias. Overall, 744 (55.85%) of all cases were successfully diagnosed: 101 sporadic ataxia, 326 SCAs, 20 of other autosomal dominant cerebellar ataxias, 186 ARCAs, 6 X-linked ataxias, 2 mitochondrial ataxias, 4 congenital ataxias, and 51 HSPs. Conclusion  This study describes the frequency of cerebellar ataxias in a large group of patients followed for the past 17 years, of whom 55% obtained a definitive clinical or molecular diagnosis. Future demographic surveys in Brazil or Latin American remain necessary.


INTRODUCTION
Clinically, the term ataxia denotes incoordination and loss of balance, 1 which is a hallmark of degenerative disorders that mainly target the cerebellum. 1 Cerebellar ataxias are a heterogeneous group of diseases comprising sporadic ataxias and genetic etiologies. 2 The sporadic ataxias group is characterized by adult-onset ataxias, usually over 40-years-old, with no family history for ataxia or its related symptoms and signs. 2 Ataxia may also be a presenting feature in hereditary spastic paraplegias (HSPs) and other neurological disorders. 3enetic cerebellar ataxias and HSPs are rare neurodegenerative disorders, generally related to degeneration of the cerebellum and its connections. 4Additionally, they share considerable clinical overlap, presenting progressive gait impairment, permanent disability, and premature death. 5he frequency of these diseases in different populations and their natural history are relevant knowledge for health authorities to develop care strategies. 6,7Nevertheless, it is worth mentioning that epidemiological data on these disorders are scarce, particularly in underdeveloped countries.Hence, their true global distribution and prevalence remains uncertain. 8Moreover, regardless the recent advances of diagnostic genetic techniques, the genetic diagnosis of most patients is still undefined. 6n this original article, we perform a descriptive analysis of the frequency and etiology of sporadic ataxias, genetic cerebellar ataxias, and HSPs, evaluated over 17 years in a reference center of ataxia in São Paulo, Brazil.

METHODS
We present a cross-sectional and monocentric study of 1,332 heterogenous patients with ataxia or spastic paraplegias that were referred to our service, the Ataxia Unit at Hospital São Paulo, from Universidade Federal de São Paulo, Brazil.To describe epidemiological and genetic features, two independent investigators (BKM and MTDG) reviewed medical records of patients who were being followed from January 2007 to December 2023.Data were independently reviewed by the authors and disagreements were resolved through discussion until a consensus was reached.The approval of an institutional review board was not required for this research.
Diagnosed patients were classified accordingly to the following nine groups: sporadic ataxias, spinocerebellar ataxias (SCAs), other autosomal dominant cerebellar ataxias, autosomal recessive cerebellar ataxias (ARCAs), mitochondrial ataxias, congenital ataxias, X-linked ataxias, HSPs, and others.Patients were included based on the following criteria: diagnosis of sporadic ataxias according to the appropriate diagnostic criteria at the time of medical evaluation; 1 definitive diagnosis of hereditary genetic diseases were considered only with genetic confirmation for each case.Furthermore, patients with incomplete data preventing confirmation of any specific disease were excluded.We used descriptive statistics to present our results as frequencies and percentages of the overall analysis.
with SCA31.Our findings suggest that familial, late-onset, pure cerebellar symptoms, variably associated with hearing impairment, should be tested for SCA31 particularly if there is Japanese ancestry and negative test results for type 6. 28 Recently, ARCAs are classified into primary ARCAs and the group of other metabolic or complex autosomal recessive disorders that have ataxia as an associated feature. 3Consistently, FRDA has been recognized as the most common cause of ARCAs worldwide, with an estimated prevalence of 1 to 2 cases every 100,000 people. 5,8,29The second most common cause of ataxia varies between AOA and AT, depending on the study that is considered. 5,6,29In our study, FDRA was the most prevalent ARCAs (44.08%), followed by AT (15.05%), which is consistent with the literature.
Sporadic ataxias are adult-onset nonfamilial progressive ataxias. 1 In the present study, the most common sporadic ataxia was MSA (n ¼ 51; 50.49%).The estimated annual prevalence of this disease is 3 cases every 100 thousand people in populations over 50 years. 1MSA is the diagnosis of up to 24% of sporadic adult onset ataxia patients within 4 to 5 years. 30,31urthermore, there were 8 immune-mediated cerebellar ataxias, including 6 related to neuronal antigens anti-GAD (n ¼ 4), anti-Hu (n ¼ 1), and anti-Yo (n ¼ 1).Cerebellar ataxia may be the initial manifestation of autoimmune encephalitis, as the cerebellum is an important immunological target. 1 Thus, there was suspicion of an immune-mediated cerebellar ataxia, precluding screening for antineuronal antibodies, including autoimmune and paraneoplastic panels. 32he current study shows a local epidemiological analysis of ataxias in the Brazilian population, with patients evaluated in the state of São Paulo.Among the 1,156 patients with known place of residence that were referred to the center in search for the diagnosis and the adequate genetic test, the geographic distribution of patients by each region of Brazil are as follows: North (n ¼ 29), Northeast (n ¼ 28), Central-West (n ¼ 15), Southeast (n ¼ 1,068), and South (n ¼ 16).Moreover, among the 808 patients with known state of birth and place of residence, 211 of them had moved to São Paulo at the time of their first evaluation.This difference between the state of birth and residence may help to illustrate the intense migration over different regions of Brazil, which certainly contributes to the difficult task of having a unique Brazilian demographic panorama of hereditary diseases.Although this could represent a limitation, it illustrates the regional heterogenous genetic background, differing from the United States/Europe. 33ur findings also have practical relevance.From a diagnostic perspective, these diseases remain a challenge for neurologists.Although the overall frequence of many diseases discussed above in the general population might be relatively low, they still should not be dismissed.A high level of suspicion for these disorders is vital to reach diagnosis.Besides the obstacle of the clinical suspicion, molecular tests are important bottlenecks to the etiological diagnosis of complex genetic disorders, such as ataxias and HSPs.The first problem is the limited access to genetic tests due to their high cost, especially in a developing country like Brazil.Second, there is the decision of which test is more suitable in the clinical setting to avoid unnecessary expendings and misinterpretations (such as triplet repeat primed polymerase chain reaction [TP-PCR] for repeat-expansion disorders, such as FRDA, and the most common forms of SCA).The third challenge to note is the necessity of periodic reanalysis of inconclusive tests and VUSs, due to the constant renewal of scientific knowledge with the discovery of new causative genes, molecular pathways, and other pathogenic mechanisms.
Overall, despite the difficulties, the etiological diagnosis should be thoroughly pursued, as patients can benefit both individually and collectively.On the individual level, the etiology allows a more accurate and personalized genetic counselling, by elucidating the pattern of inheritance, predicting risk of future offspring of developing the disorder, designing strategies to minimize this risk, and, for some conditions, specific therapeutic options shall be discussed.Collectively, there must be several benefits from research projects and drug trials that may only be possible if a considerable number of patients are diagnosed.
Our study has some limitations.We analyzed diagnostic frequencies for reference purposes only.Additionally, it should be noted that we did not characterize the phenotype of each case.All descriptive data was not exclusive of isolated patients.Consequently, the occurrence of possible family clusters of hereditary disease may have to be considered to forward prevalence conclusions.Comparison of our findings with other series of neurological outpatients is difficult since historically our service focuses on ataxia patients, and just recently has added a predilection to spastic paraplegias.
In summary, 55% of the patients included in this survey reached a definitive diagnosis.The goal of the study was to provide a descriptive analysis of the prevalence ataxias and HSPs that have being evaluated over 17 years in our Ataxia Unit in the state of São Paulo, Brazil.There is still much to discover about the molecular basis of these diseases with high genetic heterogeneity. 5,25Future population-based systematic surveys in Brazil or Latin American remain necessary.

Table 1
Demographics of the study sample