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

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.

ANTECEDENTES: Ataxias cerebelares compreendem as etiologias esporádicas e genéticas. Ataxia também pode ser uma característica das paraplegias espásticas hereditárias (HSPs). OBJETIVO: Relatar uma análise descritiva da frequência das diferentes formas de ataxias cerebelares avaliadas ao longo de 17 anos no Setor da Ataxias da Universidade Federal de São Paulo, Brasil. MéTODOS: Prontuários de pacientes acompanhados de janeiro de 2007 a dezembro de 2023 foram revisados. Usamos análise descritiva para apresentar nossos resultados como frequências e percentuais. Os pacientes foram classificados de acordo com os 9 grupos seguintes: ataxias esporádicas, ataxias espinocerebelares (SCA), outras ataxias cerebelares autossômicas dominantes, ataxias cerebelares autossômicas recessivas (ARCA), ataxias mitocondriais, ataxias congênitas, ataxias ligadas ao X, PEH e outros. RESULTADOS: Foram avaliados 1.332 pacientes. Desse total, 744 tiveram um diagnóstico definitivo: 101 ataxias esporádicas, 326 SCA, 20 outras ataxias cerebelares autossômicas dominantes, 186 (ARCA), 6 ataxias ligadas ao X, 2 ataxias mitocondriais, 4 ataxias congênitas e 51 HSP. CONCLUSãO: Esse estudo descreve a frequência e a etiologia das ataxias em um grande grupo de pacientes acompanhados nos últimos 17 anos, dos quais 55% obtiveram diagnóstico clínico ou molecular definitivos. Estudos demográficos futuros do Brasil ou da América Latina continuam sendo necessários.

Cerebrovascular disease in patients with antiphospholipid antibody syndrome: a transcranial Doppler and magnetic resonance imaging study.

Objective: Transcranial Doppler (TCD) and brain MRI may be useful in evaluating patients with APS, helping to stratify the risk of cerebrovascular ischaemic events in this population. This study aimed to assess the frequency of brain MRI abnormalities in patients with primary antiphospholipid syndrome, secondary antiphospholipid syndrome and SLE and correlate to TCD findings. Methods: The study, conducted over four years at two autoimmune disease referral centres, included 22 primary antiphospholipid syndrome patients, 24 secondary antiphospholipid syndrome patients, 27 SLE patients without APS and 21 healthy controls. All participants underwent TCD to assess cerebral haemodynamics, detect microembolic signals and evaluate right-to-left shunts, followed by brain MRI and magnetic resonance angiography. MRI scans were reviewed for acute microembolism, localized cortical infarctions, border infarctions, lacunar infarctions, ischaemic lesions, white matter hyperintensity, micro and macro haemorrhages and arterial stenosis ≥50% of the cervical carotid artery, by two neuroradiologists blinded to the clinical data. Results: Brain MRI findings were similar between the groups, except for lacunar infarction, more frequent in patients with secondary antiphospholipid syndrome (P = 0.022). Patients with intracranial stenosis detected by TCD had a higher frequency of territorial infarction (40% vs 7.5%, P = 0.02), lacunar (40% vs 11.3%, P = 0.075) and border zone infarcts (20% vs 1.9%, P = 0.034). Conclusions: Patients with intracranial stenosis presented a higher frequency of territorial, lacunar and border zone infarcts, suggesting that evaluating the intracranial vasculature should not be neglected in patients with APS and stroke.

Clinical Reasoning: A 24-Year-Old Man With Gait Impairment, Hearing Loss, and Recurrent Fever.

We present a case study of a 24-year-old man who reported mild balance and walking difficulties for 2 years. He had a history of recurrent fever, skin lesions, headache, and elbow pain, but most of these events resolved spontaneously. There was no significant family history. On examination, we observed frontal bossing, sensorineural hearing loss, and gait ataxia. This case underscores the significance of identifying clinical indicators in patients with neurologic symptoms, particularly recurrent fever, to establish a precise and thorough differential diagnosis.

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

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

Clinical, neuroimaging and genetic findings in Brazilian patients with neurodegeneration with brain iron accumulation.

Neurodegeneration with brain iron accumulation (NBIA) encompasses a clinically and genetically heterogeneous group of rare disorders. Here, we report clinical, neuroimaging and genetic studies in twenty three Brazilian NBIA patients. In thirteen subjects, deleterious variants were detected in known NBIA-causing genes (PANK2, PLA2G6, C9ORF12, WDR45 and FA2H), including previously unreported variants in PANK2 and PLA2G6. Two patients carried rare, likely pathogenic variants in genes not previously associated with NBIA: KMT2A c.11785A > C (p.Ile3929Leu), and TIMM8A c.127T > C (p.Cys43Arg), suggesting an expansion of their associated phenotypes to include NBIA. In eight patients the etiology remains unsolved, suggesting variants undetectable by the adopted methods, or the existence of additional NBIA-causing genes.

Hereditary motor and sensory neuropathy Okinawa type mimicking proximal myopathy.

Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P), or, Okinawa type, is a rare neuromuscular disorder characterized by proximal dominant neurogenic atrophy and distal sensory alterations with an autosomal dominant inheritance pattern. We present a case of a Brazilian woman of Okinawan ancestry, with symmetrical proximal weakness, fasciculations, absent patellar reflexes and positive familial history for the same symptoms. These findings led to genetic testing, which identified a variant in the TFG gene (c.854 C>T;p.(Pro285Leu), confirming the diagnosis of HMSN-P. HMSN-P seemed to be restricted to populations in Okinawa, however, other HMSN-P cases were described in several parts of the world, especially in South America. This case report emphasizes the importance of considering HMSN-P in patients presenting with clinical features resembling proximal myopathy, especially in individuals with Okinawan ancestry.

Prevalence and Diagnostic Journey of Friedreich's Ataxia in the State of São Paulo, Brazil.

Friedreich's Ataxia (FRDA) is the leading cause of ataxia worldwide, but data on epidemiology and diagnostic journey are scarce, particularly in Latin America. Herein we estimated the prevalence of FRDA in the most populous Brazilian state and characterized the diagnostic odyssey of the disease. We received anonymized data of patients with FRDA from advocacy groups and physicians. Prevalence was estimated dividing the number of patients by the population of the state as reported in the last census. Patients were invited to answer an online survey to describe clinical data and diagnostic journey of the disease. FRDA estimated prevalence was 0.367:100,000, with a slight predominance of women (58.2% vs 41.7%). One hundred and four patients answered the survey (mean age of 37.3 ± 13.8 years; 75.9% classical and 24.0% late onset). On average, 6.2 ± 4.1 physicians were visited before reaching the diagnosis. Mean diagnostic delay was 7.8 ± 6.7 years; no difference between classical and LOFA groups was found. Most of the patients reported unsteadiness and gait abnormalities as the first symptom. Neurologists and orthopedical surgeons were the main specialties first sought by patients. We found a prevalence of 0.36:100,000 for FRDA in the state of São Paulo, Brazil. The disease is characterized by remarkable diagnostic delay, with no relevant differences between classical and LOFA patients.

Genotype-specific spinal cord damage in spinocerebellar ataxias: an ENIGMA-Ataxia study.

BACKGROUND: Spinal cord damage is a feature of many spinocerebellar ataxias (SCAs), but well-powered in vivo studies are lacking and links with disease severity and progression remain unclear. Here we characterise cervical spinal cord morphometric abnormalities in SCA1, SCA2, SCA3 and SCA6 using a large multisite MRI dataset. METHODS: Upper spinal cord (vertebrae C1-C4) cross-sectional area (CSA) and eccentricity (flattening) were assessed using MRI data from nine sites within the ENIGMA-Ataxia consortium, including 364 people with ataxic SCA, 56 individuals with preataxic SCA and 394 nonataxic controls. Correlations and subgroup analyses within the SCA cohorts were undertaken based on disease duration and ataxia severity. RESULTS: Individuals in the ataxic stage of SCA1, SCA2 and SCA3, relative to non-ataxic controls, had significantly reduced CSA and increased eccentricity at all examined levels. CSA showed large effect sizes (d>2.0) and correlated with ataxia severity (r<-0.43) and disease duration (r<-0.21). Eccentricity correlated only with ataxia severity in SCA2 (r=0.28). No significant spinal cord differences were evident in SCA6. In preataxic individuals, CSA was significantly reduced in SCA2 (d=1.6) and SCA3 (d=1.7), and the SCA2 group also showed increased eccentricity (d=1.1) relative to nonataxic controls. Subgroup analyses confirmed that CSA and eccentricity are abnormal in early disease stages in SCA1, SCA2 and SCA3. CSA declined with disease progression in all, whereas eccentricity progressed only in SCA2. CONCLUSIONS: Spinal cord abnormalities are an early and progressive feature of SCA1, SCA2 and SCA3, but not SCA6, which can be captured using quantitative MRI.

Expanding the phenotypic spectrum of CLCN2-related leucoencephalopathy and ataxia.

Mutations in CLCN2 are a rare cause of autosomal recessive leucoencephalopathy with ataxia and specific imaging abnormalities. Very few cases have been reported to date. Here, we describe the clinical and imaging phenotype of 12 additional CLCN2 patients and expand the known phenotypic spectrum of this disorder. Informed consent was obtained for all patients. Patients underwent either whole-exome sequencing or focused/panel-based sequencing to identify variants. Twelve patients with biallelic CLCN2 variants are described. This includes three novel likely pathogenic missense variants. All patients demonstrated typical MRI changes, including hyperintensity on T2-weighted images in the posterior limbs of the internal capsules, midbrain cerebral peduncles, middle cerebellar peduncles and cerebral white matter. Clinical features included a variable combination of ataxia, headache, spasticity, seizures and other symptoms with a broad range of age of onset. This report is now the largest case series of patients with CLCN2-related leucoencephalopathy and reinforces the finding that, although the imaging appearance is uniform, the phenotypic expression of this disorder is highly heterogeneous. Our findings expand the phenotypic spectrum of CLCN2-related leucoencephalopathy by adding prominent seizures, severe spastic paraplegia and developmental delay.

Cranial Nerve Thinning Distinguishes RFC1-Related Disorder from Other Late-Onset Ataxias.

BACKGROUND: RFC1-related disorder (RFC1/CANVAS) shares clinical features with other late-onset ataxias, such as spinocerebellar ataxias (SCA) and multiple system atrophy cerebellar type (MSA-C). Thinning of cranial nerves V (CNV) and VIII (CNVIII) has been reported in magnetic resonance imaging (MRI) scans of RFC1/CANVAS, but its specificity remains unclear. OBJECTIVES: To assess the usefulness of CNV and CNVIII thinning to differentiate RFC1/CANVAS from SCA and MSA-C. METHODS: Seventeen individuals with RFC1/CANVAS, 57 with SCA (types 2, 3 and 6), 11 with MSA-C and 15 healthy controls were enrolled. The Balanced Fast Field Echo sequence was used for assessment of cranial nerves. Images were reviewed by a neuroradiologist, who classified these nerves as atrophic or normal, and subsequently the CNV was segmented manually by an experienced neurologist. Both assessments were blinded to patient and clinical data. Non-parametric tests were used to assess between-group comparisons. RESULTS: Atrophy of CNV and CNVIII, both alone and in combination, was significantly more frequent in the RFC1/CANVAS group than in healthy controls and all other ataxia groups. Atrophy of CNV had the highest sensitivity (82%) and combined CNV and CNVIII atrophy had the best specificity (92%) for diagnosing RFC1/CANVAS. In the quantitative analyses, CNV was significantly thinner in the RFC1/CANVAS group relative to all other groups. The cutoff CNV diameter that best identified RFC1/CANVAS was ≤2.2 mm (AUC = 0.91; sensitivity 88.2%, specificity 95.6%). CONCLUSION: MRI evaluation of CNV and CNVIII using a dedicated sequence is an easy-to-use tool that helps to distinguish RFC1/CANVAS from SCA and MSA-C.

Spinocerebellar ataxia type 2 has multiple ancestral origins.

INTRODUCTION: Spinocerebellar ataxia type 2 (SCA2) is a dominant neurodegenerative disorder due to expansions of a CAG repeat tract (CAGexp) at the ATXN2 gene. Previous studies found only one ancestral haplotype worldwide, with a C allele at rs695871. This homogeneity was unexpected, given the severe anticipations related to SCA2. We aimed to describe informative ancestral haplotypes found in South American SCA2 families. METHODS: Seventy-seven SCA2 index cases were recruited from Brazil, Peru, and Uruguay; 263 normal chromosomes were used as controls. The SNPs rs9300319, rs3809274, rs695871, rs1236900 and rs593226, and the STRs D12S1329, D12S1333, D12S1672 and D12S1332, were used to reconstruct haplotypes. RESULTS: Eleven ancestral haplotypes were found in SCA2 families. The most frequent ones were A-G-C-C-C (46.7 % of families), G-C-C-C-C (24.6 %) and A-C-C-C-C (10.3 %) and their mean (sd) CAGexp were 41.68 (3.55), 40.42 (4.11) and 45.67 (9.70) (p = 0.055), respectively. In contrast, the mean (sd) CAG lengths at normal alleles grouped per haplotypes G-C-G-A-T, A-G-C-C-C and G-C-C-C-C were 22.97 (3.93), 23.85 (3.59), and 30.81 (4.27) (p < 0.001), respectively. The other SCA2 haplotypes were rare: among them, a G-C-G-A-T lineage was found, evidencing a G allele in rs695871. CONCLUSION: We identified several distinct ancestral haplotypes in SCA2 families, including an unexpected lineage with a G allele at rs695871, a variation never found in hundreds of SCA2 patients studied worldwide. SCA2 has multiple origins in South America, and more studies should be done in other regions of the world.

Functional ataxia in a specialized ataxia center.

BACKGROUND: Functional gait is a disorder of ambulation and balance internally inconsistent and incongruent with the phenotypic spectrum of neurological gait disorders. OBJECTIVES: This paper aims to clinically characterize patients with functional ataxia. METHODS: Patients with functional ataxia were analyzed out of 1350 patients in Ataxia Unit of the Federal University of São Paulo circa 2008 to 2022. RESULTS: Thirteen patients (1 %) presented with functional ataxia; all female, with a median age of 34.8 years. Six (46.2 %) had psychiatric comorbidities and 7 (53.8 %) endorsed a trigger. Diagnostic features included variable base and stride (100 %), "huffing and puffing" (30.7 %), knee-buckling (30.7 %), uneconomic posturing (38.5 %), tightrope walking (23 %), and trembling gait (15.4 %). Remarkably, no falls were reported in any case. 53.8 % recovered fully or partially, despite no treatment. CONCLUSIONS: Variability of base and stride are universal features of functional ataxia, yet falls are inconspicuous. Functional Ataxia is rare even in a specialized ataxia center.

Sarcoid optic neuropathy.

A 45-year-old woman presented with sudden complete vision loss in her left eye and retroorbital pain worsened by eye movements. A previous milder episode of vision loss had occurred in the same eye 1 year before, with complete recovery after high-dose intravenous methylprednisolone. She had no light perception in the left eye with a swollen optic disc, but with a normal right optic disc. There were no systemic manifestations or infections. MR scan of the brain showed extensive enlargement and enhancement of the left optic nerve and optic chiasm. After excluding infections and autoimmune markers, a left optic nerve biopsy confirmed non-caseating granulomas, leading to a diagnosis of neurosarcoidosis.

Optic Disc and Retinal Architecture Changes in Patients with Spinocerebellar Ataxia Type 2.

BACKGROUND: ATXN2 is the causative gene of spinocerebellar ataxia type 2 (SCA2) and has been implicated in glaucoma pathogenesis. Therefore, studying ocular changes in SCA2 could uncover clinically relevant changes. OBJECTIVE: The aim was to investigate optic disc and retinal architecture in SCA2. METHODS: We evaluated 14 patients with SCA2 and 26 controls who underwent intraocular pressure measurement, fundoscopy, and macular and peripapillary spectral domain optical coherence tomography (SD-OCT). We compared SD-OCT measurements in SCA2 and controls, and the frequency of glaucomatous changes among SCA2, controls, and 76 patients with other SCAs (types 1, 3, 6, and 7). RESULTS: The macula, peripapillary retinal nerve fiber and inner plexiform layers were thinner in SCA2 than in controls. Increased cup-to-disc ratio was more frequent in SCA2 than in controls and other SCAs. CONCLUSIONS: Ocular changes are part of SCA2 phenotype. Future studies should further investigate retinal and optic nerve architecture in this disorder.

Sjogren's syndrome: a neurological perspective.

Sjogren's syndrome (SS) is a complex autoimmune disease characterized by lymphocytic infiltration of salivary and lacrimal glands, resulting in sicca symptoms. Additionally, SS presents with neurological manifestations that significantly impact the nervous system. This review aims to provide a comprehensive overview of the neurological aspects of SSj, covering both the peripheral and central nervous system involvement, while emphasizing diagnosis, treatment, and prognosis.

A síndrome de Sjogren (SS) é uma doença autoimune complexa caracterizada pela infiltração linfocítica das glândulas salivares e lacrimais, resultando em sintomas sicca. Além disso, a SS apresenta manifestações neurológicas que afetam significativamente o sistema nervoso. Esta revisão tem como objetivo fornecer uma visão abrangente dos aspectos neurológicos da SSj, abordando tanto o envolvimento do sistema nervoso periférico quanto do central, com ênfase no diagnóstico, tratamento e prognóstico.