RESUMO
Background: Whether low-frequency deep brain stimulation (DBS) in the caudal zona incerta (cZi) can improve cerebellar ataxia symptoms remains unexplored. Case Report: We report a 66-year-old man initially diagnosed with essential tremor and subsequently developed cerebellar ataxia after bilateral cZi DBS implantation. We tested the effects of low-frequency DBS stimulations (sham, 10 Hz, 15 Hz, 30 Hz) on ataxia severity. Discussion: Low-frequency cZi DBS improves ataxic speech at 30 Hz, but not at 10 Hz or 15 Hz in this patient. Low-frequency DBS did not improve gait or stance. Therefore, low-frequency stimulation may play a role in treating ataxic speech. Highlights: The finding of this case study suggests that bilateral low-frequency DBS at 30 Hz in the caudal zona incerta has the potential to improve ataxic speech but has limited impact on gait and stance. The involvement of zona incerta in speech warrants further investigation.
Assuntos
Ataxia Cerebelar , Estimulação Encefálica Profunda , Tremor Essencial , Zona Incerta , Humanos , Estimulação Encefálica Profunda/métodos , Masculino , Idoso , Zona Incerta/fisiopatologia , Ataxia Cerebelar/terapia , Ataxia Cerebelar/fisiopatologia , Tremor Essencial/terapia , Tremor Essencial/fisiopatologia , Tremor/terapia , Tremor/fisiopatologia , Tremor/etiologiaRESUMO
OBJECTIVE: Antibodies against glutamic acid decarboxylase (GAD), originally associated with stiff person syndrome (SPS), define the GAD antibody-spectrum disorders that also include cerebellar ataxia, autoimmune epilepsy, limbic encephalitis, progressive encephalomyelitis with rigidity and myoclonus (PERM), and eye movement disorders, all of which are characterized by autoimmune neuronal excitability. This article elaborates on the diagnostic criteria for SPS and SPS spectrum disorders, highlights disease mimics and misdiagnoses, describes the electrophysiologic mechanisms and underlying autoimmunity of stiffness and spasms, and provides a step-by-step therapeutic scheme. LATEST DEVELOPMENTS: Very-high serum GAD antibody titers are diagnostic for GAD antibody-spectrum disorders and also predict the presence of GAD antibodies in the CSF, increased intrathecal synthesis, and reduced CSF γ-aminobutyric acid (GABA) levels. Low serum GAD antibody titers or the absence of antibodies generates diagnostic challenges that require careful distinction in patients with a variety of painful spasms and stiffness, including functional neurologic disorders. Antibodies against glycine receptors, first found in patients with PERM, are seen in 13% to 15% of patients with SPS, whereas amphiphysin and gephyrin antibodies, seen in 5% of patients with SPS spectrum disorders, predict a paraneoplastic association. GAD-IgG from different SPS spectrum disorders recognizes the same dominant GAD intracellular epitope and, although the pathogenicity is unclear, is an excellent diagnostic marker. The biological basis of muscle stiffness and spasms is related to autoimmune neuronal hyperexcitability caused by impaired reciprocal γ-aminobutyric acid-mediated (GABA-ergic) inhibition, which explains the therapeutic response to GABA-enhancing agents and immunotherapies. ESSENTIAL POINTS: It is essential to distinguish SPS spectrum disorders from disease mimics to avoid both overdiagnoses and misdiagnoses, considering that SPS is treatable if managed correctly from the outset to prevent disease progression. A step-by-step, combination therapy of GABA-enhancing medications along with immunotherapies ensures prolonged clinical benefits.
Assuntos
Autoanticorpos , Glutamato Descarboxilase , Rigidez Muscular Espasmódica , Humanos , Rigidez Muscular Espasmódica/diagnóstico , Rigidez Muscular Espasmódica/imunologia , Rigidez Muscular Espasmódica/fisiopatologia , Rigidez Muscular Espasmódica/sangue , Glutamato Descarboxilase/imunologia , Autoanticorpos/sangue , Masculino , Feminino , Rigidez Muscular/diagnóstico , Rigidez Muscular/imunologia , Rigidez Muscular/tratamento farmacológico , Encefalomielite/diagnóstico , Encefalomielite/imunologia , Encefalomielite/sangue , Pessoa de Meia-Idade , Adulto , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/imunologia , Ataxia Cerebelar/sangue , Ataxia Cerebelar/fisiopatologia , Encefalite Límbica/diagnóstico , Encefalite Límbica/imunologia , Encefalite Límbica/terapia , Encefalite Límbica/sangue , Encefalite Límbica/fisiopatologiaRESUMO
OBJECTIVE: This article reviews the clinical and antibody spectrum of autoimmune cerebellar ataxia and other autoimmune movement disorders. It highlights characteristic phenotypes and red flags to the diagnosis and how these rare, but treatable, disorders are integrated into a differential diagnosis. LATEST DEVELOPMENTS: An increasing number of neuronal antibodies have been identified in patients with cerebellar ataxia, for example, against Kelch-like protein 11 (KLHL11), seizure-related 6 homolog-like 2, septin-3 and septin-5, or tripartite motif containing protein 9 (TRIM9), TRIM46, and TRIM67. Ig-like cell adhesion molecule 5 (IgLON5) antibody-associated syndromes have emerged as an important alternative diagnostic consideration to various neurodegenerative diseases such as Huntington disease or atypical parkinsonism. Opsoclonus-myoclonus syndrome emerged as the most relevant parainfectious movement disorder related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ESSENTIAL POINTS: Autoimmune cerebellar ataxia and other autoimmune movement disorders encompass a broad spectrum of different clinical syndromes, antibodies, and immunopathophysiologic mechanisms. Clinical acumen is key to identifying the cases that should undergo testing for neuronal antibodies. Given the overlap between phenotypes and antibodies, panel testing in serum and CSF is recommended.
Assuntos
Transtornos dos Movimentos , Humanos , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/imunologia , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/imunologia , Feminino , Masculino , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/imunologia , Pessoa de Meia-Idade , Adulto , Autoanticorpos/sangue , Autoanticorpos/líquido cefalorraquidiano , COVID-19/imunologia , COVID-19/diagnóstico , COVID-19/complicações , Diagnóstico Diferencial , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/imunologiaRESUMO
Toll-like receptor (TLR) 4 contributes to be the induction of neuroinflammation by recognizing pathology-associated ligands and activating microglia. In addition, numerous physiological signaling factors act as agonists or antagonists of TLR4 expressed by non-immune cells. Recently, TLR4 was found to be highly expressed in cerebellar Purkinje neurons (PNs) and involved in the maintenance of motor coordination through non-immune pathways, but the precise mechanisms remain unclear. Here we report that mice with PN specific TLR4 deletion (TLR4PKO mice) exhibited motor impairments consistent with cerebellar ataxia, reduced PN dendritic arborization and spine density, fewer parallel fiber (PF) - PN and climbing fiber (CF) - PN synapses, reduced BK channel expression, and impaired BK-mediated after-hyperpolarization, collectively leading to abnormal PN firing. Moreover, the impaired PN firing in TLR4PKO mice could be rescued with BK channel opener. The PNs of TLR4PKO mice also exhibited abnormal mitochondrial structure, disrupted mitochondrial endoplasmic reticulum tethering, and reduced cytosolic calcium, changes that may underly abnormal PN firing and ultimately drive ataxia. These results identify a previously unknown role for TLR4 in regulating PN firing and maintaining cerebellar function.
Assuntos
Cálcio , Ataxia Cerebelar , Canais de Potássio Ativados por Cálcio de Condutância Alta , Células de Purkinje , Receptor 4 Toll-Like , Animais , Camundongos , Cálcio/metabolismo , Ataxia Cerebelar/metabolismo , Ataxia Cerebelar/patologia , Ataxia Cerebelar/genética , Citosol/metabolismo , Homeostase , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Alta/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Células de Purkinje/metabolismo , Células de Purkinje/patologia , Receptor 4 Toll-Like/metabolismoRESUMO
A Caucasian male in his 60s presented with acute onset of dizziness, dysarthria, and gait ataxia. Upon extensive workup, positive findings were cerebrospinal fluid (CSF) showing lymphocytic pleocytosis with oligoclonal bands, positive celiac disease autoantibodies in blood, a duodenal biopsy indicating lymphocytic infiltration, and positive anti-mGluR1 antibody titers in CSF. The patient was started on a strict gluten-free diet and intravenous immunoglobulin therapy for 5 days and showed mild consecutive improvements each day of treatment. He was discharged after 22 days, and was encouraged to continue gluten adherence, physical and speech therapy, and follow up with neuroimmunology. This report demonstrates that autoimmune encephalitis due to anti-mGluR1antibodies and gluten ataxia are both immune-mediated disorders that should be considered in acute cerebellar ataxia cases. By broadening the differential diagnosis and a comprehensive CSF analysis, identification of gluten ataxia and autoimmune encephalitis were beneficial in the management of this particular patient.
Assuntos
Doença Celíaca , Ataxia Cerebelar , Encefalite , Humanos , Masculino , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/etiologia , Encefalite/diagnóstico , Diagnóstico Diferencial , Doença Celíaca/diagnóstico , Doença Celíaca/complicações , Doença de Hashimoto/diagnóstico , Doença de Hashimoto/complicações , Receptores de Glutamato Metabotrópico , Dieta Livre de Glúten , Autoanticorpos/sangue , Pessoa de Meia-Idade , Glutens/efeitos adversos , Doenças Autoimunes do Sistema Nervoso/diagnósticoRESUMO
INTRODUCTION: The last decade has witnessed major breakthroughs in identifying novel genetic causes of hereditary ataxias, deepening our understanding of disease mechanisms, and developing therapies for these debilitating disorders. AREAS COVERED: This article reviews the currently approved and most promising candidate pharmacotherapies in relation to the known disease mechanisms of the most prevalent autosomal recessive ataxias. Omaveloxolone is an Nrf2 activator that increases antioxidant defense and was recently approved for treatment of Friedreich ataxia. Its therapeutic effect is modest, and further research is needed to find synergistic treatments that would halt or reverse disease progression. Promising approaches include upregulation of frataxin expression by epigenetic mechanisms, direct protein replacement, and gene replacement therapy. For ataxia-telangiectasia, promising approaches include splice-switching antisense oligonucleotides and small molecules targeting oxidative stress, inflammation, and mitochondrial function. Rare recessive ataxias for which disease-modifying therapies exist are also reviewed, emphasizing recently approved therapies. Evidence supporting the use of riluzole and acetyl-leucine in recessive ataxias is discussed. EXPERT OPINION: Advances in genetic therapies for other neurogenetic conditions have paved the way to implement feasible approaches with potential dramatic benefits. Particularly, as we develop effective treatments for these conditions, we may need to combine therapies, consider newborn testing for pre-symptomatic treatment, and optimize non-pharmacological approaches.
Assuntos
Ataxia Cerebelar , Humanos , Ataxia Cerebelar/tratamento farmacológico , Ataxia Cerebelar/genética , Terapia Genética/métodos , Ataxia de Friedreich/tratamento farmacológico , Ataxia de Friedreich/genética , Ataxia de Friedreich/terapiaRESUMO
We report two patients with autoimmune cerebellar ataxia who fulfilled the diagnostic criteria of multiple system atrophy (MSA) and responded to immunotherapies. Patient 1 was a 72-year-old man who was diagnosed with clinically probable MSA according to Movement Disorder Society criteria. Patient 2 was a 68-year-old man who was diagnosed with clinically established MSA according to Movement Disorder Society criteria. Both patients showed cerebellar ataxia, autonomic dysfunction, and pyramidal tract signs; however, they also had atypical clinical features. Patient 1 exhibited self-|limiting mild improvement of clinical symptoms and had inflammatory findings in his cerebrospinal fluid. Patient 2 showed a rapidly progressive clinical course. We therefore examined anti-neuronal antibodies using tissue-based immunohistochemical assays with frozen rat cerebellum sections. We detected autoantibodies that mainly reacted with the cytoplasm of Purkinje cells. The two patients then underwent immunotherapies, which led to substantial improvements in their clinical symptoms. Our findings indicate that some patients with autoimmune cerebella ataxia have clinical features that resemble MSA, and respond well to immunotherapies.
Assuntos
Ataxia Cerebelar , Atrofia de Múltiplos Sistemas , Humanos , Masculino , Idoso , Ataxia Cerebelar/imunologia , Ataxia Cerebelar/etiologia , Ataxia Cerebelar/terapia , Atrofia de Múltiplos Sistemas/imunologia , Atrofia de Múltiplos Sistemas/terapia , Autoanticorpos/líquido cefalorraquidiano , Imunoterapia , Doenças Autoimunes/terapia , Doenças Autoimunes/imunologia , Doenças Autoimunes/diagnóstico , Resultado do TratamentoRESUMO
Background: Severe hypomagnesemia is an increasingly recognized cause of acute and reversible cerebellar ataxia, often accompanied by cerebellar oculomotor signs such as jerky horizontal or downbeat nystagmus and very rarely ocular flutter. Phenomenology Shown: This video illustrates horizontal pendular nystagmus in a patient with acute onset cerebellar ataxia associated with severe hypomagnesemia. Educational value: Acquired pendular nystagmus can be distinguished from macrosaccadic oscillations and ocular flutter in that the former is composed of two slow phases of equal velocity and the latter of two fast phases of saccadic type with or without intersaccadic interval, respectively. It is most commonly associated with demyelinating, toxic, metabolic, and genetic disorders, but has not been reported in association with severe hypomagnesemia.
Assuntos
Ataxia Cerebelar , Nistagmo Patológico , Humanos , Nistagmo Patológico/etiologia , Nistagmo Patológico/fisiopatologia , Ataxia Cerebelar/complicações , Ataxia Cerebelar/fisiopatologia , Deficiência de Magnésio/complicações , Masculino , Feminino , Pessoa de Meia-IdadeRESUMO
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.
Assuntos
Ataxia Cerebelar , Humanos , Brasil/epidemiologia , Feminino , Masculino , Adulto , Ataxia Cerebelar/epidemiologia , Ataxia Cerebelar/genética , Pessoa de Meia-Idade , Adolescente , Criança , Adulto Jovem , Estudos Retrospectivos , Pré-Escolar , Idoso , Ataxias Espinocerebelares/epidemiologia , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/congênitoRESUMO
BACKGROUND: Autosomal-dominant spinocerebellar ataxia (ADCA) due to intronic GAA repeat expansion in FGF14 (SCA27B) is a recent, relatively common form of late-onset ataxia. OBJECTIVE: Here, we aimed to: (1) investigate the relative frequency of SCA27B in different clinically defined disease subgroups with late-onset ataxia collected among 16 tertiary Italian centers; (2) characterize phenotype and diagnostic findings of patients with SCA27B; (3) compare the Italian cohort with other cohorts reported in recent studies. METHODS: We screened 396 clinically diagnosed late-onset cerebellar ataxias of unknown cause, subdivided in sporadic cerebellar ataxia, ADCA, and multisystem atrophy cerebellar type. We identified 72 new genetically defined subjects with SCA27B. Then, we analyzed the clinical, neurophysiological, and imaging features of 64 symptomatic cases. RESULTS: In our cohort, the prevalence of SCA27B was 13.4% (53/396) with as high as 38.5% (22/57) in ADCA. The median age of onset of SCA27B patients was 62 years. All symptomatic individuals showed evidence of impaired balance and gait; cerebellar ocular motor signs were also frequent. Episodic manifestations at onset occurred in 31% of patients. Extrapyramidal features (17%) and cognitive impairment (25%) were also reported. Brain magnetic resonance imaging showed cerebellar atrophy in most cases (78%). Pseudo-longitudinal assessments indicated slow progression of ataxia and minimal functional impairment. CONCLUSION: Patients with SCA27B in Italy present as an adult-onset, slowly progressive cerebellar ataxia with predominant axial involvement and frequent cerebellar ocular motor signs. The high consistency of clinical features in SCA27B cohorts in multiple populations paves the way toward large-scale, multicenter studies.
Assuntos
Progressão da Doença , Humanos , Pessoa de Meia-Idade , Itália/epidemiologia , Masculino , Feminino , Idoso , Estudos de Coortes , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/epidemiologia , Adulto , Ataxia Cerebelar/genética , Ataxia Cerebelar/epidemiologia , Ataxia Cerebelar/diagnóstico por imagem , Ataxia Cerebelar/fisiopatologia , Idade de Início , Fatores de Crescimento de Fibroblastos , Degenerações EspinocerebelaresRESUMO
OBJECTIVE: Transcranial sonography (TCS) is a noninvasive neuroimaging technique, visualizing deep brain structures and the ventricular system. Although widely employed in diagnosing various movement disorders, such as Parkinson's disease and dystonia, by detecting disease-specific abnormalities, the specific characteristics of the TCS in cerebellar ataxia remain inconclusive. We aimed to assess the potential value of TCS in patients with cerebellar ataxias for disease diagnosis and severity assessment. METHODS: TCS on patients with genetic and acquired cerebellar ataxia, including 94 with spinocerebellar ataxias (SCAs) containing 10 asymptomatic carriers, 95 with cerebellar subtype of multiple system atrophy (MSA-C), and 100 healthy controls (HC), was conducted. Assessments included third ventricle width, substantia nigra (SN) and lentiform nucleus (LN) echogenicity, along with comprehensive clinical evaluations and genetic testing. RESULTS: The study revealed significant TCS abnormalities in patients with cerebellar ataxia, such as enlarged third ventricle widths and elevated rates of hyperechogenic SN and LN. TCS showed high accuracy in distinguishing patients with SCA or MSA-C from HC, with an AUC of 0.870 and 0.931, respectively. TCS abnormalities aided in identifying asymptomatic SCA carriers, effectively differentiating them from HC, with an AUC of 0.725. Furthermore, third ventricle width was significantly correlated with SARA and ICARS scores in patients with SCA3 and SCOPA-AUT scores in patients with MSA-C. The SN area and SARA or ICARS scores in patients with SCA3 were also positively correlated. INTERPRETATION: Our findings illustrate remarkable TCS abnormalities in patients with cerebellar ataxia, serving as potential biomarkers for clinical diagnosis and progression assessment.
Assuntos
Ataxia Cerebelar , Ultrassonografia Doppler Transcraniana , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Ultrassonografia Doppler Transcraniana/métodos , Ultrassonografia Doppler Transcraniana/normas , Ataxia Cerebelar/diagnóstico por imagem , Adulto , Idoso , Atrofia de Múltiplos Sistemas/diagnóstico por imagem , Ataxias Espinocerebelares/diagnóstico por imagem , Substância Negra/diagnóstico por imagem , Biomarcadores , Terceiro Ventrículo/diagnóstico por imagemRESUMO
Mutations in the SACS gene are associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay disease (ARSACS) or complex clinical phenotypes of Charcot-Marie-Tooth disease (CMT). This study aimed to identify SACS mutations in a Korean CMT cohort with cerebellar ataxia and spasticity by whole exome sequencing (WES). As a result, eight pathogenic SACS mutations in four families were identified as the underlying causes of these complex phenotypes. The prevalence of CMT families with SACS mutations was determined to be 0.3%. All the patients showed sensory, motor, and gait disturbances with increased deep tendon reflexes. Lower limb magnetic resonance imaging (MRI) was performed in four patients and all had fatty replacements. Of note, they all had similar fatty infiltrations between the proximal and distal lower limb muscles, different from the neuromuscular imaging feature in most CMT patients without SACS mutations who had distal dominant fatty involvement. Therefore, these findings were considered a characteristic feature in CMT patients with SACS mutations. Although further studies with more cases are needed, our results highlight lower extremity MRI findings in CMT patients with SACS mutations and broaden the clinical spectrum. We suggest screening for SACS in recessive CMT patients with complex phenotypes of ataxia and spasticity.
Assuntos
Doença de Charcot-Marie-Tooth , Heterozigoto , Espasticidade Muscular , Mutação , Humanos , Masculino , Doença de Charcot-Marie-Tooth/genética , Feminino , Adulto , República da Coreia/epidemiologia , Espasticidade Muscular/genética , Espasticidade Muscular/diagnóstico por imagem , Estudos de Coortes , Pessoa de Meia-Idade , Imageamento por Ressonância Magnética , Proteínas de Choque Térmico/genética , Linhagem , Sequenciamento do Exoma , Ataxia Cerebelar/genética , Ataxia Cerebelar/diagnóstico por imagem , Fenótipo , Adolescente , Adulto JovemRESUMO
The interpretability of gait analysis studies in people with rare diseases, such as those with primary hereditary cerebellar ataxia (pwCA), is frequently limited by the small sample sizes and unbalanced datasets. The purpose of this study was to assess the effectiveness of data balancing and generative artificial intelligence (AI) algorithms in generating synthetic data reflecting the actual gait abnormalities of pwCA. Gait data of 30 pwCA (age: 51.6 ± 12.2 years; 13 females, 17 males) and 100 healthy subjects (age: 57.1 ± 10.4; 60 females, 40 males) were collected at the lumbar level with an inertial measurement unit. Subsampling, oversampling, synthetic minority oversampling, generative adversarial networks, and conditional tabular generative adversarial networks (ctGAN) were applied to generate datasets to be input to a random forest classifier. Consistency and explainability metrics were also calculated to assess the coherence of the generated dataset with known gait abnormalities of pwCA. ctGAN significantly improved the classification performance compared with the original dataset and traditional data augmentation methods. ctGAN are effective methods for balancing tabular datasets from populations with rare diseases, owing to their ability to improve diagnostic models with consistent explainability.
Assuntos
Algoritmos , Inteligência Artificial , Ataxia Cerebelar , Marcha , Doenças Raras , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Marcha/fisiologia , Ataxia Cerebelar/genética , Ataxia Cerebelar/fisiopatologia , Ataxia Cerebelar/diagnóstico , Adulto , Análise da Marcha/métodos , IdosoRESUMO
Retinitis pigmentosa (RP) is an inherited retinal dystrophy caused by the loss of photoreceptors and retinal pigment epithelial atrophy, leading to severe visual impairment or blindness. RP can be classified as nonsyndromic or syndromic with complex clinical phenotypes. Three unrelated Polish probands affected with retinitis pigmentosa coexisting with cerebellar ataxia were recruited for this study. Clinical heterogeneity and delayed appearance of typical disease symptoms significantly prolonged the patients' diagnostic process. Therefore, many clinical and genetic tests have been performed in the past. Here, we provide detailed clinical and genetic analysis results of the patients. Whole-exome sequencing (WES) and targeted NGS analysis allow the identification of four novel and two previously reported variants in the following genes: ABHD12, FLVCR1, and PNPLA6. The use of next-generation sequencing (NGS) methods finally allowed for confirmation of the clinical diagnosis. Ultra-rare diseases such as PHARC, PCARP, and Oliver-McFarlane syndromes were diagnosed in patients, respectively. Our findings confirmed the importance of the application of next-generation sequencing methods, especially in ultra-rare genetic disorders with overlapping features.
Assuntos
Sequenciamento do Exoma , Retinose Pigmentar , Humanos , Retinose Pigmentar/genética , Retinose Pigmentar/diagnóstico , Masculino , Feminino , Linhagem , Sequenciamento de Nucleotídeos em Larga Escala , Adulto , Ataxia Cerebelar/genética , Ataxia Cerebelar/diagnóstico , Proteínas de Membrana Transportadoras/genética , Monoacilglicerol Lipases/genética , Mutação , Ataxia/genética , Ataxia/diagnóstico , Fenótipo , Aciltransferases , Catarata , Fosfolipases , PolineuropatiasRESUMO
Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is a late onset neurodegenerative disorder. Its genetic basis has recently been identified in the gene encoding a subunit of the Replication Factor C (RFC1). We present the case of a 62-year-old woman who experienced a history of a biphasic presentation of imbalance and gait disorders, with rapid onset of symptoms followed by slow and progressive neurological deterioration. The diagnostic process was challenging, and numerous tests were conducted to rule out acquired and genetic causes of ataxia, leading to a diagnosis of late-onset idiopathic cerebellar ataxia. Subsequently, vestibular function tests identified severe bilateral vestibulopathy. This led to considering CANVAS among the diagnoses, which was ultimately confirmed through genetic testing (biallelic expansion of the pentanucleotide AAGGG in the RFC1 gene). This case highlights the importance of this new described genetic disease and its subacute presentation variant, emphasizing the relevance of objective vestibular function tests in idiopathic ataxias to achieve proper diagnosis and eventual genetic counseling for offspring.
El síndrome de ataxia cerebelosa, neuropatía y arreflexia vestibular (CANVAS) es un trastorno neurodegenerativo progresivo que se manifiesta en etapas tardías de la vida. Su base genética ha sido recientemente identificada en el gen que codifica la subunidad 1 del factor C de replicación (RFC1). Presentamos el caso de una mujer de 62 años con una historial de desequilibrio y deterioro de la marcha de presentación bifásica, con un inicio rápido de los síntomas seguido de un deterioro neurológico lento y progresivo. El proceso diagnóstico fue complejo y se realizaron numerosas pruebas para descartar causas adquiridas y genéticas de la ataxia, arribando al diagnóstico de ataxia cerebelosa de inicio tardío idiopática. Ulteriormente, las pruebas de función vestibular identificaron una grave vestibulopatía bilateral. Esto llevó a considerar el CANVAS entre los diagnósticos, que finalmente fue confirmado mediante pruebas genéticas (expansión bialélica del penta-nucleótido AAGGG en el gen RFC1). Este caso subraya la importancia de esta nueva enfermedad genética y su variante de presentación subaguda y enfatiza la relevancia de las pruebas objetivas de función vestibular en las ataxias consideradas idiopáticas para lograr un diagnóstico adecuado y un eventual asesoramiento genético a la descendencia.
Assuntos
Ataxia Cerebelar , Humanos , Feminino , Pessoa de Meia-Idade , Ataxia Cerebelar/genética , Ataxia Cerebelar/diagnóstico , Vestibulopatia Bilateral/diagnóstico , Vestibulopatia Bilateral/genética , Vestibulopatia Bilateral/complicações , Síndrome , Proteína de Replicação C/genética , Testes de Função VestibularRESUMO
Ataxias are characterized by aberrant movement patterns closely related to cerebellar dysfunction. Purkinje cell axons are the sole outputs from the cerebellar cortex, and dysfunctional activity of Purkinje cells has been associated with ataxic movements. However, the synaptic characteristics of Purkinje cells in cases of ataxia are not yet well understood. The nicotinamide antagonist 3-acethylpyridine (3-AP) selectively destroys inferior olivary nucleus neurons so it is widely used to induce cerebellar ataxia. Five days after 3-AP treatment (65mg/kg) in adult male Sprague-Dawley rats, motor incoordination was revealed through BBB and Rotarod testing. In addition, in Purkinje cells from lobules V-VII of the cerebellar vermis studied by the Golgi method, the density of dendritic spines decreased, especially the thin and mushroom types. Western blot analysis showed a decrease in AMPA and PSD-95 content with an increase of the α-catenin protein, while GAD-67 and synaptophysin were unchanged. Findings suggest a limited capacity of Purkinje cells to acquire and consolidate afferent excitatory inputs and an aberrant, rigid profile in the movement-related output patterns of Purkinje neurons that likely contributes to the motor-related impairments characteristic of cerebellar ataxias.
Assuntos
Cerebelo , Células de Purkinje , Ratos Sprague-Dawley , Animais , Células de Purkinje/efeitos dos fármacos , Células de Purkinje/patologia , Masculino , Ratos , Cerebelo/efeitos dos fármacos , Ataxia Cerebelar/induzido quimicamente , Piridinas/farmacologia , Plasticidade Neuronal/efeitos dos fármacosRESUMO
BACKGROUND: Cerebellar ataxia, neuropathy and bilateral vestibular areflexia (CANVAS) is a rare neurodegenerative disease affecting the cerebellum, the peripheral nervous system and the vestibular system. Due to the lack of approved drugs, therapy comprises physiotherapy and speech therapy. Transcranial magnetic stimulation is a promising non-invasive therapeutic option to complement classical symptomatic therapies. OBJECTIVE: To test feasibility of the combination of transcranial magnetic stimulation using an accelerated protocol and standard symptomatic therapy in patients with CANVAS. METHODS: Eight patients with genetically confirmed CANVAS were assigned to either verum or sham cerebellar transcranial magnetic stimulation using an accelerated protocol. Treatment duration was limited to 5 days. Additionally, patients in both groups received symptomatic therapy (speech and physiotherapy) for the duration of the study. RESULTS: All patients completed the stimulation protocol. Adverse events were rare. Ataxia severity improved in the verum group only. CONCLUSION: The combination of transcranial magnetic stimulation and classic symptomatic therapy is feasible in a neuro-rehabilitation setting and potentially ameliorates ataxia severity.
Assuntos
Estudos de Viabilidade , Modalidades de Fisioterapia , Estimulação Magnética Transcraniana , Humanos , Estimulação Magnética Transcraniana/métodos , Projetos Piloto , Masculino , Pessoa de Meia-Idade , Feminino , Terapia Combinada , Adulto , Cerebelo , Idoso , Ataxia Cerebelar/reabilitação , Ataxia Cerebelar/terapia , Resultado do Tratamento , Doenças Vestibulares/reabilitação , Doenças Vestibulares/terapiaRESUMO
BACKGROUND: Spinocerebellar ataxia 29 (SCA29) is a rare genetic disorder characterized by early-onset ataxia, gross motor delay, and infantile hypotonia, and is primarily associated with variants in the ITPR1 gene. Cases of SCA29 in Asia are rarely reported, limiting our understanding of this disease. METHODS: A female Korean infant, demonstrating clinical features of SCA29, underwent evaluation and rehabilitation at our outpatient clinic from the age of 3 months to the current age of 4 years. Trio-based genome sequencing tests were performed on the patient and her biological parents. RESULTS: The infant initially presented with macrocephaly, hypotonia, and nystagmus, with nonspecific findings on initial neuroimaging. Subsequent follow-up revealed gross motor delay, early onset ataxia, strabismus, and cognitive impairment. Further neuroimaging revealed atrophy of the cerebellum and vermis, and genetic analysis revealed a de novo pathogenic heterozygous c.800C>T, p.Thr267Met missense mutation in the ITPR1 gene (NM_001378452.1). CONCLUSION: This is the first reported case of SCA29 in a Korean patient, expanding the genetic and phenotypic spectrum of ITPR1-related ataxias. Our case highlights the importance of recognizing early-onset ataxic symptoms, central hypotonia, and gross motor delays with poor ocular fixation, cognitive deficits, and isolated cerebellar atrophy as crucial clinical indicators of SCA29.
Assuntos
Receptores de Inositol 1,4,5-Trifosfato , Mutação de Sentido Incorreto , Degenerações Espinocerebelares , Humanos , Feminino , Receptores de Inositol 1,4,5-Trifosfato/genética , Degenerações Espinocerebelares/genética , Degenerações Espinocerebelares/patologia , Pré-Escolar , Ataxia Cerebelar/genética , Ataxia Cerebelar/patologia , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/patologia , LactenteRESUMO
L-2-Hydroxyglutaric aciduria (L2HGA) is a rare, autosomal recessive neurometabolic disease, which presents with elevated L-2-hydroxyglutarate acid. Generally, L2HGA appear as slowly progressing central nervous system function deterioration during infancy, and a rapid progression in adulthood is uncommon for the syndrome's classic phenotype.
Assuntos
Oxirredutases do Álcool , Encefalopatias Metabólicas Congênitas , Ataxia Cerebelar , Adulto , Humanos , Oxirredutases do Álcool/genética , Encefalopatias Metabólicas/genética , Encefalopatias Metabólicas/diagnóstico , Encefalopatias Metabólicas Congênitas/genética , Encefalopatias Metabólicas Congênitas/diagnóstico , Ataxia Cerebelar/genética , População do Leste Asiático , Mutação da Fase de Leitura/genéticaRESUMO
INTRODUCTION: A common complaint in patients is chronic cough (CC), which may be refractory (RCC) or unexplained (UCC). Recent studies point, as a possible cause of CC, to the hereditary cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS), with an estimated carrier prevalence of 1 in 20000. AIM: In patients with CC, determine the prevalence of the biallelic (AAGGG)exp mutation in replication factor C subunit 1 (RFC1) responsible for CANVAS, test the usefulness of the Rydel-Seiffer fork test, and evaluate patient quality of life (QoL). METHODS: Clinical and functional data were collected for the 33 included patients undergoing CC studies in our specialized unit. Performed were an etiological study of CC following European Respiratory Society recommendations, a genetic study of RFC1 mutations, and Rydel-Seiffer fork testing to detect possible peripheral vibratory sensitivity impairment. Administered to evaluate QoL were 4 questionnaires. RESULTS: Prevalence of biallelic (AAGGG)exp in RFC1 was 6.1% (n=2) overall, increasing to 7.1% in the RCC subgroup, and to 33.3% in the Rydel-Seiffer fork altered results subgroup. Prevalence of monoallelic (AAGGG)exp in RFC1 was 18.2% (n=6) overall, rising to 50.0% (n=2) in the UCC subgroup. CONCLUSION: Genetic screening for (AAGGG)exp in RFC1, and also use of the Rydel-Seiffer fork test, should be considered in specialized CC consultations for patients with RCC and UCC. Detecting possible CANVAS symptoms in CC studies would identify candidates for early genetic screening, of interest in reducing the disease burden for patients and health systems alike.