Progressive Ataxia Research Articles

Severe, Subacute, Progressive, Sensory Predominant Polyneuropathy in a Patient with Chronic Progressive Cerebellar Ataxia and Antibodies to ITPR-1 (P1-14.013)

Severe, Subacute, Progressive, Sensory Predominant Polyneuropathy in a Patient with Chronic Progressive Cerebellar Ataxia and Antibodies to ITPR-1 (P1-14.013)

Clinical and Molecular Spectrum of Autosomal Recessive CA8-Related Cerebellar Ataxia.

Based on a limited number of reported families, biallelic CA8 variants have currently been associated with a recessive neurological disorder named, cerebellar ataxia, mental retardation, and dysequilibrium syndrome 3 (CAMRQ-3). We aim to comprehensively investigate CA8-related disorders (CA8-RD) by reviewing existing literature and exploring neurological, neuroradiological, and molecular observations in a cohort of newly identified patients. We analyzed the phenotype of 27 affected individuals from 14 families with biallelic CA8 variants (including data from 15 newly identified patients from eight families), ages 4 to 35 years. Clinical, genetic, and radiological assessments were performed, and zebrafish models with ca8 knockout were used for functional analysis. Patients exhibited varying degrees of neurodevelopmental disorders (NDD), along with predominantly progressive cerebellar ataxia and pyramidal signs and variable bradykinesia, dystonia, and sensory impairment. Quadrupedal gait was present in only 10 of 27 patients. Progressive selective cerebellar atrophy, predominantly affecting the superior vermis, was a key diagnostic finding in all patients. Seven novel homozygous CA8 variants were identified. Zebrafish models demonstrated impaired early neurodevelopment and motor behavior on ca8 knockout. Our comprehensive analysis of phenotypic features indicates that CA8-RD exhibits a wide range of clinical manifestations, setting it apart from other subtypes within the category of CAMRQ. CA8-RD is characterized by cerebellar atrophy and should be recognized as part of the autosomal-recessive cerebellar ataxias associated with NDD. Notably, the presence of progressive superior vermis atrophy serves as a valuable diagnostic indicator. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The genetic basis of early-onset hereditary ataxia in Iran: results of a national registry of a heterogeneous population

BackgroundTo investigate the genetics of early-onset progressive cerebellar ataxia in Iran, we conducted a study at the Children’s Medical Center (CMC), the primary referral center for pediatric disorders in the country, over a three-year period from 2019 to 2022. In this report, we provide the initial findings from the national registry.MethodsWe selected all early-onset patients with an autosomal recessive mode of inheritance to assess their phenotype, paraclinical tests, and genotypes. The clinical data encompassed clinical features, the Scale for the Assessment and Rating of Ataxia (SARA) scores, Magnetic Resonance Imaging (MRI) results, Electrodiagnostic exams (EDX), and biomarker features. Our genetic investigations included single-gene testing, Whole Exome Sequencing (WES), and Whole Genome Sequencing (WGS).ResultsOur study enrolled 162 patients from various geographic regions of our country. Among our subpopulations, we identified known and novel pathogenic variants in 42 genes in 97 families. The overall genetic diagnostic rate was 59.9%. Notably, we observed PLA2G6, ATM, SACS, and SCA variants in 19, 14, 12, and 10 families, respectively. Remarkably, more than 59% of the cases were attributed to pathogenic variants in these genes.ConclusionsIran, being at the crossroad of the Middle East, exhibits a highly diverse genetic etiology for autosomal recessive hereditary ataxia. In light of this heterogeneity, the development of preventive strategies and targeted molecular therapeutics becomes crucial. A national guideline for the diagnosis and management of patients with these conditions could significantly aid in advancing healthcare approaches and improving patient outcomes.

Immune‐mediated spastic ataxia masquerading as clinically probable multisystem atrophy in an elderly woman

AbstractBackgroundAutoimmune neurological syndromes pose diagnostic challenges due to their resemblance to neurodegenerative conditions. Autoimmune spastic ataxia is a rare phenomenon. This case presents a 56‐y‐old woman with subacute‐onset spastic ataxia, highlighting the complexities in diagnosis and the role of autoimmunity in such cases.Case PresentationA woman in her fifties developed progressive spastic ataxia over a year and presented to our outpatient department for evaluation. The patient exhibited clinical signs including saccadic intrusions, gaze‐evoked nystagmus, mixed dysarthria, spasticity, exaggerated reflexes, and cerebellar dysfunction. Brain magnetic resonance imaging (MRI) displayed the “hot cross bun sign” and cerebral and cerebellar atrophy. Initial tests yielded minimal abnormalities, but a positive antinuclear antibody (ANA) emerged. The patient initially declined immunotherapy. Upon symptom progression, a repeat cerebrospinal fluid (CSF) analysis showed inflammatory changes and a whole‐body positron emission tomography (PET) scan indicated reduced uptake in the cerebellum and brainstem. Subsequent paraneoplastic antibody testing revealed an unspecified neuronal antibody targeting capillaries and arterioles. Treatment with steroids, plasmapheresis, and azathioprine led to sustained improvement, reducing spasticity, and enabling her to walk short distances.ConclusionsThis case emphasizes the diagnostic complexity of autoimmune neurological syndromes, particularly spastic ataxia. Autoimmune etiology should be considered even when neurodegenerative conditions seem likely. The presence of neuronal antibodies, inflammatory CSF, and response to immunotherapy underscores the role of autoimmunity in this case. Additionally, the “hot cross bun sign” may not always signify neurodegeneration, but can indicate immune‐mediated neural damage. Recognizing autoimmune involvement early offers therapeutic possibilities and highlights the need for a comprehensive diagnostic approach in such cases.

Central nervous system adverse events of immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICI) may trigger immune-related adverse events which rarely affect the central nervous system (CNS-irAEs). Over the past few years, cumulative data have led to the characterization of well defined syndromes with distinct cancer and antibody associations as well as different outcomes. The most frequent CNS-irAE is encephalitis, which includes three main groups: meningoencephalitis, a nonfocal syndrome usually responsive to corticosteroids; limbic encephalitis, associated with high-risk paraneoplastic neurological syndromes (PNS) antibodies (e.g. anti-Hu, anti-Ma2) and neuroendocrine cancers, characterized by poor treatment response and outcomes; and cerebellar ataxia, with variable outcomes (worse when high-risk PNS antibodies are detected). Additionally, a diffuse encephalopathy without inflammatory findings, with poor response to corticosteroids and high mortality has been described. The spectrum of CNS-irAEs also includes meningitis, myelitis, and rarer presentations. A subset of CNS-irAEs (i.e. limbic encephalitis and/or rapidly progressive cerebellar ataxia) is undistinguishable from ICI-naïve PNS. The clinical and outcomes diversity of CNS-irAEs suggests different pathogenic mechanisms, which need to be understood to establish more effective and specific treatment modalities. It is crucial to identify biomarkers able to predict which patients will experience severe CNS-irAEs, to anticipate their diagnosis, and to predict long-term outcomes.

ANO10-Related Spinocerebellar Ataxia: MDSGene Systematic Literature Review and a Romani Case Series.

Biallelic pathogenic variants in the ANO10 gene cause autosomal recessive progressive ataxia (ATX-ANO10). Following the MDSGene protocol, we systematically investigated genotype-phenotype relationships in ATX-ANO10 based on the clinical and genetic data from 82 published and 12 newly identified patients. Most patients (>80%) had loss-of-function (LOF) variants. The most common variant was c.1150_1151del, found in all 29 patients of Romani ancestry, who had a 14-year earlier mean age at onset than patients homozygous for other LOF variants. We identified previously undescribed clinical features of ATX-ANO10 (e.g., facial muscle involvement and strabismus) suggesting the involvement of brainstem pathology, and we propose a diagnostic algorithm that may aid clinical ATX-ANO10 diagnosis. The early disease onset in patients with c.1150_1151del may indicate the existence of genetic/environmental disease-modifying factors in the Romani population. Our findings will inform patient counseling and may improve our understanding of the disease mechanism. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Steroid-responsive dual neuronal antibody-positive paraneoplastic encephalitis

Here, we report the case of an elderly African male with multifocal neuraxial involvement in the form of progressive parkinsonism and ataxia over a year. On evaluation, dual neuronal antibody positivity was detected. A diagnosis of paraneoplastic encephalitis was made without any detection of primary neoplasm. He was successfully managed with pulse steroid therapy followed by oral steroid and steroid-sparing oral immunosuppressive drug without any need for intravenous immunoglobulin or plasma exchange.

Negative Myoclonus: Neurophysiological Study and Clinical Impact in Progressive Myoclonus Ataxia.

Negative myoclonus (NM) is an involuntary movement caused by a sudden interruption of muscular activity, resulting in gait problems and falls. To establish frequency, clinical impact, and neurophysiology of NM in progressive myoclonus ataxia (PMA) patients. Clinical, neurophysiological, and genetic data of 14 PMA individuals from University Medical Centre Groningen (UMCG) Expertise Center Movement Disorder Groningen were retrospectively collected. Neurophysiological examination included video-electromyography-accelerometry assessment in all patients and electroencephalography (EEG) examination in 13 individuals. Jerk-locked (or silent period-locked) back-averaging and cortico-muscular coherence (CMC) analysis aided the classification of myoclonus. NM was present in 6 (NM+) and absent in 8 (NM-) PMA patients. NM+ individuals have more frequent falls (100% vs. 37.5%) and higher scores on the Gross Motor Function Classification System (GMFCS) (4.3 ±0.74 vs. 2.5 ±1.2) than NM- individuals. Genetic background of NM+ included GOSR2 and SEMA6B, while that of NM- included ATM, KCNC3, NUS1, STPBN2, and GOSR2. NM was frequently preceded by positive myoclonus (PM) and silent-period length was between 88 and 194 ms. EEG epileptiform discharges were associated with NM in 2 cases. PM was classified as cortical in 5 NM+ and 2 NM- through EEG inspection, jerk-locked back-averaging, or CMC analysis. Neurophysiological examination is crucial for detecting NM that could be missed on clinical examination due to a preceding PM. Evidence points to a cortical origin of NM, an association with more severe motor phenotype, and suggests the presence of genetic disorders causing either a PMA or progressive myoclonus epilepsy, rather than pure PMA phenotype. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Infratentorial superficial siderosis: report of six cases and review of the literature.

To investigate the etiology, clinical manifestations, imaging features, and treatment of patients with infratentorial superficial siderosis (iSS), enhance clinicians' comprehension of this rare disease, and conduct oral deferiprone intervention and subsequent monitoring. Six patients diagnosed with iSS based on magnetic resonance imaging (MRI) and susceptibility weighted imaging (SWI) were enrolled from 2021 to 2023 at the First Affiliated Hospital of Fujian Medical University. Their clinical datas were summarized, and the etiology and imaging characteristics were analyzed. Follow-up was conducted through telephone or outpatient visits. Among the 6 patients, there were 3 males and 3 females. The onset age ranged from 35 to 71 years, with an average onset age of 53 years. The clinical symptoms mainly included acoustic disturbances (6/6), gait imbalance (6/6), dysolfactory (6/6), cognitive impairment (2/6), epilepsy (2/6), and pyramidal tract sign (2/6). Evidence of superficial siderosis was observed on MRI across the cortex, brainstem, cerebellum, and spinal cord in all patients. T2-space sequence MRI revealed two instances of dural tear. During the follow-up period ranging from 1 month to 3 years, three patients who received oral deferiprone treatment showed improvement, whereas the remaining three patients who declined deferiprone treatment demonstrated progression. The primary clinical manifestations of iSS include bilateral sensorineural hearing disturbances, progressive cerebellar ataxia, and spinal cord lesions. The key diagnostic criteria involve the presence of linear hypointensity on T2-WI in the surface region of the nervous system. Dural tear caused by various factors is considered to be the most common cause of iSS, and its treatment mainly involves surgical intervention for hemorrhagic primary diseases as well as pharmacotherapy with deferiprone.

A-T neurodegeneration and DNA damage-induced transcriptional stress

Loss of the ATM protein kinase in humans results in Ataxia-telangiectasia, a disorder characterized by childhood-onset neurodegeneration of the cerebellum as well as cancer predisposition and immunodeficiency. Although many aspects of ATM function are well-understood, the mechanistic basis of the progressive cerebellar ataxia that occurs in patients is not. Here we review recent progress related to the role of ATM in neurons and the cerebellum that comes from many sources: animal models, post-mortem brain tissue samples, and human neurons in culture. These observations have revealed new insights into the consequences of ATM loss on DNA damage, gene expression, and immune signaling in the brain. Many results point to the importance of reactive oxygen species as well as single-strand DNA breaks in the progression of molecular events leading to neuronal dysfunction. In addition, innate immunity signaling pathways appear to play a critical role in ATM functions in microglia, responding to various forms of nucleic acid sensors and regulating survival of neurons and other cell types. Overall, the results lead to an updated view of transcriptional stress and DNA damage resulting from ATM loss that results in changes in gene expression as well as neuroinflammation that contribute to the cerebellar neurodegeneration observed in patients.

NDUFS7 variant in dogs with Leigh syndrome and its functional validation in a Drosophila melanogaster model

Two Jack-Russell Terrier × Chihuahua mixed-breed littermates with Leigh syndrome were investigated. The dogs presented with progressive ataxia, dystonia, and increased lactate levels. Brain MRI showed characteristic bilateral symmetrical T2 hyperintense lesions, histologically representing encephalomalacia. Muscle histopathology revealed accumulation of mitochondria. Whole genome sequencing identified a missense variant in a gene associated with human Leigh syndrome, NDUFS7:c.535G > A or p.(Val179Met). The genotypes at the variant co-segregated with the phenotype in the investigated litter as expected for a monogenic autosomal recessive mode of inheritance. We investigated the functional consequences of the missense variant in a Drosophila melanogaster model by expressing recombinant wildtype or mutant canine NDUFS7 in a ubiquitous knockdown model of the fly ortholog ND-20. Neither of the investigated overexpression lines completely rescued the lethality upon knockdown of the endogenous ND-20. However, a partial rescue was found upon overexpression of wildtype NDUFS7, where pupal lethality was moved to later developmental stages, which was not seen upon canine mutant overexpression, thus providing additional evidence for the pathogenicity of the identified variant. Our results show the potential of the fruit fly as a model for canine disease allele validation and establish NDUFS7:p.(Val179Met) as causative variant for the investigated canine Leigh syndrome.

Mitofusin 2 Variant Presenting With a Phenotype of Multiple System Atrophy of Cerebellar Subtype.

To investigate the etiology of cerebellar ataxia in an adult male patient. We performed standard neurologic assessment and genome sequencing of a 62-year-old man with rapidly progressive balance and gait abnormalities. The propositus exhibited cognitive dysfunction, mild appendicular bradykinesia, prominent appendicular ataxia, dysarthria, and hypomimia with minimal dysautonomic symptoms. Nerve conduction studies showed mild peripheral sensory neuropathy and normal motor nerve conduction velocities. Brain imaging showed progressive cerebellar atrophy and gliosis of the olivopontocerebellar fibers, characterized by T2 hyperintensity within the pons. Genetic testing revealed a likely pathogenic germline variant in MFN2 (NM_014874: c.[838C>T];[=], p.(R280C)) in the GTPase domain (G) interface; pathogenic variants of MFN2 typically cause hereditary sensory and motor neuropathy VI or Charcot-Marie-Tooth disease 2A. The presence of progressive ataxia, "hot cross bun" sign, and dysautonomia has been associated with multiple system atrophy, cerebellar type (MSA-C). We describe progressive cerebellar ataxia in an individual with a deleterious variant in MFN2. Our findings suggest that pathogenic variants in MFN2 can result in a spectrum of phenotypes including cerebellar ataxia with cerebellar-pontine atrophy in the absence of significant neuropathy and in a manner closely resembling MSA-C.

Paroxysmal Ataxia: A Characteristic Feature of FGF14 Repeat Expansion (SCA27B).

Paroxysmal ataxia is typically characterized by early-onset attacks of cerebellar ataxia. Late-onset cerebellar ataxia (LOCA) comprises a group of neurodegenerative disorders mainly characterized by adult-onset progressive cerebellar ataxia. A deep intronic expansion of a GAA triplet in the FGF14 gene encoding fibroblast growth factor 14 has recently been identified as a frequent cause of LOCA. We describe a patient with paroxysmal ataxia/dysarthria due to a FGF14 repeat expansion and 3 affected family members. The 4 patients had paroxysmal ataxia/dysarthria occurring between 45 and 50 years as the initial manifestation of a FGF14 repeat expansion. The index case was investigated in detail. We have provided a video showing one of her paroxysmal episodes that could be triggered by alcohol, coffee, exertion, emotion, or cigarette smoking. Brain MRI revealed mild cerebellar atrophy, and oculography showed a subclinical downbeat nystagmus. Treatment with acetazolamide resulted in remarkable improvement. Paroxysmal dysarthria/ataxia should prompt the clinician to test for FGF14 repeat expansion/SCA27B, especially when the paroxysmal attacks are associated with late-onset cerebellar ataxia and/or a family history consistent with a dominant disorder.

Diagnosis of lymphoma based on magnetic resonance imaging, analysis of cerebrospinal fluid, intraocular fluid and fine‐needle aspirate of a uveal mass lesion in a dog

AbstractA 10.5‐year‐old, male, entire labrador retriever dog was presented for chronic progressive ataxia and recent onset of a left‐sided head tilt and salivation. Neurological examination findings were deemed consistent with a multifocal brain and spinal cord neuroanatomic localisation. Ophthalmological examination of the right eye revealed pupil shape abnormality (dyscoria), a pale uveal mass lesion and white cellular sediment in the anterior chamber. Magnetic resonance imaging of the brain, eyes, thoracolumbar and lumbosacral spinal cord and surrounding structures showed multiple lesions affecting the central nervous system (brain), peripheral nervous system (left trigeminal nerve) and right eye. Cerebrospinal fluid, right eye anterior chamber fluid and fine‐needle aspirate biopsy of the uveal mass lesion yielded a cytological diagnosis of lymphoma (suspected large granular lymphocytic). The dog was discharged with palliative treatment and euthanased at home 4 days later. This case report documents the cytological diagnosis of lymphoma in the cerebrospinal fluid, intraocular fluid and fine‐needle aspirate of a uveal mass in a dog.

Genotyping KIF1C (c.608G>A) Mutant Reveals a Wide Distribution of Progressive Ataxia in German Charolais Cattle

Bovine progressive ataxia in Charolais cattle was first described in the 1970s; then, cases were reported in Charolais worldwide. A homozygous loss-of-function mutation within the KIF1C gene (c.608G>A) was found to be responsible for this neurodegenerative disease. The aim of this study was to determine whether the mutated KIF1C allele segregates in the German Charolais population and whether the estimated breeding values for growth and muscle conformation are associated with the mutated genotypes. Genetic test results of the KIF1C:c.608G>A variant were available for 1315 Charolais cattle from 35 herds located in Germany. In addition, 324 samples from eight other beef cattle breeds were tested for the mutated KIF1C allele. We were able to demonstrate that the KIF1C mutation is common, with a frequency of 11.75% in the German Charolais population. All but two of the eight (2/8 = 25%) homozygous mutated individuals showed clinical signs consistent with progressive ataxia. The estimated breeding values of muscle conformation in 200- and 365-day-old animals indicated a significant superiority for homozygous mutated animals when compared either with heterozygous or homozygous wild-type genotypes; this was also the case for heterozygous genotypes in comparison with homozygous wild-type genotypes. For the estimated breeding values of daily weight gain in 200- and 365-day-old animals, the significant differences between homozygous mutated and heterozygous or wild-type genotypes were in favour of the homozygous mutant animals. There were no differences in the estimated maternal breeding values among all three KIF1C genotypes. For the first time, two German Angus cattle carrying the KIF1C mutation heterozygous were detected. The breeders’ survey highlighted that increased awareness would facilitate increased conviction among breeders of the need for genetic testing in order to eliminate the lethal KIF1C allele.

Targeted therapy improves cellular dysfunction, ataxia, and seizure susceptibility in a model of a progressive myoclonus epilepsy

The recurrent variant KCNC1-p.Arg320His causes progressive myoclonus epilepsy (EPM) type 7, defined by progressive myoclonus, epilepsy, and ataxia, and is without effective treatment. KCNC1 encodes the voltage-gated potassium channel subunit Kv3.1, specifically expressed in high-frequency-firing neurons. Variant subunits act via loss of function; hence, EPM7 pathogenesis may involve impaired excitability of Kv3.1-expressing neurons, while enhancing Kv3 activity could represent a viable therapeutic strategy. We generate a mouse model, Kcnc1-p.Arg320His/+, which recapitulates the core features of EPM7, including progressive ataxia and seizure susceptibility. Kv3.1-expressing cerebellar granule cells and neocortical parvalbumin-positive GABAergic interneurons exhibit abnormalities consistent with Kv3 channel dysfunction. A Kv3-specific positive modulator (AUT00206) selectively enhances the firing frequency of Kv3.1-expressing neurons and improves motor function and seizure susceptibility in Kcnc1-Arg320His/+ mice. This work identifies a cellular and circuit basis of dysfunction in EPM7 and demonstrates that Kv3 positive modulators such as AUT00206 have therapeutic potential for the treatment of EPM7.

Case report of leukoencephalopathy with predominant brainstem and spinal cord involvement and lactate elevation behind the mask of multiple sclerosis

Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare or underdiagnosed autosomal-recessive mitochondrial disease that sometimes mimics progressive multiple sclerosis (MS). Difficulties in diagnosing LBSL are due to the possibility of the onset of the disease in adulthood, and the nonspecific clinical picture in the form of slowly progressive neurological symptoms (pyramidal, cerebellar, sensory and cognitive impairments) without the involvement of other organs and systems characteristic of mitochondrial pathology. However, a notable feature of LBSL is its pathognomonic magnetic resonance imaging of the white matter of the brain and spinal cord, which allows a reliable diagnosis when certain criteria are met. Currently, there are no drugs registered for the specific treatment of LBSL, however, correct diagnosis is necessary to complete the epidemiological data, and to prevent the prescription of drugs with side effects that worsen the quality of life of patients. The number of clinical publications about LBSL is small, both in Russian and foreign publications, and therefore each identified case is of great interest. The article presents a brief review of the literature and a case report of a patient with the adult-onset LBSL, who received disease modifying therapy of multiple sclerosis for a long time. The patient’s main problems were progressive lower paraparesis and ataxia. To make clinicians more aware, we have reviewed the difficulties in differential diagnosis between LBSL and MS, we provided detailed medical history, neurological status, and magnetic resonance imaging findings.

A Case Report of Machado-Joseph Disease in Young Male Patient

Spinocerebellar ataxia type-3, also known as machado-joseph disease is an autosomal dominant CAG trinucleotide repeat disease that present in young to middle age adults.clinically, it is characterized by gradually progressive ataxia and progressive degenerative changes in cerebellum and spinal cord along with basal ganglia and cortex [1].

The Phenotypic Spectrum of Spinocerebellar Ataxia Type 19 in a Series of Latin American Patients.

Spinocerebellar ataxia 19 (SCA19) represents a rare autosomal dominant genetic disorder resulting in progressive ataxia and cerebellar atrophy. SCA19 is caused by variants in the KCND3 gene, which encodes a voltage-gated potassium channel subunit essential for cerebellar Purkinje cell function. We describe six cases from Chile and Mexico, representing the largest report on SCA19 in Latin America. These cases encompass a range of clinical presentations, highlighting the phenotypic variability within SCA19 from an early-onset, severe disease to a late-onset, slowly progressive condition with normal lifespan. While some patients present with pure ataxia, others also show cognitive impairment, dystonia, and other neurological symptoms. The correlations between specific KCND3 variants and phenotypic outcomes are complex and warrant further investigation. As the genomic landscape of spinocerebellar ataxias evolves, comprehensive genetic testing is becoming pivotal in improving diagnostic accuracy. This study contributes to a better understanding of the clinical spectrum of SCA19, laying the groundwork for further genotype-phenotype correlations and functional studies to elucidate the underlying pathophysiology.

Neuroprotective Effects of Metformin Through AMPK Activation in a Neurotoxin-Based Model of Cerebellar Ataxia.

Cerebellar ataxia is a heterogeneous group of neural disorders clinically characterized by cerebellar dysfunction. The diagnosis of patients with progressive cerebellar ataxia is complex due to the direct correlation with other neuron diseases. Although there is still no cure for this pathological condition, some metabolic, hereditary, inflammatory, and immunological factors affecting cerebellar ataxia are being studied and may become therapeutic targets. Advances in studying the neuroanatomy, pathophysiology, and molecular biology of the cerebellum (CE) contribute to a better understanding of the mechanisms behind the development of this disorder. In this study, Wistar rats aged 30 to 35 days were injected intraperitoneally with 3-acetylpyridine (3-AP) and/or metformin (for AMP-activated protein kinase (AMPK) enzyme activation) and euthanized in 24 hours and 4 days after injection. We analyzed the neuromodulatory role of the AMPK on cerebellar ataxia induced by the neurotoxin 3-AP in the brain stem (BS) and CE, after pre-treatment for 7 and 15 days with metformin, a pharmacological indirect activator of AMPK. The results shown here suggest that AMPK activation in the BS and CE leads to a significant reduction in neuroinflammation in these regions. AMPK was able to restore the changes in fatty acid composition and pro-inflammatory cytokines caused by 3-AP, suggesting that the action of AMPK seems to result in a possible neuroprotection on the cerebellar ataxia model.