Cerebellar Degeneration Research Articles

Reinforcement Motor Learning After Cerebellar Damage Is Related to State Estimation.

Recent work showed that individuals with cerebellar degeneration could leverage intact reinforcement learning (RL) to alter their movement. However, there was marked inter-individual variability in learning, and the factors underlying it were unclear. Cerebellum-dependent sensory prediction may contribute to RL in motor contexts by enhancing body state estimates, which are necessary to solve the credit-assignment problem. The objective of this study was to test the relationship between the predictive component of state estimation and RL in individuals with cerebellar degeneration. Individuals with cerebellar degeneration and neurotypical control participants completed two tasks: an RL task that required them to alter the angle of reaching movements and a state estimation task that tested the somatosensory perception of active and passive movement. The state estimation task permitted the calculation of the active benefit shown by each participant, which is thought to reflect the cerebellum-dependent predictive component of state estimation. We found that the cerebellar and control groups showed similar magnitudes of learning with reinforcement and active benefit on average, but there was substantial variability across individuals. Using multiple regression, we assessed potential predictors of RL. Our analysis included active benefit, somatosensory acuity, clinical ataxia severity, movement variability, movement speed, and age. We found a significant relationship in which greater active benefit predicted better learning with reinforcement in the cerebellar, but not the control group. No other variables showed significant relationships with learning. Overall, our results support the hypothesis that the integrity of sensory prediction is a strong predictor of RL after cerebellar damage.

Anti-Ma2 Antibody-Mediated Paraneoplastic Cerebellar Degeneration and Myeloneuropathy Secondary to Lymphoma.

A 61-year-old woman with a history of untreated low-grade B-cell lymphoma presented with blurry vision, unsteadiness, and worsening pain on touching skin of the upper trunk was enrolled. Blurry vision was attributed to oscillopsia from downbeat nystagmus, which later evolved into macrosaccadic oscillations. MRI brain and spine showed mild, longitudinally extensive T2 hyperintensity in the central gray matter of the spinal cord extending from the medulla to T11 level. Serum paraneoplastic panel was negative; however, she had very high titers of anti-Ma2 antibodies in cerebrospinal fluid. The diagnosis of paraneoplastic neurological syndrome was made. Empiric treatment with high dose of intravenous steroids followed by intravenous immunoglobulin infusions did not improve her symptoms. An extensive search for an underlying tumor commenced and was initially unrevealing. However, two-month follow-up positron emission tomography scan showed increased uptake in a right pulmonary nodule, which when biopsied confirmed diagnosis of extranodal marginal zone lymphoma. The final diagnosis was anti-Ma2 antibody-mediated paraneoplastic cerebellar degeneration and myeloneuropathy secondary to lymphoma.

Aβ1-42 Accumulation Accompanies Changed Expression of Ly6/uPAR Proteins, Dysregulation of the Cholinergic System, and Degeneration of Astrocytes in the Cerebellum of Mouse Model of Early Alzheimer Disease.

Alzheimer disease (AD) is a widespread neurodegenerative disease characterized by the accumulation of oligomeric toxic forms of β-amyloid (Aβ1-42) and dysfunction of the cholinergic system in the different brain regions. However, the exact mechanisms of AD pathogenesis and the role of the nicotinic acetylcholine receptors (nAChRs) in the disease progression remain unclear. Here, we revealed a decreased expression of a number of the Ly6/uPAR proteins targeting nAChRs in the cerebellum of 2xTg-AD mice (model of early AD) in comparison with non-transgenic mice both at mRNA and protein levels. We showed that co-localization of one of them, - neuromodulator Lynx1, with α7-nAChR was diminished in the vicinity of cerebellar astrocytes of 2xTg-AD mice, while Aβ1-42 co-localization with this receptor present was increased. Moreover, the expression of anti-inflammatory transcription factor KLF4 regulating transcription of the Ly6/uPAR genes was decreased in the cerebellum of 2xTg-AD mice, while expression of inflammatory cytokine TNF-α was increased. Based on these data together with observed astrocyte degeneration in the cerebellum of 2xTg-AD mice, we suggest the mechanism by which expression of the Ly6/uPAR proteins upon Aβ pathology results in dysregulation of the cholinergic system and particularly of α7-nAChR function in the cerebellum. This leads to enhanced neuroinflammation and cerebellar astrocyte degeneration.

Paraneoplastic cerebellar degeneration

Introduction. Paraneoplastic cerebellar degeneration (PCD) is an immune-mediated and rapidly progressive cerebellar syndrome that develops as a result of a cross-immune response to the common antigens for the tumor and cerebellar cells. Timely diagnosis and treatment of PCD improves the functional status and survival of these patients.Objective. To analyze the clinical, laboratory and neuroimaging characteristics of PCD case series in comparison with literature data.Material and methods. 16 patients with PCD (13 women, 3 men) were examined. An assessment of the clinical presentation, brain MRI study, blood and cerebrospinal fl uid laboratory tests were carried out, the data of cancer search and patients follow-up were analyzed.Results. The median age of PCD patients was 55 years, the duration of the disease was 8.5 months (range 4 to 16 months). In 12 patients, PCD was the fi rst manifestation of cancer. The clinical prentation was presented by rapidly progressive cerebellar ataxia, often in combination with oculomotor disturbances, pyramidal and bulbar syndrome, hand tremor and dystonia. An associated cancers were detected in 13 patients (81%). Antineuronal antibodies were found in 14 patients (88%): anti-Yo-1, antibodies to amphiphysin, anti-Hu, anti-CV2 and anti-GAD. Mild atrophic changes of the cerebellum were found in 6 patients, and in 2 cases cerebellar hemiatrophy was observed.Conclusion. PCD is a rare disabling but potentially curable disease. The basis of diagnosis is the analysis of the clinical presentation and neuroimaging data, the detection of antineuronal antibodies and in fl ammatory changes in the cerebrospinal fl uid, as well as a thorough cancer search.

Cerebellar syndrome: cause cured, but symptoms persist

Subacute cerebellar syndromes have a broad differential diagnosis, which includes paraneoplasia. Paraneoplastic cerebellar degeneration needs to be considered in this clinical situation even if initial brain imaging is normal, and the neurological prognosis is guarded even if the underlying tumour can be successfully treated.

Cerebellar Degeneration Associated with HIV Infection

Cerebellar Degeneration Associated with HIV Infection

Historical and more common nongenetic movement disorders from Asia.

Nongenetic movement disorders are common throughout the world. The movement disorders encountered may vary depending on the prevalence of certain disorders across various geographical regions. In this paper, we review historical and more common nongenetic movement disorders in Asia. The underlying causes of these movement disorders are diverse and include, among others, nutritional deficiencies, toxic and metabolic causes, and cultural Latah syndrome, contributed by geographical, economic, and cultural differences across Asia. The industrial revolution in Japan and Korea has led to diseases related to environmental toxin poisoning, such as Minamata disease and β-fluoroethyl acetate (FEA)-associated cerebellar degeneration, respectively, while religious dietary restriction in the Indian subcontinent has led to infantile tremor syndrome related to vitamin B12 deficiency. In this review, we identify the salient features and key contributing factors in the development of these disorders.

A SACS deletion variant in Great Pyrenees dogs causes autosomal recessive neuronal degeneration.

ARSACS (autosomal recessive spastic ataxia of Charlevoix-Saguenay) is a human neurological disorder characterized by progressive cerebellar ataxia and peripheral neuropathy. A recently recognized disorder in Great Pyrenees dogs is similarly characterized by widespread central nervous system degeneration leading to progressive cerebellar ataxia and spasticity, combined with peripheral neuropathy. Onset of clinical signs occurred in puppies as young as 4 months of age, with slow progression over several years. A multi-generation pedigree suggested an autosomal recessive mode of inheritance. Histopathology revealed consistent cerebellar Purkinje cell degeneration, neuronal degeneration in brainstem nuclei, widespread spinal cord white matter degeneration, ganglion cell degeneration, inappropriately thin myelin sheaths or fully demyelinated peripheral nerve fibers, and normal or only mild patterns of denervation atrophy in skeletal muscles. Genome-wide single nucleotide polymorphism (SNP) genotype data was collected from 6 cases and 26 controls, where homozygosity mapping identified a 3.3Mb region on CFA25 in which all cases were homozygous and all controls were either heterozygous or homozygous for alternate haplotypes. This region tagged the SACS gene where variants are known to cause ARSACS. Sanger sequencing of SACS in affected dogs identified a 4bp deletion that causes a frame shift and truncates 343 amino acids from the C terminus of the encoded sacsin protein (p.Val4244AlafsTer32). Our clinical and histopathological descriptions of this canine disorder contribute to the description of human ARSACS and represents the first naturally occurring large animal model of this disorder.

Neuronal ceroid lipofuscinosis: A case report

Neuronal ceroid lipofuscinoses (NCL) represent severe neurodegenerative conditions which is one of the lysosomal storage disorders. There are four main clinical forms of NCL among which late infantile variety is the second most common condition. Here, we discuss a case concerning a boy aged 5 years and 4 months who exhibited a continuous decline in cognitive and motor functions starting from the age of 4. As the disorder advanced, he experienced gradual deterioration of his eyesight, unsteady walking and myoclonic seizures. An electroencephalogram performed on the child demonstrated widespread instances of sharp and slow wave discharges alongside a slowed background activity. Magnetic resonance imaging revealed extensive cerebral and noticeable cerebellar degeneration. A skin biopsy extracted from the armpit area displayed distinctive eosinophilic inclusions within the cells and structures in the eccrine ducts which stained positively for periodic acid-Schiff. These findings indicated a possibility of neuronal ceroid lipofuscinoses. Bangabandhu Sheikh Mujib Medical University Journal 2023;16(3): 174-177

B-111 Parallel Detection of Antibodies against CDR2L and CDR2 Increases the Diagnostic Specificity in Serological Diagnostics of Paraneoplastic Cerebellar Degeneration

Abstract Background Onconeuronal anti-Yo antibodies are key diagnostic markers for paraneoplastic cerebellar degeneration (PCD) and often associated with gynaecologic/breast cancer. Cerebellar degeneration-related protein 2-like (CDR2L), but not cerebellar degeneration-related protein 2 (CDR2), has recently been shown to be the major anti-Yo target (1, 2). This study investigated if inclusion of CDR2L in diagnostic tests results in increased specificity for PCD. Methods Three panels were examined for reactivity against CDR2L and CDR2 by line blot analysis (EUROLINE). Panel A comprised 14 preselected sera from women with Yo-specific reactivity by indirect immunofluorescence assay (IFA) on rat cerebellum, presenting with cerebellar ataxia (n = 13) or peripheral neuropathy (n = 1) and underlying gynaecologic/breast cancers (n = 14). Panel B included 2132 non-selected consecutive serum/CSF samples from patients with neurological symptoms. Panel C consisted of 150 samples from healthy blood donors. Results In Panel A, all samples (100%) from patients with typical clinical characteristics for Yo-associated PCD showed strong positive reactivity to both CDR2L and CDR2. In Panel B, seven (0.3%) sera were anti-CDR2 negative, but anti-CDR2L positive, all of them from patients (6M/1F) without PCD and two with cancer or pre-cancerous condition. Eleven (0.5%) patients (9M/2F) were found to be anti-CDR2 positive, but anti-CDR2L negative, including two with cerebellar ataxia and three with cancer or pre-cancerous condition. In all 18 cases, IFA on rat cerebellum was negative, suggesting non-specific line blot reactivity to CDR2L or CDR2. In Panel C, 0/150 sera were anti-CDR2L and 1/150 anti-CDR2 positive, corresponding to specificities of 100% and 99.3%, respectively. The anti-CDR2 positive blood donor was male with negative IFA result. Conclusion Using CDR2L in addition to CDR2 increases the specificity in diagnosing anti-Yo-associated PCD. Positive line blot reactivity against both parameters seems to confirm the diagnosis. In contrast, results showing isolated reactivity against either CDR2L or CDR2 have to be interpreted carefully as they may apply to non-PCD cases.

Human SHQ1 variants R335C and A426V lead to severe ribosome biogenesis defects when expressed in yeast.

SHQ1 is an essential chaperone that binds the pseudouridine synthase dyskerin in the cytoplasm and escorts the enzyme to the nucleus, where dyskerin is assembled into small nucleolar RNPs (snoRNPs) of the H/ACA class. These particles carry out pseudouridine formation in ribosomal RNAs (rRNAs) and participate in maturation of rRNA precursors (pre-rRNAs). Variants of human SHQ1 have been linked to neurodevelopmental deficiencies; here we focused on two compound heterozygous mutations identified in a child showing a severe neurological disorder comprising cerebellar degeneration. To investigate the molecular defects caused by mutations R335C and A426V we used a conditional yeast strain that can be depleted of the endogenous Shq1 protein while constitutively expressing human SHQ1 (wild-type or variants). Although wild-type SHQ1 complemented the Shq1-depleted strain, cells expressing variant R335C could not support growth, and cells expressing variant A426V were temperature-sensitive. When shifted to restrictive conditions, yeast cells progressively lost H/ACA snoRNAs and accumulated unprocessed pre-rRNAs, which led to reduced production of ribosomes. Levels of Cbf5 (yeast homologue of dyskerin) were decreased in yeast cells expressing SHQ1 variants under restrictive conditions. Immunoprecipitation experiments revealed that interaction of Cbf5 with SHQ1 variants was weakened but not abolished, and yeast two-hybrid assays showed that mutation R335C is more deleterious than mutation A426V. Our data provide additional evidence for the critical role of SHQ1 in chaperoning the pseudouridine synthase dyskerin, and how its inadequate function has detrimental consequences on the production of H/ACA snoRNPs and ribosomes.

Cerebellar manifestation secondary to rectal neoplasia

The condition known as paraneoplastic cerebellar degeneration (PCD) is among the most disabling examples of a cancer's remote effects. Serology for paraneoplastic antibodies, clinical suspicion, and a targeted search for malignancy all play a role in the diagnosis. Tests for neuronal autoantibodies aid in diagnosis and point the way for the search for malignancy. Unfortunately, even with an early diagnosis, existing therapeutic approaches only have little success. Here we present the case of a young male who developed cerebellar syndrome secondary to rectal neoplasia.

Downregulation of lncRNA SATB2‑AS1 facilitates glioma cell proliferation by sponging miR‑671‑5p.

The antisense transcript of SATB2 protein (SATB2-AS1) is a novel long non-coding RNA (lncRNA) which is involved in the development of colorectal cancer, breast cancer and hepatocellular carcinoma. In the present study, it was aimed to investigate the consequent situation of SATB2-AS1 in tissue and cell lines of glioma. The expression of SATB2-AS1 in glioma cases was analyzed in The Cancer Genome Atlas datasets. The glycolytic metabolism was determined in glioma cells by detection of extracellular glucose level, oxygen consumption rate and extracellular acidification rate. Cell Counting Kit-8 assay and flow cytometry were used to assess cell proliferation and apoptosis in glioma cells. The interaction between SATB2-AS1 and microRNA (miR)-671-5p was verified by bioinformatic analysis, reverse transcription-quantitative PCR, dual luciferase reporter assay and RNA immunoprecipitation assay. The expression levels of the downstream targets of SATB2-AS1 were studied by western blotting. Results demonstrated that SATB2-AS1 was a downregulated lncRNA in low grade glioma and glioblastoma. Gain-of-function assay demonstrated that SATB2-AS1 inhibited cell proliferation, and glycolytic metabolism, while induced cell apoptosis in glioma cells. SATB2-AS1 sponged and suppressed the expression of an oncogenic miRNA miR-671-5p. By regulation of miR-671-5p, SATB2-AS1 upregulated cerebellar degeneration related protein 1 (CDR1) and Visinin-like 1 (VSNL1) expression in glioma cells. miR-671-5p overexpression partially reversed the antitumor effect of SATB2-AS1 in glioma. In conclusion, the current study demonstrated that there was a downregulation of SATB2-AS1 in glioma, and SATB2-AS1 regulated miR-671-5p/CDR1 axis and miR-671-5p/VSNL1 axis in glioma.

A child with polyarthritis and chronic lung disease: a case report of ataxia-telangiectasia

BackgroundAtaxia-telangiectasia (A-T) is a rare autosomal recessive DNA repair disorder, characterized by progressive cerebellar degeneration, telangiectasia, immunodeficiency, recurrent sinopulmonary infections, radiation sensitivity, premature aging and predisposition to cancer. Although the association with autoimmune and chronic inflammatory conditions such as vitiligo, thrombocytopenia and arthritis has occasionally been reported, an onset with articular involvement at presentation is rare.Case presentationWe herein report the case of a 7-year-old Caucasian girl who was admitted to the Rheumatology Department with a history of febrile chough and polyarthritis which led initially to the suspicion of an autoinflammatory disease. She had overt polyarthritis with knees deformities and presented with severe pneumonia. A chest Computed Tomography (CT) scan showed bilateral bronchiectasis, parenchymal consolidation and interstitial lung disease; rheumatoid factor and type I interferon signature resulted negative, therefore excluding COatomer Protein subunit Alpha (COPA) syndrome. A diagnosis of sarcoidosis had been suspected based on histological evidence of granulomatous liver inflammation, but ruled out after detecting normal angiotensin converting enzyme and chitotriosidase blood levels. Based on her past medical history characterized by at least six episodes of pneumonia in the previous 4 years, immunological phenotyping was performed. This showed complete IgA and IgE deficiency with defective antigen-specific antibodies to Pneumococcal, Tetanus toxin and Hemophilus Influenzae B vaccines. Additionally, low numbers of B cells and recent thymic emigrants (RTE) were found (CD4Ra 1.4%), along with a low CD4+/CD8 + T cells ratio (< 1). Finally, based on gait disturbances (wobbly wide-based walking), serum alfa-fetoprotein was dosed, which resulted increased at 276 ng/ml (normal value < 7 ng/ml). A diagnosis of Ataxia-Telangiectasia was made, strengthened by the presence of bulbar telangiectasia, and then confirmed by Whole Exome Sequencing (WES).ConclusionsAlthough rare, A-T should always be ruled out in case of pulmonary bronchiectasis and gait disturbances even in the absence of bulbar or skin telangiectasia. Autoimmune and granulomatous disorders must to be considered as differential diagnosis.

Survival and process outgrowth of human iPSC-derived cells expressing Purkinje cell markers in a mouse model for spinocerebellar degenerative disease

Purkinje cells are the sole output neurons of the cerebellar cortex and play central roles in the integration of cerebellum-related motor coordination and memory. The loss or dysfunction of Purkinje cells due to cerebellar atrophy leads to severe ataxia. Here we used in vivo transplantation to examine the function of human iPS cell-derived cerebellar progenitors in adult transgenic mice in which Purkinje-specific cell death occurs due to cytotoxicity of polyglutamines. Transplantation using cerebellar organoids (42–48 days in culture), which are rich in neural progenitors, showed a viability of >50% 4 weeks after transplantation. STEM121+ grafted cells extended their processes toward the deep cerebellar nuclei, superior cerebellar peduncle, and vestibulocerebellar nuclei. The transplanted cells were mostly located in the white matter, and they were not found in the Purkinje cell layer. MAP2-positive fibers seen in the molecular layer of cerebellar cortex received VGluT2 inputs from climbing fibers. Transplanted neural progenitors overgrew in the host cerebellum but were suppressed by pretreatment with the γ-secretase inhibitor DAPT. Hyperproliferation was also suppressed by transplantation with more differentiated organoids (86 days in culture) or KIRREL2-positive cells purified by FACS sorting. Transplanted cells expressed Purkinje cell markers, GABA, CALB1 and L7, though they did not show fan-shaped morphology. We attempted to improve neuronal integration of stem cell-derived cerebellar progenitors by transplantation into the adult mouse, but this was not successfully achieved. Our findings in the present study contribute to regenerative medical application for cerebellar degeneration and provide new insights into cerebellar development in future.

A retrospective study of autoimmune cerebellar ataxia over a 20-year period in a single institution.

It is important to differentiate autoimmune cerebellar ataxia (ACA) from neurodegenerative CA, but this is sometimes difficult. We performed a retrospective study in a single institution in Japan over a 20-year period to reveal the clinical features of ACA. Patients with CA as the primary neurological symptom were enrolled from those admitted to the Department of Neurology, Hokkaido University Hospital between April 2002 and March 2022. ACA was diagnosed retrospectively according to the following criteria: (1) CA being the predominant symptom; (2) identification of cancer within 2years of onset; (3) improvement in cerebellar symptoms following immunotherapy; and (4) ruling out alternative causes of CA. Patients fulfilling criteria (1), (2), and (4) were classified as paraneoplastic cerebellar degeneration (PCD), while those fulfilling (1), (3), and (4) were classified as non-PCD and enrolled as patients with ACA. Neurodegenerative diseases, e.g., multiple system atrophy (MSA), were confirmed retrospectively based on generally used diagnostic criteria and enrolled. Furthermore, the ACA diagnostic criteria proposed by Dalmau and Graus were applied retrospectively to the ACA patients to examine the validity of the diagnoses. Among the 243 patients with CA, 13 were enrolled as ACA; five were PCD and eight were non-PCD. Eight of these cases met the proposed diagnostic criteria by Dalmau and Graus. MSA was the most prevalent disease among CA patients, with 93 cases. The incidence of cerebellar atrophy was significantly lower in ACA (3/13) than in MSA (92/92). Cerebrospinal fluid (CSF) pleocytosis was significantly more frequent in ACA than in MSA (4/13 vs. 2/55, respectively). However, there was no significant difference in the presence of oligoclonal bands, increased protein in CSF, and laterality differences in ataxia. ACA was present in ~ 5% of Japanese CA patients. The absence of cerebellar atrophy, despite the presence of CA, strongly supports ACA over MSA. While CSF pleocytosis was observed more often in ACA, the positivity rate was only ~ 30%. Since ACA is treatable, further studies are needed to identify additional clinical features and accurate diagnostic biomarkers.

Teaching NeuroImage: Paraneoplastic Cerebellar Degeneration and Antibodies to TRIM 9 and 67 Secondary to Melanoma.

Teaching NeuroImage: Paraneoplastic Cerebellar Degeneration and Antibodies to TRIM 9 and 67 Secondary to Melanoma.

A novel ELOVL4 variant, L168S, causes early childhood-onset Spinocerebellar ataxia-34 and retinal dysfunction: a case report

Spinocerebellar ataxia 34 (SCA34) is an autosomal dominant inherited disease characterized by age-related cerebellar degeneration and ataxia caused by mutations in the Elongation of Very Long Chain Fatty Acid-4 (ELOVL4) gene. The ELOVL4 enzyme catalyzes the biosynthesis of both very long chain saturated fatty acids (VLC-SFA) and very long chain polyunsaturated fatty acids (VLC-PUFA) that are important for neuronal, reproductive, and skin function. Several variants in ELOVL4 have been shown to cause different tissue-specific disorders including SCA34 with or without Erythrokeratodermia Variabilis (EKV), a skin condition characterized by dry, scaly skin, Autosomal Dominant Stargardt-Like Macular Dystrophy (STGD3), and seizures associated with neuro-ichthyotic disorders. What is puzzling is how different mutations in the same gene seem to cause different tissue-specific disorders. To date, no SCA34 patients have presented with both SCA34 and STGD3 pathology that is caused by ELOVL4 variants that cause truncation of ELOVL4. Here, we report a novel case of an early childhood onset and rapidly progressive cerebellar degeneration and retinal dysfunction in a Belgian-Italian girl who developed severe dysarthria and gait problems starting at about 3.5 years of age and progressed to immobility by 4.5 years of age. Brain magnetic resonance imaging (MRI) revealed progressive vermian, cerebellar, cortical atrophy, progressive corpus callosum slimming, and hot cross bun sign visible on the MRI. Ophthalmological examinations also revealed progressive macular dysfunction as measured by electroretinography. Using exome sequencing, we identified a novel heterozygous ELOVL4 variant, c.503 T > C (p. L168S) in the patient. To understand the enzymatic function of this novel ELOVL4 variant and how it alters the levels of VLC-PUFA and VLC-SFA biosynthesis to contribute to cerebellar and retinal dysfunction, we expressed wild-type ELOVL4 or the L168S ELOVL4 variant in cell culture and supplemented the cultures with VLC-PUFA or VLC-SFA precursors. We showed that the L168S ELOVL4 variant is deficient in the biosynthesis of VLC-SFA and VLC-PUFA. Our work suggests that differential depletion of these fatty acids may be a contributing factor to the pathogenic mechanism of SCA34 with or without EKV. Further studies will help further define how the different ELOVL4 variants cause different tissue-specific disorders with variable ages of onset.

A rare case of phenytoin-induced cerebellar atrophy

Epilepsy is a common health problem and affects humans of any age. Phenytoin is indicated in all types of seizure except in absence epilepsy. It has a wide range of pharmacokinetic properties with a narrow therapeutic range thus often leading to toxicity. Long-term neurological side effects of phenytoin include cerebellar atrophy. Therefore, monitoring of plasma levels should be done in patients on long-term phenytoin. Here, we describe a case of cerebellar degeneration in a post-operated brain abscess patient on chronic phenytoin therapy.

A chlorzoxazone–folic acid combination improves cognitive affective decline in SCA2-58Q mice

Spinocerebellar ataxia type 2 (SCA2) is a polyglutamine disorder caused by a pathological expansion of CAG repeats in ATXN2 gene. SCA2 is accompanied by cerebellar degeneration and progressive motor decline. Cerebellar Purkinje cells (PCs) seem to be primarily affected in this disorder. The majority of the ataxia research is focused on the motor decline observed in ataxic patients and animal models of the disease. However, recent evidence from patients and ataxic mice suggests that SCA2 can also share the symptoms of the cerebellar cognitive affective syndrome. We previously reported that SCA2-58Q PC-specific transgenic mice exhibit anxiolytic behavior, decline in spatial memory, and a depressive-like state. Here we studied the effect of the activation of the small conductance calcium-activated potassium channels (SK channels) by chlorzoxazone (CHZ) combined with the folic acid (FA) on the PC firing and also motor, cognitive and affective symptoms in SCA2-58Q mice. We realized that CHZ-FA combination improved motor and cognitive decline as well as ameliorated mood alterations in SCA2-58Q mice without affecting the firing rate of their cerebellar PCs. Our results support the idea of the combination therapy for both ataxia and non-motor symptoms in ataxic mice without affecting the firing frequency of PCs.