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Spinocerebellar ataxia type 11 (SCA11): TTBK2 variants, functions and associated disease mechanisms.Cerebellum (London, England) Apr 2024Spinocerebellar ataxia type 11 (SCA11) is a rare type of autosomal dominant cerebellar ataxia, mainly characterized by progressive cerebellar ataxia, abnormal eye signs... (Review)
Review
Spinocerebellar ataxia type 11 (SCA11) is a rare type of autosomal dominant cerebellar ataxia, mainly characterized by progressive cerebellar ataxia, abnormal eye signs and dysarthria. SCA11 is caused by variants in TTBK2, which encodes tau tubulin kinase 2 (TTBK2) protein. Only a few families with SCA11 were described to date, all harbouring small deletions or insertions that result in frameshifts and truncated TTBK2 proteins. In addition, TTBK2 missense variants were also reported but they were either benign or still needed functional validation to ascertain their pathogenic potential in SCA11. The mechanisms behind cerebellar neurodegeneration mediated by TTBK2 pathogenic alleles are not clearly established. There is only one neuropathological report and a few functional studies in cell or animal models published to date. Moreover, it is still unclear whether the disease is caused by TTBK2 haploinsufficiency of by a dominant negative effect of TTBK2 truncated forms on the normal allele. Some studies point to a lack of kinase activity and mislocalization of mutated TTBK2, while others reported a disruption of normal TTBK2 function caused by SCA11 alleles, particularly during ciliogenesis. Although TTBK2 has a proven function in cilia formation, the phenotype caused by heterozygous TTBK2 truncating variants are not clearly typical of ciliopathies. Thus, other cellular mechanisms may explain the phenotype seen in SCA11. Neurotoxicity caused by impaired TTBK2 kinase activity against known neuronal targets, such as tau, TDP-43, neurotransmitter receptors or transporters, may contribute to neurodegeneration in SCA11.
Topics: Animals; Humans; Cerebellar Ataxia; Spinocerebellar Ataxias; Spinocerebellar Degenerations; Frameshift Mutation
PubMed: 36892783
DOI: 10.1007/s12311-023-01540-6 -
Neurotherapeutics : the Journal of the... Apr 2019Autosomal dominant cerebellar ataxias (ADCAs) are a group of neurodegenerative disorders characterized by degeneration of the cerebellum and its connections. All ADCAs... (Review)
Review
Autosomal dominant cerebellar ataxias (ADCAs) are a group of neurodegenerative disorders characterized by degeneration of the cerebellum and its connections. All ADCAs have progressive ataxia as their main clinical feature, frequently accompanied by dysarthria and oculomotor deficits. The most common spinocerebellar ataxias (SCAs) are 6 polyglutamine (polyQ) SCAs. These diseases are all caused by a CAG repeat expansion in the coding region of a gene. Currently, no curative treatment is available for any of the polyQ SCAs, but increasing knowledge on the genetics and the pathological mechanisms of these polyQ SCAs has provided promising therapeutic targets to potentially slow disease progression. Potential treatments can be divided into pharmacological and gene therapies that target the toxic downstream effects, gene therapies that target the polyQ SCA genes, and stem cell replacement therapies. Here, we will provide a review on the genetics, mechanisms, and therapeutic progress in polyglutamine spinocerebellar ataxias.
Topics: Humans; Peptides; Spinocerebellar Ataxias; Trinucleotide Repeat Expansion
PubMed: 30607747
DOI: 10.1007/s13311-018-00696-y -
Current Neurology and Neuroscience... Mar 2024Spinocerebellar ataxias (SCAs) are autosomal dominant degenerative syndromes that present with ataxia and brain stem abnormalities. This review describes the cognitive... (Review)
Review
PURPOSE OF REVIEW
Spinocerebellar ataxias (SCAs) are autosomal dominant degenerative syndromes that present with ataxia and brain stem abnormalities. This review describes the cognitive and behavioral symptoms of SCAs in the context of recent knowledge of the role of the cerebellum in higher intellectual function.
RECENT FINDINGS
Recent studies suggest that patients with spinocerebellar ataxia can display cognitive deficits even early in the disease. These have been given the term cerebellar cognitive affective syndrome (CCAS). CCAS can be tracked using newly developed rating scales. In addition, patients with spinocerebellar ataxia also display impulsive and compulsive behavior, depression, anxiety, fatigue, and sleep disturbances. This review stresses the importance of recognizing non-motor symptoms in SCAs. There is a pressing need for novel therapeutic interventions to address these symptoms given their deleterious impact on patients' quality of life.
Topics: Humans; Quality of Life; Spinocerebellar Ataxias; Cerebellum; Emotions; Cognition
PubMed: 38270820
DOI: 10.1007/s11910-024-01331-4 -
Neurogenetics Oct 2021The term SCA refers to a phenotypically and genetically heterogeneous group of autosomal dominant spinocerebellar ataxias. Phenotypically they present as gait ataxia... (Review)
Review
The term SCA refers to a phenotypically and genetically heterogeneous group of autosomal dominant spinocerebellar ataxias. Phenotypically they present as gait ataxia frequently in combination with dysarthria and oculomotor problems. Additional signs and symptoms are common and can include various pyramidal and extrapyramidal signs and intellectual impairment. Genetic causes of SCAs are either repeat expansions within disease genes or common mutations (point mutations, deletions, insertions etc.). Frequently the two types of mutations cause indistinguishable phenotypes (locus heterogeneity). This article focuses on SCAs caused by common mutations. It describes phenotype and genotype of the presently 27 types known and discusses the molecular pathogenesis in those 21 types where the disease gene has been identified. Apart from the dominant types, the article also summarizes findings in a variant caused by mutations in a mitochondrial gene. Possible common disease mechanisms are considered based on findings in the various SCAs described.
Topics: Humans; Genes, Mitochondrial; Genotype; Mutation; Phenotype; Spinocerebellar Ataxias
PubMed: 34401960
DOI: 10.1007/s10048-021-00662-5 -
Cells Oct 2022While astrocyte heterogeneity is an important feature of the healthy brain, less is understood about spatiotemporal heterogeneity of astrocytes in brain disease....
While astrocyte heterogeneity is an important feature of the healthy brain, less is understood about spatiotemporal heterogeneity of astrocytes in brain disease. Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by a CAG repeat expansion in the gene (). We characterized astrocytes across disease progression in the four clinically relevant brain regions, cerebellum, brainstem, hippocampus, and motor cortex, of mice, a knock-in mouse model of SCA1. We found brain region-specific changes in astrocyte density and GFAP expression and area, early in the disease and prior to neuronal loss. Expression of astrocytic core homeostatic genes was also altered in a brain region-specific manner and correlated with neuronal activity, indicating that astrocytes may compensate or exacerbate neuronal dysfunction. Late in disease, expression of astrocytic homeostatic genes was reduced in all four brain regions, indicating loss of astrocyte functions. We observed no obvious correlation between spatiotemporal changes in microglia and spatiotemporal astrocyte alterations, indicating a complex orchestration of glial phenotypes in disease. These results support spatiotemporal diversity of glial phenotypes as an important feature of the brain disease that may contribute to SCA1 pathogenesis in a brain region and disease stage-specific manner.
Topics: Mice; Animals; Ataxin-1; Astrocytes; Spinocerebellar Ataxias; Cerebellum; Phenotype
PubMed: 36291186
DOI: 10.3390/cells11203323 -
European Neurology 2009It has been reported that patients with spinocerebellar degenerations (SCDs) have cognitive dysfunction as well as limb and truncal ataxia, dysarthria and dysphagia. We... (Review)
Review
It has been reported that patients with spinocerebellar degenerations (SCDs) have cognitive dysfunction as well as limb and truncal ataxia, dysarthria and dysphagia. We review cognitive dysfunction in common types of SCD, including spinocerebellar ataxia types 1, 2, 3, 6, and 17, dentatorubral-pallidoluysian atrophy, Friedreich's ataxia, and multiple system atrophy. There are few studies that address cognitive function in SCD. Although there are few comparison studies among the various SCDs, cognitive dysfunction may be more common and severe in spinocerebellar ataxia type 17 and dentatorubral-pallidoluysian atrophy. While cognitive dysfunction in SCD appears to represent frontal dysfunction, the mechanisms of cognitive dysfunction have not been directly clarified. Nevertheless, various lesions, including those in the cerebrocerebellar circuitry, cortico-striatal-thalamocortical circuitry, and the frontal lobe, may influence cognitive function to various degrees for each disease.
Topics: Brain; Cognition Disorders; Friedreich Ataxia; Humans; Multiple System Atrophy; Spinocerebellar Ataxias; Spinocerebellar Degenerations
PubMed: 19295212
DOI: 10.1159/000206850 -
Acta Neurologica Scandinavica Aug 2015Spinocerebellar ataxias (SCA) are a group of rare hereditary neurodegenerative disorders. Rare cases of two SCA mutations in the same individual have been reported in...
BACKGROUND
Spinocerebellar ataxias (SCA) are a group of rare hereditary neurodegenerative disorders. Rare cases of two SCA mutations in the same individual have been reported in the literature, however, family descriptions are lacking.
AIMS
To characterize a family with combined SCA2 and SCA10 mutations.
MATERIALS & METHODS
Analysis of the clinical features and genetic findings of a Bolivian family expressing both SCA2 and SCA10 mutations.
RESULTS
The index case and his mother had both SCA2 and SCA10 mutations with a combined clinical phenotype of both disorders, including slow saccades (SCA2) and seizures (SCA10). The uncle of the index case had only an SCA10 mutation.
DISCUSSION
Although the presence of two SCA mutations in the same individuals may be coincidental, the low probability of having both mutations suggests that these mutations might be particularly prevalent in Bolivian population.
CONCLUSION
This is the first description of a family with two SCA mutations with affected subjects having a combined SCA2 and SCA10 phenotype.
Topics: Ataxin-10; Ataxin-2; Bolivia; DNA Repeat Expansion; Female; Humans; Male; Middle Aged; Mutation; Pedigree; Phenotype; Spinocerebellar Ataxias
PubMed: 25630585
DOI: 10.1111/ane.12371 -
Spinocerebellar ataxia type 7: clinical course, phenotype-genotype correlations, and neuropathology.Cerebellum (London, England) Apr 2013Spinocerebellar ataxia type 7 is a neurodegenerative polyglutamine disease characterized by ataxia and retinal degeneration. The longitudinal course is unknown, and...
Spinocerebellar ataxia type 7 is a neurodegenerative polyglutamine disease characterized by ataxia and retinal degeneration. The longitudinal course is unknown, and relationships between repeat expansion, clinical manifestations, and neuropathology remain uncertain. We followed 16 affected individuals of a 61-member kindred over 27 years with electroretinograms, neurological examinations including the Brief Ataxia Rating Scale, neuroimaging in five, and autopsy in four cases. We identified four stages of the illness: Stage 0, gene-positive but phenotypically silent; Stage 1, no symptoms, but hyperreflexia and/or abnormal electroretinograms; Stage 2, symptoms and signs progress modestly; and Stage 3, rapid clinical progression. CAG repeat length correlated inversely with age of onset of visual or motor signs (r = -0.74, p = 0.002). Stage 3 rate of progression did not differ between cases (p = 0.18). Electroretinograms correlated with Brief Ataxia Rating Scale score and were a biomarker of disease onset and progression. All symptomatic patients developed gait ataxia, extremity dysmetria, dysarthria, dysrhythmia, and oculomotor abnormalities. Funduscopy revealed pale optic discs and pigmentary disturbances. Visual acuity declined to blindness in those with longer CAG expansions. Hyperreflexia was present from Stage 1 onwards. Restless legs syndrome and sensory impairment were common. Neuropathological hallmarks were neuronal loss in cerebellar cortex, deep cerebellar nuclei, inferior olive, and anterior horns of the spinal cord, and axonal loss in spinocerebellar tracts, dorsal nerve roots, and posterior columns. Retinal pathology included photoreceptor degeneration and disruption of retinal pigment epithelium. Spinocerebellar ataxia type 7 evolves through four clinical stages; neuropathological findings underlie the clinical presentation; electroretinograms are a potential biomarker of disease progression.
Topics: Adult; Age Factors; Aged; Aged, 80 and over; Ataxin-7; Brain; Diagnosis; Electroretinography; Family Health; Female; Genetic Association Studies; Humans; Intranuclear Inclusion Bodies; Longitudinal Studies; Magnetic Resonance Imaging; Male; Middle Aged; Nerve Tissue Proteins; Neurons; Photic Stimulation; Retrospective Studies; Severity of Illness Index; Spinocerebellar Ataxias; Trinucleotide Repeats; Young Adult
PubMed: 22915085
DOI: 10.1007/s12311-012-0412-4 -
Cell Death & Disease Nov 2021Spinocerebellar ataxia type 2 (SCA2) is an incurable and genetic neurodegenerative disorder. The disease is characterized by progressive degeneration of several brain...
Spinocerebellar ataxia type 2 (SCA2) is an incurable and genetic neurodegenerative disorder. The disease is characterized by progressive degeneration of several brain regions, resulting in severe motor and non-motor clinical manifestations. The mutation causing SCA2 disease is an abnormal expansion of CAG trinucleotide repeats in the ATXN2 gene, leading to a toxic expanded polyglutamine segment in the translated ataxin-2 protein. While the genetic cause is well established, the exact mechanisms behind neuronal death induced by mutant ataxin-2 are not yet completely understood. Thus, the goal of this study is to investigate the role of autophagy in SCA2 pathogenesis and investigate its suitability as a target for therapeutic intervention. For that, we developed and characterized a new striatal lentiviral mouse model that resembled several neuropathological hallmarks observed in SCA2 disease, including formation of aggregates, neuronal marker loss, cell death and neuroinflammation. In this new model, we analyzed autophagic markers, which were also analyzed in a SCA2 cellular model and in human post-mortem brain samples. Our results showed altered levels of SQSTM1 and LC3B in cells and tissues expressing mutant ataxin-2. Moreover, an abnormal accumulation of these markers was detected in SCA2 patients' striatum and cerebellum. Importantly, the molecular activation of autophagy, using the compound cordycepin, mitigated the phenotypic alterations observed in disease models. Overall, our study suggests an important role for autophagy in the context of SCA2 pathology, proposing that targeting this pathway could be a potential target to treat SCA2 patients.
Topics: Animals; Autophagy; Disease Models, Animal; Female; Humans; Male; Mice; Spinocerebellar Ataxias; Transfection
PubMed: 34845184
DOI: 10.1038/s41419-021-04404-1 -
Medicine Dec 2021Spinocerebellar ataxia (SCA) is a common neurogenetic disease that mainly manifests as ataxia of posture, gait, and limbs, cerebellar dysarthria, and cerebellar and... (Review)
Review
RATIONALE
Spinocerebellar ataxia (SCA) is a common neurogenetic disease that mainly manifests as ataxia of posture, gait, and limbs, cerebellar dysarthria, and cerebellar and supranuclear eye movement disorders. SCA has been found to include many subtypes, which are mainly mapped to 2 genetic patterns: autosomal dominant cerebellar ataxia and autosomal recessive cerebellar ataxia. Molecular genetic diagnosis functions as a necessity in its clinical diagnosis and treatment. In preliminary clinical work, we identified a family of SCA28 with rare gene mutation.
PATIENT CONCERNS
There are 5 patients in this family. The proband is a 32 year-old male, he mainly manifest unsteady steps for more than 7 months. The daughter of his younger maternal uncle gradually had unsteady steps and unclear speech for 5 years. The proband's mother, uncle and grandfather had similar symptoms, but they all died.
DIAGNOSIS
After Brain magnetic resonance imaging, whole exome sequencing and Sanger validation, the patients presented a c.1852A > G missense mutation in the exon region of AFG3L2 gene. The other family members revealed no AFG3L2 mutations. SCA28 is the one uniquely caused by a pathogenic variation in the mitochondrial protein AFG3L2. Combined with the clinical manifestations, auxiliary examinations and sequencing results of the patients (III-3 and III-5), the diagnosis of SCA28 was suspected.
INTERVENTIONS
The patients did not receive any drug treatment and the proband receive rehabilitation treatment.
OUTCOMES
The symptoms of ataxia were still progressively aggravated.
LESSONS
Molecular genetic diagnosis is necessary for ataxia. We here report the case and review the literature.
Topics: ATP-Dependent Proteases; ATPases Associated with Diverse Cellular Activities; Adult; Brain; Cerebellar Ataxia; China; Humans; Magnetic Resonance Imaging; Male; Mutation; Pedigree; Spinocerebellar Ataxias; Exome Sequencing
PubMed: 34918652
DOI: 10.1097/MD.0000000000028008