Pattern of Peripheral Nerve Involvement in Spinocerebellar Ataxia Type 2: a Neurophysiological Assessment

Bezerra, Márcio Luiz Escórcio; Pedroso, José Luiz; Braga‐Neto, Pedro; Abrahão, Agessandro; Albuquerque, Marcus Vinicius Cristino; Borges, Franklin Roberto Pereira; Saraiva-Pereira, Maria Luiza; Jardim, Laura Bannach; Braga, Nadia Iandoli de Oliveira; Manzano, Gilberto Mastrocola; Barsottini, Orlando Graziani Póvoas

doi:10.1007/s12311-015-0753-x

Cited by 8 publications

(2 citation statements)

References 31 publications

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“…We have previously generated the novel Atxn2 -CAG100-KnockIn mouse and shown for the cerebellum that (i) the temporal evolution of locomotor deficits and progressive atrophy, (ii) the spatial distribution of its pathology, and (iii) the neurochemical anomalies upon brain imaging faithfully reflect the known features of SCA2 [185]. For the spinal cord pathology as well, the current study confirms that this mouse mutant represents an authentic SCA2 model: Neurophysiologically, the distinctive features of SCA2 patients around clinical manifestation include an early sensory neuropathy by predominantly axonal lesion with signs of myelin damage [16, 146, 166, 168, 169, 211, 212], before the degeneration of lower and upper motor neurons starts with cranio-cervical preference [214-216, 219, 220]. Similarly, the Atxn2 -CAG100-KIN showed sensory neuropathy as earliest peripheral manifestation of disease at the age of 9-10 months.…”

Section: Discussionsupporting

confidence: 66%

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

Canet-Pons

Sen

Arsovic

et al. 2019

Preprint

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Large polyglutamine expansions in Ataxin-2 (ATXN2) cause multi-system nervous atrophy in Spinocerebellar Ataxia type 2 (SCA2). Intermediate size expansions carry a risk for selective motor neuron degeneration, known as Amyotrophic Lateral Sclerosis (ALS). Conversely, the depletion of ATXN2 prevents disease progression in ALS. Although ATXN2 interacts directly with RNA, and in ALS pathogenesis there is a crucial role of RNA toxicity, the affected functional pathways remain ill defined. Here, we examined an authentic SCA2 mouse model with Atxn2-CAG100-KnockIn for a first definition of molecular mechanisms in spinal cord pathology.Neurophysiology of lower limbs detected sensory neuropathy rather than motor denervation. Triple immunofluorescence demonstrated cytosolic ATXN2 aggregates sequestrating TDP43 and TIA1 from the nucleus. In immunoblots, this was accompanied by elevated CASP3, RIPK1 and PQBP1 abundance. RT-qPCR showed increase of Grn, Tlr7 and Rnaset2 mRNA versus Eif5a2, Dcp2, Uhmk1 and Kif5a decrease. These SCA2 findings overlap well with known ALS features. Similar to other ataxias and dystonias, decreased mRNA levels for Unc80, Tacr1, Gnal, Ano3, Kcna2, Elovl5 and Cdr1 contrasted with Gpnmb increase. Preterminal stage tissue showed strongly activated microglia containing ATXN2 aggregates, with parallel astrogliosis. Global transcriptome profiles from stages of incipient motor deficit versus preterminal age identified molecules with progressive downregulation, where a cluster of cholesterol biosynthesis enzymes including Dhcr24, Msmo1, Idi1and Hmgcs1 was prominent. Gas chromatography demonstrated a massive loss of crucial cholesterol precursor metabolites. Overall, the ATXN2 protein aggregation process affects diverse subcellular compartments, in particular stress granules, endoplasmic reticulum and receptor tyrosine kinase signaling. These findings identify new targets and potential biomarkers for neuroprotective therapies. Introduction:Within the dynamic research field into neurodegenerative disorders, the rare monogenic variant SCA2 (Spinocerebellar Ataxia type 2) gained much attention over the past decade, since its pathogenesis is intertwined with the motor neuron diseases ALS/FTLD (Amyotrophic Lateral Sclerosis / Fronto-Temporal Lobar Dementia) and with extrapyramidal syndromes such as Parkinson/PSP (Progressive Supranuclear Palsy). Particularly in the past year, it received massive interest since antisense-oligonucleotides were shown to effectively prevent the disease in mouse models, with clinical trials now being imminent. Still, there is an urgent unmet need to define the molecular events of pathogenesis and to identify biomarkers of progression in SCA2 patients, which reflect therapeutic benefits much more rapidly than clinical rating scales, brain imaging volumetry or neurophysiology measures.SCA2 was first described as separate entity in Indian patients, based on the characteristic early slowing of eye saccadic movements [222]. A molecularly homogeneous founder population of ~1,000 patients in...

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Section: Discussionsupporting

confidence: 66%

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

Canet-Pons

Sen

Arsovic

et al. 2019

Preprint

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“…Sensory and motor neuronopathy are present in most of the cases, usually more pronounced than in SCA3 individuals [9,12,13]. Eventually there are signs of ongoing diffuse denervation, resembling MND [12].…”

Section: Spinocerebellar Ataxias (Autosomal Dominant)-scasmentioning

confidence: 99%

The Intersection Between Cerebellar Ataxia and Neuropathy: a Proposed Classification and a Diagnostic Approach

et al. 2021

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Neuropathy is a common associated feature of different types of genetic or sporadic cerebellar ataxias. The pattern of peripheral nerve involvement and its associated clinical features can be an invaluable aspect for narrowing the etiologic diagnosis in the investigation of cerebellar ataxias. In this review, we discuss the differential diagnosis of the intersection between peripheral nerve and cerebellar involvement, and classify them in accordance with the predominant features. Genetics, clinical features, neuroimaging, and neurophysiologic characteristics are discussed. Furthermore, a diagnostic approach for cerebellar ataxia with neuropathy is proposed according to the different clinical characteristics. This is an Educational and Descriptive review with the aim of medical education for the approach to the patients with cerebellar ataxia and neuropathy. The diagnostic approach to the patient with cerebellar ataxia with neuropathy requires a detailed medical history, phenotyping, characterization of disease progression and family history. Neuroimaging features and the neurophysiological findings play pivotal roles in defining the diagnosis. Establishing an organized classification method for the disorders based on the clinical features may be very helpful, and could be divided as those with predominant cerebellar features, predominant neuropathic feature, or conditions with both cerebellar ataxia and neuropathy. Second, determining the mode of inheritance is critical on cerebellar ataxias: autosomal dominant and recessive cerebellar ataxias, mitochondrial or sporadic types. Third, one must carefully assess neurophysiologic findings in order to better characterize the predominant pattern of involvement: damage location, mechanism of lesion (axonal or demyelinating), motor, sensory or sensory motor compromise, large or small fibers, and autonomic system abnormalities.

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Comprehensive Analysis of a Japanese Pedigree with Biallelic ACAGG Expansions in RFC1 Manifesting Motor Neuronopathy with Painful Muscle Cramps

Izumi,

Warita,

Niihori

et al. 2024

Cerebellum

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Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is an autosomal recessive multisystem neurologic disorder caused by biallelic intronic repeats in RFC1. Although the phenotype of CANVAS has been expanding via diagnostic case accumulation, there are scant pedigree analyses to reveal disease penetrance, intergenerational fluctuations in repeat length, or clinical phenomena (including heterozygous carriers). We identified biallelic RFC1 ACAGG expansions of 1000 ~ repeats in three affected siblings having sensorimotor neuronopathy with spinocerebellar atrophy initially presenting with painful muscle cramps and paroxysmal dry cough. They exhibit almost homogeneous clinical and histopathological features, indicating motor neuronopathy. Over 10 years of follow-up, painful intractable muscle cramps ascended from legs to trunks and hands, followed by amyotrophy and subsequent leg pyramidal signs. The disease course combined with the electrophysical and imagery data suggest initial and prolonged hyperexcitability and the ensuing spinal motor neuron loss, which may progress from the lumbar to the rostral anterior horns and later expand to the corticospinal tract. Genetically, heterozygous ACAGG expansions of similar length were transmitted in unaffected family members of three successive generations, and some of them experienced muscle cramps. Leukocyte telomere length assays revealed comparatively shorter telomeres in affected individuals. This comprehensive pedigree analysis demonstrated a non-anticipating ACAGG transmission and high penetrance of manifestations with a biallelic state, especially motor neuronopathy in which muscle cramps serve as a prodromal and disease progress marker. CANVAS and RFC1 spectrum disorder should be considered when diagnosing lower dominant motor neuron disease, idiopathic muscle cramps, or neuromuscular hyperexcitability syndromes.

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Pattern of Peripheral Nerve Involvement in Spinocerebellar Ataxia Type 2: a Neurophysiological Assessment

Cited by 8 publications

References 31 publications

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

The Intersection Between Cerebellar Ataxia and Neuropathy: a Proposed Classification and a Diagnostic Approach

Comprehensive Analysis of a Japanese Pedigree with Biallelic ACAGG Expansions in RFC1 Manifesting Motor Neuronopathy with Painful Muscle Cramps

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