Involvement of the Peripheral Nervous System in Episodic Ataxias

Koźmiński, Wojciech; Pera, Joanna

doi:10.3390/biomedicines8110448

Cited by 4 publications

(6 citation statements)

References 73 publications

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“…Voltage-dependent P/Q-type calcium channels (Cacna1a), involved in multiple calcium-dependent processes, such as neurotransmitter release. 31 Lamb2, a laminin subunit and synaptic space protein expressed at the NMJ. 27 Bdnf, enhances motoneuron survival, growth and is implicated in both formation and maturation of NMJs.…”

Section: Discussionmentioning

confidence: 99%

Direct electrical stimulation impacts on neuromuscular junction morphology on both stimulated and unstimulated contralateral soleus

Lee

Cacciani

Wen

et al. 2023

J cachexia sarcopenia muscle

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Background There is increasing evidence of crosstalk between organs. The neuromuscular junction (NMJ) is a peripheral chemical synapse whose function and morphology are sensitive to acetylcholine (ACh) release and muscle depolarization. In an attempt to improve our understanding of NMJ plasticity and muscle crosstalk, the effects of unilateral direct electrical stimulation of a hindlimb muscle on the NMJ were investigated in rats exposed long-term post-synaptic neuromuscular blockade. Methods Sprague Dawley rats were subjected to post-synaptic blockade of neuromuscular transmission by systemic administration of α-cobrotoxin and mechanically ventilated for up to 8 days and compared with untreated sham operated controls and animals exposed to unilateral chronic electrical stimulation 12 h/day for 5 or 8 days. Results NMJs produced axonal and glial sprouts (growth of processes that extend beyond the confines of the synapse defined by high-density aggregates of acetylcholine receptors [AChRs]) in response to post-synaptic neuromuscular blockade, but less than reported after peripheral denervation or pre-synaptic blockade. Direct electrical soleus muscle stimulation reduced the terminal Schwann cell (tSC) and axonal sprouting in both stimulated and non-stimulated contralateral soleus. Eight days chronic stimulation reduced (P < 0.001) the number of tSC sprouts on stimulated and non-stimulated soleus from 6.7 ± 0.5 and 6.9 ± 0.5 sprouts per NMJ, respectively, compared with 10.3 ± 0.9 tSC per NMJ (P < 0.001) in non-stimulated soleus from rats immobilized for 8 days. A similar reduction of axonal sprouts (P < 0.001) was observed in stimulated and non-stimulated contralateral soleus in response to chronic electrical stimulation. RNAseq-based gene expression analyses confirmed a restoring effect on both stimulated and unstimulated contralateral muscle. The cross-over effect was paralleled by increased cytokine/chemokine levels in stimulated and contralateral unstimulated muscle as well as in plasma. Conclusions Motor axon terminals and terminal Schwann cells at NMJs of rats subjected to post-synaptic neuromuscular blockade exhibited sprouting responses. These axonal and glial responses were likely dampened by a muscle-derived myokines released in an activity-dependent manner with both local and systemic effects.

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Section: Discussionmentioning

confidence: 99%

Direct electrical stimulation impacts on neuromuscular junction morphology on both stimulated and unstimulated contralateral soleus

Lee

Cacciani

Wen

et al. 2023

J cachexia sarcopenia muscle

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“…As previously reported, interictal myokymia, when present, may be the feature suggesting KCNA1 variant presence. However, it may be clinically evident or detectable only by EMG and underreported (as seen in our review with missing data in 60%) [42]. It can be misinterpreted as tremor or myoclonus, making diagnosis challenging [35].…”

Section: Discussionmentioning

confidence: 99%

“…To allow comparison with our work, we examined reviews published between January 1993 and June 15, 2022, where at least two EA genes were discussed in detail to enable comparison between genes (n = 38, Table S5) [8,35,[37][38][39][40][41][42][43][44][45][46][47][48][49][50] Twenty-four of the 38 reviews were dedicated solely to PxMD-KCNA1 and PxMD-CACNA1A (Table S5).…”

Section: Comparison With Other Reviewsmentioning

confidence: 99%

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Genotype–phenotype relations for episodic ataxia genes: MDSGene systematic review

Olszewska,

Shetty,

Rajalingam

et al. 2023

Euro J of Neurology

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BackgroundMost episodic ataxias (EA) are autosomal dominantly inherited and characterized by recurrent attacks of ataxia and other paroxysmal and non‐paroxysmal features. EA is often caused by pathogenic variants in the CACNA1A, KCNA1, PDHA1, and SLC1A3 genes, listed as paroxysmal movement disorders (PxMD) by the MDS Task Force on the Nomenclature of Genetic Movement Disorders. Little is known about the genotype–phenotype correlation of the different genetic EA forms.MethodsWe performed a systematic review of the literature to identify individuals affected by an episodic movement disorder harboring pathogenic variants in one of the four genes. We applied the standardized MDSGene literature search and data extraction protocol to summarize the clinical and genetic features. All data are available via the MDSGene protocol and platform on the MDSGene website (https://www.mdsgene.org/).ResultsInformation on 717 patients (CACNA1A: 491, KCNA1: 125, PDHA1: 90, and SLC1A3: 11) carrying 287 different pathogenic variants from 229 papers was identified and summarized. We show the profound phenotypic variability and overlap leading to the absence of frank genotype–phenotype correlation aside from a few key ‘red flags’.ConclusionGiven this overlap, a broad approach to genetic testing using a panel or whole exome or genome approach is most practical in most circumstances.

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“…K v 1.1 channels are Shaker-related delayed-rectifier channels, which are present both in the PNS and central nervous system (CNS) [ 35 ]. This isoform was described in the juxtaparanodal regions, at branch points of myelinated motor axons and in basket cells of the cerebellum [ 34 , 35 , 36 ]. K v 1.2 channels, also members of the Shaker K+ channel family, are voltage-gated potassium channels, which play a crucial role in maintaining neuronal excitability [ 37 , 38 , 39 ].…”

Section: Anatomymentioning

confidence: 99%

Pathology of Initial Axon Segments in Chronic Inflammatory Demyelinating Polyradiculoneuropathy and Related Disorders

Dziadkowiak

Nowakowska-Kotas

Budrewićz

et al. 2022

IJMS

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The diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is based on a combination of clinical, electrodiagnostic and laboratory features. The different entities of the disease include chronic immune sensory polyradiculopathy (CISP) and autoimmune nodopathies. It is debatable whether CIDP occurring in the course of other conditions, i.e., monoclonal IgG or IgA gammopathy, should be treated as a separate disease entity from idiopathic CIDP. This study aims to evaluate the molecular differences of the nodes of Ranvier and the initial axon segment (AIS) and juxtaparanode region (JXP) as the potential cause of phenotypic variation of CIDP while also seeking new pathomechanisms since JXP is sequestered behind the paranode and autoantibodies may not access the site easily. The authors initially present the structure of the different parts of the neuron and its functional significance, then discuss the problem of whether damage to the juxtaparanodal region, Schwann cells and axons could cause CIDP or if these damages should be separated as separate disease entities. In particular, AIS’s importance for modulating neural excitability and carrying out transport along the axon is highlighted. The disclosure of specific pathomechanisms, including novel target antigens, in the heterogeneous CIDP syndrome is important for diagnosing and treating these patients.

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Involvement of the Peripheral Nervous System in Episodic Ataxias

Cited by 4 publications

References 73 publications

Direct electrical stimulation impacts on neuromuscular junction morphology on both stimulated and unstimulated contralateral soleus

Direct electrical stimulation impacts on neuromuscular junction morphology on both stimulated and unstimulated contralateral soleus

Genotype–phenotype relations for episodic ataxia genes: MDSGene systematic review

Pathology of Initial Axon Segments in Chronic Inflammatory Demyelinating Polyradiculoneuropathy and Related Disorders

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