In vivo impact of presynaptic calcium channel dysfunction on motor axons in episodic ataxia type 2.
In vivo impact of presynaptic calcium channel dysfunction on motor axons in episodic ataxia type 2.
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DOI：
10.1093/brain/awv380
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发表时间：
2016-02
期刊：
影响因子：
--
通讯作者：
Hanna MG
中科院分区：
文献类型：
--
作者：
Tomlinson SE;Tan SV;Burke D;Labrum RW;Haworth A;Gibbons VS;Sweeney MG;Griggs RC;Kullmann DM;Bostock H;Hanna MG
Episodic ataxia type 2 is caused by mutations in CACNA1A, which encodes the pore-forming subunit of the voltage-gated calcium channel Cav2.1. Tomlinson et al. reveal altered peripheral axonal excitability in patients compared to controls. The changes may reflect malformation of the nodes of Ranvier, as demonstrated in animal models. Episodic ataxia type 2 is caused by mutations in CACNA1A, which encodes the pore-forming subunit of the voltage-gated calcium channel Cav2.1. Tomlinson et al. reveal altered peripheral axonal excitability in patients compared to controls. The changes may reflect malformation of the nodes of Ranvier, as demonstrated in animal models. Ion channel dysfunction causes a range of neurological disorders by altering transmembrane ion fluxes, neuronal or muscle excitability, and neurotransmitter release. Genetic neuronal channelopathies affecting peripheral axons provide a unique opportunity to examine the impact of dysfunction of a single channel subtype in detail in vivo. Episodic ataxia type 2 is caused by mutations in CACNA1A, which encodes the pore-forming subunit of the neuronal voltage-gated calcium channel Cav2.1. In peripheral motor axons, this channel is highly expressed at the presynaptic neuromuscular junction where it contributes to action potential-evoked neurotransmitter release, but it is not expressed mid-axon or thought to contribute to action potential generation. Eight patients from five families with genetically confirmed episodic ataxia type 2 underwent neurophysiological assessment to determine whether axonal excitability was normal and, if not, whether changes could be explained by Cav2.1 dysfunction. New mutations in the CACNA1A gene were identified in two families. Nerve conduction studies were normal, but increased jitter in single-fibre EMG studies indicated unstable neuromuscular transmission in two patients. Excitability properties of median motor axons were compared with those in 30 age-matched healthy control subjects. All patients had similar excitability abnormalities, including a high electrical threshold and increased responses to hyperpolarizing (P < 0.00007) and depolarizing currents (P < 0.001) in threshold electrotonus. In the recovery cycle, refractoriness (P < 0.0002) and superexcitability (P < 0.006) were increased. Cav2.1 dysfunction in episodic ataxia type 2 thus has unexpected effects on axon excitability, which may reflect an indirect effect of abnormal calcium current fluxes during development. Episodic ataxia type 2 is caused by mutations in CACNA1A, which encodes the pore-forming subunit of the voltage-gated calcium channel Cav2.1. Tomlinson et al. reveal altered peripheral axonal excitability in patients compared to controls. The changes may reflect malformation of the nodes of Ranvier, as demonstrated in animal models.
