Abstract
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.
Highlights
Episodic ataxia type 2 (EA2) is an autosomal dominant disorder caused by mutations in the CACNA1A gene, which encodes the 1A subunit of the presynaptic P/Q-type calcium channel Cav2.1 (Gancher and Nutt, 1986; Ophoff et al, 1996)
We have previously reported highly stereotypic changes in the excitability of motor axons in the median nerve of patients with episodic ataxia type 1 (EA1), which is caused by loss-of-function mutations of the potassium channel gene KCNA1 (Tomlinson et al, 2010)
EA2, with changes that can be modelled by an increase in shunt conductance between the internodal axolemma and exterior
Summary
Episodic ataxia type 2 (EA2) is an autosomal dominant disorder caused by mutations in the CACNA1A gene, which encodes the 1A subunit of the presynaptic P/Q-type calcium channel Cav2.1 (Gancher and Nutt, 1986; Ophoff et al, 1996). Large myelinated motor axons in peripheral nerve express Cav2.1 calcium channels at the presynaptic membrane at the neuromuscular junction, where, together with N-type Cav2.2 channels, they trigger action potential-evoked neurotransmitter release (Day et al, 1997), but in rodents, Cav2.1 channels are not normally expressed in peripheral axons between the cell body and the neuromuscular junction (Ousley and Froehner, 1994; Vogel and Schwarz, 1995; Plant et al, 1998). This seems to be true for human axons (Schwarz et al, 1995; Protti et al, 1996). It was hypothesized that disrupting calcium channel localization has either a ‘direct’ effect on node of Ranvier development due to a disruption in vesicle docking at the nodal axolemma, or an ‘indirect’ effect, stemming from a reduction in axonal excitability (Alix et al, 2008)
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