title: In vivo impact of presynaptic calcium channel dysfunction on motor axons in episodic ataxia type 2.
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.
authors.affiliation: 1 Sydney Medical School, University of Sydney, Australia 2 Department of Neurology, St Vincent's Hospital, Sydney, Australia susan.tomlinson@sydney.edu.au.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Tomlinson
authors.affiliation: 3 Institute of Neurology, University College London and MRC Centre for Neuromuscular Disease, Queen Square, UK.
authors.forename: S Veronica
authors.initials: SV
authors.lastname: Tan
authors.affiliation: 1 Sydney Medical School, University of Sydney, Australia 4 Department of Neurology, Royal Prince Alfred Hospital, Sydney, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Burke
authors.affiliation: 5 Neurogenetics Unit, National Hospital for Neurology, Queen Square, UK.
authors.forename: Robyn W
authors.initials: RW
authors.lastname: Labrum
authors.affiliation: 5 Neurogenetics Unit, National Hospital for Neurology, Queen Square, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Haworth
authors.affiliation: 5 Neurogenetics Unit, National Hospital for Neurology, Queen Square, UK.
authors.forename: Vaneesha S
authors.initials: VS
authors.lastname: Gibbons
authors.affiliation: 5 Neurogenetics Unit, National Hospital for Neurology, Queen Square, UK.
authors.forename: Mary G
authors.initials: MG
authors.lastname: Sweeney
authors.affiliation: 6 University of Rochester, New York, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Griggs
authors.affiliation: 3 Institute of Neurology, University College London and MRC Centre for Neuromuscular Disease, Queen Square, UK 5 Neurogenetics Unit, National Hospital for Neurology, Queen Square, UK.
authors.forename: Dimitri M
authors.initials: DM
authors.lastname: Kullmann
authors.affiliation: 3 Institute of Neurology, University College London and MRC Centre for Neuromuscular Disease, Queen Square, UK.
authors.forename: Hugh
authors.initials: H
authors.lastname: Bostock
authors.affiliation: 3 Institute of Neurology, University College London and MRC Centre for Neuromuscular Disease, Queen Square, UK 5 Neurogenetics Unit, National Hospital for Neurology, Queen Square, UK.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hanna
mesh_terms: D000328:Adult; D000368:Aged; D001259:Ataxia / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D001369:Axons / Q000502:physiology*; D015220:Calcium Channels / Q000235:genetics; D020864:Calcium Channels, N-Type / Q000502:physiology*; D004576:Electromyography / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000502:physiology*; D009759:Nystagmus, Pathologic / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D017729:Presynaptic Terminals / Q000502:physiology*; D055815:Young Adult
chemical_list: D015220:Calcium Channels; D020864:Calcium Channels, N-Type; C105656:CACNA1A protein, human
keywords: axonal excitability; channelopathy