Alternating Hemiplegia of Childhood-Related Neural and Behavioural Phenotypes in Na+,K+-ATPase α3 Missense Mutant Mice

Abstract

Missense mutations in ATP1A3 encoding Na+,K+-ATPase α3 have been identified as the primary cause of alternating hemiplegia of childhood (AHC), a motor disorder with onset typically before the age of 6 months. Affected children tend to be of short stature and can also have epilepsy, ataxia and learning disability. The Na+,K+-ATPase has a well-known role in maintaining electrochemical gradients across cell membranes, but our understanding of how the mutations cause AHC is limited. Myshkin mutant mice carry an amino acid change (I810N) that affects the same position in Na+,K+-ATPase α3 as I810S found in AHC. Using molecular modelling, we show that the Myshkin and AHC mutations display similarly severe structural impacts on Na+,K+-ATPase α3, including upon the K+ pore and predicted K+ binding sites. Behavioural analysis of Myshkin mice revealed phenotypic abnormalities similar to symptoms of AHC, including motor dysfunction and cognitive impairment. 2-DG imaging of Myshkin mice identified compromised thalamocortical functioning that includes a deficit in frontal cortex functioning (hypofrontality), directly mirroring that reported in AHC, along with reduced thalamocortical functional connectivity. Our results thus provide validation for missense mutations in Na+,K+-ATPase α3 as a cause of AHC, and highlight Myshkin mice as a starting point for the exploration of disease mechanisms and novel treatments in AHC.

Na+/K+ ATPase 1 and 3 Isoforms Are Differentially Expressed in - and -Motoneurons

“…We also noted that the proportion of NKA␣3-expressing neurons is higher in cervical DRG than in lumbar. This indication that there is a higher proportion of cervical DRG neurons with potential proprioceptive function than lumbar DRG neurons is supported by the observation that up to 65% of cervical DRG neurons project to the dorsal column nuclei compared with15% of lumbar DRG neurons in the rat (Giuffrida and Rustioni, 1992). Although it must be noted that not all dorsal column nuclei projecting neurons are involved in proprioception, these proportions tally well with those of the NKA␣3-positive sensory neurons in this study.…”

“…The selective expression of NKA␣3 in muscle spindle afferents peripherally is likely to be of further physiological importance, placing this exquisitely ouabain-sensitive form of the NKA throughout the fusimotor system. This system is thus likely to be selectively and tonically influenced by the adrenocortically produced hormone known as endogenous ouabain (EO), present in the circulation in the nanomolar range (Harwood and Yaqoob, 2005), which is sufficient to inhibit NKA␣3 rather than NKA␣1. As low concentrations of ouabain increased firing rates of ␥-motoneurons in spinal cord slices, both spindle afferents and ␥-motoneurons are likely to be more excitable in vivo due to EO.…”

Heterozygous mice deficient in Atp1a3 exhibit motor deficits by chronic restraint stress

“…Myk/ + mice have low body weight, motor deficits including gait abnormality, and cognitive impairment under non-stress conditions. Such phenotypes are also observed in AHC patients [13,28]. However, none of the above mice are reported to show spontaneous dystonia movement.…”

“…Although we did not observe limb dystonia, bradykinesia, and impairment of postural reflex, Atp1a3 +/− exhibited gait abnormalities from 6-to 10-weeks of age under stress loading, like RDP patients. Myk/ + mice are reported to show unsteady and tremorous gait at 4 weeks of age and shorter stride length and wider hind base from 8-to 12-weeks of age in the absence of experimental stress [28]. In contrast, 4-week-old Atp1a3 +/− showed mild gait abnormality with shorter stride and no gait abnormality at 6-12 weeks in the absence of stress, but showed stress-dependent gait abnormality at 6-12 week-old.…”

Excellent Response to a Ketogenic Diet in a Patient with Alternating Hemiplegia of Childhood

“…KD might act similarly in AHC. Indeed, cerebral glucose hypometabolism is observed in AHC patients, as well as in AHC model mice and, interestingly, in the only rapid-onset-dystonia-parkinsonism patient studied by means of F-18 fluorodeoxyglucose positron emission tomography, who harboured precisely the same ATP1A3 mutation (p.Asp923Asn) as the family described here (Sasaki et al 2009;Kirshenbaum et al 2013;Anselm et al 2009). KD might also reduce neuronal excitability (for reviews see Lutas and Yellen 2013;Stafstrom and Rho 2012;Dhamija et al 2013), thereby correcting the altered membrane excitability due to ATP1A3 dysfunction and thus reducing the frequency and/or severity of the paroxysmal features of AHC.…”