Alternating hemiplegia of childhood in Denmark: Clinical manifestations and ATP1A3 mutation status

Hoei‐Hansen, Christina E.; Dali, Christine í; Lyngbye, Troels; Dunø, Morten; Uldall, Peter

doi:10.1016/j.ejpn.2013.08.007

Cited by 37 publications

(33 citation statements)

References 25 publications

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“…Likewise, CAPOS can be induced by fever [9]. Furthermore, exposure to both cold and warm temperatures has been reported to trigger attacks in AHC patients [10, 15]. Nevertheless, given that hyperthermia seems to be a common trigger in ATP1A3 patients, we also tested this in the α 3 +/D801Y mice by exposing them to a heated environment that raised their body temperature to 40.4 ± 0.3°C, a physiologically relevant fever level.…”

Section: Discussionmentioning

confidence: 99%

Hypothermia-induced dystonia and abnormal cerebellar activity in a mouse model with a single disease-mutation in the sodium-potassium pump

et al. 2017

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Mutations in the neuron-specific α3 isoform of the Na+/K+-ATPase are found in patients suffering from Rapid onset Dystonia Parkinsonism and Alternating Hemiplegia of Childhood, two closely related movement disorders. We show that mice harboring a heterozygous hot spot disease mutation, D801Y (α3+/D801Y), suffer abrupt hypothermia-induced dystonia identified by electromyographic recordings. Single-neuron in vivo recordings in awake α3+/D801Y mice revealed irregular firing of Purkinje cells and their synaptic targets, the deep cerebellar nuclei neurons, which was further exacerbated during dystonia and evolved into abnormal high-frequency burst-like firing. Biophysically, we show that the D-to-Y mutation abolished pump-mediated Na+/K+ exchange, but allowed the pumps to bind Na+ and become phosphorylated. These findings implicate aberrant cerebellar activity in α3 isoform-related dystonia and add to the functional understanding of the scarce and severe mutations in the α3 isoform Na+/K+-ATPase.

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Section: Discussionmentioning

confidence: 99%

Hypothermia-induced dystonia and abnormal cerebellar activity in a mouse model with a single disease-mutation in the sodium-potassium pump

et al. 2017

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“…33,34,57 . However, one small study evaluating the phenotypes of 35 AHC patients with ATP1A3 mutations, reports that patients with the E815K mutation tend to have earlier onset of symptoms, more severe motor and cognitive disabilities, and more often report status epilepticus and respiratory paralysis compared to AHC patients with other ATP1A3 mutation.…”

Section: Diseases Caused By Mutations In Atp1a3mentioning

confidence: 99%

“… § compiled from refs 18–30,33–35,57 □ Mutation c.658G>A;p.D220N previously reported as causal in Heinzen and co-workers 33 was later shown to be a rare, inherited mutation, and that the disease-causing mutation in this patient is a previously overlooked de novo D801N ATP1A3 mutation (unpublished data). As such D220N has been removed from this table and one additional patient has been counted as having a D801N mutation.…”

Section: Figurementioning

confidence: 99%

Distinct neurological disorders with ATP1A3 mutations

Heinzen

Arzimanoglou

Brashear

et al. 2014

The Lancet Neurology

213

218

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Genetic research has shown that mutations that modify the protein-coding sequence of ATP1A3, the gene encoding the α3 subunit of Na+/K+-ATPase, cause both rapid-onset dystonia parkinsonism and alternating hemiplegia of childhood. These discoveries link two clinically distinct neurological diseases to the same gene, however, ATP1A3 mutations are, with one exception, disease-specific. Although the exact mechanism of how these mutations lead to disease is still unknown, much knowledge has been gained about functional consequences of ATP1A3 mutations using a range of in vitro and animal model systems, and the role of Na+/K+-ATPases in the brain. Researchers and clinicians are attempting to further characterise neurological manifestations associated with mutations in ATP1A3, and to build on the existing molecular knowledge to understand how specific mutations can lead to different diseases.

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“…In fact, amino acid substitutions in the same position have been shown to cause RDP or AHC. One example of this is the disease hot spot amino acid position 801, where currently four different mutations are known; D801Y causes RDP111 or AHC12, and D801N, D801E and D801V cause or AHC23131415.…”

mentioning

confidence: 99%

Cognitive deficits caused by a disease-mutation in the α3 Na+/K+-ATPase isoform

Holm

Isaksen

Glerup

et al. 2016

Sci Rep

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The Na+/K+-ATPases maintain Na+ and K+ electrochemical gradients across the plasma membrane, a prerequisite for electrical excitability and secondary transport in neurons. Autosomal dominant mutations in the human ATP1A3 gene encoding the neuron-specific Na+/K+-ATPase α3 isoform cause different neurological diseases, including rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood (AHC) with overlapping symptoms, including hemiplegia, dystonia, ataxia, hyperactivity, epileptic seizures, and cognitive deficits. Position D801 in the α3 isoform is a mutational hotspot, with the D801N, D801E and D801V mutations causing AHC and the D801Y mutation causing RDP or mild AHC. Despite intensive research, mechanisms underlying these disorders remain largely unknown. To study the genotype-to-phenotype relationship, a heterozygous knock-in mouse harboring the D801Y mutation (α3+/D801Y) was generated. The α3+/D801Y mice displayed hyperactivity, increased sensitivity to chemically induced epileptic seizures and cognitive deficits. Interestingly, no change in the excitability of CA1 pyramidal neurons in the α3+/D801Y mice was observed. The cognitive deficits were rescued by administration of the benzodiazepine, clonazepam, a GABA positive allosteric modulator. Our findings reveal the functional significance of the Na+/K+-ATPase α3 isoform in the control of spatial learning and memory and suggest a link to GABA transmission.

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Alternating hemiplegia of childhood in Denmark: Clinical manifestations and ATP1A3 mutation status

Cited by 37 publications

References 25 publications

Hypothermia-induced dystonia and abnormal cerebellar activity in a mouse model with a single disease-mutation in the sodium-potassium pump

Hypothermia-induced dystonia and abnormal cerebellar activity in a mouse model with a single disease-mutation in the sodium-potassium pump

Distinct neurological disorders with ATP1A3 mutations

Cognitive deficits caused by a disease-mutation in the α3 Na+/K+-ATPase isoform

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