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Delayed postnatal loss of P/Q-type calcium channels recapitulates the absence epilepsy, dyskinesia, and ataxia phenotypes of genomic Cacna1a mutations.

ABSTRACT: Inherited loss of P/Q-type calcium channel function causes human absence epilepsy, episodic dyskinesia, and ataxia, but the molecular "birthdate" of the neurological syndrome and its dependence on prenatal pathophysiology is unknown. Since these channels mediate transmitter release at synapses throughout the brain and are expressed early in embryonic development, delineating the critical circuitry and onset underlying each of the emergent phenotypes requires targeted control of gene expression. To visualize P/Q-type Ca(2+) channels and dissect their role in neuronal networks at distinct developmental stages, we created a novel conditional Cacna1a knock-in mouse by inserting the floxed green fluorescent protein derivative Citrine into the first exon of Cacna1a and then crossed it with a postnatally expressing PCP2-Cre line for delayed Purkinje cell (PC) gene deletion within the cerebellum and sparsely in forebrain (purky). PCs in purky mice lacked P/Q-type calcium channel protein and currents within the first month after birth, displayed altered spontaneous firing, and showed impaired neurotransmission. Unexpectedly, adult purky mice exhibited the full spectrum of neurological deficits seen in mice with genomic Cacna1a ablation. Our results show that the ataxia, dyskinesia, and absence epilepsy caused by inherited disorders of the P/Q-type channel arise from signaling defects beginning in late infancy, revealing an early window of opportunity for therapeutic intervention.

SUBMITTER: Mark MD

PROVIDER: S-EPMC3065835 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundParoxysmal kinesigenic dyskinesia (PKD) and epilepsy share common pathogenic mechanisms but their pathophysiological connections remain unknown. Our study reports an individual with both disorders as a consequence of pseudohypoparathyroidism (PHP). This observation suggests potential shared pathophysiological mechanisms between PKD and epilepsy.MethodsWe report the case of a 15-year-old male with pre-diagnosed PKD and symptomatic epilepsy. We recorded the symptoms and carried out comprehensive biochemical, genetic, imaging, and EEG analyses to examine the characteristics and potentially shared etiology of these conditions.ResultsIn this case, the patient's PKD and symptomatic epilepsy were secondary to pseudohypoparathyroidism (PHP). The patient had a seven-year history of intermittent, involuntary paroxysmal episodic movements, and a six-year history of a loss of consciousness with convulsions. The electroencephalography results showed that the paroxysmal low and medium amplitude slow waves, isolated sharp waves, and sharp slow-wave release occurred in the right prefrontal temporal cortex. Serum analysis indicated a calcium concentration of 1.91 mmol/L, a phosphorus concentration of 2.68 mmol/L, an alkaline phosphatase concentration of 114 IU/L, and a parathyroid hormone concentration of 109 pg/ml. Computerized tomography and magnetic resonance imaging results showed multiple calcifications in the bilateral frontal and parietal lobe cortex, bilateral thalamus, basal ganglia, and centrum semiovale. Furthermore, GNAS methylation abnormalities were discovered during methylation testing. There was no recurrence of abnormal movements or epileptic seizures, and calcium concentrations returned to healthy levels, following the pharmacological treatment of PHP.ConclusionIn this case, PKD and symptomatic epilepsy were caused by PHP. This report underscores the importance of looking for biochemical abnormalities in PKD and symptomatic epilepsy patients. We suggest that all such intractable epilepsy seizure patients should be screened for PHP.

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Delayed postnatal loss of P/Q-type calcium channels recapitulates the absence epilepsy, dyskinesia, and ataxia phenotypes of genomic Cacna1a mutations.

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