DominantKCNA2mutation causes episodic ataxia and pharmacoresponsive epilepsy

Abstract

Objective: To identify the genetic basis of a family segregating episodic ataxia, infantile seizures, and heterogeneous epilepsies and to study the phenotypic spectrum of KCNA2 mutations.Methods: A family with 7 affected individuals over 3 generations underwent detailed phenotyping. Whole genome sequencing was performed on a mildly affected grandmother and her grandson with epileptic encephalopathy (EE). Segregating variants were filtered and prioritized based on functional annotations. The effects of the mutation on channel function were analyzed in vitro by voltage clamp assay and in silico by molecular modeling. KCNA2 was sequenced in 35 probands with heterogeneous phenotypes.Results: The 7 family members had episodic ataxia (5), self-limited infantile seizures (5), evolving to genetic generalized epilepsy (4), focal seizures (2), and EE (1). They had a segregating novel mutation in the shaker type voltage-gated potassium channel KCNA2 (CCDS_827.1: c.765_773del; p.255_257del). A rare missense SCN2A (rs200884216) variant was also found in 2 affected siblings and their unaffected mother. The p.255_257del mutation caused dominant negative loss of channel function. Molecular modeling predicted repositioning of critical arginine residues in the voltage-sensing domain. KCNA2 sequencing revealed 1 de novo mutation (CCDS_827.1: c.890G.A; p.Arg297Gln) in a girl with EE, ataxia, and tremor.Conclusions: A KCNA2 mutation caused dominantly inherited episodic ataxia, mild infantile-onset seizures, and later generalized and focal epilepsies in the setting of normal intellect. This observation expands the KCNA2 phenotypic spectrum from EE often associated with chronic ataxia, reflecting the marked variation in severity observed in many ion channel disorders. Neurology ® 2016;87:1975-1984 GLOSSARY EA 5 episodic ataxia; EE 5 epileptic encephalopathy; GATK 5 genome analysis toolkit; GGE 5 genetic generalized epilepsies; GTCS 5 generalized tonic-clonic seizures; ICCA 5 infantile convulsions choreoathetosis syndrome; RMS 5 root mean square.De novo mutations of KCNA2 have recently been reported in infantile-onset epileptic encephalopathies (EEs) in which infants present with uncontrolled seizures, developmental slowing or regression, and frequent epileptiform activity on EEG.1-6 Inherited mutations have not been described. KCNA2 has not been implicated in common pharmacoresponsive epilepsies such as the genetic generalized epilepsies (GGE), nor has an association with paroxysmal movement disorders been established.Paroxysmal neurologic disorders are often due to disorders of ion channel function. The episodic ataxias (EAs) are usually dominantly inherited and associated with a range of ion channel *These authors contributed equally to this work.

Ion Channels in Genetic Epilepsy: From Genes and Mechanisms to Disease-Targeted Therapies

“…Seizure onset is between 5 and 17 months, with a phenotypic spectrum including febrile and afebrile, hemiclonic, myoclonic, myoclonicatonic, absence, focal dyscognitive, focal, and generalized seizures; mild to moderate intellectual disability; delayed speech development; and severe ataxia (Pena and Coimbra, 2015;Syrbe et al, 2015). The KCNA2 spectrum also encompasses milder familial epilepsy (Corbett et al, 2016). De novo KCNA2 mutations in patients with neurodegenerative hereditary spastic paraplegia and ataxia have also been reported (Helbig et al, 2016; Manole et al, 2017).…”

Network effects of the neuropsychiatric 15q13.3 microdeletion on the transcriptome and epigenome in human induced neurons

“…At the iN stage, a number of genes were identified as differentially expressed that have been previously implicated in neuropsychiatric disorders associated with the 15q13.3 microdeletion. These genes include VIPR2, PRODH, and DGCR6 for schizophrenia [33][34][35]; CACNG3, SCN8A, SPATA5, and KCNA2 for epilepsy [36][37][38][39]; and LINS1 and DCPS for intellectual disability [40][41][42].…”

Novel clinical manifestations in patients with KCNA2 mutations

“…Both gain and loss of function mutations in this gene have been associated with the development of epileptic encephalopathy [2]. KCNA2 mutations also cause spastic paraplegia [7] and ataxia [3,8]. To our knowledge there are only 10 reported cases of KCNA2 associated epilepsy (Table 1).…”