| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q24.1 | {Epilepsy, idiopathic generalized, susceptibility to, 18} | 619521 | Autosomal dominant | 3 | HCN4 | 605206 |
A number sign (#) is used with this entry because of evidence that susceptibility to idiopathic generalized epilepsy-18 (EIG18; 619521) is conferred by heterozygous mutation in the HCN4 gene (605206) on chromosome 15q24. One such family has been reported.
Idiopathic generalized epilepsy is characterized by various types of seizures, including childhood and juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic-clonic seizures upon awakening (EGTCA). EEG often shows spike-wave discharges. EIG18 is an autosomal dominant disorder manifest as myoclonic seizures in infancy. Although the seizures remit, some patients may have later speech or cognitive impairment (summary by Becker et al., 2017 and Campostrini et al., 2018).
For a general phenotypic description and a discussion of genetic heterogeneity of idiopathic generalized epilepsy (IGE), see 600669.
Campostrini et al. (2018) reported 2 brothers, born of unrelated parents, who presented in the first year of life with myoclonic seizures involving all limbs and loss of consciousness. EEG showed generalized epileptiform activity associated with the seizures; brain imaging was normal. Treatment with valproate achieved full remission, and the boys stopped medication around 2.5 years of age with no recurrence. Both had mild language delay, and 1 had mild intellectual disability (IQ of 76). Detailed cardiac workup in the brothers and father, who had an unknown early medical history, showed mildly decreased heart rate bordering bradycardia. None had clinical cardiac manifestations. The authors suggested that the epileptic phenotype may be restricted to infancy.
The transmission pattern of EIG18 in the family reported by Campostrini et al. (2018) was consistent with autosomal dominant inheritance with incomplete penetrance.
In 2 brothers with EIG18, Campostrini et al. (2018) identified a heterozygous missense mutation in the HCN4 gene (R550C; 605206.0011). Electrophysiologic studies in CHO cells showed that the mutation caused a negative shift in the activation curve compared to wildtype, consistent with a loss of channel function. Neuronal hyperexcitability and increased firing was observed in neuronal cells transfected with the mutation, which exerted a dominant effect when coexpressed with wildtype. Campostrini et al. (2018) concluded that reduced HCN4 current contribution may affect input membrane resistance and resting membrane potential, causing cell hyperexcitability. The patients were ascertained from a cohort of 88 patients with various types of epilepsy.
Becker et al. (2017) identified a heterozygous missense variant (E153G) in the HCN4 gene in a girl who had a single generalized tonic-clonic seizures at 17 years of age. The variant, which was found by direct sequencing, was not present in the ExAC database. However, there were 4 additional family members with various types of seizures who did not carry the variant. Electrophysiologic studies showed that the variant caused a hyperpolarizing shift in the voltage dependence of activation, resulting in reduced function at a physiologic relevant voltage range. The authors suggested that the variant alone is unlikely to cause epilepsy, but that it may contribute along with variants in other genes to the polygenic nature of the disorder.
Becker, F., Reid, C. A., Hallmann, K., Tae, H.-S., Phillips, A. M., Teodorescu, G., Weber, Y. G., Kleefuss-Lie, A., Elger, C., Perez-Reyes, E., Petrou, S., Kunz, WS., Lerche, H., Maljevic, S. Functional variants in HCN4 and CACNA1H may contribute to genetic generalized epilepsy. Epilepsia Open 2: 334-342, 2017. [PubMed: 29588962] [Full Text: https://doi.org/10.1002/epi4.12068]
Campostrini, G., DiFrancesco, J. C., Castellotti, B., Milanesi, R., Gnecchi-Ruscone, T., Bonzanni, M., Bucchi, A., Baruscotti, M., Ferrarese, C., Franceschetti, S., Canafoglia, L., Ragona, F., Freri, E., Labate, A., Gambardella, A., Costa, C., Gellera, C., Granata, T., Barbuti, A., DiFrancesco, D. A loss-of-function HCN4 mutation associated with familial benign myoclonic epilepsy in infancy causes increased neuronal excitability. Front. Molec. Neurosci. 11: 269, 2018. [PubMed: 30127718] [Full Text: https://doi.org/10.3389/fnmol.2018.00269]