Severe Epileptic Encephalopathy in Siblings due to a Novel Heterozygous CACNA1A Gene Mutation

Background: The CACNA1A gene encodes the alpha-1 subunit of a voltage-gated P/Q-type calcium channel. Mutations in CACNA1A gene are known for familial hemiplegic migraine, episodic ataxia type 2 and spinocerebellar ataxia type 6, and recently, developmental disorders.

Material and Method: We describe 3 siblings with severe muscular hypotension, epileptic seizures, optic atrophy and dysphagia. Child 1 (m) died without any prior diagnosis at 5 months of age at suspicion of SIDS. The one year older brother (child 2) died of severe epileptic encephalopathy with refractory seizures at 14 months of age. According to clinical criteria, the PEHO (progressive encephalopathy, edema, hypsarrhythmia, optic atrophy) syndrome was suspected. . Repeated cranial MRI were without any pathological findings. After an interval of 9 years, the third child (m, currently 2 years old) was born. From the early neonatal period, child 3 showed a severe progressive encephalopathy with muscular hypotension (floppy infant), increasing respiratory and swallowing insufficiency, as well as seizures with apnea. Electroencephalography revealed suppression burst. Family medical history: In the meantime, mother and uncle (maternal) have been identified as carriers of a known CACNA1A mutation (Exon 19: c.2602delG heterozygously, p. (Ala868Profs*24)) with a diagnosis of episodic ataxia type 2.

Results: The familial mutation c.2602delG in exon 19 in the CACNA1A gene could be detected in the third child heterozygously. Due to the severity of the symptoms, trio-exome sequencing was added. A mutation in the CACNA1A gene (Exon 36: c.5476delC heterozygous, p. (His1826Thrfs*30) was also detected in the father. From asserved DNA, compound heterozygosity for the two mutations in the CACNA1A gene could also be detected in the second and third child. The mutations corresponded to the maternal and paternal frameshift mutations.

Discussion: Using the trio analyses of exome sequencing, we identified the etiology of severe early infantile progressive epileptic encephalopathy in three siblings Leading symptoms were floppy infant, refractory epileptic seizures with deep apnea, and optic atrophy.

Conclusion: Encephalopathy due to CACNA1A mutations with early infantile manifestation are exclusively described in association with compound heterozygosity. Here we describe the course of progressive epileptic CACNA1A encephalopathy in 3 siblings based on the novel compound heterozygosity for two frameshift mutations, maternal (c.2602delG p. (Ala868Profs*24)) and paternal (c.5476delC p. (His1826Thrfs*3)) inherited mutations.