The CACNA1A gene encodes the transmembrane pore-forming alpha-1A subunit of the Cav 2.1 P/Q-type voltage-gated calcium channel. Several heterozygous mutations within this gene, including nonsense mutations, missense mutations, and expansion of cytosine-adenine-guanine repeats, are known to cause three allelic autosomal dominant conditions-episodic ataxia type 2, familial hemiplegic migraine type 1, and spinocerebellar ataxia type 6. An association with epilepsy and CACNA1A mutations has also been described. However, the link with epileptic encephalopathies has emerged only recently. Here we describe two patients, sister and brother, with compound heterozygous mutations in CACNA1A. Exome sequencing detected biallelic mutations in CACNA1A: A missense mutation c.4315T>A (p.Trp1439Arg) in exon 27, and a seven base pair deletion c.472_478delGCCTTCC (p.Ala158Thrfs*6) in exon 3. Both patients were normal at birth, but developed daily recurrent seizures in early infancy with concomitant extreme muscular hypotonia, hypokinesia, and global developmental delay. The brain MRI images showed progressive cerebral, cerebellar, and optic nerve atrophy. At the age of 5, both patients were blind and bedridden with a profound developmental delay. The elder sister died at that age. Their parents and two siblings were heterozygotes for one of those pathogenic mutations and expressed a milder phenotype. Both of them have intellectual disability and in addition the mother has adult onset cerebellar ataxia with a slowly progressive cerebellar atrophy. Compound heterozygous mutations in the CACNA1A gene presumably cause early onset epileptic encephalopathy, and progressive cerebral, cerebellar and optic nerve atrophy with reduced lifespan. © 2016 Wiley Periodicals, Inc.

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Phelan-McDermid syndrome, also known as the 22q13 deletion syndrome, is a chromosomal microdeletion syndrome characterized by neonatal hypotonia, normal growth, profound developmental delay, absent or delayed speech, and minor dysmorphic features. Almost all of the 22q13 deletions published so far have been described as terminal. It is believed that the SHANK3 gene is the major candidate gene for the neurologic features of the syndrome. Here we describe a patient with a 0.72-Mb interstitial 22q13.2 deletion, intellectual disability, autistic behavior, epilepsy, mild dysmorphic features, and no deletion in the SHANK3 gene. The patient also has urticarial rash and an elevated level of immunoglobulin E, the latter has previously been described only once in a patient with monosomy 22q13.2-qter and SHANK3 gene deletion. To our knowledge, this is one of the smallest interstitial deletion in this region which has been published up to now. Although the patient has the classic phenotype of the 22q13 terminal deletion syndrome, the etiology for the neurologic and immunological features must be due to genes located more proximal to SHANK3 and this is also supported by other previously published cases of interstitial 22q13.2 deletions. The deleted area in our patient is gene-rich (26 genes), containing several known genes with different functions. Two of them-NFAM1 and TNFRSF13C are involved in immune system functioning. We suggest the haploinsufficiency of these genes might be related to hyper IgE syndrome in our patient.