Array-CGH detection of a de novo 0.7-Mb deletion in 19p13.13 including CACNA1A associated with mental retardation and epilepsy with infantile spasms
Article first published online: 23 OCT 2009
© 2009 International League Against Epilepsy
Volume 50, Issue 11, pages 2501–2503, November 2009
How to Cite
Auvin, S., Holder-Espinasse, M., Lamblin, M.-D. and Andrieux, J. (2009), Array-CGH detection of a de novo 0.7-Mb deletion in 19p13.13 including CACNA1A associated with mental retardation and epilepsy with infantile spasms. Epilepsia, 50: 2501–2503. doi: 10.1111/j.1528-1167.2009.02189.x
- Issue published online: 23 OCT 2009
- Article first published online: 23 OCT 2009
Infantile spasms (IS) are the most frequent epileptic syndromes of the first year of life. Patients with chromosomal abnormalities account for 13% of prenatal etiologies of IS. Several chromosomal abnormalities have been reported in association with IS. Mutations in X-linked genes have also been described in association with IS: ARX (OMIM300382) and CDLK5 (RTT, OMIM312750 and ISSX, OMIM308350). The CACNA1A gene, located on chromosome 19p13, encodes the main subunit (1A) of the neuronal P/Q type voltage-gated calcium-ion channel. In humans, mutations in CACNA1A have been described in episodic ataxia type 2, spinocerebellar ataxia type 6, and familial hemiplegic migraine (Ophoff et al., 1996).
We report the case of a boy referred for psychomotor delay and overgrowth. He was born after a normal pregnancy, at 40 weeks of gestation. At birth, growth parameters were normal. Hypotonia and severe constipation were noted since the neonatal period. A few days before his hospital admission (at 12 months), his mother observed several clusters of spasms. Physical examination revealed hypotonia, psychomotor delay, and overgrowth [weight and height +2 standard deviations (SDs) and head circumference +3.5 SDs]. Dysmorphic features were noted (Fig. 1). At the age of 2 years, he was sitting independently and starting to pull himself up for standing. Weight was at +2 SDs, height was above +3 SDs, and head circumference (HC) at +2.5 SDs. Since we recorded both symmetric spasms in clusters and focal onset seizures on electroencephalography (EEG) (Fig. S1), vigabatrin was prescribed for 2 years. The patient is still seizure-free 18 months after vigabatrin withdrawn, at 4½ years of age.
Brain magnetic resonance imaging (MRI), ophthalmologic, hearing, endocrine tests, and renal scan were normal. Advanced bone age was noted (3 years at 15 months). High-resolution karyotype was normal (46, XY). Because developmental delay was associated with overgrowth, we performed NSD1 molecular analysis (Sotos syndrome), which was normal. Array-CGH (Human Genome CGH microarray 44B kit, Agilent Technologies, Santa Clara, CA, U.S.A.) analysis identified a cryptic 19p13.13 deletion that encompasses 32 genes (Fig. 1). The minimal deleted region spanned 664 kb, corresponding to breakpoints from 12,615,927 to 13,280,259 bp from the 19p telomere (human genome 18 – build 36), and the maximal deleted interval was 736 kb. A de novo 19p13.13 deletion was confirmed by fluorescence in situ hybridization (FISH) (CTC-250I14 (AC011446) probe located from 13,100,859 to 13,216,789bp from the 19p telomere.
This is the first report of a patient presenting IS and partial seizures with a de novo 19p13.13 microdeletion including CACNA1A gene identified by array-CGH. Deletion of chromosome 19 is uncommon. This deletion encompasses 32 genes, among which 3 could be a candidate for the genotype–phenotype relationship (Fig. 1): BEST2, NFIX, and CACNA1A.
BEST2 (bestrophin 2), a member of the bestrophin gene family of anion channels, is highly expressed in the colon epithelium and may be interesting to study regarding the severe constipation in our patient (OMIM607335).
NFIX [nuclear factor I/X (CCAAT-binding transcription factor)] is essential for normal brain and skeletal development. Three members of the Nfi gene family of transcription factors—Nfia, Nfib, and Nfix—are highly expressed in the developing mouse brain. Both Nfia and Nfib knockout mice display agenesis of the corpus callosum and a malformed hippocampal commissure, as well as severe defects in the formation of midline glial populations. Nfix−/− mice develop deformation of the spine, which is caused by a delay in ossification of the vertebral bodies and progressive degeneration of the intervertebral disks (OMIM164005).
CACNA1A (calcium channel alpha 1A subunit) is involved in the voltage-dependent Ca2+ channels. Mutations in CACNA1A have been described previously (Ophoff et al., 1996). Mutations in this gene have been reported in association with epilepsy and status epilepticus (Jouvenceau et al., 2001; Beauvais et al., 2004; Kors et al., 2004). An association between idiopathic generalized epilepsy and a single nucleotide polymorphism in exon 8 has also been reported (Chioza et al., 2001). In addition, CACNA1A mutations appear to be involved in the occurrence of developmental delay (Vahedi et al., 2000; Guerin et al., 2008).
We suggest that CACNA1A may be involved in the pathogenesis of epilepsy in our patient. However, we cannot exclude the involvement of two or more genes. We also hypothesize that the implication of several genes might explain the mild epileptic phenotype. A recent publication (Glasscock et al., 2007) may provide some insight into this apparent paradox. To examine whether interactions between ion-channel variants could be responsible for the severity of epilepsy, these investigators generated a double-mutant mouse—a digenic mouse model of human idiopathic epilepsy—that carries epileptic alleles of two different ion-channel subunit genes, Kcna1 and Cacna1a. They found that these digenic mice were more resistant to seizures than were the parent mutant strains.
This is the first report of IS with a 19p13 deletion including the CACNA1A gene. We hypothesize that this gene might be involved in the pathophysiology of epilepsy in our patient, although we cannot exclude the implication of other genes.
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None of the authors has any conflict of interest to disclose.
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Figure S1. Additional material: EEG recording at 8-month-old associated with right and left deltoid EMG electrods (two last lines). Ictal EEG: cluster of spasm (Horizontal bar: 1 second/ vertical bar: 20 μVolt.) and hypsarrhyyhmia.
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