Biallelic CACNA1A mutations cause early onset epileptic encephalopathy with progressive cerebral, cerebellar, and optic nerve atrophy

Abstract

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.

The neuropsychiatric phenotype in CACNA1A mutations: a retrospective single center study and review of the literature

“…In all reported cases chronic cerebellar signs at examination and/or imaging evidence of cerebellar atrophy were documented [].…”

“…In episodic CACNA1A disorders, the most common finding was a developmental delay after a normal birth and an unremarkable neonatal period (25 FHM1 and 10 EA2 pedigrees, respectively) [5,10,11,13,14,17,[19][20][21][22][23][24][26][27][28][31][32][33][34][35]. Delayed motor milestones or mental retardation were usually observed in the offspring of patients previously diagnosed with EA2 or FHM1, before the onset of episodic symptoms.…”

Bi-allelic variants inTSPOAP1, encoding the active zone protein RIMBP1, cause autosomal recessive dystonia

“…Pathogenic dominant variants in the RIMBP1 binding partners CACNA1A and KCNMA1, encoding Cav2.1 and BK-channels respectively, have been linked to a variety of human movement disorders, including episodic ataxia (46) and paroxysmal dyskinesias (47,48). Moreover, recessive variants in CACNA1A, CACNA1B and KCNMA1 cause progressive epileptic encephalopathy variably associated with cerebellar atrophy (49,50) or dyskinesias (51). Furthermore, PNKD, another gene linked to a paroxysmal dyskinetic movement disorder, has been recently shown to localize at synapses where it interacts with RIM1 and RIM2 modulating neurotransmitter release (52).…”

Personalized medicine in epilepsy patients

“…Micro-deletions that encompass CACNA1A and a single truncating mutation have been associated with severe epileptic encephalopathies that include infantile spasms and West syndrome. De novo missense mutations have been convincingly shown to cause severe epileptic encephalopathies with seizure types that typically include focal, tonic, and tonic-clonic seizures, severe intellectual disability and motor impairment [127,128] . It is known that acetazolamide and 4-aminopyridine are able to decrease, in tottering mice, the high-power low-frequency oscillations, which are thought to be a marker of cortical excitability, so these drugs are evaluated as treatment options for episodic ataxia 2 [129] .…”