CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms

Abstract

CACNA1A loss-of-function mutations classically present as episodic ataxia type 2 (EA2), with brief episodes of ataxia and nystagmus, or with progressive spinocerebellar ataxia (SCA6). A minority of patients carrying CACNA1A mutations develops epilepsy. Non-motor symptoms associated with these mutations are often overlooked. In this study, we report 16 affected individuals from four unrelated families presenting with a spectrum of cognitive impairment including intellectual deficiency, executive dysfunction, ADHD and/or autism, as well as childhood-onset epileptic encephalopathy with refractory absence epilepsy, febrile seizures, downbeat nystagmus and episodic ataxia. Sequencing revealed one CACNA1A gene deletion, two deleterious CACNA1A point mutations including one known stop-gain and one new frameshift variant and a new splice-site variant. This report illustrates the phenotypic heterogeneity of CACNA1A loss-of-function mutations and stresses the cognitive and epileptic manifestations caused by the loss of Ca V 2.1 channels function, presumably affecting cerebellar, cortical and limbic networks.

Dramatic Response After Lamotrigine in a Patient With Epileptic Encephalopathy and a De Novo CACNA1A Variant

“…Based on literature review, the patient's phenotype is most consistent with a loss-of-function effect; we did not perform functional studies. 5,8 Several naturally occurring mouse models with homologous variants in CACNA1A are characterized by ataxia, absence seizures and paroxysmal dyskinesia, though a mouse model with a pathogenic variant in the cytoplasmic linkage domain from S4 to S5 does not exist. 9,12 …”

“…4 This may explain why lamotrigine is considered a first or second line agent in generalized epilepsies while many agents that act at sodium channels are otherwise avoided 14 Positive responses to lamotrigine and valproic acid as well as levetiracetam and valproic acid have been reported in other patients with pathogenic variants in CACNA1A, though not as robust as the case described in this report. 5 This could be due to several factors including clinical synergistic effect of lamotrigine and divalproex sodium, a genotype-phenotype response, or lamotrigine dose. 15 Our patient was not trialed on lamotrigine monotherapy, though we would consider this a reasonable strategy if she had not already been on divalproex sodium.…”

“…Shortly after familial testing resulted, Demaj and colleagues published a case series of patients with pathogenic variants in CACNA1A that included subjects with epileptic encephalopathy, cognitive impairment and cerebellar signs. 5 Referencing this citation, our patient's exome report was amended and the CACNA1A c.4118 C>T (p.S1373L) variant re-classified as likely pathogenic. Our group submitted this variant to ClinVar.…”

“…There is significant inter- and intra-family variability and phenotypic overlap between the three conditions. 5-7 A minority of patients with pathogenic variants in CACNA1A have epilepsy with multiple seizure types. 1,7-9 Tantsis and colleagues described various eye movement disorders, including paroxysmal tonic upgaze, abnormal saccades and nystagmus as some of the earliest signs in individuals with a CACNA1A pathogenic variant.…”

“…10 Patients with additional features have been described, including a cohort of patients with epileptic encephalopathy, cognitive impairment and cerebellar dysfunction and a patient with congenital hypotonia and developmental delay, further expanding the phenotypic spectrum. 5,11 …”