A Cross-Sectional Study of the Neuropsychiatric Phenotype of CACNA1C-Related Disorder
Rebecca Levy1, Katherine Timothy2, Jack Underwood3, Jeremy Hall3, Jonathan Bernstein4, Sergiu Pasca5
1Stanford LPCH Child Neurology, 2Timothy Syndrome Foundation, 3Neuroscience & Mental Health Innovation Institute, Cardiff University, 4Division of Medical Genetics, Department of Pediatrics, 5Department of Psychiatry and Behavioral Sciences, Stanford
Objective:
To investigate the full neurologic, psychiatric, and developmental phenotypic spectrum of individuals with CACNA1C-related disorder.
Background:
CACNA1C encodes the voltage gated L-type CaV1.2 calcium channel. A specific gain of function pathogenic variant in CACNA1C causes Timothy syndrome type 1 (TS1) with multi-system involvement including cardiac long QT syndrome, syndactyly, and neuropsychiatric symptoms. We found that the TS1 variant alters neuronal activity-dependent signaling and interneuron migration. The broader spectrum of CACNA1C-related disorder (CRD) includes isolated cardiac disease, isolated neurologic deficits, and TS, but it is unknown how the clinical presentation of CRD variants other than TS relate to neural defects. We surveyed individuals with CRD to define the neuropsychiatric and developmental phenotype to guide future research into the role of calcium channels in neural development.
Design/Methods:
Caregivers of and individuals with CRD completed an online survey of pre- and perinatal events, cardiac events, developmental milestones, neuropsychiatric symptoms, and neuropsychiatric diagnoses. Multiple Mann-Whitney tests were used for comparison of categorical values and Fisher’s exact test for comparison of categorical variables between participants with and without LQTS.
Results:
Twenty-four participants with germline CACNA1C variants completed the survey. The most common neuropsychiatric symptoms and/or diagnoses were developmental delay in 92%, incoordination in 71%, hypotonia in 67%, autism spectrum disorder in 50% (autistic features in 92%), seizures in 37.5%, and attention deficit hyperactivity disorder in 21% of participants. There were no significant differences in symptoms between participants with and without LQTS.
Conclusions:
In our CRD cohort there was an increased prevalence of multiple neuropsychiatric symptoms compared with the general population. These findings indicate the key role of CaV1.2 in brain development and the clinical importance of screening and treating neuropsychiatric symptoms in all individuals with CRD. Future directions include deep phenotyping of neuropsychiatric symptoms and efforts to relate these symptoms to specific cellular defects.