CACNA1A Mutations Causing Early Onset Ataxia: Profiling Clinical, Dysmorphic and Structural-Functional Findings

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• The CACNA1A gene encodes the α1A subunit of the CaV2.1 calcium channel, crucial for neurotransmission.
• CACNA1A mutations lead to diverse neurological phenotypes, often with progressive or paroxysmal symptoms.
• Infantile presentations can be nonspecific, lacking characteristic dysmorphic features.

Observation:

• Three patients with congenital ataxia, including one with a novel CACNA1A variant, were studied.
• Clinical, radiological, and evolutionary features were analyzed, alongside structural localization and functional consequences of variants.
• Patients exhibited a consistent facial gestalt: oval face, prominent forehead, hypertelorism, downslanting palpebral fissures, and a narrow nasal bridge.

Findings:

• Congenital ataxia showed improvement over time despite progressive cerebellar atrophy.
• Responses to treatments were variable: inconsistent to acetazolamide, positive to methylphenidate.
• Two affected residues (F1394L, R1664Q/R1669Q) are highly conserved and located in the channel pore and voltage sensor, predicted to cause gain- and loss-of-function, respectively.

Implications:

• Non-progressive congenital ataxia, developmental delay, and dysmorphic features may constitute a recognizable syndromic neurodevelopmental disorder linked to CACNA1A.
• Understanding the functional impact of CACNA1A variants aids in diagnosing and managing related neurodevelopmental disorders.
• This study highlights the clinical heterogeneity of CACNA1A-related disorders and identifies a specific syndromic presentation.