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Novel CACNA1A mutation(s) associated with slow saccade velocities
Stefan Kipfer1, Simon Jung, Johannes R Lemke
1Perception and Eye Movement Laboratory, Departments of Clinical Research and Neurology, Inselspital, Bern University Hospital, and University of Bern, Freiburgstrasse 10, 3010, Bern, Switzerland, s.kipfer@gmx.ch.
Abstract:
Mutations in the voltage-gated Cav2.1 P/Q-type calcium channel (CACNA1A) can cause a wide spectrum of phenotypes, including the episodic ataxia type 2. Beside the growing number of descriptions of novel CACNA1A mutations with episodic ataxia type 2 phenotype; there are only rare reports on interictal oculomotor signs other than nystagmus. We describe a novel CACNA1A mutation and an unclassified CACNA1A in-frame variant in a Swiss family presenting as the episodic ataxia type 2 phenotype associated with reduced saccade velocity. In this case series interictal clinical examination showed only minimal neurological findings as mild limb ataxia and nystagmus, but most interestingly saccade analysis of all three affected individuals demonstrated reduced mean saccade velocity. Genetic testing of CACNA1A revealed a de novo frame-shift mutation (c.2691dupC/p.Thyr898Leufs 170) in the index patient in addition to an unclassified in-frame variant (c.6657_6659dupCCA/p.His2220dup) segregating in all three affected individuals. The de novo frame-shift CACNA1A mutation and the unclassified in-frame CACNA1A variant were associated with the episodic ataxia type 2 phenotype and reduced mean saccade velocity, which suggests involvement of brainstem or neural pathways connecting brainstem and the cerebellum in this disease.
Insights
Novel mutations in the CACNA1A gene are linked to episodic ataxia type 2 and reduced saccade velocity. This study identifies a new CACNA1A mutation and variant associated with these neurological symptoms.
Area of Science:
- Neurogenetics
- Channelopathies
- Neurology
Background:
- Mutations in the CACNA1A gene, encoding the Cav2.1 P/Q-type calcium channel, are associated with episodic ataxia type 2 (EA2).
- Interictal oculomotor abnormalities beyond nystagmus are infrequently reported in EA2 patients.
Purpose of the Study:
- To report a novel CACNA1A mutation and an unclassified variant in a Swiss family with EA2.
- To investigate the association of these genetic findings with reduced saccade velocity.
Main Methods:
- Clinical examination of affected individuals.
- Saccade velocity analysis.
- Genetic testing of the CACNA1A gene.
Main Results:
- A de novo frame-shift mutation (c.2691dupC/p.Thyr898Leufs 170) and an unclassified in-frame variant (c.6657_6659dupCCA/p.His2220dup) in CACNA1A were identified.
- All affected individuals exhibited reduced mean saccade velocity.
- Clinical presentation included EA2 phenotype with mild limb ataxia and nystagmus.
Conclusions:
- The identified CACNA1A mutations are associated with EA2 and reduced saccade velocity.
- This suggests the involvement of brainstem or related neural pathways in the pathophysiology of EA2.
- Reduced saccade velocity may serve as a key interictal oculomotor sign in CACNA1A-related disorders.
