Episodic Vestibulocerebellar Ataxia Associated with a CACNA1G Missense Variant

Area of Science:

• Neurogenetics
• Channelopathies
• Rare diseases

Background:

• Episodic vestibulocerebellar ataxias are rare neurological disorders often linked to ion channel mutations.
• Understanding the genetic basis and clinical spectrum of these ataxias is crucial for diagnosis and treatment.

Observation:

• A kindred presented with episodic vestibular dysfunction and ataxia, including dizziness and gait instability triggered by head movements.
• Affected individuals exhibited abnormal horizontal head impulse test (HIT) responses and reduced vestibulo-ocular reflex gain.
• Symptoms were alleviated by carbamazepine (CBZ), while other medications were ineffective or worsened instability.

Findings:

• Whole-exome sequencing identified a novel heterozygous CACNA1G missense variant (c.6958G>T, p.Gly2320Cys) segregating with the disease in affected family members.
• CACNA1G encodes the α1G subunit of T-type voltage-gated calcium channels (VGCCs), implicated in epilepsy and spinocerebellar ataxia.
• This variant is proposed as the cause of a new form of episodic vestibulocerebellar ataxia, potentially designated type 10.

Implications:

• This discovery expands the known spectrum of CACNA1G-related disorders.
• Carbamazepine's efficacy suggests a therapeutic strategy for this specific type of episodic vestibulocerebellar ataxia.
• Further research is needed to elucidate the precise vestibular and neurological mechanisms underlying this novel variant.