Phenotypic variability in a four generation family with a p.Thr666Met CACNA1A gene mutation

Familial hemiplegic migraine type 1, episodic ataxia type 2, and spinocerebellar ataxia type 6 are distinct neurological disorders associated with mutations in the CACNA1A gene. Phenotypic variability and clinical overlap are recognized.

We describe a 2-year-old child with transiently decreased consciousness and clinical and radiological signs of early-onset cerebellar atrophy. The family history was significant, and 11 affected members across four generations indicated an unusually wide clinical spectrum including migraine, hemiplegia, coma, and progressive cerebellar ataxia.

The p.Thr666Met mutation of the CACNA1A gene was identified in the index patient and in five of his affected relatives who were analyzed. Our patient is the youngest one of this entity diagnosed to date.

Taking into account such a wide clinical expression of these gene mutations, it could be more accurate to speak about "channel-related diseases" to characterize the clinical expression according to the genetic analysis and to the phenotypes associated with each CACNA1A gene mutation.