Next-generation sequencing identified a novel CACNA1A I1379F variant in a familial hemiplegic migraine type 1 pedigree

Abstract

Rationale: Familial hemiplegic migraine (FHM) is a rare, autosomal dominant migraine with aura. CACNA1A encodes the α1A subunit of P/Q-type voltage-gated calcium channels, and its mutations have been associated with a wide spectrum of episodic and chronic neurological disorders, including FHM type 1 (FHM1). Patient concerns: A Chinese girl and some of her relatives who presented with hemiplegia with or without migraine were found to carry a novel heterozygous missense variant, I1379F, in CACNA1A by whole-exome sequencing. The variant consegregated with the disease and was predicted to be pathogenic. Diagnosis: The patient was diagnosed with FHM1 clinically and genetically. Interventions: Prophylactic therapy with flunarizine 5 mg daily was prescribed to the patient. Outcomes: Therapy with flunarizine was terminated after a few weeks. The intensity of the attacks was the same as before. Lessons: This case indicates that FHM should be considered when a patient manifests with episodic hemiplegia without migraine. In addition, genetic testing is an indispensable method to identify atypical attacks of hemiplegic migraine.

Case Report: A Novel CACNA1A Mutation Caused Flunarizine-Responsive Type 2 Episodic Ataxia and Hemiplegic Migraine With Abnormal MRI of Cerebral White Matter

“…Recent guidelines for HM suggest oral flunarizine at 10 mg/day but this recommendation was largely based on studies in adults with no focus on CACNA1A-caused HM ( 5 , 6 ). Instead, previous CACNA1A-related cases showing the efficacy of flunarizine were both at the daily dose of 5 mg, involving one FHM1 family and noteworthily, a woman suffering from episodic ataxia and HM ( 9 , 10 ). A study summarizing 11 years' experience in treating childhood migraine found flunarizine effective in HM at an initial dose of 5 mg daily.…”

“…EA2 and HM can coexist within the same family ( 7 , 8 ) and even in the same patient ( 9 ). The similarity of symptoms and signs makes the diagnosis of these disorders difficult, highlighting that genetic testing is necessary ( 4 , 10 ). Brain MRI of EA2 patients typically reveals cerebellar atrophy or no notable findings, with cerebral white matter appearing to be rarely affected ( 11 ).…”

“…However, in patients with SHM, reversible subcortical hyperintensities on images are relatively common ( 12 ). It has been reported that flunarizine is useful in treating certain CACNA1A-related disorders, such as HM, but its efficacy in EA2 remains largely unknown ( 9 , 10 ). Here we describe a case of concurrent EA2 and SHM caused by a novel nonsense mutant of CACNA1A, with a slightly atrophic cerebellum, hyperintense lesions of cerebral white matter, and a favorable response to flunarizine.…”