Expansion of the phenotypic spectrum of the CACNA1A T666M mutation: a German family with FHM1, cerebellar atrophy and mental retardation

Background: Familial hemiplegic migraine (FHM) is a rare monogenic variant of migraine with aura characterized by some degree of hemiparesis during the aura. Mutations in three different genes have been identified in affected pedigrees: CACNA1A (FHM1), ATP1A2 (FHM2), and SCN1A (FHM3). More than 50% of pedigrees and all families with FHM plus cerebellar signs are linked to the FHM1 locus.

Mental retardation (MR) has previously been recognized as part of the phenotypic spectrum of FHM. So far, it has been predominantly reported in families with FHM2.

Here, we present clinical, neuropsychological and genetic data of a German FHM1 family with the CACNA1A T666M mutation, in which several individuals had permanent MR.

Patients and methods: All individuals were personally examined with a detailed semi-structured headache interview. FHM diagnosis was based on the criteria of the International Headache Society. All affected individuals were subjected to neuropsychological testing and imaging analysis.

Blood samples were obtained from all available individuals, and DNA was extracted from leukocytes according to standard procedures. In the index patient, all CACNA1A exons were analysed for mutations by direct sequencing. Direct sequencing was also used to confirm cosegregation of the identified mutation within the pedigree.

Results: The previously described CACNA1A T666M mutation was identified in the proband and all other affecteds. Frequency, duration and severity of hemiplegic attacks were at the lower end of the phenotypic spectrum in all individuals. No unusual aura features such as confusion, fever, epileptic seizures or coma were observed. All individuals had permanent cerebellar ataxia (with or without cerebellar atrophy). The proband and two additional mutation carriers were mentally retarded (IQs of 70, 76 and 80). Other etiologies of MR were ruled out. There was no evident causal relationship between the course of FHM attacks and cognitive dysfunction. Age at onset of MR was prior to the onset of FHM in all patients.

Conclusion: MR is part of the phenotypic spectrum of FHM and may be present in the setting of a relatively mild FHM phenotype, without frequent or particularly severe attacks. Further studies are needed to explore the mechanisms of MR in FHM1.