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A Description of 5 Families With Familial Hemiplegic Migraine

E. E. Kors, MD; J. Haan, PhD; N. J. Giffin, MD; L. Pazdera, MD; C. Schnittger, MD; G. G. Lennox, MD; G. M. Terwindt, PhD; F. L. M. J. Vermeulen, MSc; A. M. J. M. Van den Maagdenberg, PhD; R. R. Frants, PhD; M. D. Ferrari, PhD

Arch Neurol. 2003;60:684-688.

Background  Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura. Missense mutations in the chromosome 19 CACNA1A calcium channel gene have been found in approximately half of the families. The T666M mutation, replacing a threonine by a methionine at residue number 666, is the most frequent mutation, reported in 14 independent FHM families; other mutations have so far been described in only 1 or 2 families each. The clinical features of T666M families have been reported, but the course is unknown.

Objective  To present a detailed description of the clinical features of new FHM families in which we identified the T666M mutation in our CACNA1A screening program.

Methods  As part of our ongoing genetic screening, mutation analysis of the CACNA1A gene was performed by single-strand conformational polymorphism analysis in 33 probands of families with FHM.

Results  We identified the T666M mutation in 5 unrelated FHM families. In 3 of the families, patients displayed cerebellar ataxia. In 1 family, some affected members with the mutation had attacks with confusion but without hemiparesis. In 1 family, patients had progressive cognitive dysfunction.

Conclusions  The T666M mutation is the most frequent CACNA1A mutation in FHM; it was found in 5 of 33 FHM families at our laboratory, and in 19 of 39 families with a known mutation reported in the literature (including the present study). Screening for the T666M mutation should therefore be the first step when screening families with FHM. There is a remarkable clinical heterogeneity among families with the T666M mutation.

From the Departments of Neurology (Drs Kors, Haan, Terwindt, and Ferrari) and Clinical and Human Genetics (Mr Vermeulen and Drs Van den Maagdenberg and Frants), Leiden University Medical Centre, Leiden, the Netherlands; Department of Neurology, Rijnland Hospital, Leiderdorp, the Netherlands (Dr Haan); Institute of Neurology, London, England (Dr Giffin); Department of Neurology, Rychnov nad Knznou, Czech Republic (Dr Pazdera); Department of Internal Medicine, Borromäus Hospital, Leer, Germany (Dr Schnittger); and Department of Neurology, Addenbrooke's Hospital, Cambridge, England (Dr Lennox).

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