Abstract
Clinical examinations and mutational analyses were carried out in three patients of a Japanese familial hemiplegic migraine (FHM) pedigree. Each affected member demonstrated a broad clinical spectrum that included hemiplegic migraine with progressive cerebellar ataxia, migraine without aura, and episodic ataxia. Despite this variability, all members exhibited marked downbeat positioning nystagmus, and magnetic resonance images (MRI) all showed cerebellar atrophy predominantly of the cerebellar vermis. All affected members had a T666M missense mutation in the protein encoded by the CACNA1A gene (calcium channel, voltage-dependent, P/Q type, alpha 1A subunit). Although clinical features associated with the T666M CACNA1A mutation are highly variable, downbeat positioning nystagmus may be an important clinical feature of this disease.
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References
Alonso I, Barros J, Tuna A, et al. (2003) Phenotypes of spinocerebellar ataxia type 6 and familial hemiplegic migraine caused by a unique CACNA1A missense mutation in patients from a large family. Arch Neurol 60:610–614
Bertholon P, Bronstein AM, Davies RA, et al. (2002) Positional down beating nystagmus in 50 patients: cerebellar disorders and possible anterior semicircular canalithiasis. J Neurol Neurosurg Psychiatr 72:366–372
De Fusco M, Marconi R, Silvestri L, et al. (2003) Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha-2 subunit associated with familial hemiplegic migraine type 2. Nature Genet 33:192–196
Dichgans M, Freilinger T, Eckstein G, et al. (2005) Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet 366:371–377
Ducros A, Denier C, Joutel A, et al. (1999) Recurrence of the T666M calcium channel CACNA1A gene mutation in familial hemiplegic migraine with progressive cerebellar ataxia. Am J Hum Genet 64:89–98
Ducros A, Denier C, Joutel A, et al. (2001) The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel. N Engl J Med 345:17–24
Fukushima K, Fukushima J, Kaneko CR, et al. (1999) Vertical Purkinje cells of the monkey floccular lobe: simplespike activity during pursuit and passive whole body rotation. J Neurophysiol 82:787–803
Geschwind DH, Perlman S, Figueroa KP, et al. (1997) Spinocerebellar ataxia type 6. Frequency of the mutation and genotype-phenotype correlations. Neurology 49:1247–1251
Headache Classification Subcommittee of the International Headache Society (2004) The International Classification of Headache Disorders: 2nd edition. Cephalalgia 24(Suppl 1):9–160
Iwabuchi K, Tsuchiya K, Uchihara T, et al. (1999) Autosomal dominant spinocerebellar degenerations. Clinical, pathological, and genetic correlations. Rev Neurol 155:255–270
Jen J, Kim GW, Baloh RW (2004) Clinical spectrum of episodic ataxia type 2. Neurology 62:17–22
Jen JC, Yue Q, Karrim J, et al. (1998) Spinocerebellar ataxia type 6 with positional vertigo and acetazolamide responsive episodic ataxia. J Neurol Neurosurg Psychiatry 65:565–568
Ophoff RA, Terwindt GM, Vergouwe MN, et al. (1996) Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2 channel gene CACNL1A4. Cell 87:543–552
Takeichi N, Fukushima K, Sasaki H, et al. (2000) Dissociation of smooth pursuit and vestibulo-ocular reflex cancellation in SCA-6. Neurology 54:860–866
Thomsen LL, Kirchmann M, Bjornsson A, et al. (2007) The genetic spectrum of a population-based sample of familial hemiplegic migraine. Brain 130:346–356
Vahedi K, Taupin P, Djomby R, et al. (2002) Efficacy and tolerability of acetazolamide in migraine prophylaxis: a randomised placebo-controlled trial. J Neurol 249:206–211
Wada T, Kobayashi N, Takahashi Y, et al. (2002) Wide clinical variability in a family with a CACNA1A T666m mutation: hemiplegic migraine, coma, and progressive ataxia. Pediatr Neurol 26:47–50
Yabe I, Sasaki H, Matsuura T, et al. (1998) SCA6 mutation analysis in a large cohort of the Japanese patients with late-onset pure cerebellar ataxia. J Neurol Sci 156:89–95
Yabe I, Sasaki H, Takeichi N, et al. (2003) Positional vertigo and macroscopic downbeat positioning nystagmus in spinocerebellar ataxia type 6 (SCA6). J Neurol 250:440–443
Zee DS, Yamazaki A, Butler PH, et al. (1981) Effects of ablation of flocculus and paraflocculus of eye movements in primate. J Neurophysiol 46:878–899
Zhuchenko O, Bailey J, Bonnen P, et al. (1997) Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the α1Avoltage-dependent calcium channel. Nat Genet 15:62–69
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Yabe, I., Kitagawa, M., Suzuki, Y. et al. Downbeat positioning nystagmus is a common clinical feature despite variable phenotypes in an FHM1 family. J Neurol 255, 1541–1544 (2008). https://doi.org/10.1007/s00415-008-0970-z
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DOI: https://doi.org/10.1007/s00415-008-0970-z