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Japanese cases of familial hemiplegic migraine with cerebellar ataxia carrying a T666M mutation in the CACNA1A gene
  1. T Takahashi,
  2. S Igarashi,
  3. T Kimura,
  4. I Hozumi,
  5. I Kawachi,
  6. O Onodera,
  7. H Takano,
  8. M Saito,
  9. S Tsuji
  1. Department of Neurology, Brain Research Institute, Niigata University, 1-757 Asahimachi, Niigata 951-8585, Japan
  1. Correspondence to:
 Professor Tsuji;

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Familial hemiplegic migraine (FHM) is an autosomal dominantly inherited disorder characterised by migraine attacks preceded by transient hemiparesis. In 1993, Joutel et al mapped the locus for FHM to chromosome 19p13 by linkage analysis,1 and the causative gene was subsequently identified as the CACNA1A gene, encoding a P/Q-type calcium channel α1A subunit. Cases involving the CACNA1A gene have been found in approximately 50% of FHM cases, and linkage to chromosome 1 has been shown in some of the other families.

FHM with progressive cerebellar ataxia (FHM/PCA) has been described only in cases carrying CACNA1A mutations. Other clinical phenotypes associated with ataxia may also be caused by mutations in the CACNA1A gene, which include episodic ataxia type 2 (EA-2) and spinocerebellar ataxia type 6 (SCA6). EA-2 is characterised by recurrent episodes of attacks of cerebellar ataxia accompanied by interictal nystagmus. In SCA6, expansion of a CAG trinucleotide repeat coding for a polyglutamine stretch at the carboxyl terminus of the CACNA1A has been identified as the causative mutation.

These data suggest that mutations in the CACNA1A gene can lead to a broad spectrum of clinical presentations, and the relation between clinical phenotypes and genotypes in FHM has been discussed in recent reports.2–5 Here we describe a Japanese family with FHM/PCA, and discuss implications for genotype–phenotype correlations.

Case 1

A 67 year old woman was admitted to our hospital in 1995 for evaluation of cerebellar ataxia. She was born to first cousin parents. At age 30, she had an episode of unconsciousness for three days. She had suffered from reversible hemiparesis followed by throbbing migraine headaches lasting for several hours since she was 47. The hemiplegic episodes recurred often until the age of 52 years but gradually improved in frequency and severity without any treatment. She had begun to experience difficulty in walking since the age of about 62 years, and her gait difficulty had gradually progressed.

On neurological examination at the age of 67 years, she had horizontal gaze nystagmus and mild dysarthria. Her gait was ataxic, and she could stand on one foot only for a few seconds. Her tandem gait was unstable. Mild limb ataxia was also noted. Her muscle power was normal. No abnormal findings were noted in her sensory or autonomic nervous system. Her complete blood count, electrolytes, serum creatinine, and glucose levels were normal. Cerebrospinal fluid protein and sugar levels were normal. Brain magnetic resonance imaging (MRI) showed marked cerebellar vermian atrophy, but no areas of abnormal intensity were detected (fig 1). Single photon emission computed tomography (SPECT) showed low perfusion of the cerebellum. During her hospital admission, a throbbing headache followed by the sudden onset of numbness and dysaesthesia of the left upper limb were recorded.

Figure 1

T1 weighted magnetic resonance imaging showing marked atrophy of the cerebellar vermis.

Case 2

A 63 year old woman, a younger sister of case 1, had slight difficulty in speaking since the age of 36. Dysarthria, truncal ataxia, limb incoordination, and gaze nystagmus were noted by a neurologist at that time, and she was diagnosed as having spinocerebellar degeneration (autosomal dominant spinocerebellar ataxia presenting with pure cerebellar ataxia). At the age of 40, she had an episode of unconsciousness lasting two days (details unknown). She began to show a staggering gait at the same age. She had been suffering from reversible hemiparesis followed by throbbing migraine headaches since the age of 55. Neurological examination revealed horizontal gaze nystagmus, mild dysarthria, and mild truncal and limb incoordination, similar to those of her elder sister. The presence of cerebellar atrophy was confirmed by MRI (data not shown).

Case 3

A 37 year old man, a son of case 2, had had progressive gait and speech disturbances since childhood. He had never had migraine headache episodes. Neurological examination showed limb and truncal ataxia, nystagmus, scanning speech, hyperreflexia, and neck dystonia. MRI revealed cerebellar atrophy, particularly in the vermis.

Genetic features

Mutational analyses of the CACNA1A gene were performed in cases 1 and 2 by direct nucleotide sequence analysis of exons 4, 16, 17, and 36, in which the first four missense mutations—namely, R192Q, T666M, V714A and I1811L—were reported.6 The analysis was performed using an ABI377 automated sequencer with cycle sequencing. A C→T transition (T666M) in the CACNA1A gene was identified in both case 1 and case 2. The number of CAG repeat units of the CACNA1A gene of case 1 was 11/11. As molecular diagnosis was performed only in cases 1 and 2, there remains the possibility of a phenocopy in case 3.


Although FHM cases confirmed by DNA analyses have been reported in the USA, the United Kingdom, Italy, France, Netherlands, and Denmark, this is the first report confirming the mutation in the CACNA1A gene in FHM cases in Japan. Compared with other FHM cases associated with cerebellar ataxia, characteristic clinical features of the cases of the two sisters are that migraine attacks began in their fifth decade, and that the younger sister had shown only cerebellar ataxia for more than 10 years before her first migraine attack.

The findings in our patients emphasise that the clinical presentation of FHM/PCA is more varied than previously described and that even the same mutation can lead to considerably different clinical presentations, suggesting that other genetic or environmental factors may modify the phenotype.


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