Article Text

Download PDFPDF
Late onset hereditary episodic ataxia
  1. M Damak1,
  2. F Riant2,3,5,
  3. M Boukobza2,4,
  4. E Tournier-Lasserve2,3,5,
  5. M-G Bousser1,2,5,
  6. K Vahedi1,2
  1. 1
    Assistance Publique-Hôpitaux de Paris, Hôpital Lariboisière, Service de Neurologie, Paris, France
  2. 2
    Assistance Publique-Hôpitaux de Paris, Hôpital Lariboisière, Centre de Référence pour les Maladies Vasculaires Rares du Système Nerveux Central et de la Rétine, Paris, France
  3. 3
    Assistance Publique-Hôpitaux de Paris, Hôpital Lariboisière, Laboratoire de Cytogénétique, Paris, France
  4. 4
    Assistance Publique-Hôpitaux de Paris, Hôpital Lariboisière, Service de Neuroradiologie, Paris, France
  5. 5
    Unité Inserm U740, Université Paris VII, Paris, France
  1. Dr K Vahedi, Department of Neurology, Hôpital Lariboisière, 2 rue Ambroise Paré, 75010 Paris, France; katayoun.vahedi{at}


Objective: Episodic ataxias (EA) are hereditary paroxysmal neurological diseases with considerable clinical and genetic heterogeneity. So far seven loci have been reported and four different genes have been identified. Analysis of additional sporadic or familial cases is needed to better delineate the clinical and genetic spectrum of EA.

Methods: A two generation French family with late onset episodic ataxia was examined. All consenting family members had a brain MRI with volumetric analysis of the cerebellum. Haplotype analysis was performed for the EA2 locus (19p13), the EA5 locus (2q22), the EA6 locus (5p13) and the EA7 locus (19q13). Mutation screening was performed for all exons of CACNA1A (EA2), EAAT1 (EA6) and the coding sequence of KCNA1 (EA1).

Results: Four family members had episodic ataxia with onset between 48 and 56 years of age but with heterogeneity in the severity and duration of symptoms. The two most severely affected had daily attacks of EA with a slowly progressive and disabling permanent cerebellar ataxia and a poor response to acetazolamide. Brain MRI showed in three affected members a decrease in the ratio of cerebellar volume:total intracranial volume, indicating cerebellar atrophy. No deleterious mutation was found in CACNA1A, SCA6, EAAT1 or KCNA1. In addition, the EA5 locus was excluded.

Conclusions: A new phenotype of episodic ataxia has been described, characterised clinically by a late onset and progressive permanent cerebellar signs, and genetically by exclusion of the genes so far identified in EA.

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Episodic ataxias (EA) are rare paroxysmal neurological conditions caused by mutations in neuronal voltage gated ion channels with considerable clinical and genetic heterogeneity. At present, six different forms have been identified with different genetic variants for each.

The most frequent is episodic ataxia type 2 (EA2), caused by mutations in CACNA1A, a gene that encodes the α1A subunit of the main transmembrane neuronal voltage gated calcium channel.1 EA2 is typically characterised by the association of recurrent attacks of cerebellar ataxia starting in childhood or early adulthood, and permanent usually mild cerebellar signs.2 3

Episodic ataxia type 1 (EA1) is clinically distinct from EA2 as attacks are typically of short duration with associated permanent myokymia although a variant without myokymia and with prolonged attacks has recently been reported.4 EA1 is caused by mutations in the neuronal potassium channel gene KCNA1 on chromosome 12p and may be associated with seizures.5

EA3, described in a single Canadian family, shares features of EA1 such as short attacks of ataxia, vertigo and tinnitus, and interictal myokymia.6 The KCNA1 locus was however excluded. A linkage analysis conducted in this family suggested that the locus might be mapped to 1q42.6 However, in our opinion, the reported data did not allow precise mapping to the locus.

Rare mutations in the β4 subunit of the neuronal voltage dependent calcium channel gene CACNB4 on chromosome 2q (EA5) and in the glutamate transporter EAAT1 gene (SLC1A3) on chromosome 5p13 (EA6) have also been reported as causative of EA, either isolated or associated with attacks of hemiplegia and brain oedema.7 8

The clinical and genetic spectrum of EA may be even larger as affected families without an identified genetic defect and with unusual clinical features (late age of onset, episodic oscillopsia or diplopia) have been reported.912

We describe a family with late onset episodic ataxia (in the late fourth and fifth decades) with a poor response to acetazolamide and disabling permanent cerebellar signs with cerebellar atrophy. No deleterious mutation was found after sequencing of CACNA1A, SCA6, EAAT1 (SLC1A3) and KCNA1. In addition, the EA5 locus was excluded. We discuss the marked intrafamilial phenotypic heterogeneity and we emphasise the importance of frequently considering the diagnosis of EA given their large clinical and genetic spectrum.


Five family members from a two generation French family with EA were examined after their informed consent was obtained. All five family members had brain MRI examination and had blood drawn for genetic analysis.

Brain MRI examination

For each subject, the following series of images were acquired (1.5 T; GE Medical Systems, Milwaukee, USA): T1-SE, sagittal with or without axial and coronal slices; T2-SE, FLAIR, DWI, T2*SW, axial slices and three dimensional time of flight sequence (3D-TOF) on the cerebral arteries. In addition, for volumetric analysis, high resolution 3D T1 weighted gradient echo acquisition of the whole brain was obtained for each subject. Measurements of total intracranial volume (TICV) and cerebellum volume were based on 3D MR images and performed semiautomatically with the help of Voxtool 3.0.54 kappa.13 TICV included brain and CSF volumes, extending caudally to the foramen magnum. The cerebellar peduncles were included in the cerebellar volume. Absolute and percentage of TICV and of cerebellar volumes were used for evaluation of cerebellar atrophy. For all measurements, the mean of three measures was calculated and compared with an age and sex matched healthy control group. The controls were composed of three age and gender groups, including a total of 30 subjects (10 women, mean age 55.6 (3.3) years (range 51–59); 10 men, mean age 53.1 (3.5) years (range 50–58); 10 women, mean age 74 (3.7) years (range 70–81)). All measurements were performed by the same neuroradiologist (MB) who was blinded to the clinical status of each subject.

Genetic analysis

Haplotype analysis was performed for the EA2 locus (19p13), the EA5 locus (2q22), the EA6 locus (5p13) and the EA7 locus (19q13). We used the following markers: D19S221, D19S1150 (intragenic), D19S226 and D19S415 for the EA2 locus; D2S222, D2S2277, D2S2275, D2S2236, D2S2299 and D2S321 for the EA5 locus; D5S426, D5S395, D5S1964 and D5S418 for the EA6 locus; and D19S606, D19S879, D19S867, D19S246 and D19S571 for the EA7 locus. The length of the 3′ CAG repeat (SCA6) was also determined for the five members of the family. Mutation screening was performed for all 47 exons of CACNA1A, for KCNA1 and for the 10 exons of SLC1A3. In addition, the search for deletion in the CACNA1A gene was done using Quantitative Multiplex PCR of Short Fluorescent fragment (QMPSF).


The pedigree of the family is shown in fig 1. This family originates from the north of France. Four members were clinically symptomatic (table 1). The proband (II-4), a 51-year-old-man, had suffered from recurrent stereotyped attacks of ataxia and dysarthria without nausea, headache or tinnitus since the age of 48 years. Attacks sometimes included diplopia and vertigo. Triggering factors included emotional stress, overwork, physical exertion, coffee and alcohol but not kinetic factors. Duration of attacks varied from 5 min to 2 h. Their frequency and severity increased over years from one every 2 or 3 months at 48 years of age to several per day by age 51. Neurological examination during the attacks showed severe cerebellar gait ataxia, severe dysarthria, four limb incoordination and nystagmus. Neurological examination was otherwise normal.

Figure 1

Pedigree of the family and genotyping. Haplotype analysis was performed for the episodic ataxia (EA)5 locus (2q22) and for the EA7 locus (19q13). The data allowed us to exclude linkage to the EA5 locus (CACNB4). Because of the small number of members, the EA7 locus could not be excluded. Black symbol, affected member with episodic ataxia; ?, unknown status.

Table 1 Clinical characteristics of the four symptomatic family members

From the age of 49 years, the patient also had slowly progressive gait ataxia associated with dysarthria and gaze evoked nystagmus persisting between the attacks. He also had chronic depressive disorder but no paroxysmal psychiatric attack. Routine laboratory examination and CSF analysis were normal. With acetazolamide 500 mg daily, a mild decrease in the severity of attacks was observed but no change in their frequency and no improvement in the permanent cerebellar signs. Valproic acid at 1000 mg daily and aspirin at 500 mg daily had no clinical effect.

The proband’s 79-year-old mother (I-1) reported recurrent attacks of gait ataxia with vertigo and nausea, since the age of 55 years, that were milder and shorter (5–15 min) than those of her son. There was no dysarthria, headache or tinnitus. Attacks were precipitated by alcohol. The frequency of attacks increased over years with daily attacks since the age of 70 years. In addition, after age 59 years, she started to have a slowly progressive permanent cerebellar ataxia that recently became disabling with frequent falls. When examined at age 79 years, she was unable to walk a long distance without assistance and had cerebellar gait ataxia, dysarthria, four limb dysmetria and gaze evoked nystagmus.

Two of the proband’s sisters (II-1, II-2), aged 57 and 59 years, respectively, started in the past 2–3 years to have brief (1–5 min) mild recurrent episodes of gait ataxia and vertigo. Neurological examination was normal except for a gaze evoked nystagmus in the elder sister (II-1). The proband’s youngest sister (II-3), aged 55 years, reported no neurological symptoms except for migraine without aura and had a normal neurological examination.

MRI findings

The ratio cerebellar volume:TICV was decreased in three family members (I-1, II-4 and II-2) compared with controls. The ratio was also decreased but less markedly in subject II-1 and it was within the normal range in subject II-3. There were no other MR signal abnormalities except for small periventricular hypersignals on FLAIR imaging in subject II-1.

Genetic results

Haplotyping data allowed us to exclude linkage of this family to the CACNB4 locus (EA5) (fig 1). Because of the small number of members, other loci could not be excluded. The 47 exons of CACNA1A were sequenced and did not show deleterious mutations, and QMPSF analysis of the 47 exons of CACNA1A gave no argument for a deletion. In addition, the length of the 3′ CAG repeat was in the normal range. Sequencing of the 10 exons of SLC1A3 did not show any mutation. No mutation was identified in KCNA1.


We have reported a two generation French family with clinical and genetic features distinct from other forms of EA. Several features differentiate this condition from EA2. Firstly, the late onset of attacks (48–56 years) in all four affected family members contrasting with the early childhood onset of EA2. Secondly, the absent or poor response to acetazolamide. Thirdly, the absence of deleterious mutations found after complete sequencing and QMPSF analysis of the CACNA1A gene, thus excluding EA2.

The disorder in our family is also distinct from EA1 and EA3 because of the presence of cerebellar atrophy with progressive permanent cerebellar ataxia, the lack of interictal myokymia, weakness or stiffness, and the absence of tinnitus during attacks.8 11 Furthermore, no deleterious mutation was found in the KCNA1 gene responsible for EA1. Finally, genetic analysis excluded the EA5 locus and SLC1A3 mutation (EA6). EA7 could not be excluded with haplotyping analysis but no gene has yet been identified.

The present family shares some features with other familial or sporadic cases of late onset episodic ataxia (onset in their 60s), which were also unresponsive to acetazolamide and for which genetic analysis also excluded EA1, EA2 and SCA6.10 14 However, brain MRI did not show the cerebellar atrophy which was present in affected members of our family.

In conclusion, the clinical and genetic features of this family enlarge the spectrum of EA that should be considered, even in older patients.


The authors thanks Dr D Rougemont for referring the patient.



  • See Research paper, p 518

  • Competing interests: None.

  • Ethics approval: Ethics approval was obtained.

  • Patient consent: Obtained.

Linked Articles

  • Research paper
    D Genis I Ferrer J Valls Solé J Corral V Volpini H San Nicolás J Gich L Ramió-Torrentà M Ferrándiz J Puig F Márquez