A novel CACNA1A mutation results in episodic ataxia with migrainous features without headache

Abstract

Background:

The mechanisms subtending migrainous features, like sensoriphobia, remain poorly understood even though recent works have shed new light on their mechanisms.

Case report:

A 24-year-old woman consulted the headache clinic because of frequent paroxysmal attacks of strong sensoriphobia, digestive signs, moderate ataxia and a need to lie in the dark, without any headache. The symptoms had begun in infancy and the patient had been treated for hysteria, then for epilepsy. As she had some typical features of episodic ataxia type 2, an analysis of CACNA1A gene was performed and demonstrated a novel c3995 + 1G>A mutation. The same mutation was also discovered in her young son, who had an ataxia of unknown origin. Both remarkably improved under acetazolamide.

Conclusions:

This observation suggests that paroxysmal sensoriphobia and digestive signs can occur together in bouts in neurological conditions other than migraine, and in the absence of head pain. It raises interesting hypotheses about the central pathways driving these symptoms.

Case report

‘Believe me, I am a migraineur but I have no headache’. A 24-year-old young woman introduced herself with these words at her first consultation in our headache clinic (CHR Citadelle, Liège, Belgium). Since the age of 2.5 years, she had suffered from recurrent attacks of strong photophobia, phonophobia, nausea and vomiting, blurred vision and moderate ataxia, without any head pain, but with a need to lie in the dark for up to 48 hours. According to her medical file, however, her parents had also reported migraine without aura episodes preceded by a short vertigo (seconds) in late childhood, of favourable spontaneous resolution and without any ataxia. At that time the sensoriphobic/ataxic episodes were believed to be of psychosomatic origin. The attack frequency rose from two to three per month in infancy to two to three per week at adult age. Stress and emotions were identified as trigger factors. At the age of 17, the patient presented a single generalised tonico-clonic seizure, with brief generalised spike-wave activities on one electroencephalography (EEG) recording (24 h EEG was normal). The diagnosis was therefore ‘epilepsy with psychopathological features’. Hence, she was treated with several anticonvulsants (valproate, levetiracetam, topiramate), with no or little amelioration. She decided to consult our headache clinic when she read information about the diagnostic criteria of migraine. She had been struck by the strong sensoriphobia, digestive signs and need to lie in the dark described in migraine and realised that she presented all of these symptoms… except headache. Her clinical exam between attacks was normal, and her brain magnetic resonance imaging (MRI) showed small numbers of non-enhancing white-matter lesions that remained stable with time. She had a son aged 3 who had permanent ataxia, convergent strabism and hypotonia of unknown origin, with normal brain MRI. The little boy also had mental retardation that was attributed to a 15q13.2–q13.3 deletion coming from his father. At the age of 4.5 years, however, after following a physical therapy revalidation program, his ataxia also became episodic, evolving in attacks similar to those of his mother. The mother of the patient suffered from migraine without aura, and we learnt later that her father had infrequent episodes of ataxia.

Since CACNA1A gene mutations can produce migraine and episodic ataxia type 2 (EA2) (1), we ordered a molecular screening of the CACNA1A gene in the proband and then in her son; unfortunately we did not manage to obtain DNA from the proband’s parents. In both mother and son, the analysis revealed a CACNA1A c3995 + 1G>A mutation (heterozygous state), a + 1 mutation in intron 24 that has not been described before to the best of our knowledge. This mutation should result in a splice site disappearance, with a skipping of exon 24 leading to a frame shift and then to a premature stop codon. It is thus probably highly pathogenic.

We replaced the anticonvulsants with acetazolamide 125 mg BID in our patient whereafter she rapidly mentioned complete disappearance of the attacks for several months. Thereafter the attacks recurred at a frequency of two to three times/month. Unfortunately the dose of acetazolamide could not be increased because of renal complications. Acetazolamide was also administered to her son, which resulted in complete disappearance of his ataxia.

Discussion

We report here the case of a patient suffering from EA2 because of a novel CACNA1A mutation (chromosome 19) and responsive to acetazolamide. CACNA1A codes the α subunit of neuronal voltage-gated calcium channel Ca_v 2.1. Mutations of this gene can either produce familial hemiplegic migraine type 1 (FHM-1), which is a monogenic subtype of migraine with aura, or EA2. Both phenotypes can be found within the same family (2). The clinical spectrum of episodic ataxias is broad, the more common associated symptoms being vertigo, digestive signs and headache (1,3).

In our proband paroxysmal sensoriphobia (i.e. abnormal sensitivity to visual, auditory and olfactory stimuli) dominates the clinical presentation together with digestive signs, while ataxia is present but rather moderate. The patient does not fulfil the second edition of the International Classification of Headache Disorders (ICHD-II) criteria for migraine as she has no headache (4). The sensoriphobia trait has rarely been underlined in the description of the EA2 clinical spectrum (2,3). A case of early-onset intense episodic ataxia with a need to lie down and sleep (‘due to impaired balance’) was recently described in a patient with a large CACNA1A deletion, but no sensoriphobia was mentioned (5).

The pathophysiology of sensoriphobia remains poorly understood. It is a key symptom of migraine but is not specific to this pathology and can be found in various neurological diseases. For example, a proposed mechanism for abnormal sensitivity to light during migraine is the convergence of nociceptive inputs from the meninges to thalamic neurons projecting directly to the primary and secondary visual cortices, leading to hypersensitivity (6). Interestingly, besides in the cerebellum, P/Q calcium channels are widely expressed in the trigeminovascular system and thalamus (7,8), where they play a dominant role in the control of neurotransmitter release and contribute to subthreshold rhythmic oscillations of membrane potentials that may be important for coordinating activity and excitability of afferent neuronal populations. Aberrant interactions among these populations of neurons may be responsible for the recently observed interictal impaired control of cortical excitability in EA2, which could provide an explanation for the paroxysmal neural dysfunction in response to triggering stimuli (9).

To conclude, we report the case of a patient with a novel mutation of the CACNA1A gene, in whom paroxysmal sensoriphobia and digestive signs dominate the clinical presentation and ataxia remains moderate. This observation highlights that these so-called ‘migrainous’ features can occur in bouts in diseases other than migraine, but might share similar central mechanisms involving impaired thalamocortical pathways (10).