Abstract
Background
SCN1A is the most relevant gene in epilepsy. Only seven SCN1A mutations have been identified in 10 familial hemiplegic migraine (FHM) kindreds worldwide.
Cases and kindreds
In 2009, we presented a kindred with FHM due to the L263V SCN1A mutation. In the current study, we report a novel FHM3 kindred from the same village. The first family exhibited the co-occurrence of FHM and epilepsy. No case of epilepsy was observed in the new kindred. An L263V mutation was found in all patients, and the haplotype analysis supports a unique mutational event.
Comments
Despite its bioelectric activity, the SCN1A L263V mutation most likely requires a combination of several endogenous or environmental induction stimuli to attain an epileptogenic threshold.
Introduction
Familial hemiplegic migraine (FHM) is a rare autosomal dominant migraine with aura (MA). Diagnostic criteria for FHM require mandatory documentation of reversible motor deficit associated with other transient neurological symptoms, and identical episodes in at least one first- or second-degree relative. Three types of FHM have been previously described (FHM1, FHM2 and FHM3), which are associated with mutations in the ion transport genes CACNA1A, ATP1A2 and SCN1A, respectively. Minor head trauma is frequently reported as a trigger for FHM1 and FHM2 (1).
Thousands of sequence variants in the SCN1A gene have been associated with a wide range of epilepsies (2,3). Suggesting a biological link between epilepsy and migraine, seven SCN1A mutations have been described in FHM, with 10 kindreds identified worldwide. The Q1489K and L1649Q mutations have been reported in three German (4) families and one Caucasian-American (5) family with pure FHM, respectively. The T1174S mutation has been previously ascribed to ataxic migraine syndrome in one multiethnic ancestry kindred (6) and has been previously described in an Italian family with both epileptic and FHM phenotypes (7). The F1499L and Q1489H mutations have been linked to FHM3 with elicited repetitive daily blindness in one French (8) and one Swiss (9) kindred, respectively. More recently, the I1498M mutation has been described in a Spanish family with pure FHM (10).
In 2009, we presented a Portuguese family with FHM due to an L263V mutation, in which some family members exhibited epilepsy that occurred independently of migraine (11). Moreover, functional studies have demonstrated that this mutation was a gain-of-function mutation (12). In the current study, we report a new kindred with FHM3. Both families share the L263V mutation and likely have a common ancestor.
Cases and kindreds
Kindred 1 (Figure 1) exhibited the co-occurrence of FHM and epilepsy as a result of the SCN1A gene L263V mutation (11). Members of kindred 2 (Figure 2) also presented with FHM, but no other paroxysmal or permanent neurological symptoms were observed. All individuals had normal neurological examination. Brain magnetic resonance imaging (MRI) (III:4, IV:7; IV:5, V:3) was normal. In addition, the mutation c.787C > G (p.L263V) in SCN1A was confirmed in all patients.
Pedigree structure of kindred 1. Black-filled symbols indicate hemiplegic migraine; black-filled quadrant, migraine without aura; underlined numbers, epileptic seizures; vertical bar, affected by hearsay. Plus sign indicates carriers of the mutation; minus sign, relatives who have been tested and did not carry the mutation. Arrow indicates proband; squares, males; circles, females; and diagonal lines, deceased. Pedigree structure of kindred 2. Black-filled symbols indicate hemiplegic migraine; grey-filled, migraine with typical aura; vertical bar, affected by hearsay. Plus sign indicates carriers of the mutation; minus sign, relatives who have been tested and did not carry the mutation. Arrow indicates proband; squares, males; circles, females; and diagonal lines, deceased. All patients carry the mutation.
The most remote ancestors suspected of suffering from FHM were born in a rural village in the Douro River Valley (Figure 3). Both families migrated to the coastal area at the beginning of the 20th century.
The Douro River Valley. The cross represents the rural village of provenance of both families.
Three microsatellite markers spanning 4.1 Mb within the SCN1A-locus region were genotyped and revealed that the mutation found in both families occurred on a common genetic background. This shared haplotype suggested that this mutation was inherited from a common ancestor and supported a unique mutational event for the L263V mutation.
Kindred 1
The matriarch originated from two branches, one of which is unknown. We evaluated five individuals who suffered from migraine with multiple auras, which fulfilled diagnostic criteria for FHM. Mean age of these patients at the last assessment was 48.4 years, and their mean age at onset was 14 years (10–18 years). Motor and sensory aura shifted sides within a single episode in one patient, and other patients exhibited episodes where the aura simultaneously affected the upper right and lower left limbs (or vice versa). Aphasic aura occurred concomitantly with right- or left-sided sensory-motor aura. Most patients presented with headache on the contralateral side of the aura, although two cases presented with bilateral headache. Four individuals achieved apparent remission at ages ranging from 37 to 60 years.
Epileptic seizures co-segregated with hemiplegic migraine in three patients, and most likely also in one deceased person (II:3). In summary:
III:2. Five nocturnal generalised tonic-clonic seizures and one partial complex seizure, between the age of 14 and 29 years old. Initially, she was treated with phenytoin/phenobarbital (association). We did not have access to the electroencephalogram (EEG) performed at that time; currently is normal. III:6. Scarce generalised tonic-clonic seizures, which may have occurred annually, since the age of 18 years old. He was treated with carbamazepine (600 mg/day). EEG revealed frontal bilateral theta-waves and right anterior spike-and-slow-wave complexes. IV:7. Scarce generalised tonic-clonic seizures by the age of 8 years old. Normal EEG.
Main clinical features of kindred 1.
Seizures: Fa: face; T: tongue; UL: upper limb; LL: lower limb; Tr: trunk; N: nausea; V: vomiting; Pt: photophobia; Pn: phonophobia; S: somnolence; M: male; F: female; h: hours; yrs: years; mins: minutes.
Kindred 2
In 2010, a young man (V:3) was first observed in our emergency room for an episode of migraine with aura, including transient motor deficit. Thereafter, all of the available relatives were examined.
The kindred included four members who met diagnostic criteria for FHM, as well as one individual with visual and sensory aura, without paresis. Mean age at onset was 8 years (6–14 years), and 47.4 years at the last assessment. All patients exhibited dozens of episodes over their lifetime. In most patients, the aura lasted for approximately 60 minutes, with one patient exhibiting long-lasting and recurrent auras for a total duration of up to nine hours. Scintillating scotoma, sensory aura and hemiplegia were reported by four patients, and aphasic aura by two patients. Four patients presented side-shifting auras, while another always presented right-sided auras. In three patients, the sensorimotor auras shifted sides within an episode, and one patient reported an episode in which the sensory aura shifted sides multiple times. Aphasia was more often associated with right-sided sensorimotor aura, but on some occasions, it was associated with left-sided symptoms. Headaches lasted an average of 27.6 hours, and were throbbing and severe. An adult (IV:1) demonstrated marked worsening in episode frequency and severity, between the age of 51 and 53 years, after a coma due to mild head trauma. No patient reported other types of paroxysmal episodes.
Main clinical features of kindred 2.
Fa: face; T: tongue; UL: upper limb; LL: lower limb; Tr: trunk; N: nausea; V: vomiting; Pt: photophobia; Pn: phonophobia; S: somnolence; M: male; F: female; h: hours; yrs: years; mins: minutes.
Comments
The occurrence of FHM3 in two families originating from the same village is an improbable coincidence because of the very rare occurrence of this type of hemiplegic migraine (only 10 families have been reported worldwide (4–11)). In fact, the haplotype analysis showed that the mutation occurred on a common genetic background, suggesting that it was inherited from a common ancestor and from a single mutational event. This possibility makes intriguing the apparent absence of other families with identical phenotypes in that village. Migration to urban centres, low penetrance and underdiagnoses are potential explanations.
In 2009, we described for the first time, the coexistence, but separate occurrence, of hemiplegic migraine and epilepsy in FHM3 (11). Functional studies (12) have suggested that the causative mutation induces a gain-of-function that favours a hyperexcitability common to both conditions, which is similar to the intimate and classical association between migraine and epilepsy. Nevertheless, the reason for the same pathophysiological mechanism eliciting a seizure in one instance and migraine in another remains to be elucidated. Seizures presented by the individuals in kindred 1 were scarce and self-limited. No case of epilepsy (concomitant or co-occurring) was observed in kindred 2, which was similar to previously reported families with loss-of-function mutations (Q1489K and L1649Q) (10). Epileptic cases may be limited to a family branch by chance or by polygenic or environmental variables. In either case, the manifestations of epilepsy seizures were scarce and few individuals were affected. Despite its bioelectric activity, the SCN1A L263V mutation most likely requires an interaction with endogenous (other genes, hormones) or environmental induction stimuli to attain an epileptogenic threshold. As a result, the mandatory, simultaneous and unlikely combination of several factors makes epilepsy a rare occurrence. Thus, we concluded that loss or gain-of-function induced by the mutation was not a determining factor for a family with FHM3 to exhibit associated epilepsy.
We lastly propose that head trauma may be a precipitant factor (IV:1). It is a well-known phenomenon in FHM1 and FHM2 but has not previously been associated with FHM3.
We believe that the present study will contribute to enhancing the phenotypic characterisation of FHM3, which is based on a very small number of families, and will contribute to a better understanding of the physiopathogenesis of this disorder.
Clinical implications
Familial hemiplegic migraine 3 (FHM3) is clinically heterogeneous, with variable penetrance, even among individuals sharing the same mutation. Epilepsy is an occasional and unpredictable FHM3 phenotype. Head trauma is a potential trigger for FHM3, as well as for FHM1 and FHM2.
Footnotes
Funding
This study was supported by the Fundação para a Ciência e Tecnologia (grant PIC/IC/83232/2007), the Sociedade Portuguesa de Cefaleias (Tecnifar award and grant) and the Sociedade Portuguesa de Neurologia (SPN award and grant). Isabel Alonso is funded by the Programa Ciência, POPH-QREN–Tipologia 4.2–Promoção do Emprego Científico, cofunded by the European Social Fund, and has received national funds from the Ministério da Ciência e Ensino Superior.
Conflict of interest
None declared.
Acknowledgements
We thank the patients and families for participating in the study. We acknowledge Dr Carla Fraga (Centro Hospitalar de Tâmega e Sousa, Penafiel), Dr Miguel Carvalho and Dr Rui Figueiredo (Centro de Saúde do Marco de Canavezes) for their effort in finding similar cases in their clinical files. The map was drawn by Isabel Monteiro (Nextcolor).