Abstract
Background
Familial hemiplegic migraine type 3 is a monogenic subtype of migraine caused by missense mutations in the neuronal voltage-gated sodium channel gene SCN1A, with 10 different mutations reported so far. In two familial hemiplegic migraine type 3 families, partial cosegregation with a rare eye phenotype (elicited repetitive daily blindness) was previously reported.
Methods
Two novel familial hemiplegic migraine pedigrees were subjected to genetic analysis and detailed work-up of associated clinical features.
Results
In both pedigrees, we identified SCN1A mutation p.F1499L, which has been previously associated with familial hemiplegic migraine type 3 and elicited repetitive daily blindness. Both families displayed a pure familial hemiplegic migraine phenotype without evidence of an episodic eye phenotype.
Conclusion
Like a substantial proportion of other familial hemiplegic migraine type 3 mutations, p.F1499L affects the intracellular linker between domains III and IV of SCN1A, which seems to be a mutational hot-spot. Our new data establish p.F1499L as a recurrent familial hemiplegic migraine type 3 mutation. Elicited repetitive daily blindness seems to be a rare phenomenon in familial hemiplegic migraine type 3, even in carriers of the same mutation.
Introduction
Familial hemiplegic migraine (FHM) is a rare monogenic subtype of migraine with aura, characterized by some degree of fully reversible unilateral motor weakness in addition to other neurological aura symptoms (1). The clinical presentation is highly variable, featuring various other manifestations. This may include permanent neurological symptoms (e.g. cerebellar ataxia) (2), but also other paroxysmal symptoms such as epileptic seizures. These may occur as a complicating feature of severe HM attacks, but also separately from HM.
Genetically, FHM is heterogeneous: To date, mutations in three different causative ion channel/transporter genes have been identified: CACNA1A (chromosome 19; FHM1) (3), ATP1A2 (chromosome 1; FHM2) (4) and SCN1A (chromosome 2; FHM3) (5). According to our current understanding, mutations in these genes, by different mechanisms, increase glutamatergic neurotransmission and enhance susceptibility to cortical spreading depression (CSD), the correlate of migraine aura.
SCN1A, which encodes a voltage-gated sodium channel on inhibitory interneurons, had previously been associated with monogenic forms of epilepsy (6). In 2005, it was identified as the FHM3 gene by a positional cloning approach in three unrelated German families, which were all found to carry mutation Q1489K (5). In subsequent years, nine other mutations were found in FHM pedigrees, making FHM3 the rarest FHM subtype so far.
While the majority of FHM3 patients seem to have a “pure” FHM phenotype without associated features, a peculiar visual phenomenon coined “elicited repetitive daily blindness” (ERDB) was reported for some rare individuals. ERDB was first described by Le Fort et al. in a Swiss FHM family (7). The majority of patients affected by FHM reported visual loss of one or both eyes for 10 seconds spreading from the periphery to the central visual field followed by a refractory period of 30 seconds. During these attacks, patients showed dilated pupils and lost pupillary reflexes. Ophthalmologic examination between the attacks was normal. Symptoms could be triggered by eye rubbing, sudden exposure to light or orthostatic reaction. The attacks occurred up to 10 times daily and were not related to the occurrence of hemiplegic attacks or migraine.
In 2009, a second French FHM family with partial co-segregation of FHM and ERDB was reported by Vahedi et al. (8). Genetic analysis of these two pedigrees revealed causative SCN1A mutations in both (p.Q1489H in the Swiss family and p.F1499L in the second, French family). The authors postulated a process of “retinal spreading depression”, in analogy to CSD, as the pathophysiological substrate of ERDB.
Here, we report clinical and genetic details on two novel FHM families caused by SCN1A mutation p.F1499L, i.e. the identical mutation that had been detected in the French FHM/ERDB family.
Clinical data
Family A: The index patient (Figure 1, V.8) is a 41-year-old female who presented to our outpatient headache unit with hemiplegic attacks since age 11. Attacks usually began with visual aura symptoms lasting for one hour followed by spreading unilateral sensory and motor deficits for about 30 minutes. These symptoms could sometimes re-occur in consecutive cycles of unilaterally spreading deficits over a maximum of several hours. Deficits were accompanied or followed by nausea and migrainous headache located contralaterally to the motor deficits. At the time of initial presentation, HM attack frequency was about one per week. Except for Graves’ disease, treated by thyroidectomy and substitution of thyroid hormones, the past medical history was unremarkable; in particular, there was no evidence of seizures or episodes of transient visual loss. Neurological examination and cranial magnetic resonance imaging (cMRI) were unremarkable.
Pedigree of family A.
Clinical characteristics of affected patients.
Note: Symbols in parenthesis indicate that the respective clinical feature was not consistently present during attacks.
Family B: During the preparation of this manuscript, we ascertained a 28-year-old patient with monthly attacks of hemiplegic migraine since age 12 (details in Table 1). The aura (duration: hours up to several days) started with visual symptoms followed by spreading unilateral sensory or motor deficits, which compromised his ability to walk properly or stand on the affected leg. Severe bilateral headache with nausea, photophobia and phonophobia usually began about 45 minutes after the first aura symptoms. Cranial magnetic resonance imaging during an acute attack was unremarkable, and previous work-up with EEG and duplex sonography of the extracranial brain vessels had also been normal. Neither during an episode we directly observed at our hospital nor on previous occasions there were any symptoms suggestive of ERDB. He was on no daily medication. His family originated from Croatia; however, his mother and himself were the only descendants living in Germany. He reported that his mother and four other maternal relatives suffered from similar episodes of unilateral motor weakness followed by headache, but we were unable to establish a direct contact with them.
Family A could not report any known relation to family B over four generations.
Genetic data
DNA was extracted from peripheral blood cells following standard protocols. Sequencing analysis of the established FHM genes (family A: Sequencing of CACNA1A and SCN1A; family B: CACNA1A, ATP1A2 and SCN1A) in the index patients of both families revealed the previously reported SCN1A mutation c.4495T>C / p.F1499L. The presence of this same mutation was confirmed in all other available FHM patients from family A (V.6, V.7, IV.12, IV.23; Figure 1), while no DNA samples from other affected individuals could be obtained in family B.
Informed consent regarding publication of clinical and genetic details was obtained from family A and the index from family B.
Discussion
We here report two novel FHM3 families with SCN1A mutation p.F1499L, that is, the same mutation that was previously found by Vahedi et al. in a French family with partial cosegregation with ERDB (8). Several aspects of our finding deserve attention.
First, it is becoming increasingly clear that a substantial proportion of FHM3-causing SCN1A mutations (three mutations in a total of seven families, Figure 2) affect the intracellular linker between domains III and IV of the SCN1A channel, which seems to be a hot-spot for FHM3 mutations (Figure 2). Specifically, p.F1499L and p.I1498M are both part of the functionally-relevant so called “IFMT motif”, which encodes a hydrophobic latch responsible for closure of the ion pore and inactivation of the SCN1A channel.
Transmembrane topology of the SCN1A channel.
Secondly, similar to mutation p.Q1489K, described by Dichgans et al. in three unrelated European families (5), p.F1499L, in light of the new data presented here, has now also been recognized as a recurrent mutation. Family A descends from Croatian ancestry and is distributed over Croatia and Germany, but has no relatives in France over at least four generations, making common ancestry with the published French family highly unlikely. Regarding family B, there was only limited information.
In any case, except for p.Q1489K and p.F1499L, there are no other FHM3 mutations with unequivocal evidence for recurrence: SCN1A mutation p.L263V was described in two independent reports (9,10), but additional data suggested that both Portuguese families derived from common ancestry. Finally, mutation T1174S was also described in two reports (11,12), but in one of the two families there was no clear-cut FHM phenotype (11). Thus, in summary, p.F1499L is the second recurrent FHM3 variant associated with a pure FHM phenotype.
Finally, we found no evidence of symptoms suggestive of ERDB in any family member. Although only five out of seven living FHM patients from family A and the index patient from family B could be reached for direct interview, we performed thorough clinical evaluation, paying particular attention to possible eye symptoms. Together with the data reported by Vahedi et al., with ERDB in only one out of four FHM patients (8), our observation highlights the fact that ERDB is obviously not a consistent finding in p.F1499L mutation carriers, which may point towards reduced penetrance. Of note, this is in contrast to the family reported by Le Fort et al., in which four out of five FHM patients experienced ERDB (7).
From a more general perspective, however, it should be noted that ERDB seems to be an explicitly rare phenomenon, reported in only two out of 10 published FHM3 families. Interestingly, ERDB was not detected in the three initial FHM3 families with mutation Q1489K, which affects the same amino acid residue mutated in the Swiss FHM/ERDB family (Q1489H). The same is true for the Spanish family reported by Weller et al. with mutation p.I1498M, which affects the amino acid residue directly neighbouring F1499. Also, to the best of our knowledge, ERDB or a similar eye phenotype was not reported in any FHM1 or FHM2 families. Of course, we cannot exclude with certainty the possibility that ERDB symptoms may have been missed in some of the published FHM3 pedigrees, but we regard this as highly unlikely given the striking clinical presentation of ERDB and the meticulous work-up of the clinical phenotype in the published families. Genetic variation in SCN1A seems to be an important determinant of ERDB susceptibility, since the only known occurrences of ERDB are in SCN1A mutation carriers; however, additional yet unidentified (genetic or environmental) factors seem to play an important role for its pathophysiology.
Summing up, we report the second recurrent SCN1A mutation causing a pure FHM phenotype and provide evidence that ERDB is a rare occurrence in FHM3 patients, even in carriers of the same mutation.
Clinical implications
The intracellular linker between domains III and IV of SCN1A seems to be a hot-spot for FHM3-causing SCN1A mutations. SCN1A mutation p.F1499L is the second recurrent SCN1A mutation associated with a pure FHM phenotype. ERDB seems to be a very rare phenomenon in FHM3 patients, even in carriers of the same mutation.
Footnotes
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.