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Bonemazzi, I.; Brunello, F.; Pin, J.N.; Pecoraro, M.; Sartori, S.; Nosadini, M.; Toldo, I. Clinical Diagnosis and Genetics of Hemiplegic Migraine. Encyclopedia. Available online: https://encyclopedia.pub/entry/45706 (accessed on 27 July 2024).
Bonemazzi I, Brunello F, Pin JN, Pecoraro M, Sartori S, Nosadini M, et al. Clinical Diagnosis and Genetics of Hemiplegic Migraine. Encyclopedia. Available at: https://encyclopedia.pub/entry/45706. Accessed July 27, 2024.
Bonemazzi, Ilaria, Francesco Brunello, Jacopo Norberto Pin, Mattia Pecoraro, Stefano Sartori, Margherita Nosadini, Irene Toldo. "Clinical Diagnosis and Genetics of Hemiplegic Migraine" Encyclopedia, https://encyclopedia.pub/entry/45706 (accessed July 27, 2024).
Bonemazzi, I., Brunello, F., Pin, J.N., Pecoraro, M., Sartori, S., Nosadini, M., & Toldo, I. (2023, June 16). Clinical Diagnosis and Genetics of Hemiplegic Migraine. In Encyclopedia. https://encyclopedia.pub/entry/45706
Bonemazzi, Ilaria, et al. "Clinical Diagnosis and Genetics of Hemiplegic Migraine." Encyclopedia. Web. 16 June, 2023.
Clinical Diagnosis and Genetics of Hemiplegic Migraine
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This entry is adapted from the peer-reviewed paper 10.3390/jcm12113783

Hemiplegic migraine (HM) is a rare form of migraine with an aura characterized by transient motor weakness or hemiparesis (motor aura). HM is also associated with other non-motor aura manifestations (visual, sensory, aphasic, or basilar-type/brainstem symptoms) and with other symptoms typically accompanying migraine, such as nausea, vomiting, photophobia, or phonophobia. A motor aura represents the peculiarity of HM compared to other forms of migraine with aura (MA), and its diagnostic criteria have been updated in the latest classification of headache disorders. HM can be sporadic (SHM) or familial (FHM), with autosomal dominant inheritance.

hemiplegic migraine familial hemiplegic migraine sporadic hemiplegic migraine children

1. Introduction

SHM and FHM are similar with respect to epidemiology, trigger factors, clinical features, and neuroradiological and neurophysiological findings, but the two forms differ in terms of age of onset, genetics, and associated neurological picture [1][2][3].
Although a strong familial history is common among all types of migraine, HM is the only one in which monogenic conditions have been identified, and mutations in CACNA1A, ATP1A2, and SCN1A determine a significant number of familial clusters and sporadic cases. Nevertheless, other genes have been recently associated with HM, and in a relevant number of sporadic cases, it is possible that an underlying genetic cause is yet to be identified [1][4][5].
HM can affect both children and adults, with onset frequently occurring at a pediatric age [3][4][5][6][7][8][9][10]. Early transient neurological symptoms (isolated seizures, transient hemiparesis without a headache, and prolonged clumsiness after minor head trauma) can occur between the ages of 1 and 4 and long before the very first episode of HM is observed [4].
HM presents with similar clinical features both in adults and children; however, some remarkable differences have been reported. The prevalence of non-motor auras among children is lower than it is among adults [3][4]. In addition, the frequency, intensity, and duration of HM attacks often decrease during adulthood [1][6][11]. Moreover, HM prevalence in adults is greater among females than it is among males (6:1) [3], while gender representation is similar in children [4][12].

2. Clinical Diagnosis

HM is a subtype of migraine with aura, and the aura is characterized by motor weakness (or plegic symptoms), typically with a duration of less than 72 h [13]. The diagnostic criteria of the International Classification of Headache Disorders (ICHD-3) [13] are reported in Table 1.
Table 1. ICHD-3 diagnostic criteria of HM [13].
HM Diagnostic Criteria
A. Attacks fulfilling criteria for 1 MA and criterion B below.
B. Aura consisting of both of the following:
1. Fully reversible motor weakness;
2. Fully reversible visual, sensory, and/or speech/language symptoms.
1 MA = migraine with aura.
Thomsen et al. [1][5] proposed some minor revisions to the diagnostic criteria, which are summarized in Table 2.
Table 2. Revisions of diagnostic criteria of HM proposed by Thomsen et al. [1][5].
HM Diagnostic Criteria Minor Revisions
Aura (B2 in Table 1) could consist of at least 2 symptoms instead of 3
A gradual development of aura (in at least 60 min)
Presence of headache is not mandatory
1 BM could be included as a symptom
1 BM = basilar migraine.
Basilar migraine (BM) or “migraine with brainstem aura”, is a type of MA clearly originating from the brainstem, but without motor weakness. BM may have at least two of the following fully reversible brainstem symptoms: dysarthria, vertigo, tinnitus, hypoacusis, diplopia, ataxia not attributable to the sensory deficit, and decreased level of consciousness (GCS < 13), but no motor or retinal symptoms [13].
Moreover, if at least one first- or second-degree relative has had attacks fulfilling the criteria for HM, a diagnosis of FHM can be conducted, otherwise the diagnosis of SHM is established [13].

3. Genetics and Relation with Other Migraine Types

Specific genetic subforms of FHM have been identified: FHM type 1 (FHM1) is associated with mutations of the CACNA1A gene (coding for a calcium channel) on chromosome 19 p13; FHM type 2 (FHM2) with mutations of the ATP1A2 gene (coding for a K/Na-ATPase) on chromosome 1q23; and FHM type 3 (FHM3) with mutations of the SCN1A gene (coding for a sodium channel) on chromosome 2 [13]. The ICHD-3 has recognized each genetic subform (FHM1, 2, 3) as a distinct entity [13]. The diagnostic criteria are listed in Table 3.
Table 3. ICHD-3 diagnostic criteria of FHM1, FHM2, and FHM3 [13].
FHM 1 FHM 2 FHM 3
A. Attacks fulfilling criteria for FHM A. Attacks fulfilling criteria for FHM A. Attacks fulfilling criteria for FHM
B. A mutation on the CACNA1A gene has been demonstrated. B. A mutation on the ATP1A2 gene has been demonstrated. B. A mutation on the SCN1A gene has been demonstrated.
ICHD-3 has also introduced the definition of “FHM, other loci”, in order to include all patients who fulfilled the clinical diagnostic criteria for FHM, but with no mutation detected on the CACNA1A, ATP1A2, or SCN1A genes using genetic testing [13].
Sporadic cases of HM can be determined using de novo mutations in FHM-related genes in patients without familial history of HM. The prevalence of CACNA1A, ATP1A2, and SCN1A mutations varies greatly among studies (7–63%) [3][4], mainly depending on the characteristics of the studied population. Pediatric cohorts and cohorts including only patients with early and severe disease onset showed a higher prevalence of gene mutations [4][12][14], while it was significantly lower in wider populations mostly including adult cases; for example, Hiekkala et al. found that 7% of the Finnish FHM families and none of the SHM patients had mutations in CACNA1A or ATP1A2 genes [3].
For this reason, some authors recommend genetic screening in patients with HM onset below 6 years of age and in those with accompanying neurologic symptoms, due to a higher risk of carrying mutations in CACNA1A or ATP1A2 genes in these cases [7][15]. Moreover, early paroxysmal motor or non-motor manifestations in childhood can precede the first HM attack, especially in mutated patients. These paroxysmal manifestations should be further investigated, especially in cases with a family history of HM [4].
Mutated patients could manifest a more severe phenotype: more extensive ictal motor weakness, attacks more often associated with confusion, brain edema, brainstem manifestations, abnormal neurological examination with mental retardation, and progressive ataxia [16]. A more frequent occurrence of HM triggered by mild head trauma is also reported in genetically positive patients [16].
Other rarer genes have been associated with HM clinical spectrum, such as PRRT2 [17][18], SLC4A4 [19], and SLC1A3 [20]. Ten pediatric patients with Glut1 deficiency syndrome due to SLC1A2 mutations showed HM-like attacks; only three were tested for typical HM genes and one showed a coexisting mutation in the CACNA1A gene. Further studies are needed to better understand if SLC1A2 mutations alone could cause HM-like acute manifestation or if other secondary mutations are needed to determine the HM phenotype [21].
Interestingly, genes associated with HM are pleiotropic and different mutations can result in mixed clinical or familial phenotypes, including different paroxysmal neurological disorders [20]. The phenotypic spectrum of the main HM genes has been summarized in Table 4.
Table 4. Phenotypic spectrum of the main HM genes.
Gene Phenotypic Spectrum
CACNA1A 1 HM, transient focal neurologic deficit without headache, coma after minor brain injury, progressive cerebella ataxia [9][22]
ATP1A2 HM, epilepsy, intellectual disability, prolonged HM attacks, confusion, and coma, 2 BM [11][23]
SCN1A HM, epilepsy [24]
PRRT2 benign familial childhood epilepsy, episodic kinesigenic dyskinesia, familial childhood seizures with paroxysmal choreoathetosis [17]
SLC4A4 HM, renal tubular acidosis, glaucoma [19]
SLC1A3 HM [20]
SLC1A2 epilepsy—Glut1 deficiency syndrome, HM-like attacks [21]
1 HM = hemiplegic migraine. 2 BM = basilar migraine.
Despite all the remarkable findings about the genetic background of HM in recent years, the genetic cause still remains unknown in a significant proportion of HM cases and in the pediatric population. Polygenic interaction and/or multifactorial conditions could account for a considerable part of non-monogenic HM cases, as in other more common types of migraine [20]. However, there may be other unknown loci associated with HM [13].
The correlation between HM and more common types of migraine (MA, migraine without aura—MWA, BA), from a pathophysiological and genetic perspective is still debated [1][2]. However, patients with FHM have 7 times increased risk of MA than the general population [2]. In addition, 70% of SHM and 94% of FHM patients have one or more first-degree relatives with attacks of common MA, MWA, or both [4][6][10][11][15].
SHM patients have a significantly higher risk of MA but not of MWA [9][25].
Compared with the general population, first-degree relatives of probands exclusively having SHM exhibited a 2 times higher risk of MA [2].
Interestingly, mutations in HM-related genes were also found in common types of MA, MWA, and BM [6].
Ducros et al. reported that 11% (13/117) of subjects with mutations in the CACNA1A gene had no attacks of HM, in particular: 15% (2/13) of cases had no symptoms, 38.5% (5/13) were affected by MA, 8% (1/13) by MWA, 8% (1/13) by recurrent headaches with loss of consciousness, and 23% (3/13) had single transient episodes of unknown clinical significance (dysarthria, unilateral paresthesia, and confusion with fever) [1][7]. These findings could support the hypothesis that even the monogenic forms of SHM and FHM could represent a small part of a broader phenotypic spectrum in continuity with more common types of migraine [6].

References

  1. Thomsen, L.L.; Eriksen, M.K.; Roemer, S.F.; Andersen, I.; Olesen, J.; Russell, M.B. A Population-Based Study of Familial Hemiplegic Migraine Suggests Revised Diagnostic Criteria. Brain 2002, 125, 1379–1391.
  2. Thomsen, L.L.; Ostergaard, E.; Olesen, J.; Russell, M.B. Evidence for a Separate Type of Migraine with Aura Sporadic Hemiplegic Migraine. Neurology 2003, 60, 595–601.
  3. Hiekkala, M.E.; Vuola, P.; Artto, V.; Häppölä, P.; Häppölä, E.; Vepsäläinen, S.; Cuenca-León, E.; Lal, D.; Gormley, P.; Hämäläinen, E.; et al. The Contribution of CACNA1A, ATP1A2 and SCN1A Mutations in Hemiplegic Migraine: A Clinical and Genetic Study in Finnish Migraine Families. Cephalalgia 2018, 38, 1849–1863.
  4. Toldo, I.; Brunello, F.; Morao, V.; Perissinotto, E.; Valeriani, M.; Pruna, D.; Tozzi, E.; Moscano, F.; Farello, G.; Frusciante, R.; et al. First Attack and Clinical Presentation of Hemiplegic Migraine in Pediatric Age: A Multicenter Retrospective Study and Literature Review. Front. Neurol. 2019, 10, 1079.
  5. Pelzer, N.; Haan, J.; Stam, A.H.; Vijfhuizen, L.S.; Koelewijn, S.C.; Smagge, A.; De Vries, B.; Ferrari, M.D.; Van Den Maagdenberg, A.M.J.M.; Terwindt, G.M. Clinical Spectrum of Hemiplegic Migraine and Chances of Finding a Pathogenic Mutation. Neurology 2018, 90, e575–e582.
  6. Cuenca-León, E.; Corominas, R.; Fernàndez-Castillo, N.; Volpini, V.; Del Toro, M.; Roig, M.; MacAya, A.; Cormand, B. Genetic Analysis of 27 Spanish Patients with Hemiplegic Migraine, Basilar-Type Migraine and Childhood Periodic Syndromes. Cephalalgia 2008, 28, 1039–1047.
  7. Ducros, A.; Denier, C.; Joutel, A.; Cecillon, M.; Lescoat, C.; Vahedi, K.; Darcel, F.; Vicaut, E.; Bousser, M.G.; Tournier-Lasserve, E. The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channel. N. Engl. J. Med. 2001, 345, 17–24.
  8. Marconi, R.; De Fusco, M.; Aridon, P.; Plewnia, K.; Rossi, M.; Carapelli, S.; Ballabio, A.; Morgante, L.; Musolino, R.; Epifanio, A.; et al. Familial Hemiplegic Migraine Type 2 Is Linked to 0.9Mb Region on Chromosome 1q23. Ann. Neurol. 2003, 53, 376–381.
  9. Barros, J.; Ferreira, A.; Brandão, A.F.; Lemos, C.; Correia, F.; Damásio, J.; Tuna, A.; Sequeiros, J.; Coutinho, P.; Alonso, I.; et al. Familial Hemiplegic Migraine Due to L263V SCN1A Mutation: Discordance for Epilepsy between Two Kindreds from Douro Valley. Cephalalgia 2014, 34, 1015–1020.
  10. Terwindt, G.; Kors, E.; Haan, J.; Vermeulen, F.; Van den Maagdenberg, A.; Frants, R.; Ferrari, M. Mutation analysis of the CACNA1A calcium channel subunit gene in 27 patients with sporadic hemiplegic migraine. Arch. Neurol. 2002, 59, 1016–1018.
  11. Jurkat-Rott, K.; Freilinger, T.; Dreier, J.P.; Herzog, J.; Göbel, H.; Petzold, G.C.; Montagna, P.; Gasser, T.; Lehmann-Horn, F.; Dichgans, M. Variability of Familial Hemiplegic Migraine with Novel A1A2 Na/K-ATPase Variants. Neurology 2004, 62, 1857–1861.
  12. Riant, F.; Ducros, P.A.; Ploton, C.; Barbance, C.; Depienne, C.; Tournier-Lasserve, E. De Novo Mutations in ATP1A2 and CACNA1A are Frequent in Early-Onset Sporadic Hemiplegic Migraine. Neurology 2010, 75, 967–972.
  13. International Headache Society (IHS). The International Classification of Headache Disorders, 3rd ed.; International Headache Society: London, UK, 2018; Volume 38, pp. 1–211.
  14. De Vries, B.; Frants, R.R.; Ferrari, M.D.; van den Maagdenberg, A.M.J.M. Molecular Genetics of Migraine. Hum. Genet. 2009, 126, 115–132.
  15. Eriksen, M.K.; Thomsen, L.L.; Olesen, J. Implications of Clinical Subtypes of Migraine with Aura. Headache 2006, 46, 286–297.
  16. De Vries, B.; Freilinger, T.; Vanmolkot, K.R.J.; Koenderink, J.B.; Stam, A.H.; Terwindt, G.M.; Babini, E.; Van Den Boogerd, E.H.; Van Den Heuvel, B.J.J.M.W.; Frants, B.R.R.; et al. Systematic Analysis of Three FHM Genes in 39 Sporadic Patients with Hemiplegic Migraine. Neurology 2007, 69, 2170–2176.
  17. Riant, F.; Roze, E.; Barbance, C.; Méneret, A.; Guyant-Maréchal, L.; Lucas, C.; Sabouraud, P.; Trébuchon, A.; Depienne, C.; Tournier-Lasserve, E. PRRT2 Mutations Cause Hemiplegic Migraine. Neurology 2012, 79, 2122–2124.
  18. Riant, F.; Roos, C.; Roubertie, A.; Barbance, C.; Hadjadj, J.; Auvin, S.; Baille, G.; Beltramone, M.; Boulanger, C.; Cahn, A.; et al. Hemiplegic Migraine Associated with PRRT2 Variations. Neurology 2022, 98, e51–e61.
  19. Suzuki, M.; Van Paesschen, W.; Stalmans, I.; Horita, S.; Yamada, H.; Bergmans, B.A.; Legius, E.; Riant, F.; De Jonghe, P.; Li, Y.; et al. Defective Membrane Expression of the Na+-HCO3− Cotransporter NBCe1 Is Associated with Familial Migraine. Proc. Natl. Acad. Sci. USA 2010, 107, 15963–15968.
  20. Russell, M.B.; Ducros, A. Sporadic and Familial Hemiplegic Migraine: Pathophysiological Mechanisms, Clinical Characteristics, Diagnosis, and Management. Lancet Neurol. 2011, 10, 457–470.
  21. Scoppola, C.; Magli, G.; Conti, M.; Fadda, M.; Luzzu, G.M.; Simula, D.M.; Carta, A.; Sotgiu, S.; Casellato, S. CACNA1A-Linked Hemiplegic Migraine in GLUT 1 Deficiency Syndrome: A Case Report. Front. Neurol. 2021, 12, 679354.
  22. Romozzi, M.; Primiano, G.; Rollo, E.; Travaglini, L.; Calabresi, P.; Servidei, S.; Vollono, C. CACNA1A-p.Thr501Met mutation associated with familial hemiplegic migraine: A family report. J. Headache Pain 2021, 22, 85.
  23. Ambrosini, A.; Grieco, G.; Di Mambro, A.; Montagna, G.; Fortini, D.; Nicoletti, F.; Nappi, G.; Sances, G.; Schoenen, J.; Buzzi, M.; et al. Familial Basilar Migraine Associated with a New Mutation in the ATP1A2 Gene. Neurology 2005, 65, 1826–1828.
  24. Claes, L.; Del-Favero, J.; Ceulemans, B.; Lagae, L.; Van Broeckhoven, C.; De Jonghe, P. De Novo Mutations in the Sodium-Channel Gene SCN1A Cause Severe Myoclonic Epilepsy of Infancy. Am. J. Hum. Genet. 2001, 68, 1327–1332.
  25. Thomsen, L.; Ostergaard, E.; Romer, S.; Andersen, I.; Eriksen, M.; Olesen, J.; Russell, M.; Lykke Thomsen, L. Sporadic Hemiplegic Migraine is an Aetiologically Heterogeneous Disorder. Cephalalgia 2003, 23, 921–928.
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Subjects: Pediatrics
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Ilaria Bonemazzi
,
Francesco Brunello
,
Jacopo Norberto Pin
,
Mattia Pecoraro
,
Stefano Sartori
,
Margherita Nosadini
,
Irene Toldo
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Revisions: 3 times (View History)
Update Date: 19 Jun 2023
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