Clinical characteristics.

Familial hemiplegic migraine (FHM) falls within the category of migraine with aura. In migraine with aura (including FHM) the neurologic symptoms of aura are unequivocally localizable to the cerebral cortex or brain stem and include visual disturbance (most common), sensory loss (e.g., numbness or paresthesias of the face or an extremity), and dysphasia (difficulty with speech). FHM must include motor involvement, such as hemiparesis (weakness of an extremity). Hemiparesis occurs with at least one other symptom during FHM aura. Neurologic deficits with FHM attacks can be prolonged for hours to days and may outlast the associated migrainous headache. FHM is often earlier in onset than typical migraine, frequently beginning in the first or second decade; the frequency of attacks tends to decrease with age. Approximately 40%-50% of families with CACNA1A-FHM have cerebellar signs ranging from nystagmus to progressive, usually late-onset mild ataxia.

Diagnosis/testing.

The clinical diagnosis of FHM can be established in a proband: (1) who fulfills criteria for migraine with aura; (2) in whom the aura includes fully reversible motor weakness and visual, sensory, or language symptoms; and (3) who has at least one first- or second-degree relative with similar attacks that fulfill the diagnostic criteria for hemiplegic migraine. The molecular diagnosis can be established in a proband by identification of a heterozygous pathogenic variant in ATP1A2, CACNA1A, PRRT2, or SCN1A.

Management.

Treatment of manifestations: A trial of acetazolamide for individuals with CACNA1A-FHM or a trial of prophylactic migraine medications (e.g., tricyclic antidepressants, beta-blockers, calcium channel blockers, anti-seizure medications) for all FHM types may be warranted for frequent attacks. Anti-seizure treatment may be necessary for seizures, which are prevalent in ATP1A2-FHM. Corticosteroids in children with cerebral edema to reduce life-threatening manifestations.

Surveillance: Neurologic evaluation to assess change in attack frequency and/or seizures, development of movement disorder, developmental delay, and/or learning disability annually or more frequently for worsening symptoms.

Agents/circumstances to avoid: Vasoconstricting agents because of the risk of stroke; cerebral angiography as it may precipitate a severe attack.

Genetic counseling.

FHM and simplex hemiplegic migraine caused by a heterozygous ATP1A2, CACNA1A, PRRT2, or SCN1A pathogenic variant are inherited in an autosomal dominant manner. Because the diagnosis of FHM requires at least one affected first-degree relative, most individuals diagnosed with FHM have an affected parent. Individuals with simplex hemiplegic migraine (i.e., individuals with an FHM-causing pathogenic variant and an apparently negative family history) may have a de novo pathogenic variant or a pathogenic variant inherited from an asymptomatic parent. Each child of an individual with FHM has a 50% chance of inheriting the pathogenic variant. Once an FHM-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

FHM is a category of migraine with aura.

Note: Migraine with aura is a recurring disorder of neurologic symptoms unequivocally localizable to the cerebral cortex or brain stem. The aura usually develops over a period of five to 20 minutes and lasts less than 60 minutes. Headache, nausea, and/or photophobia usually follow neurologic aura symptoms, either immediately or after a symptom-free interval of less than an hour. The headache usually lasts four to 72 hours but may be completely absent (acephalgic migraine).

Diagnostic criteria for HM

• Headaches that fulfill criteria for migraine with aura
• Aura consisting of both of the following:
  • Transient (generally >72 hours but may be prolonged) but fully reversible motor weakness
  • Fully reversible visual, sensory, and/or speech/language symptoms

HM is categorized as familial if at least one first-degree relative (i.e., parent, sib, and/or offspring) or second-degree relative has similar attacks that fulfill the diagnostic criteria for HM.

Note: HM is sporadic if no first- or second-degree relative meets criteria for HM.

Diagnostic criteria for migraine with aura

• At least two episodes fulfilling criteria for migraine
• Migraine with at least one of the following fully reversible aura symptoms:
  • Visual
  • Sensory
  • Speech and/or language
  • Motor
  • Brain stem
  • Retinal
• At least three of the following characteristics:
  • At least one aura symptom spreads gradually over five minutes.
  • Two or more aura symptoms occur in succession.
  • Each individual aura symptom lasts five to 60 minutes.
  • At least one aura symptom is unilateral.
  • At least one aura symptom is positive.
  • The aura is accompanied – or followed within 60 minutes – by headache.
• Absence of other causes of headache (e.g., head trauma, vascular disorders, nonvascular intracranial disorders, substance use or their withdrawal, non-cephalic infection, metabolic disorder, pain associated with other facial or cranial disorders)

Establishing the Diagnosis

The clinical diagnosis of FHM can be established in a proband based on clinical diagnostic criteria described in Suggestive Findings, or the molecular diagnosis can be established in a proband by identification of a heterozygous pathogenic (or likely pathogenic) variant by molecular genetic testing in one of the genes listed in Table 1.

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous variant in one of the genes listed in Table 1 of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include serial single-gene testing, a multigene panel, or exome sequencing.

Note: (1) In the majority of persons with adult-onset hemiplegic migraine without nystagmus, seizures, or other unusual associated neurologic features, the yield for genetic testing is low. (2) Multiple studies have shown that pathogenic variants in the genes listed in Table 1 are not a major cause of simplex hemiplegic migraine (i.e., hemiplegic migraine in a single person in a family).

• Serial single-gene testing
  • In individuals with nystagmus, ataxia, paroxysmal tonic upgaze, or developmental delay, sequence analysis of CACNA1A can be performed first. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications [Ophoff et al 1996].
  • In individuals with epilepsy, sequence analysis of ATP1A2 can be performed first [De Fusco et al 2003].
• A multigene panel that includes some or all of the genes listed in Table 1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

In migraine with aura, including familial hemiplegic migraine (FHM), the neurologic symptoms of aura are unequivocally localizable to the cerebral cortex or brain stem and include fully reversible visual disturbance (most common), sensory loss (e.g., numbness or paresthesias of the face or an extremity), and dysphasia (difficulty with speech), and for FHM must include motor involvement (e.g., hemiparesis [weakness of an extremity]):

• Visual disturbances can include scotoma (blind spots), photopsia (flashing lights), fortification spectra (zigzag pattern), and diplopia (double vision).
• Dysphasia usually occurs when hemiplegia is right-sided.
• Hemiparesis (unilateral weakness), not necessarily hemiplegia (unilateral paralysis), occurs with at least one other symptom during FHM aura.

Some confusion and/or drowsiness may be present even without dysphasia. Impaired consciousness ranging from drowsiness to coma is well described in FHM [Terwindt et al 1998, Chabriat et al 2000, Vahedi et al 2000]. Intermittent confusion and psychosis have been reported [Feely et al 1982], including one probable family with CACNA1A-FHM and ataxia [Spranger et al 1999].

Neurologic deficits with hemiplegic migraine attacks can be prolonged for hours to days and may outlast the associated migrainous headache. Persistent attention and memory loss can last weeks to months [Kors et al 2003]. Permanent motor, sensory, language, or visual symptoms are extremely rare [Ducros et al 2001].

FHM is a rare and extreme phenotype of migraine with aura. The frequency of attacks ranges from one per day to fewer than five in a lifetime (mean: 2-3/year). Long attack-free intervals are often reported (range: 2-37 years). The frequency of FHM attacks tends to decrease with age. FHM attacks may be provoked by typical migraine triggers (e.g., foods, odors, exertion, stress), cerebral angiography, and minor head trauma.

The eventual neurologic outcome is often benign in the pure FHM group without interictal deficits (e.g., seizures/epilepsy, ataxia, nystagmus, cognitive impairment / learning disability).

Note: Cerebral infarction and death have rarely been associated with hemiplegic migraine and should instead raise the possibility of other disorders associated with migraine and stroke (see Differential Diagnosis).

Seizures are a recognized feature in those with FHM-related pathogenic variants, which reflects much clinical and mechanistic overlap between epilepsy and migraine. Seizures during severe attacks have been reported in some families with ATP1A2-FHM along with coma and encephalopathy [Echenne et al 1999, Deprez et al 2008]. Focal seizures during severe attacks have been described in two individuals with simplex CACNA1A-FHM [Chabriat et al 2000], including one with severe intellectual disability, congenital ataxia, and early cerebellar atrophy [Vahedi et al 2000]. De novo CACNA1A pathogenic variants are a common cause of epileptic encephalopathy [Allen et al 2016], and epileptic encephalopathy may be the presenting phenotype in an individual who develops CACNA1A-FHM. Heterozygous PRRT2 pathogenic variants are a major cause of childhood seizures, including self-limited (familial) infantile epilepsy (SeLIE; formerly known as benign familial infantile seizures) and paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC; formerly known as infantile convulsions and choreoathetosis) [Heron et al 2012, Schubert et al 2012, Becker et al 2013].

Paroxysmal movement disorders. Paroxysmal kinesigenic dyskinesia has been reported in individuals with a PRRT2 pathogenic variant with or without presence of hemiplegic migraine (see PRRT2-Related Disorder).

Imaging studies. There are no pathognomonic neuroradiographic findings for FHM. The only abnormalities observed on traditional imaging studies are vermian cerebellar atrophy in some families with CACNA1A-FHM [Battistini et al 1999]. Rare ictal studies demonstrated transient diffusion-weighted signal changes on brain MRI, suggesting cytotoxic edema during severe prolonged attacks in individuals with CACNA1A-FHM [Chabriat et al 2000, Vahedi et al 2000], with hemispheric cerebral atrophy usually contralateral to the hemiparesis [Hayashi et al 1998, Chabriat et al 2000, Vahedi et al 2000].

Abnormalities in the cerebellum on magnetic resonance spectroscopy have been reported [Dichgans et al 2005].

Phenotype Correlations by Gene

CACNA1A. Compared to families without an identified FHM-related pathogenic variant, families with CACNA1A-FHM have a higher incidence of cerebellar signs ranging from nystagmus to progressive ataxia, which occurs in up to 40%-50% of families with CACNA1A-FHM [Ducros et al 2000]; within such families, up to 60% of affected individuals have permanent cerebellar signs [Ducros et al 2001].

Those with identified FHM-related pathogenic variants tend to present with earlier age of onset, more severe symptoms, and associated interictal symptoms and signs (nystagmus, episodic or progressive ataxia, learning disability, epilepsy). In the report of Ducros et al [2001], the attacks started at a young age in the majority of individuals with CACNA1A-FHM (mean: 11.7±8 years; range: 1-51 years). Findings from subsequent series confirmed the observation of early age of onset and more severe attacks in those with FHM-related pathogenic variants compared to those with FHM and no pathogenic variant identified [Hiekkala et al 2018, Pelzer et al 2018].

Genotype-Phenotype Correlations

ATP1A2

• A severe phenotype with seizures, coma, and elevated temperature has been reported with the p.Gly301Arg pathogenic variant in ATP1A2 [Spadaro et al 2004, Santoro et al 2011].
• A severe phenotype with seizures and intellectual disability has been reported with the pathogenic variants p.Asp718Asn and p.Pro979Leu [Jurkat-Rott et al 2004].

CACNA1A. Although further correlation is needed, some suggestive genotype-phenotype correlations exist based on limited data regarding CACNA1A pathogenic variants commonly presenting with nystagmus and other cerebellar signs [Ophoff et al 1996, Ducros et al 2001].

• p.Arg192Gln and p.Val1456Leu [Carrera et al 1999] are associated with hemiplegic attacks only, whereas unconsciousness occurs commonly during attacks with the p.Val714Ala pathogenic variant [Terwindt et al 1998].
• p.Thr666Met, p.Ile1810Leu, p.Arg583Gln [Alonso et al 2003], and p.Asp715Glu [Ducros et al 1999] have been associated with hemiplegic attacks plus ataxia. According to Ducros et al [2001], p.Thr666Met was associated with the highest frequency of hemiplegic migraine, severe attacks of coma, and nystagmus. During attacks, unconsciousness sometimes occurs in individuals with the p.Thr666Met or p.Ile1810Leu pathogenic variant [Terwindt et al 1998].
• p.Arg583Gln can be associated with stupor, fever, and progressive ataxia [Battistini et al 1999, Ducros et al 2001]. Affected individuals were thought to have fewer attacks after treatment with acetazolamide.
• p.Asp715Glu has the lowest frequency (64%) of attacks of hemiplegic migraine [Ducros et al 2001].
• p.Ser218Leu has been associated with delayed cerebral edema and fatal coma after minor head trauma [Kors et al 2001, Stam et al 2009].

Penetrance

Penetrance appears to be high and is estimated at 80% [Jurkat-Rott et al 2004, Riant et al 2005].

Nomenclature

Although families with FHM in which attacks are strikingly identical do exist, the term FHM is often used inconsistently to describe families in which different forms of migraine occur, as most individuals with hemiplegic attacks have these attacks intermingled with more frequent attacks of migraine without hemiparesis.

Prevalence

In Denmark, Thomsen et al [2002] found the prevalence of hemiplegic migraine to be 0.01% with a M:F sex ratio of 1:3 and equal prevalence of familial and simplex cases.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with familial hemiplegic migraine (FHM) or simplex hemiplegic migraine (i.e., individuals with an FHM-causing pathogenic variant and an apparently negative family history), the evaluations summarized in this Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Symptomatic support during an episode of hemiplegic migraine is the only therapy available.

Surveillance

Agents/Circumstances to Avoid

In general, vasoconstricting agents should be avoided because of the risk of stroke.

Cerebral angiography is hazardous as it may precipitate a severe attack [Chabriat et al 2000].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Familial hemiplegic migraine (FHM) and simplex hemiplegic migraine caused by a heterozygous ATP1A2, CACNA1A, PRRT2, or SCN1A pathogenic variant are inherited in an autosomal dominant manner.

Note: The term "simplex hemiplegic migraine" is used in this section to refer to individuals with hemiplegic migraine and a heterozygous pathogenic variant in ATP1A2, CACNA1A, PRRT2, or SCN1A who do not have a first- or second-degree relative who meets criteria for hemiplegic migraine.

Risk to Family Members

Parents of a proband

• Because the diagnosis of FHM requires at least one affected first-degree relative, most individuals diagnosed with FHM have an affected parent.
• Individuals with simplex hemiplegic migraine (i.e., individuals with an FHM-causing pathogenic variant and an apparently negative family history) may have a de novo pathogenic variant [Terwindt et al 2002, de Vries et al 2007, Thomsen et al 2008, Riant et al 2010] or a pathogenic variant inherited from an asymptomatic parent.
• Recommendations for the evaluation of the parents of an individual who appears to be the only affected family member include clinical interview, neurologic examination, and molecular genetic testing if a molecular diagnosis has been established in the proband.
• If a pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with ATP1A2, CACNA1A, PRRT2, or SCN1A-related hemiplegic migraine may appear to be negative because of failure to recognize the disorder in affected family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for a causative pathogenic variant identified in the proband).

Sibs of a proband. The risk to the sibs of a proband depends on the clinical/genetic status of the parents:

• If a parent of the proband is affected and/or is known to have an FHM-causing pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. There is a high likelihood that a sib who inherits an FHM-causing pathogenic variant will have clinical manifestations of the disorder. Intrafamilial clinical variability has been observed in age at onset and severity of manifestations, including attack frequency, severity, and associated features.
  • Of note, the core PRRT2-related phenotypes (i.e., hemiplegic migraine, paroxysmal kinesigenic dyskinesia [PKD], self-limited [familial] infantile epilepsy, and PKD with infantile convulsions) can be variably observed in family members with the same PRRT2 pathogenic variant (see PRRT2-Related Disorder).
• If the proband has a known ATP1A2, CACNA1A, PRRT2, or SCN1A pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental germline mosaicism [Rahbari et al 2016].
• If the proband does not have a known FHM-related pathogenic variant and both of the proband's parents are clinically unaffected, the risk to the sibs of a proband appears to be low.

Offspring of a proband. Each child of an individual with familial hemiplegic migraine has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the genetic status of the proband's parents. If a parent is affected, the parent's family members are at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being affected.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once an FHM-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The three FHM-related genes identified to date encode ion channels and transporters important in regulating neuronal excitability and cortical synaptic transmission. The observation of seizures and epilepsy in individuals with FHM-causing variants further emphasizes the mechanistic overlap between migraine and epilepsy from dysregulation of cortical excitation/inhibition balance.

Accumulating evidence supports the hypothesis that the electrophysiologic correlate underlying migraine aura is cortical spreading depolarization (CSD) of Leão, which is characterized by a slowly propagating wave 2-6 mm/min of hyperexcitation followed by sustained depression. Mouse models generated from ATP1A2-FHM variants p.Trp887Arg or p.Gly301Arg [Leo et al 2011, Kros et al 2018] and CACNA1A variants p.Arg192Gln and p.Ser218Leu [van den Maagdenberg et al 2004, van den Maagdenberg et al 2010] all demonstrated increased susceptibility to induced CSD from decreased glutamate clearance or increased glutamate release, respectively. A newly generated mouse model with the SCN1A-FHM variant p.Leu263Val demonstrated spontaneous CSD attributed to overall gain of sodium channel function leading to hyperexcitation of GABAergic inhibitory interneurons [Jansen et al 2020].

Mechanism of disease causation

• ATP1A2. The two pathogenic variants found by De Fusco et al [2003], p.Leu764Pro and p.Trp887Arg, cause loss of function of the α2-subunit leading to haploinsufficiency, which appears to be the general rule for ATP1A2-FHM variants. Loss of transporter function would lead to impaired glutamate clearance from the synaptic cleft.
• CACNA1A. There is much clinical overlap between FHM and allelic disorders such as episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6). In general, FHM-causing variants are thought to lead to gain of channel function, while EA-causing variants are commonly truncation variants and are thought to lead to loss of function. Seizures have been associated with manifestations of hemiplegic migraine and episodic ataxia.
• PRRT2. FHM-causing variants are largely truncating variants (c.649dupC is the most common) or whole-gene deletions leading to loss of PRRT2 function with disruption of synaptic neurotransmission [Valente et al 2016] and dysregulation of voltage-gated sodium [Fruscione et al 2018] and calcium channels [Ferrante et al 2021].
• SCN1A. FHM-causing variants generally lead to gain of channel function, which contrasts with loss-of-function variants that account for the vast majority of SCN1A variants causing various epilepsy syndromes including Dravet syndrome.

Author History

Kathy Lou Gardner, MD; University of Pittsburgh (2001-2009)
Joanna C Jen, MD, PhD (2009-present)

Revision History

• 4 July 2024 (sw) Revision: information regarding PRRT2 added
• 29 April 2021 (sw) Comprehensive update posted live
• 14 May 2015 (me) Comprehensive update posted live
• 8 September 2009 (me) Comprehensive update posted live
• 15 March 2004 (me) Comprehensive update posted live
• 17 July 2001 (me) Review posted live
• October 2000 (kg) Original submission

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