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GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Disease characteristics. Familial hemiplegic migraine (FHM) falls within the category of migraine with aura. In migraine with aura, including familial hemiplegic migraine, the neurologic symptoms of aura are unequivocally localizable to the cerebral cortex or brain stem and include visual disturbance (most common), sensory loss (such as numbness or paraesthesias of the face or an extremity), and dysphasia (difficulty with speech); FHM must include motor involvement, i.e., 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. Persistent attention deficit and memory loss can last weeks to months. Cerebral infarction and death have rarely been associated with hemiplegic migraine. Familial hemiplegic migraine is often earlier in onset than typical migraine, frequently beginning in the first or second decade. The frequency of FHM attacks tends to decrease with age. About 40%-50% of families with FHM1 have cerebellar signs ranging from nystagmus to progressive, usually late-onset mild ataxia. The eventual neurologic outcome is often benign in the pure FHM group, although individuals with FHM1 can have progressive cerebellar deficit.
Diagnosis/testing. The diagnosis of FHM rests on clinical findings and family history. The diagnostic criteria are: 1) fulfills criteria for migraine with aura; 2) aura includes some degree of hemiparesis and may be prolonged; 3) at least one first-degree relative (i.e., parent, sib, offspring) has identical attacks. Approximately 50% of families with FHM, including all families with FHM/ataxia, have FHM1, caused by mutations in the CACNA1A gene. Of note, the CAG trinucleotide repeat expansion typical of alleles of individuals with SCA6 (also caused by mutations in CACNA1A) has not been observed in families with FHM1. Molecular testing for mutations in CACNA1A is available on a clinical basis. FHM2 is caused by mutations in ATP1A2 and FHM3 by mutations in SCN1A. Molecular genetic testing of ATP1A2 and SCN1A is available on a research basis only.
Management. Treatment of manifestations: A trial of acetazolamide for individuals with FHM1 or a trial of standard migraine prophylactic drugs (tricyclic antidepressants, beta blockers, calcium channel blockers) for all FHM types may be warranted for frequent attacks.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.
Genetic counseling. Because the diagnosis of FHM requires at least one affected first-degree relative, most individuals diagnosed with familial hemiplegic migraine have an affected parent. The proportion of cases caused by de novo gene mutations is unknown. The risk to the sibs of a proband depends upon the genetic status of the parents. If a parent is affected, the risk is 50%. When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. Every child of an individual with familial hemiplegic migraine has a 50% chance of inheriting the mutation. Prenatal testing may be available through laboratories offering custom prenatal testing. However, requests for prenatal testing for conditions such as FHM are uncommon.
The diagnosis of familial hemiplegic migraine (FHM) relies upon clinical diagnostic criteria. Two sets of criteria have been proposed:
Criteria Adapted from the International Headache Society (1988)
Familial hemiplegic migraine (FHM) is a category of migraine with aura (MA). Diagnostic criteria for FHM:
Fulfills criteria for migraine with aura
Aura includes some degree of hemiparesis and may be prolonged.
At least one first-degree relative (i.e., parent, sib, offspring) has identical attacks.
Migraine with aura (MA) is an idiopathic, 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 (acephalagia). Diagnostic criteria for MA:
At least two episodes characterized by three or more of the following:
One or more aura symptoms are fully reversible, indicating focal cerebral cortical and/or brain stem dysfunction.
At least one aura symptom develops gradually over more than four minutes, or two or more symptoms occur in succession.
No aura symptom lasts more than sixty minutes. If more than one aura symptom is present, duration of symptoms is proportionally increased.
Headache follows aura with a symptom-free interval of less than 60 minutes (headache may also begin before or simultaneously with the aura).
Other classes of headache are ruled out (i.e., head trauma, vascular disorders, nonvascular intracranial disorders, substance use or their withdrawal, noncephalic infection, metabolic disorder, pain associated with other facial or cranial disorders).
Criteria Proposed by Thomsen et al (2002) *
At least two attacks that meet all of the following criteria
Fully reversible symptoms including motor weakness and at least one of the following: visual, sensory or speech disturbance
At least two of the following:
At least one aura symptom develops gradually over at least five minutes or symptoms occur in succession.
Each aura symptom lasts less than 24 hours.
Some degree of headache is associated with the aura.
Not attributed to another disorder
At least one first- or second-degree relative with migraine aura including motor weakness and fulfilling all of the above criteria
* Based on findings in 147 affected individuals from 44 families
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genes. Three genes are associated with familial hemiplegic migraine:
CACNA1A, associated with familial hemiplegic migraine type 1 (FHM1)
ATP1A2, associated with familial hemiplegic migraine type 2 (FHM2) [DeFusco et al 2003]
SCN1A, associated with familial hemiplegic migraine type 3 (FHM3) [Dichgans, Freilinger et al 2005]
Clinical uses
Confirmatory diagnostic testing
Clinical testing
Sequence analysis. Approximately 50% of families with FHM1 have an identifiable CACNA1A mutation. More than 90% of families with FHM/ataxia (defined as the presence of nystagmus or other cerebellar signs) [Joutel et al 1993, Ducros et al 2000] have a CACNA1A mutation. Approximately 30% of families with hemiplegic migraine without ataxia have a CACNA1A mutation.
Research testing
Direct DNA analysis. Molecular genetic testing for ATP1A2 and SCN1A is available on a research basis only.
Table 1 summarizes molecular genetic testing for this disorder.
| Locus Name | Test Method | Mutations Detected | Mutation Detection Rate | Test Availability |
|---|---|---|---|---|
| FHM1 | Sequence analysis | CACNA1A sequence variants | 50% of families with a clinical diagnosis of FHM | Clinical
 |
| >90% of families with hemiplegic migraine and ataxia | ||||
| ~30% of families with hemiplegic migraine without ataxia | ||||
| FHM2 | Direct DNA 1 | ATP1A2 sequence variants | Unknown | Research only |
| FHM3 | SCN1A sequence variants |
1. Direct DNA methods may include targeted mutation analysis, mutation scanning, sequence analysis, or other means of molecular genetic testing to detect a genetic alteration associated with FHM2 or FHM3.
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
CACNA1A. Two other phenotypes are associated with different kinds of mutations in CACNA1A :
Episodic ataxia type 2 (EA2) involving episodes of ataxia and sometimes migrainous headache with interictal nystagmus associated with predominantly truncating mutations [Vahedi et al 1995, Ophoff et al 1996].
Spinocerebellar ataxia type 6 (SCA6) with late-onset progressive ataxia associated with CAG trinucleotide repeat expansion [Zhuchenko et al 1997]. Of note, the CAG trinucleotide repeat expansion typical of SCA6 has not been observed in families with FHM [Carrera et al 1999, Ducros et al 1999]; however, some individuals with SCA6 may have migraine.
Overlap has been described between FHM1 (associated with missense mutations), SCA6, and EA2, but especially between EA2 and SCA6. One family with a CAG trinucleotide repeat expansion characteristically observed in individuals with SCA6 had purely episodic ataxia and another family with a CAG repeat expansion had some members with episodic ataxia and others with progressive ataxia [Jodice et al 1997]. In one family with EA2, affected members experienced hemiplegia; one family member had migraine during episodes of ataxia [Jen 1999]. In one large family with a CACNA1A mutation, some individuals had only HM, some had only ataxia, and some had both [Alonso et al 2003].
SCN1A. The phenotypic spectrum associated with SCN1A-related seizures disorders includes the following:
Simple febrile seizures
Generalized epilepsy with febrile seizures plus (GEFS+)
Severe myoclonic epilepsy in infancy (SMEI)
Intractable childhood epilepsy with generalized tonic-clonic seizures (ICEGTC)
In migraine with aura, including familial hemiplegic migraine, the neurologic symptoms of aura are unequivocally localizable to the cerebral cortex or brain stem and include visual disturbance (most common), sensory loss (such as numbness or paraesthesias of the face or an extremity), and dysphasia (difficulty with speech), and for FHM must include motor involvement, i.e., hemiparesis (weakness of an extremity) [Thomsen et al 2002].
Visual disturbances can include scotoma (blind spots), photopsia (flashing lights), fortification spectra (zigzag pattern), and diplopia.
Dysphasia usually occurs when hemiplegia is right-sided.
Hemiparesis occurs with at least one other symptom during FHM aura [Ducros et al 2000].
Note: Recent family studies found that about 10% of family members with a CACNL1A4 mutation do not have hemiplegic attacks but often have migraine with or without aura [Ducros et al 2001].
Some confusion and/or drowsiness may be present even without dysphasia. Impaired consciousness ranging from drowsiness to coma is well described in FHM [Whitty 1971, Fitzsimons & Wolfenden 1985, Munte & Muller-Vahl 1990, 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 FHM1 and ataxia [Spranger et al 1999].
Neurologic deficits with FHM 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 [Whitty 1953, Kors 2003]. Permanent motor, sensory, language, or visual symptoms are extremely rare [Ducros et al 2001].
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 [Holub et al 1965] (see Differential Diagnosis).
Familial hemiplegic migraine is often earlier in onset than typical migraine, frequently beginning in the first or second decade [Whitty 1986, Terwindt et al 1996]. In the report of Ducros et al (2001), the attacks started at a young age in the majority of subjects (mean: 11.7 ±8 years; range: 1-51 years). The natural history was variable. The frequency of attacks ranged from one per day to fewer than five in a lifetime (mean: 2-3/year). Long attack-free intervals were often reported (range: 2-37 years). The frequency of FHM attacks tends to decrease with age. The eventual neurologic outcome is often benign in the pure FHM group, although FHM1 can have progressive cerebellar deficit.
FHM attacks may be provoked by typical migraine triggers (e.g., foods, odors, exertion, stress), minor head trauma [Haas & Sovner 1969, Mathews 1972, Sandyk 1983, Terwindt et al 1996, Gardner et al 1997], and cerebral angiography [Symonds 1952, Whitty 1953, Glista et al 1975, Jensen et al 1981].
Among families with hemiplegic migraine, the major significant clinical differences are presence or absence of cerebellar signs ranging from nystagmus to progressive, usually late-onset mild ataxia, which occurs in up to 40%-50% of families with FHM1 [Terwindt et al 1996, Ducros et al 2000]; within such families, up to 60% of affected individuals have permanent cerebellar signs [Ducros et al 2001].
Seizures during severe attacks have been reported in some families with FHM2 [Ducros et al 1997] along with recurrent coma in one individual [Echenne et al 1999]. Focal seizures during severe attacks have been described in two individuals with FHM1 who have no family history of FHM1 [Chabriat et al 2000], including one with severe mental retardation, congenital ataxia, and early cerebellar atrophy [Vahedi et al 2000].
The only abnormalities observed on traditional imaging studies are vermian cerebellar atrophy in some families with FHM1 [Haan et al 1994, Battistini et al 1999]. Rare exceptions include transient diffusion-weighted signal changes on head MRI suggesting cytotoxic edema during severe prolonged attacks in individuals with FHM1 [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 (MRS) have been reported [Dichgans, Herzog et al 2005].
CACNA1A. Although further correlation is needed, some suggestive genotype-phenotype correlations exist based on limited data regarding CACNA1A mutations.
The mutations R192Q [Ophoff et al 1996] and V1457L [Carrera et al 1999] are associated with hemiplegic attacks only, but unconsciousness occurs commonly during attacks with mutation V714A [Terwindt et al 1998].
The mutations T666M, I1811L [Ophoff et al 1996], R583E [Alonso et al 2003], and D715E [Ducros et al 1999] have been associated with hemiplegic attacks plus ataxia. In the Ducros et al (2001) study, T666M was associated with the highest frequency of hemiplegic migraine, severe attacks of coma, and nystagmus. During attacks, unconsciousness sometimes occurs in individuals with the T666M and I1811L mutations [Terwindt et al 1998]. Kors et al (2003) reported a family with the T666M mutation and progressive cognitive dysfunction.
The mutation R528Q [Battistini et al 1999, Ducros et al 2001] can be associated with stupor, fever, and progressive ataxia. Affected individuals were thought to have fewer attacks after treatment with acetazolamide.
The mutation D715E has the lowest frequency (64%) of attacks of hemiplegic migraine [Ducros et al 2001].
The mutations Y1384C [Chabriat et al 2000] and T1385C [Vahedi et al 2000], each identified in a single individual with no known family history of FHM, have been associated with prolonged severe attacks including focal seizures, coma, fever, and CSF neutrophilic pleocytosis. Cerebral hemispheric and cerebellar atrophy are seen on imaging studies with MRI signal changes during attacks. Additionally, the single individual with mutation T1385C had otherwise unexplained severe mental retardation, developmental delay, and congenital or early-onset ataxia.
The mutation S218L has been associated with delayed cerebral edema and fatal coma after minor head trauma [Kors et al 2001].
ATP1A2. A severe phenotype with seizures, coma, and elevated temperature has been reported with a G301R mutation in the ATP1A2 gene [Spadaro et al 2004].
A severe phenotype with seizures and mental retardation has been reported with the mutations D718N and P979L [Jurkat-Rott et al 2004].
Although families with FHM in which attacks are strikingly identical do exist, the term familial hemiplegic migraine 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 [IHS 1988].
Rare families with multiple members experiencing hemiplegic migraine are most characteristic of FHM, and reflect the autosomal dominant inheritance and high penetrance of the disorder.
In Denmark, Lykke 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 sporadic cases.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Migraine without aura. Migraine without aura (MO or MOA) (common migraine) is an idiopathic, recurring headache disorder manifesting in attacks lasting four to 72 hours. Typical characteristics of the headache are unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity, and association with nausea, photophobia, and phonophobia [IHS 1988]. This headache occurs without neurologic aura symptoms and specifically without hemiparesis. Typical migraine is thought to be genetically complex and to have undefined environmental components. A clinical distinction between familial and nonfamilial cases has long been entertained [Whitty 1986], beginning with the first report of FHM by JM Clark (1910). Wieser et al (2003) found no mutations in CACNA1A in individuals with common migraine. Some families having migraine without aura have shown linkage to 4q21 [Bjornsson et al 2003] and 14q21.2-q22.3 [Soragna et al 2003]. One family having migraine with or without aura showed linkage to 6p12.2-p21.1 [Carlsson et al 2002].
Migraine with aura. Brugnoni et al (2002)found no CACNA1A mutations in individuals with familial migraine with aura. Some families having migraine with aura show linkage to 4q24 [Wessman et al 2002].
"Sporadic" hemiplegic migraine (SHM). "Sporadic" hemiplegic migraine refers to simplex cases (i.e., affected individuals with no relatives with hemiplegic migraine). Such individuals may or may not have other family members with typical migraine. To investigate the genetic basis of hemiplegic migraine in simplex cases, Terwindt et al (2003) evaluated 27 individuals who had no family history of hemiplegic migraine and found a mutation in CACNA1A in two, one of whom had ataxia, nystagmus, and cerebellar atrophy on cranial CT; the other did not.
Other inherited disorders associated with migrainous headache that may include hemiplegic aura:
MELAS, MERRF, and other mitochondrial disorders. MELAS is a multisystem disorder with onset typically between the ages of two and ten years. The most common initial symptoms are generalized tonic-clonic seizures, recurrent headaches, anorexia, and recurrent vomiting. Seizures are often associated with stroke-like episodes of transient hemiparesis or cortical blindness, which may be associated with altered consciousness and may be recurrent. The cumulative residual effects of the stroke-like episodes gradually impair motor abilities, vision, and mentation, often by adolescence or young adulthood. Sensorineural hearing loss is common. The most common mitochondrial DNA (mtDNA) mutation, present in over 80% of individuals with typical clinical findings, is an A-to-G transition at nucleotide-3243 in the tRNALeu(UUR) of mtDNA.
CADASIL. CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, is characterized by history of migraine headaches, mid-adult (30s-60s) onset of cerebrovascular disease progressing to dementia, and diffuse white matter deficits on neuroimaging. One family with CADASIL was reported to have hemiparetic aura [Hutchinson et al 1995]. The pathologic hallmark of CADASIL is electron-dense granules in the media of arterioles that can often be identified by electron microscopic (EM) evaluation of skin biopsies. More than 90% of individuals have mutations in the NOTCH3 gene.
Hereditary hemorrhagic telangiectasia (HHT). HHT results from the presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins. Small AVMs, or telangiectases, close to the surface of skin and mucous membranes often rupture and bleed after slight trauma. The most common clinical manifestation is spontaneous and recurrent nosebleeding beginning at approximately 12 years of age. Large AVMs often cause symptoms when they occur in brain, lung, or the gastrointestinal tract; complications from bleeding or shunting may be sudden and catastrophic. Migraine with aura has been reported in 50% of affected individuals [Steele et al 1993]. HHT is caused by a mutation either in the endoglin gene ENG or the activin receptor gene ACVRL1. Inheritance is autosomal dominant.
Essential tremor. Familial progressive kinetic and postural tremor usually involves the upper extremities and head and sometimes the voice. It has been mapped to3q13 [ Gulcher et al 1997] and 2p22-p25 [Higgins et al 1997]. Autosomal dominant inheritance may be present in some families and has been associated with migraine in one study [Bain et al 1994].
Familial cerebral cavernous malformation (CCM). CCMs are vascular malformations consisting of closely clustered enlarged capillary channels (caverns) with a single layer of endothelium without normal intervening brain parenchyma or mature vessel wall elements. CCMs have been reported in infants and children, but the majority of individuals present with symptoms between the second and fifth decades. Approximately 50%-75% of persons with CCM have symptoms, including seizures, focal neurologic deficits, nonspecific headaches, and cerebral hemorrhage. Up to 25% of individuals with CCM remain symptom free throughout their lives. The three genes associated with familial CCM are KRIT1, CCM2, and CCM3. A single mutation in the KRIT1 gene (1363C>T) has been identified in about 70% of Hispanic families. Inheritance is autosomal dominant.
Dutch form of hereditary cerebral amyloid angiopathy. Associated with onset of cerebral and cerebellar hemorrhage by the fourth or fifth decade, this autosomal dominant disorder is often preceded by migraine [Wattendorff et al 1982]. Senile plaques and vascular wall amyloid are found in the brain in association with amino acid changes in the APP beta amyloid precursor protein, a protease inhibitor [Levy et al 1990].
Hemiplegia. The differential diagnosis of hemiplegia includes post-ictal weakness following seizure, transient ischemic attack (TIA), stroke, and other nongenetic causes of transient hemiparesis.
Stroke. When family history is positive for hemiparetic attacks with migraine, the presence of infarct on imaging studies raises the possibility of other inherited disorders such as MELAS, CADASIL, or thrombophilia, such as factor V Leiden [Gaustadnes et al 1999]. Additional stroke risk factors may also be present.
Caution: Even with normal imaging studies and description of spreading aura, an age-appropriate stroke evaluation should be considered at presentation. Overlap in clinical features, inaccuracies of historical family information, rarity of true familial hemiplegic migraine, and the seriousness of stroke-related disorders warrant this cautious approach. Stroke or other CNS-related disorders should be even more strongly considered if family history is negative for hemiplegic migraine.
A trial of acetazolamide [Athwal & Lennox 1996] for individuals with FHM1 or a trial of standard migraine prophylactic drugs (tricyclic antidepressants, beta blockers, calcium channel blockers) for all FHM types may be warranted for frequent attacks [Glista et al 1975, Zifkin et al 1980, Lai et al 1982, Gardner et al 1997]. Limited correlation exists between drug response and hemiplegic migraine type.
In general, vasoconstricting agents should be avoided because of the risk of stroke [Whitty 1953, Rosenbaum 1960, Bradshaw & Parsons 1965, Cohen & Taylor 1979, Solomon & Spaccavento 1982].
Cerebral angiography is hazardous as it may precipitate a severe attack [Blau & Whitty 1955, Chabriat et al 2000].
In a single case report, general anesthesia on second occasion precipitated an atypical attack. [Thurlow 1998].
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Familial hemiplegic migraine is inherited in an autosomal dominant manner.
Parents of a proband
Because the diagnosis of FHM requires at least one affected first-degree relative, most individuals diagnosed with familial hemiplegic migraine have an affected parent.
The proportion of cases caused by de novo gene mutations is unknown but probably low, although only limited data for FHM1 have been reported [Carrera et al 1999, Ducros et al 1999].
Recommendations for the evaluation of parents of an individual with an apparent de novo mutation include clinical interview, neurologic examination, and molecular genetic testing if the disease-causing mutation has been identified in the proband.
Sibs of a proband
The risk to the sibs of a proband depends upon the genetic status of the parents.
If a parent of the proband is affected, the risk to the sibs is 50%.
When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
If the proband's disease-causing mutation cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.
Offspring of a proband. Each child of an individual with familial hemiplegic migraine has a 50% chance of inheriting the mutation.
Other family members of a proband. The risk to other family members depends upon the genetic status of the proband's parents. If a parent is found to be affected, his or her family members are at risk.
Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible nonmedical explanations including alternate paternity or undisclosed adoption could also be explored.
Family planning. The optimal time for determination of genetic risk is before pregnancy.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which molecular genetic testing is available on a research basis only or the sensitivity of currently available testing is less than 100%. See DNA banking for a list of laboratories offering this service.
No laboratories offering molecular genetic testing for prenatal diagnosis for FHM are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutation has been identified in an affected family member in a research or clinical laboratory. For laboratories offering custom prenatal testing, see
.
Requests for prenatal testing for conditions such as FHM that do not affect intellect or life span are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, careful discussion of these issues is appropriate.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering PGD, see
.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
| Locus Name | Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|---|
| FHM1 | CACNA1A | 19p13 | Voltage-dependent P/Q-type calcium channel subunit alpha-1A |
| FHM2 | ATP1A2 | 1q21-q23 | Sodium/potassium-transporting ATPase alpha-2 chain |
| FHM3 | SCN1A | 2q24 | Sodium channel protein type 1 subunit alpha |
Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
| 141500 | MIGRAINE, FAMILIAL HEMIPLEGIC, 1; FHM1 |
| 182340 | ATPase, Na+/K+ TRANSPORTING, ALPHA-2 POLYPEPTIDE; ATP1A2 |
| 182389 | SODIUM CHANNEL, NEURONAL TYPE I, ALPHA SUBUNIT; SCN1A |
| 601011 | CALCIUM CHANNEL, VOLTAGE-DEPENDENT, P/Q TYPE, ALPHA-1A SUBUNIT; CACNA1A |
| 602481 | MIGRAINE, FAMILIAL HEMIPLEGIC, 2; FHM2 |
| 609634 | MIGRAINE, FAMILIAL HEMIPLEGIC, 3; FHM3 |
| Gene Symbol | Entrez Gene | HGMD |
|---|---|---|
| CACNA1A | 773 (MIM No. 601011) | CACNA1A |
| ATP1A2 | 477 (MIM No. 602481) | ATP1A2 |
| SCN1A | 6323 (MIM No. 182389) | SCN1A |
For a description of the genomic databases listed, click here.
CACNA1A
Normal allelic variants: 47 exons; 300 kb
Pathologic allelic variants: T666M is the most common mutation, with no evidence for founder effect [Ducros et al 1999].
Normal gene product: The gene encodes the alpha-1 subunit of a neural voltage-dependent P/Q-type calcium channel. The alpha-1 subunit forms the pore of the calcium channel.
Abnormal gene product: Mutations affect the pore or the voltage sensor parts of the ion channel. Tottene et al (2002) found that mutational changes of functional channel densities can be different in different cell types, and identified two functional effects common to all FHM mutations analyzed: increase of single-channnel Ca2+ influx and decrease of maximal Ca(V)2.1 current density in neurons.
ATP1A2
Pathologic allelic variants: L764P, W887R [De Fusco et al 2003]; M731T, R689Q [VanMolkot et al 2003].
Normal gene product: A heterodimeric protein with 10 transmembrane domains with a large catalytic αsubunit and a smaller ancillary βsubunit. The pump exchanges intracellular Na+ for extracellular K+.
Abnormal gene product: The two mutations found by De Fusco et al (2003) cause loss of function of the α2 subunit.
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
Migraine Awareness Group: A National Understanding for Migraineurs (MAGNUM)
113 S Saint Asaph Street Suite 100
Alexandria VA 22314
Phone: 703-739-9384
Fax: 703-739-2432
Email: comments@migraines.org
www.migraines.org
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
4 January 2007 (cd) Revision: mutations in SCN1A associated with familial hemiplegic migraine type 3
14 December 2004 (cd) Revision: sequence analysis of CACNA1A clinically available
15 March 2004 (me) Comprehensive update posted to live Web site
30 December 2003 (cd) Revision: change in test availability
3 October 2002 (kg) Author revisions
16 September 2002 (kg) Author revisions
17 July 2001 (me) Review posted to live Web site
October 2000 (kg) Original submission
