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Familial hemiplegic migraine type 1(FHM1)

MedGen UID:
331388
Concept ID:
C1832884
Disease or Syndrome
Synonyms: FHM1; Migraine, familial hemiplegic 1, with progressive cerebellar ataxia
Modes of inheritance:
Heterogeneous
MedGen UID:
67020
Concept ID:
C0242960
Organism Attribute
Source: HPO
The presence of apparently similar characters for which the genetic evidence indicates that different genes or different genetic mechanisms are involved in different pedigrees. In clinical settings genetic heterogeneity refers to the presence of a variety of genetic defects which cause the same disease, often due to mutations at different loci on the same gene, a finding common to many human diseases including ALZHEIMER DISEASE; CYSTIC FIBROSIS; LIPOPROTEIN LIPASE DEFICIENCY, FAMILIAL; and POLYCYSTIC KIDNEY DISEASES. (Rieger, et al., Glossary of Genetics: Classical and Molecular, 5th ed; Segen, Dictionary of Modern Medicine, 1992)
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
 
Gene (location): CACNA1A (19p13.13)
OMIM®: 141500

Disease characteristics

Excerpted from the GeneReview: Familial Hemiplegic Migraine
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 (e.g., numbness or paresthesias 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. 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 FHM1 have cerebellar signs ranging from nystagmus to progressive, usually late-onset mild ataxia. Cerebral infarction and death have rarely been associated with hemiplegic migraine. [from GeneReviews]
Authors:
Joanna C Jen   view full author information

Additional description

From GHR
Familial hemiplegic migraine is a form of migraine headache that runs in families. Migraines usually cause intense, throbbing pain in one area of the head, often accompanied by nausea, vomiting, and extreme sensitivity to light and sound. These recurrent headaches typically begin in childhood or adolescence and can be triggered by certain foods, emotional stress, and minor head trauma. Each headache may last from a few hours to a few days.In some types of migraine, including familial hemiplegic migraine, a pattern of neurological symptoms called an aura precedes the headache. The most common symptoms associated with an aura are temporary visual changes such as blind spots (scotomas), flashing lights, zig-zagging lines, and double vision. In people with familial hemiplegic migraine, auras are also characterized by temporary numbness or weakness, often affecting one side of the body (hemiparesis). Additional features of an aura can include difficulty with speech, confusion, and drowsiness. An aura typically develops gradually over a few minutes and lasts about an hour.Unusually severe migraine episodes have been reported in some people with familial hemiplegic migraine. These episodes have included fever, seizures, prolonged weakness, coma, and, rarely, death. Although most people with familial hemiplegic migraine recover completely between episodes, neurological symptoms such as memory loss and problems with attention can last for weeks or months. About 20 percent of people with this condition develop mild but permanent difficulty coordinating movements (ataxia), which may worsen with time, and rapid, involuntary eye movements called nystagmus.  https://ghr.nlm.nih.gov/condition/familial-hemiplegic-migraine

Clinical features

From HPO
Anxiety
MedGen UID:
1613
Concept ID:
C0003467
Finding
Apprehension of danger and dread accompanied by restlessness, tension, tachycardia, and dyspnea unattached to a clearly identifiable stimulus.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- oder overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Coma
MedGen UID:
1054
Concept ID:
C0009421
Disease or Syndrome
A profound state of unconsciousness associated with depressed cerebral activity from which the individual cannot be aroused. Coma generally occurs when there is dysfunction or injury involving both cerebral hemispheres or the brain stem RETICULAR FORMATION.
Confusion
MedGen UID:
3587
Concept ID:
C0009676
Mental or Behavioral Dysfunction
A mental state characterized by a lack of clear and orderly thought and behavior.
Drowsiness
MedGen UID:
4390
Concept ID:
C0013144
Finding
Excessive daytime sleepiness.
Hemiparesis
MedGen UID:
6783
Concept ID:
C0018989
Finding
Loss of strength in the arm, leg, and sometimes face on one side of the body. Hemiplegia refers to a complete loss of strength, whereas hemiparesis refers to an incomplete loss of strength.
Hemiplegia
MedGen UID:
9196
Concept ID:
C0018991
Sign or Symptom
Paralysis (complete loss of muscle function) in the arm, leg, and in some cases the face on one side of the body.
Psychosis
MedGen UID:
19568
Concept ID:
C0033975
Mental or Behavioral Dysfunction
A mental disorder characterized by personality change, impaired functioning, and loss of touch with reality.
Seizures
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as EPILEPSY or "seizure disorder."
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
Agitation
MedGen UID:
88447
Concept ID:
C0085631
Sign or Symptom
A state of exceeding restlessness and excessive motor activity associated with mental distress or a feeling of inner tension.
Migraine with aura
MedGen UID:
57822
Concept ID:
C0154723
Disease or Syndrome
A migraine disorder characterized by episodes that are preceded by focal neurological symptoms.
Auditory hallucinations
MedGen UID:
115932
Concept ID:
C0233762
Sign or Symptom
Perception of sound in the absence of a corresponding stimulus.
Visual hallucinations
MedGen UID:
66688
Concept ID:
C0233763
Sign or Symptom
Optical perception of an object, person or event in the absence of a corresponding stimulus.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Atrophy (wasting) of the cerebellum.
Dysphasia
MedGen UID:
242346
Concept ID:
C0973461
Disease or Syndrome
Impairment of verbal communication skills, often resulting from brain damage.
Dyscalculia
MedGen UID:
278061
Concept ID:
C1411876
Mental or Behavioral Dysfunction
A specific learning disability involving mathematics and arithmetic.
Migraine
MedGen UID:
854348
Concept ID:
C3887485
Finding
Migraine is the most common type of chronic, episodic headache, as summarized by Featherstone (1985). One locus for migraine with or without aura (MGR1) has been identified on chromosome 4q24. Other loci for migraine have been identified on 6p21.1-p12.2 (MGR3; 607498), 14q21.2-q22.3 (MGR4; 607501), 19p13 (MGR5; 607508), 1q31 (MGR6; 607516), 15q11-q13 (MGR7; 609179), 5q21 (with or without aura, MGR8, 609570; with aura, MGR9, 609670), 17p13 (MGR10; 610208), 18q12 (MGR11; 610209), 10q22-q23 (MGR12; 611706), and the X chromosome (MGR2; 300125). Mutation in the KCNK18 gene (613655) on chromosome 10q25 causes migraine with aura (MGR13; 613656). A subtype of autosomal dominant migraine with aura (MA), familial hemiplegic migraine (FHM; see 141500), is caused by mutation in the CACNA1A gene (601011) on chromosome 19p13 (FHM1; 141500), by mutation in the ATP1A2 gene (182340) on chromosome 1q21 (FHM2; 602481), or by mutation in the SCN1A gene (182389) on chromosome 2q24 (FHM3; 609634). Another locus for FHM has been mapped to chromosome 1q31 (FHM4; see 607516). There is evidence that a polymorphism in the estrogen receptor gene (ESR1; 133430.0005) and a polymorphism in the TNF gene (191160.0004) may confer susceptibility to migraine. A polymorphism in the endothelin receptor type A gene (EDNRA; 131243.0001) may confer resistance to migraine.
Fever
MedGen UID:
5169
Concept ID:
C0015967
Sign or Symptom
A condition characterized by an abnormally high body temperature. In a hyperthermic state, the hypothalamic set-point is normal but body temperature increases and overrides the ability to lose heat, resulting from exogenous heat exposure or endogenous heat production.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Involuntary movements of the eye that are divided into two types, jerk and pendular. Jerk nystagmus has a slow phase in one direction followed by a corrective fast phase in the opposite direction, and is usually caused by central or peripheral vestibular dysfunction. Pendular nystagmus features oscillations that are of equal velocity in both directions and this condition is often associated with visual loss early in life. (Adams et al., Principles of Neurology, 6th ed, p272)
Transient unilateral blurring of vision
MedGen UID:
356249
Concept ID:
C1865332
Finding
Transient blurring of vision associated with the aura phase of migraine.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  

Professional guidelines

PubMed

Burgunder JM, Finsterer J, Szolnoki Z, Fontaine B, Baets J, Van Broeckhoven C, Di Donato S, De Jonghe P, Lynch T, Mariotti C, Schöls L, Spinazzola A, Tabrizi SJ, Tallaksen C, Zeviani M, Harbo HF, Gasser T; EFNS.
Eur J Neurol 2010 May;17(5):641-8. Epub 2010 Mar 9 doi: 10.1111/j.1468-1331.2010.02985.x. PMID: 20298421

External

Orphanet, Hemiplegic Migraine (HM), 2013

Recent clinical studies

Etiology

Yemisci M, Eikermann-Haerter K
J Headache Pain 2019 May 29;20(1):63. doi: 10.1186/s10194-019-1016-x. PMID: 31142262Free PMC Article
Indelicato E, Nachbauer W, Karner E, Eigentler A, Wagner M, Unterberger I, Poewe W, Delazer M, Boesch S
Eur J Neurol 2019 Jan;26(1):66-e7. Epub 2018 Sep 3 doi: 10.1111/ene.13765. PMID: 30063100
Indelicato E, Nachbauer W, Eigentler A, Donnemiller E, Wagner M, Unterberger I, Boesch S
Cephalalgia 2018 May;38(6):1167-1176. Epub 2017 Aug 31 doi: 10.1177/0333102417715229. PMID: 28856914
Ambrosini A, D'Onofrio M, Buzzi MG, Arisi I, Grieco GS, Pierelli F, Santorelli FM, Schoenen J
Headache 2017 Jul;57(7):1136-1144. Epub 2017 Jun 1 doi: 10.1111/head.13107. PMID: 28573794
Koppen H, Boele HJ, Palm-Meinders IH, Koutstaal BJ, Horlings CG, Koekkoek BK, van der Geest J, Smit AE, van Buchem MA, Launer LJ, Terwindt GM, Bloem BR, Kruit MC, Ferrari MD, De Zeeuw CI
Cephalalgia 2017 Feb;37(2):177-190. Epub 2016 Jul 11 doi: 10.1177/0333102416643527. PMID: 27059879Free PMC Article

Diagnosis

Yemisci M, Eikermann-Haerter K
J Headache Pain 2019 May 29;20(1):63. doi: 10.1186/s10194-019-1016-x. PMID: 31142262Free PMC Article
Indelicato E, Nachbauer W, Karner E, Eigentler A, Wagner M, Unterberger I, Poewe W, Delazer M, Boesch S
Eur J Neurol 2019 Jan;26(1):66-e7. Epub 2018 Sep 3 doi: 10.1111/ene.13765. PMID: 30063100
Koppen H, Boele HJ, Palm-Meinders IH, Koutstaal BJ, Horlings CG, Koekkoek BK, van der Geest J, Smit AE, van Buchem MA, Launer LJ, Terwindt GM, Bloem BR, Kruit MC, Ferrari MD, De Zeeuw CI
Cephalalgia 2017 Feb;37(2):177-190. Epub 2016 Jul 11 doi: 10.1177/0333102416643527. PMID: 27059879Free PMC Article
Reinson K, Õiglane-Shlik E, Talvik I, Vaher U, Õunapuu A, Ennok M, Teek R, Pajusalu S, Murumets Ü, Tomberg T, Puusepp S, Piirsoo A, Reimand T, Õunap K
Am J Med Genet A 2016 Aug;170(8):2173-6. Epub 2016 Jun 2 doi: 10.1002/ajmg.a.37678. PMID: 27250579
Tashiro Y, Yamazaki T, Nagamine S, Mizuno Y, Yoshiki A, Okamoto K
Intern Med 2014;53(19):2245-50. doi: 10.2169/internalmedicine.53.0295. PMID: 25274239

Therapy

Asghar SJ, Milesi-Hallé A, Kaushik C, Glasier C, Sharp GB
Pediatr Neurol 2012 Sep;47(3):201-4. doi: 10.1016/j.pediatrneurol.2012.05.006. PMID: 22883286
Hansen JM, Thomsen LL, Olesen J, Ashina M
Cephalalgia 2008 May;28(5):496-505. Epub 2008 Mar 31 doi: 10.1111/j.1468-2982.2008.01559.x. PMID: 18384418
Cricchi F, Di Lorenzo C, Grieco GS, Rengo C, Cardinale A, Racaniello M, Santorelli FM, Nappi G, Pierelli F, Casali C
J Neurol Sci 2007 Mar 15;254(1-2):69-71. Epub 2007 Feb 12 doi: 10.1016/j.jns.2007.01.008. PMID: 17292920

Prognosis

Indelicato E, Nachbauer W, Eigentler A, Donnemiller E, Wagner M, Unterberger I, Boesch S
Cephalalgia 2018 May;38(6):1167-1176. Epub 2017 Aug 31 doi: 10.1177/0333102417715229. PMID: 28856914
Inchauspe CG, Urbano FJ, Di Guilmi MN, Forsythe ID, Ferrari MD, van den Maagdenberg AM, Uchitel OD
J Neurophysiol 2010 Jul;104(1):291-9. Epub 2010 May 19 doi: 10.1152/jn.00034.2010. PMID: 20484531Free PMC Article
Müllner C, Broos LA, van den Maagdenberg AM, Striessnig J
J Biol Chem 2004 Dec 10;279(50):51844-50. Epub 2004 Sep 23 doi: 10.1074/jbc.M408756200. PMID: 15448138
Cao YQ, Piedras-Rentería ES, Smith GB, Chen G, Harata NC, Tsien RW
Neuron 2004 Aug 5;43(3):387-400. doi: 10.1016/j.neuron.2004.07.014. PMID: 15294146

Clinical prediction guides

Franceschini A, Vilotti S, Ferrari MD, van den Maagdenberg AM, Nistri A, Fabbretti E
PLoS One 2013;8(1):e52394. Epub 2013 Jan 11 doi: 10.1371/journal.pone.0052394. PMID: 23326332Free PMC Article
Eikermann-Haerter K, Dileköz E, Kudo C, Savitz SI, Waeber C, Baum MJ, Ferrari MD, van den Maagdenberg AM, Moskowitz MA, Ayata C
J Clin Invest 2009 Jan;119(1):99-109. Epub 2008 Dec 22 doi: 10.1172/JCI36059. PMID: 19104150Free PMC Article
Barrett CF, Cao YQ, Tsien RW
J Biol Chem 2005 Jun 24;280(25):24064-71. Epub 2005 Mar 28 doi: 10.1074/jbc.M502223200. PMID: 15795222
Dichgans M, Herzog J, Freilinger T, Wilke M, Auer DP
Neurology 2005 Feb 22;64(4):608-13. doi: 10.1212/01.WNL.0000151855.98318.50. PMID: 15728280
Müllner C, Broos LA, van den Maagdenberg AM, Striessnig J
J Biol Chem 2004 Dec 10;279(50):51844-50. Epub 2004 Sep 23 doi: 10.1074/jbc.M408756200. PMID: 15448138

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