Familial hemiplegic migraine
Encyclopedia
Familial hemiplegic migraine (FHM) is an autosomal dominant classical migraine
subtype that typically includes hemiparesis
(weakness of half the body) during the aura
phase. It can be accompanied by other symptoms, such as ataxia
, coma
and epileptic seizure
s. There is clinical overlap in some FHM patients with episodic ataxia
type 2 and spinocerebellar ataxia
type 6, benign familial infantile convulsion
s, and alternating hemiplegia of childhood
. There are 3 known loci
for FHM. FHM1, which accounts for approximately 50% of FHM patients, is caused by mutations in a gene coding for the P/Q-type calcium channel
α subunit, CACNA1A. FHM1 is also associated with cerebellar degeneration. FHM2, which accounts for <25% of FHM cases, is caused by mutations in the Na+/K+-ATPase
gene ATP1A2. FHM3 is a rare subtype of FHM and is caused by mutations in a sodium channel α-subunit coding gene, SCNA1. These three subtypes do not account for all cases of FHM, suggesting the existence of at least one other locus (FHM4). Many of the non-familial cases of hemiplegic migraine (sporadic hemiplegic migraine) are also caused by mutations at these loci.
, sometimes episodic and other times progressive, that can accompany FHM1 mutations and is caused by degeneration of the cerebellum
. These cerebellar signs result in a phenotypic
overlap between FHM and both episodic ataxia
and spinocerebellar ataxia
. This is unsurprising as subtypes of these disorders (FHM1, EA2 and SCA6) are allelic, i.e., they result from mutations in the same gene. The other forms of FHM seem to be distinguishable only on the basis of their genetic cause.
There are also non-familial cases of hemiplegic migraine, termed sporadic hemiplegic migraine. These cases seem to have the same causes as the familial cases and represent de novo mutations. Sporadic cases are also clinically identical to familial cases with the exception of a lack of family history of attacks.
and, in FHM1, cerebellar
degeneration. This cerebellar degeneration can result in episodic or progressive ataxia
. FHM can also present with the same signs as benign familial infantile convulsion
s (BFIC) and alternating hemiplegia of childhood
. Other symptoms are altered consciousness (in fact, some cases seem related to head trauma), gaze-evoked nystagmus and coma
. Aura symptoms, such as numbness and blurring of vision, typically persist for 30–60 minutes. These signs typically first manifest themselves in the first or second decade of life.
It is believed that FHM mutations lead to migraine susceptibility by lowering the threshold for cortical-spreading-depression generation. The FHM1 and FHM3 mutations are occur in ion channel
s expressed in neuron
s. These mutations may lead to both the hyper and hypoexcitable neurons that might underlie cortical-spreading-depression. It is even less clear how the mutations seen in FHM2 patients might lead to FHM symptoms as the gene mutated in FHM2 is expressed primarily in astrocyte
s. One proposal states that the depolarization of astrocytes caused by haploinsufficiency
of the ATP1A2 Na+/K+-ATPase
causes increased release of compounds such as adenosine from astrocytes. These compounds then interact with neighboring neurons, altering their excitability and leading to cortical-spreading-depression and migraine.
Sporadic forms follow the same diagnostic criteria, with the exception of family history.
In all cases, family and patient history is used for diagnosis. EEG
and brain imaging techniques, such as MRI and CAT scans, are used to rule out epilepsy and to test for cerebellar degeneration, respectively. With the discovery of causative genes, genetic sequencing can also be used to verify diagnosis (though not all genetic loci
are known).
was the CACNA1A gene (originally named CACNL1A4), which encodes the P/Q-type calcium channel
CaV2.1. There are currently 17 known mutation
s in this channel, see Table 1, and these mutations are distributed throughout the channel. Some of these mutations result in patients with notable cerebellar degeneration or other dysfunction. 15 of these mutants have received at least some further analysis at the electrophysiological
level to attempt to determine how they might lead to the FHM1 phenotype. There is increasing contradiction in the literature as to the end result of these mutations on channel kinetics and neuronal excitability.
A good example of this contradiction can be seen in the literature regarding the R192Q mutation. The first investigation of this mutation, using the rabbit
isoform of the channel expressed in oocyte
s, found that it did not alter any measured channel properties. A subsequent report, using human channels expressed in HEK293 Cells, found a small hyperpolarizing shift in the midpoint for activation, a result common among FHM1 mutants. This shift results in channels that open at more negative potentials and, thus, have a higher open probability than wild-type channels at most potentials. This report also found that the R192Q mutant produced almost twice as much whole-cell current compared to wild-type channels. This is not due to a change in single channel conductance but to an equivalent increase in channel density. A subsequent group noticed that this mutation is in a region important for modulation by G protein-coupled receptor
s (GPCRs). GPCR activation leads to inhibition of wild-type CaV2.1 currents. R192Q mutant channel currents are also decreased by GPCR activation, but by a smaller amount. A more recent group has confirmed some of these results by creating a R192Q knock-in mouse. They confirmed that the R192Q mutant activates at more negative potentials and that neurons producing these channels have much larger whole-cell current. This resulted in a much larger quantal content (the number of neurotransmitter
packets released per action potential
) and generally enhanced neurotransmitter release in R192Q expressing neurons versus wild-type. Consequently, these mutant mice were more susceptible to cortical-spreading-depression than their wild-type counterparts. The most recent experiments on this mutant, however, have contradicted some of these results. In CaV2.1 knockout
neuron
s transfected with human channels, P/Q-type currents from mutant channels are actually smaller than their wild-type counterpart. They also found a significant decrease in calcium
influx during depolarization, leading to decreased quantal content, in mutant versus wild-type expressing neurons. Neurons expressing mutant channels were also less able to mediate inhibitory input and have smaller inhibitory postsynaptic currents through P/Q-type channels. Further testing with this and other mutants is required to determine their end affect on human physiology.
. This Na+/K+-ATPase is heavily expressed in astrocyte
s and helps to set and maintain their reversal potential. There are 29 known mutations in this gene associated with FHM2, Table 2, many clustering in the large intracellular loop between membrane-spanning segments 4 and 5, Figure 1. 12 of these mutations have been studied by expression in model cells. All but one have shown either complete loss of function or more complex decreases in ATPase activity or potassium sensitivity. Astrocytes expressing these mutant ion pumps will have much higher resting potentials and are believed to lead to disease through a poorly understood mechanism.
for FHM is the SCN1A gene, which encodes a sodium channel α subunit. The only study so far that has found mutations in this gene discovered the same Q1489K mutation in 3 of 20 families (15%) with 11 other kindreds (55%) already having mutations in CACNA1A or ATP1A2. This mutation is located in a highly conserved region of an intracellular loop connecting domains three and four. This mutation results in a greatly hastened (2-4 fold) recovery from inactivation compared to wild-type. As this channel is important for action potential
generation in neuron
s, it is expected that the Q1489K mutant results in hyperexcitable neurons.
Patients with FHM are encouraged to avoid activities that may trigger their attacks. Minor head trauma is a common attack precipitant, so FHM sufferers should avoid contact sports. Acetazolamide
or standard drugs are often used to treat attacks, though those leading to vasoconstriction should be avoided due to the risk of stroke
.
is high, individuals found to carry mutations should be expected to develop signs of FHM at some point in life.
Also caused by calcium channel mutations:
Migraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
subtype that typically includes hemiparesis
Hemiparesis
Hemiparesis is weakness on one side of the body. It is less severe than hemiplegia - the total paralysis of the arm, leg, and trunk on one side of the body. Thus, the patient can move the impaired side of his body, but with reduced muscular strength....
(weakness of half the body) during the aura
Aura (symptom)
An aura is a perceptual disturbance experienced by some migraine sufferers before a migraine headache, and the telltale sensation experienced by some people with epilepsy before a seizure. It often manifests as the perception of a strange light, an unpleasant smell or confusing thoughts or...
phase. It can be accompanied by other symptoms, such as ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
, coma
Coma
In medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...
and epileptic seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s. There is clinical overlap in some FHM patients with episodic ataxia
Episodic ataxia
Episodic ataxia is an autosomal dominant disorder characterized by sporadic bouts of ataxia with or without myokymia . There are seven types recognised but the majority are due to two recognized entities. Ataxia can be provoked by stress, startle, or heavy exertion such as exercise. Symptoms can...
type 2 and spinocerebellar ataxia
Spinocerebellar ataxia
Spinocerebellar ataxia is a progressive, degenerative, genetic disease with multiple types, each of which could be considered a disease in its own right.-Classification:...
type 6, benign familial infantile convulsion
Convulsion
A convulsion is a medical condition where body muscles contract and relax rapidly and repeatedly, resulting in an uncontrolled shaking of the body. Because a convulsion is often a symptom of an epileptic seizure, the term convulsion is sometimes used as a synonym for seizure...
s, and alternating hemiplegia of childhood
Alternating hemiplegia of childhood
Alternating hemiplegia of childhood is a rare neurological disorder of uncertain etiology, which is named for the transient episodes, often referred to as attacks, of hemiplegia from which those with the disorder suffer. These hemiplegic attacks can cause anything from mild weakness to complete...
. There are 3 known loci
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
for FHM. FHM1, which accounts for approximately 50% of FHM patients, is caused by mutations in a gene coding for the P/Q-type calcium channel
Calcium channel
A Calcium channel is an ion channel which displays selective permeability to calcium ions. It is sometimes synonymous as voltage-dependent calcium channel, although there are also ligand-gated calcium channels.-Comparison tables:...
α subunit, CACNA1A. FHM1 is also associated with cerebellar degeneration. FHM2, which accounts for <25% of FHM cases, is caused by mutations in the Na+/K+-ATPase
Na+/K+-ATPase
Na+/K+-ATPase is an enzyme located in the plasma membrane in all animals.- Sodium-potassium pumps :Active transport is responsible for cells containing relatively high...
gene ATP1A2. FHM3 is a rare subtype of FHM and is caused by mutations in a sodium channel α-subunit coding gene, SCNA1. These three subtypes do not account for all cases of FHM, suggesting the existence of at least one other locus (FHM4). Many of the non-familial cases of hemiplegic migraine (sporadic hemiplegic migraine) are also caused by mutations at these loci.
Classification
FHM can be loosely divided into two categories: with and without cerebellar signs. Cerebellar signs refer to ataxiaAtaxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
, sometimes episodic and other times progressive, that can accompany FHM1 mutations and is caused by degeneration of the cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
. These cerebellar signs result in a phenotypic
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
overlap between FHM and both episodic ataxia
Episodic ataxia
Episodic ataxia is an autosomal dominant disorder characterized by sporadic bouts of ataxia with or without myokymia . There are seven types recognised but the majority are due to two recognized entities. Ataxia can be provoked by stress, startle, or heavy exertion such as exercise. Symptoms can...
and spinocerebellar ataxia
Spinocerebellar ataxia
Spinocerebellar ataxia is a progressive, degenerative, genetic disease with multiple types, each of which could be considered a disease in its own right.-Classification:...
. This is unsurprising as subtypes of these disorders (FHM1, EA2 and SCA6) are allelic, i.e., they result from mutations in the same gene. The other forms of FHM seem to be distinguishable only on the basis of their genetic cause.
There are also non-familial cases of hemiplegic migraine, termed sporadic hemiplegic migraine. These cases seem to have the same causes as the familial cases and represent de novo mutations. Sporadic cases are also clinically identical to familial cases with the exception of a lack of family history of attacks.
Signs and symptoms
FHM signs overlap significantly with those of migraine with aura. In short, FHM is typified by migraine with aura associated with hemiparesisHemiparesis
Hemiparesis is weakness on one side of the body. It is less severe than hemiplegia - the total paralysis of the arm, leg, and trunk on one side of the body. Thus, the patient can move the impaired side of his body, but with reduced muscular strength....
and, in FHM1, cerebellar
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
degeneration. This cerebellar degeneration can result in episodic or progressive ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
. FHM can also present with the same signs as benign familial infantile convulsion
Convulsion
A convulsion is a medical condition where body muscles contract and relax rapidly and repeatedly, resulting in an uncontrolled shaking of the body. Because a convulsion is often a symptom of an epileptic seizure, the term convulsion is sometimes used as a synonym for seizure...
s (BFIC) and alternating hemiplegia of childhood
Alternating hemiplegia of childhood
Alternating hemiplegia of childhood is a rare neurological disorder of uncertain etiology, which is named for the transient episodes, often referred to as attacks, of hemiplegia from which those with the disorder suffer. These hemiplegic attacks can cause anything from mild weakness to complete...
. Other symptoms are altered consciousness (in fact, some cases seem related to head trauma), gaze-evoked nystagmus and coma
Coma
In medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...
. Aura symptoms, such as numbness and blurring of vision, typically persist for 30–60 minutes. These signs typically first manifest themselves in the first or second decade of life.
Causes
See the equivalent section in the main migraine article.It is believed that FHM mutations lead to migraine susceptibility by lowering the threshold for cortical-spreading-depression generation. The FHM1 and FHM3 mutations are occur in ion channel
Ion channel
Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
s expressed in neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s. These mutations may lead to both the hyper and hypoexcitable neurons that might underlie cortical-spreading-depression. It is even less clear how the mutations seen in FHM2 patients might lead to FHM symptoms as the gene mutated in FHM2 is expressed primarily in astrocyte
Astrocyte
Astrocytes , also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord...
s. One proposal states that the depolarization of astrocytes caused by haploinsufficiency
Haploinsufficiency
Haploinsufficiency occurs when a diploid organism only has a single functional copy of a gene and the single functional copy of the gene does not produce enough of a gene product to bring about a wild-type condition, leading to an abnormal or diseased state...
of the ATP1A2 Na+/K+-ATPase
Na+/K+-ATPase
Na+/K+-ATPase is an enzyme located in the plasma membrane in all animals.- Sodium-potassium pumps :Active transport is responsible for cells containing relatively high...
causes increased release of compounds such as adenosine from astrocytes. These compounds then interact with neighboring neurons, altering their excitability and leading to cortical-spreading-depression and migraine.
Diagnosis
Diagnosis of FHM is made according to the following criteria:- Two attacks of each of the following:
- AuraAura (symptom)An aura is a perceptual disturbance experienced by some migraine sufferers before a migraine headache, and the telltale sensation experienced by some people with epilepsy before a seizure. It often manifests as the perception of a strange light, an unpleasant smell or confusing thoughts or...
with motor weakness accompanied by either reversible visual symptoms (flickering lights, spots, lines, etc.), reversible sensory symptoms (pins and needles, numbness, etc.) or speech symptoms. - At least two occurrences of:
-
-
- One or more auraAura (symptom)An aura is a perceptual disturbance experienced by some migraine sufferers before a migraine headache, and the telltale sensation experienced by some people with epilepsy before a seizure. It often manifests as the perception of a strange light, an unpleasant smell or confusing thoughts or...
symptoms that develop over at least 5 minutes - These symptoms lasting more than 5 minutes and less than 24 hours
- Headache beginning within 60 minutes of aura onset. These headaches can last 4-72 hours, occur on only one side of the head, pulsate, be of moderate to severe intensity, and may be aggravated by common physical activities such as walking. These headaches must also be accompanied by nauseaNauseaNausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
/vomiting, phonophobia (avoidance of sound due to hypersensitivity) and/or photophobiaPhotophobiaPhotophobia is a symptom of abnormal intolerance to visual perception of light. As a medical symptom photophobia is not a morbid fear or phobia, but an experience of discomfort or pain to the eyes due to light exposure or by presence of actual physical photosensitivity of the eyes, though the term...
(avoidance of light due to hypersensitivity).- At least one close (first or second degree) relative with FHM
- No other likely cause
- One or more aura
-
Sporadic forms follow the same diagnostic criteria, with the exception of family history.
In all cases, family and patient history is used for diagnosis. EEG
EEG
EEG commonly refers to electroencephalography, a measurement of the electrical activity of the brain.EEG may also refer to:* Emperor Entertainment Group, a Hong Kong-based entertainment company...
and brain imaging techniques, such as MRI and CAT scans, are used to rule out epilepsy and to test for cerebellar degeneration, respectively. With the discovery of causative genes, genetic sequencing can also be used to verify diagnosis (though not all genetic loci
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
are known).
FHM1 (CACNA1A)
The first discovered FHM locusLocus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
was the CACNA1A gene (originally named CACNL1A4), which encodes the P/Q-type calcium channel
Calcium channel
A Calcium channel is an ion channel which displays selective permeability to calcium ions. It is sometimes synonymous as voltage-dependent calcium channel, although there are also ligand-gated calcium channels.-Comparison tables:...
CaV2.1. There are currently 17 known mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in this channel, see Table 1, and these mutations are distributed throughout the channel. Some of these mutations result in patients with notable cerebellar degeneration or other dysfunction. 15 of these mutants have received at least some further analysis at the electrophysiological
Electrophysiology
Electrophysiology is the study of the electrical properties of biological cells and tissues. It involves measurements of voltage change or electric current on a wide variety of scales from single ion channel proteins to whole organs like the heart...
level to attempt to determine how they might lead to the FHM1 phenotype. There is increasing contradiction in the literature as to the end result of these mutations on channel kinetics and neuronal excitability.
A good example of this contradiction can be seen in the literature regarding the R192Q mutation. The first investigation of this mutation, using the rabbit
Rabbit
Rabbits are small mammals in the family Leporidae of the order Lagomorpha, found in several parts of the world...
isoform of the channel expressed in oocyte
Oocyte
An oocyte, ovocyte, or rarely ocyte, is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in the ovary during female gametogenesis. The female germ cells produce a primordial germ cell which undergoes a mitotic...
s, found that it did not alter any measured channel properties. A subsequent report, using human channels expressed in HEK293 Cells, found a small hyperpolarizing shift in the midpoint for activation, a result common among FHM1 mutants. This shift results in channels that open at more negative potentials and, thus, have a higher open probability than wild-type channels at most potentials. This report also found that the R192Q mutant produced almost twice as much whole-cell current compared to wild-type channels. This is not due to a change in single channel conductance but to an equivalent increase in channel density. A subsequent group noticed that this mutation is in a region important for modulation by G protein-coupled receptor
G protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
s (GPCRs). GPCR activation leads to inhibition of wild-type CaV2.1 currents. R192Q mutant channel currents are also decreased by GPCR activation, but by a smaller amount. A more recent group has confirmed some of these results by creating a R192Q knock-in mouse. They confirmed that the R192Q mutant activates at more negative potentials and that neurons producing these channels have much larger whole-cell current. This resulted in a much larger quantal content (the number of neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
packets released per action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
) and generally enhanced neurotransmitter release in R192Q expressing neurons versus wild-type. Consequently, these mutant mice were more susceptible to cortical-spreading-depression than their wild-type counterparts. The most recent experiments on this mutant, however, have contradicted some of these results. In CaV2.1 knockout
Gene knockout
A gene knockout is a genetic technique in which one of an organism's genes is made inoperative . Also known as knockout organisms or simply knockouts, they are used in learning about a gene that has been sequenced, but which has an unknown or incompletely known function...
neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s transfected with human channels, P/Q-type currents from mutant channels are actually smaller than their wild-type counterpart. They also found a significant decrease in calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
influx during depolarization, leading to decreased quantal content, in mutant versus wild-type expressing neurons. Neurons expressing mutant channels were also less able to mediate inhibitory input and have smaller inhibitory postsynaptic currents through P/Q-type channels. Further testing with this and other mutants is required to determine their end affect on human physiology.
| Mutation | Position | Effect | Cerebellar signs | Reference | |
|---|---|---|---|---|---|
| Nucleotide Nucleotide Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions... |
Amino acid Amino acid Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen... |
||||
| c.G575A | R192Q | D1S4 | Increases G-protein mediated inhibition, activates at more negative potentials, increased expression, faster recovery from inactivation. In mice: greater current, activates at more negative potentials, enhances transmitter release | ? | ,,,,, |
| c.G584A | R195K | D1S4 | No | ||
| c.C653T | S218L | D1S4-5 | Increases sojourns to subconductances, activates at more negative potentials, decreased slow inactivation, increased fast inactivation | Yes | , |
| c.G1748A | R583Q* | D2S4 | Activates at more negative potentials, faster current decay, faster inactivation, slower recovery from inactivation | Yes | ,,,, |
| c.C1997T | > D2-pore | ||||
| c.T2141C | > D2S6 | ||||
| c.C2145G | > D2S6 | ||||
| c.A4003G | > D3S3-4 | ||||
| c.G4037A | > D3S4 | ||||
| c.A4151G | > D3S5 | ||||
| c.G4366T | > D3-pore | ||||
| c.C4636T | > D4S1 | ||||
| c.C4999T | > D4S4 | ||||
| c.T5047C | > D4S4-5 | ||||
| c.G5083A | > D4S5 | ||||
| c.T5126C | > D4S5 | ||||
| c.A5428C | > D4S6 | ||||
| ** | Also diagnosed as spinocerebellar ataxia Spinocerebellar ataxia Spinocerebellar ataxia is a progressive, degenerative, genetic disease with multiple types, each of which could be considered a disease in its own right.-Classification:... type-6 Also diagnosed as episodic ataxia Episodic ataxia Episodic ataxia is an autosomal dominant disorder characterized by sporadic bouts of ataxia with or without myokymia . There are seven types recognised but the majority are due to two recognized entities. Ataxia can be provoked by stress, startle, or heavy exertion such as exercise. Symptoms can... type-2 |
||||
| Sequence numbering according to NCBI National Center for Biotechnology Information The National Center for Biotechnology Information is part of the United States National Library of Medicine , a branch of the National Institutes of Health. The NCBI is located in Bethesda, Maryland and was founded in 1988 through legislation sponsored by Senator Claude Pepper... reference sequence NM_000068.2. Cerebellar signs refers to findings of cerebellar degeneration or ataxia upon clinical examination. |
|||||
FHM2 (ATP1A2)
The second subtype of familial hemiplegic migraine, FHM2, is caused by mutations in the gene ATP1A2 that encodes a Na+/K+-ATPaseNa+/K+-ATPase
Na+/K+-ATPase is an enzyme located in the plasma membrane in all animals.- Sodium-potassium pumps :Active transport is responsible for cells containing relatively high...
. This Na+/K+-ATPase is heavily expressed in astrocyte
Astrocyte
Astrocytes , also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord...
s and helps to set and maintain their reversal potential. There are 29 known mutations in this gene associated with FHM2, Table 2, many clustering in the large intracellular loop between membrane-spanning segments 4 and 5, Figure 1. 12 of these mutations have been studied by expression in model cells. All but one have shown either complete loss of function or more complex decreases in ATPase activity or potassium sensitivity. Astrocytes expressing these mutant ion pumps will have much higher resting potentials and are believed to lead to disease through a poorly understood mechanism.
| Mutation | Location | Physiological result | Reference(s) |
|---|---|---|---|
| E174K | M2-3 | No change | |
| T263M | M2-3 | ||
| G301R | M3 | ||
| T345A | M4-5 | Decreased K influx | , |
| T376M | M4-5 | ||
| R383H | M4-5 | ||
| T387N | M4-5 | ||
| C515Y | M4-5 | Loss of function (haploinsufficiency) | |
| R548H | M4-5 | ||
| R593W | M4-5 | Loss of function (haploinsufficiency) | |
| A606T | M4-5 | ||
| G615R | M4-5 | Loss of function (haploinsufficiency) | |
| V628M | M4-5 | Loss of function (haploinsufficiency) | |
| R689Q | M4-5 | Decreased catalytic turnover | ,, |
| E700K | M4-5 | ||
| D718N | M4-5 | Loss of function (haploinsufficiency) | |
| M731T | M4-5 | Decreased catalytic turnover | ,, |
| R763H | M4-5 | Loss of function (haploinsufficiency) | |
| L764P | M4-5 | Loss of function (haploinsufficiency) | ,, |
| P796R | M5-6 | ||
| M829R | M6-7 | ||
| R834Q | M6-7 | ||
| W887R | M7-8 | Loss of function (haploinsufficiency) | ,,, |
| E902K | M7-8 | ||
| 935K_940SdelinsI | M8-9 | ||
| R937P | M8-9 | ||
| S966LfsX998 | M9 | ||
| P979L | M9-10 | ||
| X1021RextX28 | C-Terminus | ||
| Numbering according to the NCBI National Center for Biotechnology Information The National Center for Biotechnology Information is part of the United States National Library of Medicine , a branch of the National Institutes of Health. The NCBI is located in Bethesda, Maryland and was founded in 1988 through legislation sponsored by Senator Claude Pepper... reference sequence NM_000702.2. |
|||
FHM3 (SCN1A)
The final known locusLocus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
for FHM is the SCN1A gene, which encodes a sodium channel α subunit. The only study so far that has found mutations in this gene discovered the same Q1489K mutation in 3 of 20 families (15%) with 11 other kindreds (55%) already having mutations in CACNA1A or ATP1A2. This mutation is located in a highly conserved region of an intracellular loop connecting domains three and four. This mutation results in a greatly hastened (2-4 fold) recovery from inactivation compared to wild-type. As this channel is important for action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
generation in neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s, it is expected that the Q1489K mutant results in hyperexcitable neurons.
FHM4 (1q31)
The final known locus for FHM maps to the q-arm of chromosome 1. There are a number of attractive candidate genes in this area, though no mutations in them have yet been linked to FHM4.Treatment/Management
See the equivalent section in the main migraine article.Patients with FHM are encouraged to avoid activities that may trigger their attacks. Minor head trauma is a common attack precipitant, so FHM sufferers should avoid contact sports. Acetazolamide
Acetazolamide
Acetazolamide, sold under the trade name Diamox, is a carbonic anhydrase inhibitor that is used to treat glaucoma, epileptic seizures, Idiopathic intracranial hypertension , altitude sickness, cystinuria, and dural ectasia...
or standard drugs are often used to treat attacks, though those leading to vasoconstriction should be avoided due to the risk of stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
.
Prevention/Screening
Prenatal screening is not typically done for FHM, however it may be performed if requested. As penetrancePenetrance
Penetrance in genetics is the proportion of individuals carrying a particular variant of a gene that also express an associated trait . In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms...
is high, individuals found to carry mutations should be expected to develop signs of FHM at some point in life.
Epidemiology
Migraine itself is a very common disorder, occurring in 15-20% of the population. Hemiplegic migraine, be it familial or spontaneous, is less prevalent, 0.01% prevalence according to one report. Women are three times more likely to be affected than males.See also
- ChannelopathyChannelopathyChannelopathies are diseases caused by disturbed function of ion channel subunits or the proteins that regulate them. These diseases may be either congenital or acquired .There are a large number of distinct dysfunctions known to be caused by ion channel...
- Calcium channelCalcium channelA Calcium channel is an ion channel which displays selective permeability to calcium ions. It is sometimes synonymous as voltage-dependent calcium channel, although there are also ligand-gated calcium channels.-Comparison tables:...
- MigraineMigraineMigraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
Also caused by calcium channel mutations:
- Childhood absence epilepsyChildhood absence epilepsyChildhood absence epilepsy , also known as pyknolepsy, is an idiopathic generalized epilepsy which occurs in otherwise normal children. The age of onset is between 4–10 years with peak age between 5–7 years. Children have absence seizures which although brief , they occur frequently, sometimes in...
- Hypokalemic periodic paralysisHypokalemic periodic paralysisHypokalemic periodic paralysis is a rare channelopathy characterized by muscle weakness or paralysis with a matching fall in potassium levels in the blood...
- Juvenile myoclonic epilepsyJuvenile myoclonic epilepsyJuvenile myoclonic epilepsy , also known as Janz syndrome, is a fairly common form of idiopathic generalized epilepsy, representing 5-10% of all epilepsies. This disorder typically first manifests itself between the ages of 12 and 18 with myoclonus occurring early in the morning. Most patients also...
- Malignant hyperthermiaMalignant hyperthermiaMalignant hyperthermia or malignant hyperpyrexia is a rare life-threatening condition that is usually triggered by exposure to certain drugs used for general anesthesia; specifically, the volatile anesthetic agents and the neuromuscular blocking agent, succinylcholine...
- Timothy syndromeTimothy syndromeTimothy syndrome is a rare autosomal dominant disorder characterized by physical malformations, as well as neurological and developmental defects, including heart QT-prolongation, heart arrhythmias, structural heart defects, syndactyly and autism spectrum disorders.Timothy syndrome often ends in...