Episodic ataxia
Encyclopedia
Episodic ataxia is an autosomal dominant disorder characterized by sporadic bouts of ataxia
(severe discoordination) with or without myokymia (continuous muscle movement). 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 first appear in infancy. There are at least 6 loci for EA, of which 4 are known genes. Some patients with EA also have migraine or progressive cerebellar degenerative disorders, symptomatic of either familial hemiplegic migraine
or spinocerebellar ataxia
. Some patients respond to acetazolamide
though others do not.
induced by startle, stress, or exertion. Some patients also have continuous tremors of various motor groups, known as myokymia
. Other patients have nystagmus, vertigo
, tinnitus
, diplopia
or seizure
s.
s in the cerebellum
. This is either due to direct malfunction of these cells, such as in EA2, or improper regulation of these cells, such as in EA1. Seizures are likely due to altered firing of hippocampal
neurons (KCNA1 null mice have seizures for this reason).
Type 1 episodic ataxia (EA1) is characterized by attacks of generalized ataxia
induced by emotion or stress, with myokymia both during and between attacks. This disorder is also known as episodic ataxia with myokymia (EAM), hereditary paroxysmal ataxia with neuromyotonia and Isaacs-Mertens syndrome. Onset of EA1 occurs during early childhood to adolescence and persists throughout the patient's life. Attacks last from seconds to minutes. Mutations of the gene KCNA1
, which encodes the voltage-gated potassium channel
KV1.1, are responsible for this subtype of episodic ataxia. KV1.1 is expressed heavily in basket cells and interneurons that form GABAergic synapses on Purkinje cell
s. The channels aid in the repolarization phase of action potentials, thus affecting inhibitory input into Purkinje cells and, thereby, all motor output from the cerebellum
. There are currently 17 KV1.1 mutations associated with EA1, Table 1 and Figure 1. 15 of these mutations have been at least partly characterized in cell culture
based electrophysiological assays wherein 14 of these 15 mutations have demonstrated drastic alterations in channel function. As described in Table 1, most of the known EA1 associated mutations result in a drastic decrease in the amount of current through KV1.1 channels. Furthermore, these channels tend to activate at more positive potentials and slower rates, demonstrated by positive shifts in their V½ values and slower τ activation time constants, respectively. Some of these mutations, moreover, produce channels that deactivate at faster rates (deactivation τ), which would also result in decreased current through these channels. While these biophysical changes in channel properties likely underlie some of the decrease in current observed in experiments, many mutations also seem to result in misfolded or otherwise mistrafficked channels, which is likely to be the major cause of dysfunction and disease pathogenesis. It is assumed, though not yet proven, that decrease in KV1.1 mediated current leads to prolonged action potentials in interneurons and basket cells. As these cells are important in the regulation of Purkinje cell activity, it is likely that this results increased and aberrant inhibitory input into Purkinje cells and, thus, disrupted Purkinje cell firing and cerebellum output.
Type 2 episodic ataxia (EA2)is characterized by acetazolamide-responsive attacks of ataxia with or without migraine. Patients with EA2 may also present with progressive cerebellar atrophy, nystagmus, vertigo, visual disturbances and dysarthria. These symptoms last from hours to days, in contrast with EA1, which lasts from seconds to minutes. Like EA1, attacks can be precipitated by emotional or physical stress, but also by coffee
and alcohol
. EA2 is caused by mutations in CACNA1A, which encodes the P/Q-type voltage-gated calcium channel CaV2.1, and is also the gene responsible for causing spinocerebellar ataxia type-6
and familial hemiplegic migraine
type-1. EA2 is also referred to as episodic ataxia with nystagmus, hereditary paroxysmal cerebellopathy, familial paroxysmal ataxia and acetazolamide-responsive hereditary paroxysmal cerebellar ataxia (AHPCA). There are currently 19 mutations associated with EA2, though only 3 have been characterized electrophysiologically, table 2 and figure 2. Of these, all result in decreased current through these channels. It is assumed that the other mutations, especially the splicing and frameshift mutations, also result in a drastic decrease in CaV2.1 currents, though this may not be the case for all mutations. CACNA1A is heavily expressed in Purkinje cell
s of the cerebellum
where it is involved in coupling action potentials with neurotransmitter release. Thus, decrease in Ca2+ entry through CaV2.1 channels is expected to result in decreased output from Purkinje cells, even though they will fire at an appropriate rate. Alternatively, some CACNA1A mutations, such as those seen in familial hemiplegic migraine
type-1, result in increased Ca2+ entry and, thereby, aberrant transmitter release. This can also result in excitotoxicity, as may occur in some cases of spinocerebellar ataxia type-6
.
and vertigo
. Patients typically present with bouts of ataxia lasting less than 30 minutes and occurring once or twice daily. During attacks, they also have vertigo, nausea, vomiting, tinnitus and diplopia
. These attacks are sometimes accompanied by headaches and precipitated by stress, fatigue, movement and arousal after sleep. Attacks generally begin in early childhood and last throughout the patients' lifetime. Acetazolamide administration has proved successful in some patients. As EA3 is extremely rare, there is currently no known causative gene. The locus for this disorder has been mapped to the long arm of chromosome 1 (1q42).
. The locus for EA4 is unknown.
These patients can present with an overlapping phenotype of ataxia and seizures similar to juvenile myoclonic epilepsy
.
In fact, juvenile myoclonic epilepsy and EA5 are allelic and produce proteins with similar dysfunction.
Patients with pure EA5 present with recurrent episodes of ataxia with vertigo.
Between attacks the have nystagmus and dysarthria
. These patients are responsive to acetazolamide
.
Both juvenile myoclonic epilepsy and EA5 are a result of mutations in CACNB4
, a gene that encodes the calcium channel
β4 subunit. This subunit coassembles with α-subunits and produces channels that slowly inactivate after opening.
EA5 patients have a cysteine
to phenylalanine
mutation at position 104.
Thus results in channels with 30% greater current than wild-type.
As this subunit is expressed in the cerebellum
, it is assumed that such increased current results in neuronal hyperexcitability
Coding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia.
to arginine
substitution in the fifth transmembrane-spanning segment of the gene SLC1A3. This gene encodes the excitatory amino acid transporter 1 (EAAT1) protein, which is responsible for glutamate uptake. In cell culture assays, this mutation results in drastically decreased glutamate uptake in a dominant-negative manner. This is likely due to decreased synthesis or protein stability. As this protein is expressed heavily in the brainstem and cerebellum
, it is likely that this mutation results in excitotoxicity and/or hyperexcitability leading to ataxia and seizures. Mutations in EAAT1 (GLAST) have subsequently been identified in a family with episodic ataxia.
therapy is useful in preventing attacks. In some cases, persistent attacks result in tendon shortening, for which surgery is required.
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...
(severe discoordination) with or without myokymia (continuous muscle movement). 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 first appear in infancy. There are at least 6 loci for EA, of which 4 are known genes. Some patients with EA also have migraine or progressive cerebellar degenerative disorders, symptomatic of either familial hemiplegic migraine
Familial hemiplegic migraine
Familial hemiplegic migraine is an autosomal dominant classical migraine subtype that typically includes hemiparesis during the aura phase. It can be accompanied by other symptoms, such as ataxia, coma and epileptic seizures...
or 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:...
. Some patients respond to 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...
though others do not.
Signs/Symptoms
Typically, episodic ataxia presents as bouts of 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...
induced by startle, stress, or exertion. Some patients also have continuous tremors of various motor groups, known as myokymia
Myokymia
Myokymia, is an involuntary, spontaneous, localized quivering of a few muscles bundles within a muscle, but which are insufficient to move a joint.One type is superior oblique myokymia....
. Other patients have nystagmus, vertigo
Vertigo (medical)
Vertigo is a type of dizziness, where there is a feeling of motion when one is stationary. The symptoms are due to a dysfunction of the vestibular system in the inner ear...
, tinnitus
Tinnitus
Tinnitus |ringing]]") is the perception of sound within the human ear in the absence of corresponding external sound.Tinnitus is not a disease, but a symptom that can result from a wide range of underlying causes: abnormally loud sounds in the ear canal for even the briefest period , ear...
, diplopia
Diplopia
Diplopia, commonly known as double vision, is the simultaneous perception of two images of a single object that may be displaced horizontally, vertically, or diagonally in relation to each other...
or 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.
Cause
The various symptoms of EA are caused by dysfunction of differing areas. Ataxia, the most common symptom, is due to misfiring of Purkinje cellPurkinje cell
For the cells of the electrical conduction system of the heart, see Purkinje fibersPurkinje cells, or Purkinje neurons , are a class of GABAergic neurons located in the cerebellar cortex...
s in 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...
. This is either due to direct malfunction of these cells, such as in EA2, or improper regulation of these cells, such as in EA1. Seizures are likely due to altered firing of hippocampal
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
neurons (KCNA1 null mice have seizures for this reason).
EA1: KCNA1
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...
induced by emotion or stress, with myokymia both during and between attacks. This disorder is also known as episodic ataxia with myokymia (EAM), hereditary paroxysmal ataxia with neuromyotonia and Isaacs-Mertens syndrome. Onset of EA1 occurs during early childhood to adolescence and persists throughout the patient's life. Attacks last from seconds to minutes. Mutations of the gene KCNA1
KCNA1
Potassium voltage-gated channel subfamily A member 1 also known as Kv1.1 is a shaker related voltage-gated potassium channel that in humans is encoded by the KCNA1 gene. The Isaacs syndrome is a result of an autoimmune reaction against the Kv1.1 ion channel.- Genomics :The gene is located on the...
, which encodes the voltage-gated potassium channel
Voltage-gated potassium channel
Voltage-gated potassium channels are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a crucial role in returning the depolarized cell to a resting state....
KV1.1, are responsible for this subtype of episodic ataxia. KV1.1 is expressed heavily in basket cells and interneurons that form GABAergic synapses on Purkinje cell
Purkinje cell
For the cells of the electrical conduction system of the heart, see Purkinje fibersPurkinje cells, or Purkinje neurons , are a class of GABAergic neurons located in the cerebellar cortex...
s. The channels aid in the repolarization phase of action potentials, thus affecting inhibitory input into Purkinje cells and, thereby, all motor output from 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...
. There are currently 17 KV1.1 mutations associated with EA1, Table 1 and Figure 1. 15 of these mutations have been at least partly characterized in cell culture
Cell culture
Cell culture is the complex process by which cells are grown under controlled conditions. In practice, the term "cell culture" has come to refer to the culturing of cells derived from singlecellular eukaryotes, especially animal cells. However, there are also cultures of plants, fungi and microbes,...
based electrophysiological assays wherein 14 of these 15 mutations have demonstrated drastic alterations in channel function. As described in Table 1, most of the known EA1 associated mutations result in a drastic decrease in the amount of current through KV1.1 channels. Furthermore, these channels tend to activate at more positive potentials and slower rates, demonstrated by positive shifts in their V½ values and slower τ activation time constants, respectively. Some of these mutations, moreover, produce channels that deactivate at faster rates (deactivation τ), which would also result in decreased current through these channels. While these biophysical changes in channel properties likely underlie some of the decrease in current observed in experiments, many mutations also seem to result in misfolded or otherwise mistrafficked channels, which is likely to be the major cause of dysfunction and disease pathogenesis. It is assumed, though not yet proven, that decrease in KV1.1 mediated current leads to prolonged action potentials in interneurons and basket cells. As these cells are important in the regulation of Purkinje cell activity, it is likely that this results increased and aberrant inhibitory input into Purkinje cells and, thus, disrupted Purkinje cell firing and cerebellum output.
| Mutation | Position | Current amplitude (% wild-type) |
Activation | Deactivation (τ) | Other | References | |
|---|---|---|---|---|---|---|---|
| V½ | τ | ||||||
| V174F | S1 | 7.6% | 25mV positive | Unchanged | Unchanged | ,,, | |
| I177N | S1 | 5.9% | 60mV positive | Slower | Faster | Shorter mean open time and smaller single channel conductance | , |
| F184C | S1 | 15.1% | 24mV positive | Slower | Slower | Fewer channels at membrane | ,,, |
| T226A | S2 | 5% | 15mV positive | Slower | Slower | , | |
| T226M | S2 | 5% | 15mV positive | Slower | Slower | , | |
| T226R | S2 | 3% | ? | ? | ? | ||
| R239S | S2 | 0% | NA | NA | NA | Improper trafficking | ,, |
| A242P | S2 | 10% | 4mV Negative | Slower | Slower | ||
| P244H | S2-3 | Unchanged | Unchanged | Unchanged | Unchanged | ||
| F249I | S2-3 | 1% | Unchanged | Unchanged | Slower | Improper trafficking | ,, |
| G311S | S3-4 | 22.9% | 30mV positive | Unchanged | Unchanged | ||
| E325D | S5 | 7.7% | 52.4mV positive | Faster | Faster | Impaired translation or stability | ,,,,, |
| L329I | S5 | ? | ? | ? | ? | ||
| S342I | S5 | ? | ? | ? | ? | ||
| V404I | S6 | Unchanged | 12mV positive | Slower | Slower | , | |
| V408A | C-terminus | 68% | Unchanged | Faster | Faster | Shorter mean open time, more and larger sIPSCs in Mice | ,,,,,,, |
| R417X | C-terminus | 2% | 9mV positive | Slower | Faster | Misfolds and form membranous aggregates | , |
| Current amplitude refers to the amount of current through mutant versus wild-type channels in cell culture or oocyte assays. Activation V½ is the potential at which the population of channels is half maximally activated which the accompanying τ is the time constant of the populations activation. Deactivation τ is similar to that of activation, referring instead to the time constant of population closing. sIPSCs are spontaneous inhibitory post synaptic currents. Cells with a red background indicate that this property will result in decreased KV1.1 current while cells with a green background indicate increased current through this channel. | |||||||
EA2: CACNA1A
Coffee
Coffee is a brewed beverage with a dark,init brooo acidic flavor prepared from the roasted seeds of the coffee plant, colloquially called coffee beans. The beans are found in coffee cherries, which grow on trees cultivated in over 70 countries, primarily in equatorial Latin America, Southeast Asia,...
and alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
. EA2 is caused by mutations in CACNA1A, which encodes the P/Q-type voltage-gated calcium channel CaV2.1, and is also the gene responsible for causing spinocerebellar ataxia type-6
Spinocerebellar ataxia type-6
Spinocerebellar ataxia type 6 is a rare, late-onset, autosomal dominant disorder, which, like other types of SCA, is characterized by dysarthria, oculomotor disorders, incontinence, peripheral neuropathy, and ataxia of gait, stance and the limbs due to cerebellar dysfunction. Unlike other types,...
and familial hemiplegic migraine
Familial hemiplegic migraine
Familial hemiplegic migraine is an autosomal dominant classical migraine subtype that typically includes hemiparesis during the aura phase. It can be accompanied by other symptoms, such as ataxia, coma and epileptic seizures...
type-1. EA2 is also referred to as episodic ataxia with nystagmus, hereditary paroxysmal cerebellopathy, familial paroxysmal ataxia and acetazolamide-responsive hereditary paroxysmal cerebellar ataxia (AHPCA). There are currently 19 mutations associated with EA2, though only 3 have been characterized electrophysiologically, table 2 and figure 2. Of these, all result in decreased current through these channels. It is assumed that the other mutations, especially the splicing and frameshift mutations, also result in a drastic decrease in CaV2.1 currents, though this may not be the case for all mutations. CACNA1A is heavily expressed in Purkinje cell
Purkinje cell
For the cells of the electrical conduction system of the heart, see Purkinje fibersPurkinje cells, or Purkinje neurons , are a class of GABAergic neurons located in the cerebellar cortex...
s 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...
where it is involved in coupling action potentials with neurotransmitter release. Thus, decrease in Ca2+ entry through CaV2.1 channels is expected to result in decreased output from Purkinje cells, even though they will fire at an appropriate rate. Alternatively, some CACNA1A mutations, such as those seen in familial hemiplegic migraine
Familial hemiplegic migraine
Familial hemiplegic migraine is an autosomal dominant classical migraine subtype that typically includes hemiparesis during the aura phase. It can be accompanied by other symptoms, such as ataxia, coma and epileptic seizures...
type-1, result in increased Ca2+ entry and, thereby, aberrant transmitter release. This can also result in excitotoxicity, as may occur in some cases of spinocerebellar ataxia type-6
Spinocerebellar ataxia type-6
Spinocerebellar ataxia type 6 is a rare, late-onset, autosomal dominant disorder, which, like other types of SCA, is characterized by dysarthria, oculomotor disorders, incontinence, peripheral neuropathy, and ataxia of gait, stance and the limbs due to cerebellar dysfunction. Unlike other types,...
.
| Mutation | Position | Effect | Cerebellar Signs | References |
|---|---|---|---|---|
| H253Y | D1-pore | ? | Yes | |
| C271Y* | D1-pore | Decreased maximal current due to protein instability | Yes | |
| G293R* | D1-pore | Decreased maximal current due to protein instability | Yes | , |
| F624LfsX657 | D2S5 | ? | Yes | |
| Q681RfsX780 | D2-pore | ? | Yes | |
| S753fsX780 | D2S6 | ? | Yes | |
| P1266LfsX1293 | D3S1 | ? | Yes | , |
| R1278X | D3S1-2 | ? | Yes | |
| F1391LfsX1429 | D3S5 | ? | Yes | |
| Y1443X | D3-pore | ? | Yes | |
| F1490K | D3S6 | No current, though expressed | Yes | |
| R1546X | D4S1 | ? | Yes | |
| A1593_Y1594delinsD | D4S2 | ? | Yes | |
| R1661H | D4S4 | ? | Yes | |
| R1664Q* | D4S4 | ? | Yes | |
| E1756K | D4-pore | ? | Yes | |
| Splicing | Intron 11 | ? | Yes | |
| Splicing | Intron 26 | ? | Yes | |
| Splicing | Intron 28 | ? | Yes | |
| Also diagnosed as Spinocerebellar ataxia type-6 Spinocerebellar ataxia type-6 Spinocerebellar ataxia type 6 is a rare, late-onset, autosomal dominant disorder, which, like other types of SCA, is characterized by dysarthria, oculomotor disorders, incontinence, peripheral neuropathy, and ataxia of gait, stance and the limbs due to cerebellar dysfunction. Unlike other types,... |
||||
EA3: 1q42
Episodic ataxia type-3 (EA3) is similar to EA1 but often also presents with tinnitusTinnitus
Tinnitus |ringing]]") is the perception of sound within the human ear in the absence of corresponding external sound.Tinnitus is not a disease, but a symptom that can result from a wide range of underlying causes: abnormally loud sounds in the ear canal for even the briefest period , ear...
and vertigo
Vertigo (medical)
Vertigo is a type of dizziness, where there is a feeling of motion when one is stationary. The symptoms are due to a dysfunction of the vestibular system in the inner ear...
. Patients typically present with bouts of ataxia lasting less than 30 minutes and occurring once or twice daily. During attacks, they also have vertigo, nausea, vomiting, tinnitus and diplopia
Diplopia
Diplopia, commonly known as double vision, is the simultaneous perception of two images of a single object that may be displaced horizontally, vertically, or diagonally in relation to each other...
. These attacks are sometimes accompanied by headaches and precipitated by stress, fatigue, movement and arousal after sleep. Attacks generally begin in early childhood and last throughout the patients' lifetime. Acetazolamide administration has proved successful in some patients. As EA3 is extremely rare, there is currently no known causative gene. The locus for this disorder has been mapped to the long arm of chromosome 1 (1q42).
EA4
Also known as periodic vestibulocerebellar ataxia, type-4 episodic ataxia (EA4) is an extremely rare form of episodic ataxia differentiated from other forms by onset in the third to sixth generation of life, defective smooth pursuit and gaze-evoked nystagmus. Patients also present with vertigo and ataxia. There are only two known families with EA4, both located in North CarolinaNorth Carolina
North Carolina is a state located in the southeastern United States. The state borders South Carolina and Georgia to the south, Tennessee to the west and Virginia to the north. North Carolina contains 100 counties. Its capital is Raleigh, and its largest city is Charlotte...
. The locus for EA4 is unknown.
EA5: CACNB4
There are two known families with type-5 episodic ataxia (EA5).These patients can present with an overlapping phenotype of ataxia and seizures similar to juvenile myoclonic epilepsy
Juvenile myoclonic epilepsy
Juvenile 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...
.
In fact, juvenile myoclonic epilepsy and EA5 are allelic and produce proteins with similar dysfunction.
Patients with pure EA5 present with recurrent episodes of ataxia with vertigo.
Between attacks the have nystagmus and dysarthria
Dysarthria
Dysarthria is a motor speech disorder resulting from neurological injury of the motor component of the motor-speech system and is characterized by poor articulation of phonemes...
. These patients are responsive to 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...
.
Both juvenile myoclonic epilepsy and EA5 are a result of mutations in CACNB4
CACNB4
Voltage-dependent L-type calcium channel subunit beta-4 is a protein that in humans is encoded by the CACNB4 gene.- Function :This gene encodes a member of the beta subunit family, a protein in the voltage-dependent calcium channel complex...
, a gene that encodes the 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:...
β4 subunit. This subunit coassembles with α-subunits and produces channels that slowly inactivate after opening.
EA5 patients have a cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
to phenylalanine
Phenylalanine
Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
mutation at position 104.
Thus results in channels with 30% greater current than wild-type.
As this subunit is expressed in 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...
, it is assumed that such increased current results in neuronal hyperexcitability
Coding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia.
EA6: SLC1A3
Type-6 episodic ataxia (EA6) is a rare form of episodic ataxia, identified initially in a 10 year-old boy who first presented with 30 minute bouts of decreased muscle tone during infancy. He required "balance therapy" as a young child to aid in walking and has a number of ataxic attacks, each separated by months to years. These attacks were precipitated by fever. He has cerebellar atrophy and subclinical seizures. During later attacks, he also presented with distortions of the left hemifield, ataxia, slurred speech, followed by headache. After enrolling in school, he developed bouts of rhythmic arm jerking with concomitant confusion, also lasting approximately 30 minutes. He also has presented, at various times, with migraines. This patient carries a prolineProline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
to arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
substitution in the fifth transmembrane-spanning segment of the gene SLC1A3. This gene encodes the excitatory amino acid transporter 1 (EAAT1) protein, which is responsible for glutamate uptake. In cell culture assays, this mutation results in drastically decreased glutamate uptake in a dominant-negative manner. This is likely due to decreased synthesis or protein stability. As this protein is expressed heavily in the brainstem and 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...
, it is likely that this mutation results in excitotoxicity and/or hyperexcitability leading to ataxia and seizures. Mutations in EAAT1 (GLAST) have subsequently been identified in a family with episodic ataxia.
Treatment
Depending on subtype, many patients find that acetazolamideAcetazolamide
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...
therapy is useful in preventing attacks. In some cases, persistent attacks result in tendon shortening, for which surgery is required.
External links
- National Ataxia Foundation
- Webpage of a patient with EA2, including information on EA in both English and Spanish including a blog on EA and a forum
- GeneReviews/NCBI/NIH/UW entry on Episodic Ataxia Type 1,Episodic Ataxia with Myokymia, Hereditary Cerebellar Ataxia with Neuromyotonia
- GeneReviews/NCBI/NIH/UW entry on Episodic ataxia type 2