Spinocerebellar ataxia type-13
Encyclopedia
Spinocerebellar ataxia type 13 (SCA13) is a rare autosomal dominant disorder, which, like other types of SCA
, is characterized by dysarthria
, nystagmus, and ataxia
of gait, stance and the limbs due to cerebellar dysfunction. Patients with SCA13 also tend to present with epilepsy
, an inability to run, and increased reflexes. This cerebellar dysfunction is permanent and progressive. SCA13 is cased by mutations in KCNC3
, a gene encoding a voltage-gated potassium channel
KV3.3. There are two known mutations in this gene causative for SCA13. Unlike many other types of SCA, these are not polyglutamine expansions but, rather, point mutations resulting in channels with no current or altered kinetics.
, mental retardation
, and nystagmus. Symptoms and age of onset can vary slightly according to the causative mutation.
s, as is the case for some other SCA subtypes, where it is believed to play an important role in facilitating high-frequency action potential
firing. There are two known mutations in this gene associated with SCA13. The first mutation, R420H, is located in the voltage-sensing S4 segment of the channel. As this mutation neutralizes a site important for voltage sensing, it is not surprising that it results in non-conducting channels. Neuron
s expressing such channels are unable to follow high-frequency input with adequate fidelity.
The second SCA13 associated mutation, F448L, results in functional channels that have altered kinetics. The voltage for half activation of these channels (V½) is shifted 13mV hyperpolarized compared to wild-type. Deactivation of these channels is also slowed drastically compared to wild-type. This results in neurons with longer after-hyperpolarizations and thus, a decreased maximal firing rate.
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:...
, is characterized by 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...
, nystagmus, and 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...
of gait, stance and the limbs due to cerebellar dysfunction. Patients with SCA13 also tend to present with epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
, an inability to run, and increased reflexes. This cerebellar dysfunction is permanent and progressive. SCA13 is cased by mutations in KCNC3
KCNC3
Potassium voltage-gated channel, Shaw-related subfamily, member 3 also known as KCNC3 or Kv3.3 is a protein which in humans is encoded by the KCNC3.- Function :...
, a gene encoding a 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....
KV3.3. There are two known mutations in this gene causative for SCA13. Unlike many other types of SCA, these are not polyglutamine expansions but, rather, point mutations resulting in channels with no current or altered kinetics.
Signs and symptoms
SCA13 is typified by early onset, mildly progressive cerebellar ataxia with accompanying dysarthriaDysarthria
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...
, mental retardation
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
, and nystagmus. Symptoms and age of onset can vary slightly according to the causative mutation.
Pathophysiology
Mutations in KCNC3 are responsible for SCA13. This gene is expressed heavily in 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, as is the case for some other SCA subtypes, where it is believed to play an important role in facilitating high-frequency 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...
firing. There are two known mutations in this gene associated with SCA13. The first mutation, R420H, is located in the voltage-sensing S4 segment of the channel. As this mutation neutralizes a site important for voltage sensing, it is not surprising that it results in non-conducting channels. 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 expressing such channels are unable to follow high-frequency input with adequate fidelity.
The second SCA13 associated mutation, F448L, results in functional channels that have altered kinetics. The voltage for half activation of these channels (V½) is shifted 13mV hyperpolarized compared to wild-type. Deactivation of these channels is also slowed drastically compared to wild-type. This results in neurons with longer after-hyperpolarizations and thus, a decreased maximal firing rate.