Spinocerebellar ataxia type-6
Encyclopedia
Spinocerebellar ataxia type 6 (SCA6) 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, SCA 6 is not fatal. This cerebellar function is permanent and progressive, differentiating it from episodic ataxia
type 2 (EA2) where said dysfunction is episodic. In some SCA6 families, some members show these classic signs of SCA6 while others show signs more similar to EA2, suggesting that there is some phenotypic overlap between the two disorders. SCA6 is caused by mutations in CACNA1A, a gene encoding a calcium channel
α subunit. These mutations tend to be trinucleotide repeats of CAG leading to stretches of glutamine
greater than 19 and these mutant proteins form intracellular aggregations. Unlike many other polyglutamine expansion disorders expansion length is not a determining factor for the age that symptoms present.
and dysarthria
, likely caused by cerebellar atrophy. Prior to diagnosis and the onset of major symptoms, patients often report a feeling of "wooziness" and momentary imbalance when turning corners or making rapid movements. The age at which symptoms first occur varies widely, from age 19 to 71, but is typically between 43 and 52. Other major signs of SCA6 are the loss of vibratory and proprioceptive
sensation and nystagmus.
While most patients present with these severe progressive symptoms, others, sometimes within the same family, display episodic non-progressive symptoms more similar to episodic ataxia. Still others present with symptoms common to both SCA6 and familial hemiplegic migraine
.
encoding gene CACNA1A. This gene has two splice forms
, "Q-type" and "P-type", and the polyglutamine
coding CAG expansion occurs in the P-type splice form. This form is expressed heavily in the cerebellum
where it is localized in Purkinje cell
s. In Purkinje cells from SCA6 patients, mutant Cav2.1 proteins form ovular intracellular inclusions, or aggregations, similar in many ways to those seen in other polyglutamine expansion disorders such as Huntington's disease
. In cell culture models of the disease, this leads to early apoptotic cell death
.
Interestingly, mutant channels that are able to traffic properly to the membrane have a negatively shifted voltage-dependence of inactivation. The result of this is that the channels are active for a shorter amount of time and, consequently, cell excitability is decreased.
There are also a number of point mutations resulting in patients with phenotypes reminiscent of episodic ataxia and SCA6 (C271Y, G293R and R1664Q) or familial hemiplegic migraine
and SCA6 (R583Q and I1710T). C287Y and G293R are both located in the pore region of domain 1 and are present in a single family each. Expression of these mutant channels results in cells with drastically decreased current density compared to wild-type expressing cells. In cell-based assays, it was found that these mutant channels aggregate in the endoplasmic reticulum
, not dissimilar from that seen in the CAG expansion mutants above. R1664Q is in the 4th transmembrane spanning segment of domain 4 and, presumably, affects the channel's voltage dependence of activation. Little is known about the point mutations resulting in overlapping phenotypes of familial hemiplegic migraine
and episodic ataxia
. R583Q is present in the 4th transmembrane spanning region of domain 2 while the I1710T mutation is segment 5 of domain 4.
, SCA6 accounts for 10-25% of all autosomal dominant cases of SCA (SCA itself having a prevalence of 1 in 100,000). This prevalence in lower in Japan
, however, where SCA6 accounts for only ~6% of spinocerebellar ataxias. In Australia
, SCA6 accounts for 30% of spinocerebellar ataxia cases while 11% in the Dutch.
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...
, oculomotor disorders, incontinence
Urinary incontinence
Urinary incontinence is any involuntary leakage of urine. It is a common and distressing problem, which may have a profound impact on quality of life. Urinary incontinence almost always results from an underlying treatable medical condition but is under-reported to medical practitioners...
, peripheral neuropathy
Peripheral neuropathy
Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness....
, 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. Unlike other types, SCA 6 is not fatal. This cerebellar function is permanent and progressive, differentiating it from 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 (EA2) where said dysfunction is episodic. In some SCA6 families, some members show these classic signs of SCA6 while others show signs more similar to EA2, suggesting that there is some phenotypic overlap between the two disorders. SCA6 is caused by mutations in CACNA1A, a gene encoding a 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. These mutations tend to be trinucleotide repeats of CAG leading to stretches of glutamine
Glutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
greater than 19 and these mutant proteins form intracellular aggregations. Unlike many other polyglutamine expansion disorders expansion length is not a determining factor for the age that symptoms present.
Signs and symptoms
SCA6 is typified by progressive and permanent cerebellar dysfunction. These cerebellar signs include 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...
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...
, likely caused by cerebellar atrophy. Prior to diagnosis and the onset of major symptoms, patients often report a feeling of "wooziness" and momentary imbalance when turning corners or making rapid movements. The age at which symptoms first occur varies widely, from age 19 to 71, but is typically between 43 and 52. Other major signs of SCA6 are the loss of vibratory and proprioceptive
Proprioception
Proprioception , from Latin proprius, meaning "one's own" and perception, is the sense of the relative position of neighbouring parts of the body and strength of effort being employed in movement...
sensation and nystagmus.
While most patients present with these severe progressive symptoms, others, sometimes within the same family, display episodic non-progressive symptoms more similar to episodic ataxia. Still others present with symptoms common to both SCA6 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...
.
Pathophysiology
Most cases of SCA6 are a result of CAG repeat expansion beyond the normal range, i.e., more than 19 repeats, in the Cav2.1 calcium channelCalcium 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:...
encoding gene CACNA1A. This gene has two splice forms
Splicing (genetics)
In molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation...
, "Q-type" and "P-type", and the polyglutamine
Glutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
coding CAG expansion occurs in the P-type splice form. This form is expressed heavily 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...
where it is localized 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. In Purkinje cells from SCA6 patients, mutant Cav2.1 proteins form ovular intracellular inclusions, or aggregations, similar in many ways to those seen in other polyglutamine expansion disorders such as Huntington's disease
Huntington's disease
Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...
. In cell culture models of the disease, this leads to early apoptotic cell death
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
.
Interestingly, mutant channels that are able to traffic properly to the membrane have a negatively shifted voltage-dependence of inactivation. The result of this is that the channels are active for a shorter amount of time and, consequently, cell excitability is decreased.
There are also a number of point mutations resulting in patients with phenotypes reminiscent of episodic ataxia and SCA6 (C271Y, G293R and R1664Q) or 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...
and SCA6 (R583Q and I1710T). C287Y and G293R are both located in the pore region of domain 1 and are present in a single family each. Expression of these mutant channels results in cells with drastically decreased current density compared to wild-type expressing cells. In cell-based assays, it was found that these mutant channels aggregate in the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
, not dissimilar from that seen in the CAG expansion mutants above. R1664Q is in the 4th transmembrane spanning segment of domain 4 and, presumably, affects the channel's voltage dependence of activation. Little is known about the point mutations resulting in overlapping phenotypes of 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...
and 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...
. R583Q is present in the 4th transmembrane spanning region of domain 2 while the I1710T mutation is segment 5 of domain 4.
Prognosis
There is currently no cure for SCA 6; however, there are supportive treatments that may be useful in managing symptoms.Prevention/Screening
There is no known prevention of spinocerebellar ataxia. Those who are believed to be at risk can have genetic sequencing of known SCA loci performed to confirm inheritance of the disorder.Epidemiology
The prevalence of SCA6 varies by culture. In GermanyGermany
Germany , officially the Federal Republic of Germany , is a federal parliamentary republic in Europe. The country consists of 16 states while the capital and largest city is Berlin. Germany covers an area of 357,021 km2 and has a largely temperate seasonal climate...
, SCA6 accounts for 10-25% of all autosomal dominant cases of SCA (SCA itself having a prevalence of 1 in 100,000). This prevalence in lower in Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...
, however, where SCA6 accounts for only ~6% of spinocerebellar ataxias. In Australia
Australia
Australia , officially the Commonwealth of Australia, is a country in the Southern Hemisphere comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands in the Indian and Pacific Oceans. It is the world's sixth-largest country by total area...
, SCA6 accounts for 30% of spinocerebellar ataxia cases while 11% in the Dutch.
See also
- 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:...
- CerebellumCerebellumThe 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...
- Episodic ataxiaEpisodic ataxiaEpisodic 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...
- Familial hemiplegic migraineFamilial hemiplegic migraineFamilial 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...
- Huntington's diseaseHuntington's diseaseHuntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...
- Spinocerebellar ataxiaSpinocerebellar ataxiaSpinocerebellar ataxia is a progressive, degenerative, genetic disease with multiple types, each of which could be considered a disease in its own right.-Classification:...