Spinocerebellar ataxia (SCA) is a progressive, degenerative, genetic disease with multiple types, each of which could be considered a neurological condition in its own right. An estimated 150,000 people in the United States have a diagnosis of spinocerebellar ataxia at any given time. SCA is hereditary, progressive, degenerative. There is no known effective treatment or cure. SCA can affect anyone of any age. The disease is caused by either a recessive or dominant gene. In many cases people are not aware that they carry a relevant gene until they have children who begin to show signs of having the disorder. Currently, research is being conducted at universities, such as the University of Minnesota, to elucidate many of the unknown characteristics of the disease.
Signs and symptoms Spinocerebellar ataxia (SCA) is one of a group of genetic disorders characterized by slowly progressive incoordination of gait and is often associated with poor coordination of hands, speech, and eye movements. A review of different clinical features among SCA subtypes was recently published describing the frequency of non-cerebellar features, like parkinsonism, chorea, pyramidalism, cognitive impairment, peripheral neuropathy, seizures, among others. As with other forms of ataxia, SCA frequently results in atrophy of the cerebellum, — Gives a concise description of SCA, along with a picture of shrunken degenerated cerebellum. loss of fine coordination of muscle movements leading to unsteady and clumsy motion, and other symptoms. Ocular deficits can be quantified using the SODA scale.
The symptoms of an ataxia vary with the specific type and with the individual patient. Many subtypes of spinocerebellar ataxia result in cases where an individual retains full mental capacity but progressively loses physical control, but nearly half of the identified subtypes result in cognitive dysfunction, dementia, and intellectual disability.
Cause The hereditary ataxias are categorized by mode of inheritance and causative gene or chromosomal locus. The hereditary ataxias can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Many types of autosomal dominant cerebellar ataxias for which specific genetic information is available are now known. Synonyms for autosomal-dominant cerebellar ataxias (ADCA) used prior to the current understanding of the molecular genetics were Marie's ataxia, inherited olivopontocerebellar atrophy, cerebello-olivary atrophy, or the more generic term "spinocerebellar degeneration". (Spinocerebellar degeneration is a rare inherited neurological disorder of the central nervous system characterized by the slow degeneration of certain areas of the brain. There are three forms of spinocerebellar degeneration: Types 1, 2, 3. Symptoms begin during adulthood.) There are five typical autosomal-recessive disorders in which ataxia is a prominent feature: Friedreich ataxia, ataxia-telangiectasia, ataxia with vitamin E deficiency, ataxia with oculomotor apraxia (AOA), spastic ataxia. Disorder subdivisions: Friedreich's ataxia, spinocerebellar ataxia, ataxia telangiectasia, vasomotor ataxia, vestibulocerebellar, ataxiadynamia, ataxiophemia, and olivopontocerebellar atrophy. There have been reported cases where a polyglutamine expansion may lengthen when passed down, which often can result in an earlier age-of-onset and a more severe disease phenotype for individuals who inherit the disease allele. This falls under the category of genetic anticipation. Several types of SCA are characterized by repeat expansion of the trinucleotide sequence CAG in DNA that encodes a polyglutamine repeat tract in protein. The expansion of CAG repeats over successive generations appears to be due to slipped strand mispairing during DNA replication or DNA repair.
Diagnosis and classification Classification A few SCAs remain unspecified and can not be precisely diagnosed, but in the last decade genetic testing has allowed precise identification of dozens of different SCAs and more tests are being added each year. In 2008, a genetic ataxia blood test developed to test for 12 types of SCA, Friedreich's ataxia, and several others. However, since not every SCA has been genetically identified some SCAs are still diagnosed by neurological examination, which may include a physical exam, family history, MRI scanning of the brain and spine, and spinal tap.www.ataxia.org
Many SCAs below fall under the category of polyglutamine diseases, which are caused when a disease-associated protein (i.e., ataxin-1, ataxin-3, etc.) contains a large number of repeats of glutamine residues, termed a polyQ sequence or a "CAG trinucleotide repeat" disease for either the one-letter designation or codon for glutamine respectively. The threshold for symptoms in most forms of SCA is around 35, though for SCA3 it extends beyond 50. Most polyglutamine diseases are dominant due to the interactions of resulting polyQ tail.
The first ataxia gene was identified in 1993 and called "Spinocerebellar ataxia type 1" (SCA1); later genes were called SCA2, SCA3, etc. Usually, the "type" number of "SCA" refers to the order in which the gene was found. At this time, there are at least 49 different gene mutations that have been found.
The following is a list of some of the many types of Spinocerebellar ataxia.
SCA TypeAverage Onset Age(Range in Years)Average Duration(Range in Years)Clinical signs and symptomsCommon originProblemswith DNASCA1 (ATXN1)4th decade(<10 to >60)15 years(10–35)Hypermetric saccades, slow saccades, upper motor neuron(note: saccades relates to eye movement) CAG repeat, 6p (Ataxin 1)SCA2 (ATXN2)3rd–4th decade(<10 to >60)10 years(1–30)Diminished velocity saccadesareflexia (absence of neurologic reflexes)CubaCAG repeat, 12qSCA3 (MJD) (ATXN3)4th decade(10–70)10 years(1–20)Also called Machado-Joseph disease (MJD)Gaze-evoked nystagmus (a rapid, involuntary, oscillatory motion of the eyeball)upper motor neuronslow saccadesAzores(Portugal)CAG repeat, 14qSCA4 (ZFHX3)4th–7th decade(19–72)Decadesareflexia (absence of neurologic reflexes) Chromosome 16qSCA5 (SPTBN2)3rd–4th decade(10–68)>25 yearsPure cerebellar Chromosome 11SCA6 (CACNA1A)5th–6th decade(19–71)>25 yearsDownbeating nystagmus, positional vertigoSymptoms can appear for the first time as late as 65 years old. CAG repeat, 19pCalcium channel geneSCA7 (ATXN7)3rd–4th decade(0.5–60)20 years(1–45; early onset correlates with shorter duration)Macular degeneration, upper motor neuron, slow saccades CAG repeat, 3p (Ataxin 7)SCA8 (IOSCA)39 yrs(18–65)Normal lifespanGait ataxia, dysarthria, Horizontal nystagmus (a rapid, involuntary, oscillatory motion of the eyeball), dysphagia, lack of coordination/clumsiness CTG repeat, 13qSCA10 (ATXN10)36 years9 yearsataxia, seizuresMexicoChromosome 22q linkedpentanucleotide repeatSCA11 (TTBK2)30 yrs(15–70)Normal lifespanMild, remain ambulatory (able to walk about on one's own) 15qSCA12 (PPP2R2B)33 yrs(8–55) Head and hand tremor,akinesia (loss of normal motor function, resulting in impaired muscle movement) CAG repeat, 5qSCA13 (KCNC3)Childhood or adulthood depending on mutationDepending on KCNC3 (a kind of gene)Intellectual disability 19qSCA14 (PRKCG)28 yrs(12–42)Decades(1–30)Myoclonus (a sudden twitching of muscles or parts of muscles, without any rhythm or pattern, occurring in various brain disorders) 19qSCA16 (ITPR1)39 yrs(20–66)1–40 yearsHead and hand tremor 8qSCA17 (TBP) CAG repeat, 6q (TATA-binding protein)SCA19, SCA22 (KCND3) Mild cerebellar syndrome, dysarthria SCA251.5–39 yrsUnknownataxia with sensory neuropathy, vomiting and gastrointestinal pain. 2pSCA27 (FGF14)15–20 yrsUnknownataxia with poor cognition, dyskinesias and tremor. FGF14 13q34SCA3540–48 yearsUnknowngait and limb ataxia, dysarthria, ocular dysmetria, intention tremor, pseudobulbar palsy, spasmodic torticollis, extensor plantar responses, reduced proprioception and hyperreflexiaChinatransglutaminase 6 (TGM6) located at chromosome 20p13SCA365th and 6th decade (adulthood)Decadesataxia, hyperrheflexia, dysarthria, fasciculations of the tongue with subsequent wasting of the tongueGalicia (Spain)NOP56SCA37AdulthoodDecadesdysarthria, slowly progressive gait and limb ataxia with severe dysmetria in the lower extremities, mild dysmetria in the upper extremities, dysphagia, and abnormal ocular movementsProvince of Huelva (Spain)DAB1
Others include SCA18, SCA20, SCA21, SCA23, SCA26, SCA28, and SCA29.
Four X-linked types have been described (, , , ), but only the first of these has so far been tied to a gene (SCAX1). Name OMIM RareDiseases Other Anemia, sideroblastic spinocerebellar ataxia; Pagon Bird Detter syndrome
Friedreich's ataxia; Spinocerebellar ataxia, Friedreich
Infantile onset Spinocerebellar ataxia
Spinocerebellar ataxia 1
Spinocerebellar ataxia 2
Spinocerebellar ataxia 3; Machado Joseph disease
Spinocerebellar ataxia 4
Spinocerebellar ataxia 5
Spinocerebellar ataxia 7
Spinocerebellar ataxia 8
Spinocerebellar ataxia 13
Spinocerebellar ataxia 18
Spinocerebellar ataxia 19
Spinocerebellar ataxia 20
Spinocerebellar ataxia 21
Spinocerebellar ataxia 23
Spinocerebellar ataxia 25
Spinocerebellar ataxia 26
Spinocerebellar ataxia 28
Spinocerebellar ataxia 30
Spinocerebellar ataxia 35
Spinocerebellar ataxia amyotrophy deafness syndrome
ORPHA:2074 at Orphanet Spinocerebellar ataxia, autosomal recessive 1
Spinocerebellar ataxia, autosomal recessive 3
Spinocerebellar ataxia, autosomal recessive 4
Spinocerebellar ataxia, autosomal recessive 5
Spinocerebellar ataxia, autosomal recessive 6
Spinocerebellar ataxia, autosomal recessive 21 - mutation in SCYL1
ORPHA:466794 Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy
Spinocerebellar ataxia, X-linked, 2
Spinocerebellar ataxia, X-linked, 3
Spinocerebellar ataxia, X-linked, 4
Treatment
Medication There is no cure for spinocerebellar ataxia, which is currently considered to be a progressive and irreversible disease, although not all types cause equally severe disability.
In general, treatments are directed towards alleviating symptoms, not the disease itself. Many patients with hereditary or idiopathic forms of ataxia have other symptoms in addition to ataxia. Medications or other therapies might be appropriate for some of these symptoms, which could include tremor, stiffness, depression, spasticity, and sleep disorders, among others. Both onset of initial symptoms and duration of disease are variable. If the disease is caused by a polyglutamine trinucleotide repeat CAG expansion, a longer expansion may lead to an earlier onset and a more radical progression of clinical symptoms. Typically, a person with this disease will eventually be unable to perform daily tasks (ADLs). However, rehabilitation therapists can help patients to maximize their ability of self-care and delay deterioration to certain extent. Researchers are exploring multiple avenues for a cure including RNA interference (RNAi) technology, the use of stem cells, and several other avenues.
On January 18, 2017, BioBlast Pharma announced completion of Phase 2a clinical trials of their medication, trehalose, in the treatment of SCA3. BioBlast has received FDA Fast Track status and orphan drug status for their treatment. The information provided by BioBlast in their research indicates that they hope this treatment may prove efficacious in other SCA treatments that have similar pathology related to PolyA and PolyQ diseases.
In addition, Dr. Beverly Davidson has been working on a methodology using RNAi technology to find a potential cure for over 2 decades. Her research began in the mid-1990s and progressed to work with mouse models about a decade later and most recently has moved to a study with non-human primates. The results from her most recent research "are supportive of clinical application of this gene therapy".