Spinocerebellar ataxia | |
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Other names | Spinocerebellar atrophy or Spinocerebellar degeneration |
Cerebellum (in blue) of the human brain | |
Specialty | Neurology |
Spinocerebellar ataxia (SCA) is a progressive, degenerative, [1] 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, and often fatal. 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. [2]
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. [3] As with other forms of ataxia, SCA frequently results in atrophy of the cerebellum, [4] 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. [5]
The symptoms of an ataxia vary with the specific type and with the individual patient. In many cases a person with ataxia retains full mental capacity but progressively loses physical control.[ citation needed ]
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.[ citation needed ]
A few SCAs remain unspecified and can not be precisely diagnosed, but in the last decade[ as of? ] genetic testing has allowed precise identification of dozens of different SCAs and more tests are being added each year. [9] 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. [10]
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.[ citation needed ]
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.[ citation needed ]
The following is a list of some of the many types of Spinocerebellar ataxia.
SCA Type | Average Onset (Range in Years) | Average Duration (Range in Years) | What the patient experiences | Common origin | Problems with DNA |
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SCA1 [11] (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 [12] (ATXN2) | 3rd–4th decade (<10 to >60) | 10 years (1–30) | Diminished velocity saccades areflexia (absence of neurologic reflexes) | Cuba | CAG repeat, 12q |
SCA3 [13] (MJD) (ATXN3) | 4th decade (10–70) | 10 years (1–20) | Also called Machado-Joseph disease (MJD) [14] Gaze-evoked nystagmus (a rapid, involuntary, oscillatory motion of the eyeball) upper motor neuron slow saccades | Azores (Portugal) | CAG repeat, 14q |
SCA4 (PLEKHG4) | 4th–7th decade (19–72) | Decades | areflexia (absence of neurologic reflexes) | Chromosome 16q | |
SCA5 (SPTBN2) | 3rd–4th decade (10–68) | >25 years | Pure cerebellar | Chromosome 11 | |
SCA6 [15] (CACNA1A) | 5th–6th decade (19–71) | >25 years | Downbeating nystagmus, positional vertigo Symptoms can appear for the first time as late as 65 years old. | CAG repeat, 19p Calcium channel gene | |
SCA7 [16] (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 [17] (IOSCA) | 39 yrs (18–65) | Normal lifespan | Horizontal nystagmus (a rapid, involuntary, oscillatory motion of the eyeball), instability, lack of coordination | CTG repeat, [18] 13q | |
SCA10 [19] (ATXN10) | 36 years | 9 years | ataxia, seizures | Mexico | Chromosome 22q linked pentanucleotide repeat |
SCA11 (TTBK2) | 30 yrs (15–70) | Normal lifespan | Mild, remain ambulatory (able to walk about on one's own) | 15q | |
SCA12 [20] (PPP2R2B) | 33 yrs (8–55) | Head and hand tremor, akinesia (loss of normal motor function, resulting in impaired muscle movement) | CAG repeat, 5q | ||
SCA13 (KCNC3) | Childhood or adulthood depending on mutation | Depending on KCNC3 (a kind of gene) | Intellectual disability | 19q | |
SCA14 [21] (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) | 19q | |
SCA16 (ITPR1) | 39 yrs (20–66) | 1–40 years | Head and hand tremor | 8q | |
SCA17 (TBP) | CAG repeat, 6q (TATA-binding protein) | ||||
SCA19, SCA22 (KCND3 [22] ) | Mild cerebellar syndrome, dysarthria | ||||
SCA25 | 1.5–39 yrs | Unknown | ataxia with sensory neuropathy, vomiting and gastrointestinal pain. | 2p | |
SCA27 [23] (FGF14 [22] ) | 15–20 yrs | Unknown | ataxia with poor cognition, dyskinesias and tremor. | FGF14 13q34 | |
SCA35 | 40–48 years | Unknown | gait and limb ataxia, dysarthria, ocular dysmetria, intention tremor, pseudobulbar palsy, spasmodic torticollis, extensor plantar responses, reduced proprioception and hyperreflexia | China | transglutaminase 6 (TGM6) located at chromosome 20p13 |
SCA36 | 5th and 6th decade (adulthood) | Decades | ataxia, hyperrheflexia, dysarthria, fasciculations of the tongue with subsequent wasting of the tongue | NOP56 | |
SCA37 | Adulthood | Decades | dysarthria, slowly progressive gait and limb ataxia with severe dysmetria in the lower extremities, mild dysmetria in the upper extremities, dysphagia, and abnormal ocular movements | DAB1 |
Others include SCA18, SCA20, SCA21, SCA23, SCA26, SCA28, and SCA29.
Four X-linked types have been described ( 302500, 302600, 301790, 301840), but only the first of these has so far been tied to a gene (SCAX1).
Name | OMIM | RareDiseases | Other |
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Anemia, sideroblastic spinocerebellar ataxia; Pagon Bird Detter syndrome | 301310 | Disease ID 668 at NIH 's Office of Rare Diseases | |
Friedreich's ataxia; Spinocerebellar ataxia, Friedreich | 229300 | Disease ID 6468 at NIH 's Office of Rare Diseases | |
Infantile onset Spinocerebellar ataxia | 605361 | Disease ID 4062 at NIH 's Office of Rare Diseases | |
Spinocerebellar ataxia 1 | 164400 | Disease ID 4071 at NIH 's Office of Rare Diseases | |
Spinocerebellar ataxia 2 | 183090 | Disease ID 4072 at NIH 's Office of Rare Diseases | |
Spinocerebellar ataxia 3; Machado Joseph disease | 109150 | Disease ID 6801 at NIH 's Office of Rare Diseases | |
Spinocerebellar ataxia 4 | 600223 | Disease ID 9970 at NIH 's Office of Rare Diseases | |
Spinocerebellar ataxia 5 | 600224 | Disease ID 4953 at NIH 's Office of Rare Diseases | |
Spinocerebellar ataxia 7 | 164500 | Disease ID 4955 at NIH 's Office of Rare Diseases | |
Spinocerebellar ataxia 8 | 603680 | Disease ID 4956 at NIH 's Office of Rare Diseases | |
Spinocerebellar ataxia 13 | 605259 | Disease ID 9611 at NIH 's Office of Rare Diseases | |
Spinocerebellar ataxia 18 | 607458 | Disease ID 9976 at NIH 's Office of Rare Diseases | |
Spinocerebellar ataxia 19 | 607346 | Disease ID 9969 at NIH 's Office of Rare Diseases | |
Spinocerebellar ataxia 20 | 608687 | Disease ID 9997 at NIH 's Office of Rare Diseases | |
Spinocerebellar ataxia 21 | 607454 | Disease ID 9999 at NIH 's Office of Rare Diseases | |
Spinocerebellar ataxia 23 | 610245 | Disease ID 9950 at NIH 's Office of Rare Diseases | |
Spinocerebellar ataxia 25 | 608703 | Disease ID 9996 at NIH 's Office of Rare Diseases | |
Spinocerebellar ataxia 26 | 609306 | Disease ID 9995 at NIH 's Office of Rare Diseases | |
Spinocerebellar ataxia 28 | 610246 | Disease ID 9951 at NIH 's Office of Rare Diseases | |
Spinocerebellar ataxia 30 | 117360 | Disease ID 9975 at NIH 's Office of Rare Diseases | |
Spinocerebellar ataxia 35 | 613908 | Disease ID at NIH 's Office of Rare Diseases | |
Spinocerebellar ataxia amyotrophy deafness syndrome | Disease ID 2451 at NIH 's Office of Rare Diseases | ORPHA:2074 at Orphanet | |
Spinocerebellar ataxia, autosomal recessive 1 | 606002 | Disease ID 4949 at NIH 's Office of Rare Diseases | |
Spinocerebellar ataxia, autosomal recessive 3 | 271250 | Disease ID 9971 at NIH 's Office of Rare Diseases | |
Spinocerebellar ataxia, autosomal recessive 4 | 607317 | Disease ID 4952 at NIH 's Office of Rare Diseases | |
Spinocerebellar ataxia, autosomal recessive 5 | 606937 | Disease ID 9977 at NIH 's Office of Rare Diseases | |
Spinocerebellar ataxia, autosomal recessive 6 | 608029 | Disease ID 4954 at NIH 's Office of Rare Diseases | |
Spinocerebellar ataxia, autosomal recessive 21 - mutation in SCYL1 | Online Mendelian Inheritance in Man (OMIM): 616719 | ORPHA:466794 | |
Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy | 607250 | Disease ID 10000 at NIH 's Office of Rare Diseases | |
Spinocerebellar ataxia, X-linked, 2 | 302600 | Disease ID 9978 at NIH 's Office of Rare Diseases | |
Spinocerebellar ataxia, X-linked, 3 | 301790 | Disease ID 9981 at NIH 's Office of Rare Diseases | |
Spinocerebellar ataxia, X-linked, 4 | 301840 | Disease ID 9980 at NIH 's Office of Rare Diseases |
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. [24]
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). [25] However, rehabilitation therapists can help patients to maximize their ability of self-care and delay deterioration to certain extent. [26] Researchers are exploring multiple avenues for a cure including RNA interference (RNAi) technology, the use of stem cells, and several other avenues. [27]
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. [28] [29]
In addition, Dr. Beverly Davidson has been working on a methodology using RNAi technology to find a potential cure for over 2 decades. [30] 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". [31]
Finally, another gene transfer technology discovered in 2011 has also been shown by Boudreau et al. to hold great promise and offers yet another avenue to a potential future cure. [32]
N-Acetyl-Leucine is an orally administered, modified amino acid that is being developed as a novel treatment for multiple rare and common neurological disorders by IntraBio Inc (Oxford, United Kingdom). [33]
N-Acetyl-Leucine has been granted multiple orphan drug designations from the U.S. Food & Drug Administration (FDA) [34] and the European Medicines Agency (EMA) [35] for the treatment of various genetic diseases, including spinocerebellar ataxias. N-Acetyl-Leucine has also been granted Orphan Drug Designations in the US and EU for the related inherited cerebellar ataxia ataxia-telangiectasia U.S. Food & Drug Administration (FDA) [36] and the European Medicines Agency (EMA). [37]
Published case series studies have demonstrated the effects of acute treatment with N-Acetyl-Leucine for the treatment of inherited cerebellar ataxias, including spinocerebellar ataxias. [38] [39] These studies further demonstrated that the treatment is well tolerated, with a good safety profile.[ citation needed ] A multinational clinical trial investigating N-Acetyl-L-Leucine for the treatment of a related inherited cerebellar ataxia, ataxia-telangiectasia, began in 2019. [40]
IntraBio is also conducting parallel clinical trials with N-Acetyl-L-Leucine for the treatment of Niemann-Pick disease type C [41] and GM2 gangliosidosis (Tay-Sachs and Sandhoff disease). [42] Future opportunities to develop N-Acetyl-Leucine include Lewy body dementia, [43] amyotrophic lateral sclerosis, restless leg syndrome, multiple sclerosis, and migraine. [44]
Physical therapists can assist patients in maintaining their level of independence through therapeutic exercise programmes. One recent research report demonstrated a gain of two SARA points (Scale for the Assessment and Rating of Ataxia) from physical therapy. [45] In general, physical therapy emphasises postural balance and gait training for ataxia patients. [46] General conditioning such as range-of-motion exercises and muscle strengthening would also be included in therapeutic exercise programmes. Research showed that spinocerebellar ataxia 2 (SCA2) patients [47] with a mild stage of the disease gained significant improvement in static balance and neurological indices after six months of a physical therapy exercise training program. [48] Occupational therapists may assist patients with incoordination or ataxia issues through the use of adaptive devices. Such devices may include a cane, crutches, walker, or wheelchair for those with impaired gait. Other devices are available to assist with writing, feeding, and self care if hand and arm coordination are impaired. A randomised clinical trial revealed that an intensive rehabilitation program with physical and occupational therapies for patients with degenerative cerebellar diseases can significantly improve functional gains in ataxia, gait, and activities of daily living. Some level of improvement was shown to be maintained 24 weeks post-treatment. [49] Speech language pathologists may use both behavioral intervention strategies as well as augmentative and alternative communication devices to help patients with impaired speech.[ citation needed ]
Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements, that indicates dysfunction of parts of the nervous system that coordinate movement, such as the cerebellum.
Hereditary spastic paraplegia (HSP) is a group of inherited diseases whose main feature is a progressive gait disorder. The disease presents with progressive stiffness (spasticity) and contraction in the lower limbs. HSP is also known as hereditary spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell disease, or Strumpell-Lorrain disease. The symptoms are a result of dysfunction of long axons in the spinal cord. The affected cells are the primary motor neurons; therefore, the disease is an upper motor neuron disease. HSP is not a form of cerebral palsy even though it physically may appear and behave much the same as spastic diplegia. The origin of HSP is different from cerebral palsy. Despite this, some of the same anti-spasticity medications used in spastic cerebral palsy are sometimes used to treat HSP symptoms.
Ataxia–telangiectasia, also referred to as ataxia–telangiectasia syndrome or Louis–Bar syndrome, is a rare, neurodegenerative disease causing severe disability. Ataxia refers to poor coordination and telangiectasia to small dilated blood vessels, both of which are hallmarks of the disease. A–T affects many parts of the body:
Friedreich's ataxia is an autosomal-recessive genetic disease that causes difficulty walking, a loss of coordination in the arms and legs, and impaired speech that worsens over time. Symptoms generally start between 5 and 20 years of age. Many develop hypertrophic cardiomyopathy and require a mobility aid such as a cane, walker, or wheelchair in their teens. As the disease progresses, some affected people lose their sight and hearing. Other complications may include scoliosis and diabetes mellitus.
Machado–Joseph disease (MJD), also known as Machado–Joseph Azorean disease, Machado's disease, Joseph's disease or spinocerebellar ataxia type 3 (SCA3), is a rare autosomal dominantly inherited neurodegenerative disease that causes progressive cerebellar ataxia, which results in a lack of muscle control and coordination of the upper and lower extremities. The symptoms are caused by a genetic mutation that results in an expansion of abnormal "CAG" trinucleotide repeats in the ATXN3 gene that results in an abnormal form of the protein ataxin which causes degeneration of cells in the hindbrain. Some symptoms, such as clumsiness and rigidity, make MJD commonly mistaken for drunkenness or Parkinson's disease.
Cerebellar ataxia is a form of ataxia originating in the cerebellum. Non-progressive congenital ataxia (NPCA) is a classical presentation of cerebral ataxias.
The GM2 gangliosidoses are a group of three related genetic disorders that result from a deficiency of the enzyme beta-hexosaminidase. This enzyme catalyzes the biodegradation of fatty acid derivatives known as gangliosides. The diseases are better known by their individual names: Tay–Sachs disease, AB variant, and Sandhoff disease.
Ataxin 7 (ATXN7) is a protein of the SCA7 gene, which contains 892 amino acids with an expandable poly(Q) region close to the N-terminus. The expandable poly(Q) motif region in the protein contributes crucially to spinocerebellar ataxia (SCA) pathogenesis by the induction of intranuclear inclusion bodies. ATXN7 is associated with both olivopontocerebellar atrophy type 3 (OPCA3) and spinocerebellar ataxia type 7 (SCA7).
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, peripheral neuropathy, and ataxia of the gait, stance, and 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 the production of mutant proteins containing stretches of 20 or more consecutive glutamine residues; these proteins have an increased tendency to form intracellular agglomerations. Unlike many other polyglutamine expansion disorders expansion length is not a determining factor for the age that symptoms present.
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 caused 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.
Ataxin-2 is a protein that in humans is encoded by the ATXN2 gene. Mutations in ATXN2 cause spinocerebellar ataxia type 2 (SCA2).
Ataxin-3 is a protein that in humans is encoded by the ATXN3 gene.
Ataxin-10 is a protein that in humans is encoded by the ATXN10 gene.
Ataxin 8 opposite strand, also known as ATXN8OS, is a human gene.
Marinesco–Sjögren syndrome (MSS), sometimes spelled Marinescu–Sjögren syndrome, is a rare autosomal recessive disorder.
Autosomal recessive cerebellar ataxia type 1 (ARCA1) is a condition characterized by progressive problems with movement. Signs and symptoms of the disorder first appear in early to mid-adulthood. People with this condition initially experience impaired speech (dysarthria), problems with coordination and balance (ataxia), or both. They may also have difficulty with movements that involve judging distance or scale (dysmetria). Other features of ARCA1 include abnormal eye movements (nystagmus) and problems following the movements of objects with their eyes. The movement problems are slowly progressive, often resulting in the need for a cane, walker, or wheelchair.
Autosomal dominant cerebellar ataxia (ADCA) is a form of spinocerebellar ataxia inherited in an autosomal dominant manner. ADCA is a genetically inherited condition that causes deterioration of the nervous system leading to disorder and a decrease or loss of function to regions of the body.
Spinocerebellar ataxia type 1 (SCA1) is a rare autosomal dominant disorder, which, like other spinocerebellar ataxias, is characterized by neurological symptoms including dysarthria, hypermetric saccades, and ataxia of gait and stance. This cerebellar dysfunction is progressive and permanent. First onset of symptoms is normally between 30 and 40 years of age, though juvenile onset can occur. Death typically occurs within 10 to 30 years from onset.
Cerebellar degeneration is a condition in which cerebellar cells, otherwise known as neurons, become damaged and progressively weaken in the cerebellum. There are two types of cerebellar degeneration; paraneoplastic cerebellar degeneration, and alcoholic or nutritional cerebellar degeneration. As the cerebellum contributes to the coordination and regulation of motor activities, as well as controlling equilibrium of the human body, any degeneration to this part of the organ can be life-threatening. Cerebellar degeneration can result in disorders in fine movement, posture, and motor learning in humans, due to a disturbance of the vestibular system. This condition may not only cause cerebellar damage on a temporary or permanent basis, but can also affect other tissues of the central nervous system, those including the cerebral cortex, spinal cord and the brainstem.
Boucher-Neuhäuser syndrome is a very rare genetic disorder which is characterized by a triad consisting of cerebellar ataxia, chorioretinal dystrophy, and hypogonadism.
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