Spinocerebellar ataxia


Spinocerebellar ataxia 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, 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.

Signs and symptoms

Spinocerebellar ataxia 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, loss of fine coordination of muscle movements leading to unsteady and clumsy motion, and other symptoms.
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.

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.

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.
Many SCAs below fall under the category of polyglutamine diseases, which are caused when a disease-associated protein 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" ; 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 29 different gene mutations that have been found.
The following is a list of some of the many types of Spinocerebellar ataxia.
SCA TypeAverage Onset
Average Duration
What the patient experiencesCommon originProblems
with DNA
SCA1 4th decade
15 years
Hypermetric saccades, slow saccades, upper motor neuron
 CAG repeat, 6p
SCA2 3rd–4th decade
10 years
Diminished velocity saccades
areflexia 		CubaCAG repeat, 12q
SCA3 4th decade
10 years
Also called Machado-Joseph disease
Gaze-evoked nystagmus
upper motor neuron
slow saccades		Azores
CAG repeat, 14q
SCA4 4th–7th decade
Decadesareflexia Chromosome 16q
SCA5 3rd–4th decade
>25 yearsPure cerebellar Chromosome 11
SCA6 5th–6th decade
>25 yearsDownbeating nystagmus, positional vertigo
Symptoms can appear for the first time as late as 65 years old.		 CAG repeat, 19p
Calcium channel gene
SCA7 3rd–4th decade
20 years
Macular degeneration, upper motor neuron, slow saccades CAG repeat, 3p
SCA8 39 yrs
Normal lifespanHorizontal nystagmus, instability, lack of coordination CTG repeat, 13q
SCA10 36 years9 yearsataxia, seizuresMexicoChromosome 22q linked
pentanucleotide repeat
SCA11 30 yrs
Normal lifespanMild, remain 15q
SCA12 33 yrs
 Head and hand tremor,
akinesia 		CAG repeat, 5q
SCA13 Childhood or adulthood depending on mutationDepending on KCNC3 Mental retardation 19q
SCA14 28 yrs
Decades
Myoclonus 19q
SCA16 39 yrs
1–40 yearsHead and hand tremor 8q
SCA17 CAG repeat, 6q
SCA19, SCA22 Mild cerebellar syndrome, dysarthria
SCA251.5–39 yrsUnknownataxia with sensory neuropathy, vomiting and gastrointestinal pain. 2p
SCA27 15–20 yrsUnknownataxia with poor cognition, dyskinesias and tremor. FGF14 13q34
SCA3540–48 yearsUnknowngait and limb ataxia, dysarthria, ocular dysmetria, intention tremor, pseudobulbar palsy, spasmodic torticollis, extensor plantar responses, reduced proprioception and hyperreflexiaChinatransglutaminase 6 located at chromosome 20p13

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.'''
NameOMIMRareDiseasesOther
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 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
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 afflicted with this disease will eventually be unable to perform daily tasks. 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 RNAi and 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". Dr. Davidson along with Dr. Pedro Gonzalez-Alegre are currently working to move this technique into a Phase 1 clinical trial.
Finally, another gene transfer technology discovered in 2011 has also been shown by Dr. Davidson to hold great promise and offers yet another avenue to a potential future cure.

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.
N-Acetyl-Leucine has been granted multiple orphan drug designations from the U.S. Food & Drug Administration and the European Medicines Agency 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 and the European Medicines Agency.
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. These studies further demonstrated that the treatment is well tolerated, with a good safety profile.
A multinational clinical trial investigating N-Acetyl-L-Leucine for the treatment of a related inherited cerebellar ataxia, Ataxia-Telangiectasia, began in 2019.
IntraBio is also conducting parallel clinical trials with N-Acetyl-L-Leucine for the treatment of Niemann-Pick disease type C and GM2 Gangliosidosis. Future opportunities to develop N-Acetyl-Leucine include Lewy Body Dementia,Amyotrophic lateral sclerosis, Restless Leg Syndrome, Multiple Sclerosis, and Migraine

Rehabilitation

can assist patients in maintaining their level of independence through therapeutic exercise programmes. One recent research report demonstrated a gain of 2 SARA points from physical therapy. In general, physical therapy emphasises postural balance and gait training for ataxia patients. 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 patients 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. 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. Speech language pathologists may use both behavioral intervention strategies as well as augmentative and alternative communication devices to help patients with impaired speech.