Spinocerebellar ataxia (SCA) is a
progressive,
degenerative,
genetic disease
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
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
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. Ataxia is a clinical manifestation indicating dysfunction of ...
(SCA) is one of a group of
genetic disorder
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
s 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
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. Ataxia is a clinical manifestation indicating dysfunction of ...
, SCA frequently results in
atrophy of the
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. In many cases a person with ataxia retains full
mental capacity
Intelligence has been defined in many ways: the capacity for abstraction, logic, understanding, self-awareness, learning, emotional knowledge, reasoning, planning, creativity, critical thinking, and problem-solving. More generally, it can b ...
but progressively loses physical control.
Cause
The
hereditary ataxias are categorized by mode of inheritance and causative
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
or
chromosomal
A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
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
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
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
Friedreich's ataxia (FRDA or FA) is an autosomal-recessive genetic disease that causes difficulty walking, a loss of sensation in the arms and legs, and impaired speech that worsens over time. Symptoms generally start between 5 and 20 year ...
,
ataxia-telangiectasia, ataxia with vitamin E deficiency, ataxia with oculomotor apraxia (AOA),
spastic ataxia
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 hereditar ...
. Disorder subdivisions: Friedreich's ataxia, Spinocerebellar ataxia, Ataxia telangiectasia, Vasomotor ataxia, Vestibulocerebellar, Ataxiadynamia, Ataxiophemia, and
Olivopontocerebellar atrophy
Olivopontocerebellar atrophy (OPCA) is the degeneration of neurons in specific areas of the brain – the cerebellum, pons, and inferior olivary nucleus. OPCA is present in several neurodegenerative syndromes, including inherited and non-inherited ...
.
* 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
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
. This falls under the category of
genetic anticipation In genetics, anticipation is a phenomenon whereby as a genetic disorder is passed on to the next generation, the symptoms of the genetic disorder become apparent at an earlier age with each generation. In most cases, an increase in the severity of ...
.
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
Slipped strand mispairing (SSM), (also known as replication slippage), is a mutation process which occurs during DNA replication. It involves denaturation and displacement of the DNA strands, resulting in mispairing of the complementary bases. ...
during
DNA replication
In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inheritanc ...
or
DNA repair
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...
.
Image:Autosomal dominant - en.svg, There are numerous types of autosomal-dominant cerebellar ataxias
Image:autorecessive.svg, There are five typical autosomal recessive disorders in which ataxia is a prominent feature
Diagnosis
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
Friedreich's ataxia (FRDA or FA) is an autosomal-recessive genetic disease that causes difficulty walking, a loss of sensation in the arms and legs, and impaired speech that worsens over time. Symptoms generally start between 5 and 20 year ...
, 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 (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
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
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 29 different gene mutations that have been found.
The following is a list of some of the many types of ''Spinocerebellar ataxia''.
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).
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
Spasticity () is a feature of altered skeletal muscle performance with a combination of paralysis, increased tendon reflex activity, and hypertonia. It is also colloquially referred to as an unusual "tightness", stiffness, or "pull" of muscles ...
, and
sleep disorder
A sleep disorder, or somnipathy, is a medical disorder of an individual's sleep patterns. Some sleep disorders are severe enough to interfere with normal physical, mental, social and emotional functioning. Polysomnography and actigraphy are tests ...
s, 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 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".
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.
N-Acetyl-Leucine
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).
N-Acetyl-Leucine has been granted multiple orphan drug designations from the
U.S. Food & Drug Administration (FDA) and the
European Medicines Agency (EMA) 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) and the
European Medicines Agency (EMA).
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 (
Tay-Sachs and
Sandhoff Disease). Future opportunities to develop N-Acetyl-Leucine include
Lewy Body Dementia
Lewy body dementias are two similar and common subtypes of dementia—dementia with Lewy bodies (DLB) and
Parkinson's disease dementia (PDD). Both are characterized by changes in thinking, movement, behavior, and mood. The two conditions have si ...
,
Amyotrophic lateral sclerosis,
Restless Leg Syndrome
Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is generally a long-term disorder that causes a strong urge to move one's legs. There is often an unpleasant feeling in the legs that improves somewhat by moving them. This ...
,
Multiple Sclerosis, and
Migraine.
Rehabilitation
Physical therapists
Physical therapy (PT), also known as physiotherapy, is one of the allied health professions. It is provided by physical therapists who promote, maintain, or restore health through physical examination, diagnosis, management, prognosis, patien ...
can assist patients in maintaining their level of independence through therapeutic exercise programmes. One recent research report demonstrated a gain of 2 SARA points (Scale for the Assessment and Rating of Ataxia) from physical therapy. In general,
physical therapy emphasises postural balance and gait training for
ataxia
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. Ataxia is a clinical manifestation indicating dysfunction of ...
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 (SCA2) 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
Occupational therapists (OTs) are health care professionals specializing in occupational therapy and occupational science. OTs and occupational therapy assistants (OTAs) use scientific bases and a holistic perspective to promote a person's abili ...
may assist patients with incoordination or
ataxia
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. Ataxia is a clinical manifestation indicating dysfunction of ...
issues through the use of adaptive devices. Such devices may include a cane, crutches, walker, or
wheelchair
A wheelchair is a chair with wheels, used when walking is difficult or impossible due to illness, injury, problems related to old age, or disability. These can include spinal cord injuries ( paraplegia, hemiplegia, and quadriplegia), cerebr ...
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
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. Ataxia is a clinical manifestation indicating dysfunction of ...
,
gait, and
activities of daily living
Activity may refer to:
* Action (philosophy), in general
* Human activity: human behavior, in sociology behavior may refer to all basic human actions, economics may study human economic activities and along with cybernetics and psychology may s ...
. 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.
References
Further reading
* In
* In
* In
* In
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External links
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{{DEFAULTSORT:Spinocerebellar Ataxia
Autosomal dominant disorders
Systemic atrophies primarily affecting the central nervous system
Neurodegenerative disorders
Cytoskeletal defects
Rare diseases