REVIEW: SYSTEMATIC (SYSTEMATIC REVIEW OF A SUBJECT)
|Year : 2013 | Volume
| Issue : 3 | Page : 295-303
An update on Spino-cerebellar ataxias
Banashree Mondal, Pritikanta Paul, Madhuparna Paul, Hrishikesh Kumar
R.G. Chamaria Medical Research Center Institute of Neurosciences, Kolkata, India
|Date of Submission||19-Nov-2012|
|Date of Decision||09-Dec-2012|
|Date of Acceptance||16-Jan-2013|
|Date of Web Publication||26-Aug-2013|
Director, R.G. Chamaria Medical Research Center, Institute of Neurosciences, 185/1 AJC Bose Road, Kolkata - 700 017
Source of Support: None, Conflict of Interest: None
| Abstract|| |
The dominantly inherited ataxias, also known as Spino-cerebellar ataxias (SCAs), are rapidly expanding entities. New mutations are being identified at remarkable regularity. Recent awareness of molecular abnormalities in SCAs has addressed some of the long sought questions, but gaps in knowledge still exist. Three major categories of SCAs, according to molecular mechanisms, have evolved over recent few years: Polyglutamate expansion ataxia, non-coding zone repeat ataxia, and ataxia due to conventional mutation. Using the fulcrum of these mechanisms, the article provides an update of SCAs. Shared and specific clinical features, genetic abnormalities, and possible links between molecular abnormalities and cerebellar degeneration have been discussed. Emphasis has been placed on the mechanisms of polyglutamate toxicity.
Keywords: Autosomal dominant cerebellar ataxia, polyglutamate, spino-cerebellar ataxia
|How to cite this article:|
Mondal B, Paul P, Paul M, Kumar H. An update on Spino-cerebellar ataxias. Ann Indian Acad Neurol 2013;16:295-303
| Introduction|| |
Genetic ataxias have long been classified according to the pattern of inheritance into autosomal dominant (AD) and autosomal recessive (AR) types. Harding's classification of Autosomal Dominant Cerebellar Ataxia (ADCA) gained wide acceptance and survived the onslaught of time, probably because of its simplicity and remarkable correlation with the later evolved classification of genetic ataxias [Table 1].  With discovery of more and more genes, the ADCA were named as Spino-cerebellar ataxias (SCA) and were given a numerical identification according to sequence of gene recognition. Discovery of ataxia resulting for abnormal deoxyribonucleic acid (DNA) repair mechanism, mitochondrial DNA mutation, and ion channel disorders widened the scope of genetic ataxia.
Over recent years, it was observed that many genetic ataxias share a similar mechanism of disease causation. To date, 22 different genes (SCA1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15, 17, 22, 23, 27, 28, 31, 35, 36, and dentatorubropallidoluysian atrophy [DRPLA]) and additionally 10 different gene loci (SCA 4, 18, 19, 20, 21, 25, 26, 29, 30, and 32) are identified.  The fact raises the need for a revision to the classification of hereditary ataxias so that current concepts of molecular mechanisms can be included. An ideal system of classification would be based on clinical presentation, mode of inheritance, and include molecular/genetic/biochemical pathogenesis. Such an ideal system is difficult to formulate at present because of the gaps in the knowledge of molecular mechanism.
AD versus AR ataxias
AD forms of ataxia are distinguished from AR forms by inheritance pattern but sporadic mutation, incomplete penetrance, and pseudo-dominant inheritance of recessive ataxias might be misleading. Following pointers help in differentiating them:
- AD forms are usually adult onset and AR forms are childhood onset. But adult onset forms of AR ataxia have been increasingly recognized and awareness about them is important. Adult onset forms of Friedreich's ataxia (FA), Tay Sach's disease, and Niemann Pick's disease are few examples.
- Non-neurological manifestations are more common in AR form (e.g., Diabetes mellitus and cardiomyopathy in FA).
- AD ataxia can show clinical overlap with other AD neurodegenerative conditions such as familial Parkinson's disease and Huntington's disease (HD).
SCAs formerly known as ADCAs are a heterogenous group of neurodegenerative disorder characterized by cerebellar ataxia, variably associated with other neurological signs. Thirty-one genes and gene loci have been identified till the time of writing. They bear the numerical identification according to temporal sequence of discovery. But the list keeps on expanding and a genetic locus for new SCA is discovered almost every year. Along with Episodic ataxias and DRPLA, they form the whole block of dominantly inherited ataxias. Genetic loci and salient features of various SCAs have been produced in [Table 1] for easy reference. In many instances, the phenotype is not restricted to cerebellar dysfunction but includes complex multi-systemic neurological deficits. The name Spino-cereballar ataxia indicates the involvement of at least two systems: The spinal cord and the cerebellum. Eleven of 22 known SCA gene mutations are caused by repeat expansions in the corresponding proteins, sharing the same mutational mechanism. All other SCAs are caused by either conventional mutations or large rearrangements in genes with different functions. That includes glutamate signaling, (SCA5), calcium signaling (SCA 15,16), channel functions (SCA13, SCA14, SCA27, tau regulation (SCA11), mitochondrial activity (SCA28) and Ribonucleic Acid alteration (SCA31).  SCA in apparently sporadic cases can be explained by reduced penetrance, death of relative before appearance of symptom, presence of marked anticipation, adoption, and de novo mutation.
SCAs have estimated prevalence of 0.8-3.0/100000 population but it is highly variable depending upon the geographical area and population studied. , SCA 3 is the most common type worldwide. 
Age of onset
Usual age of onset is third to fourth decade but there is marked variability. Many of the SCAs show phenomenon of anticipation where there is decrease in age of onset and increased severity in successive generations. Homozygosity has also shown to lower the age of onset in SCA 3, SCA 6, and DRPLA. ,
Categories of SCA according to molecular mechanism
- SCA having expansion of χΨτoσinε αδεninε guαninε (CAG) repeat at coding sequence :  SCA 1, 2, 3, 6, 7, 12, and 17. CAG codes for glutamine and expanded CAG repeat disorders with ataxias are collectively called as Polyglutamate SCA. DRPLA, HD, and Bulbo-spinal muscular atrophy (Kennedy disease) also share the same CAG repeat abnormality. These disorders have a number of common clinical, genetic, and physiological features.
- SCAs having expansion of non-coding area (micro-satellite expansion): SCA 8, 10, 31, 36.
- Conventional mutation in specific genes (deletion, missense, non-sense, and splice site mutations): SCA5, 13, 14, 27, 35.
SCAs caused by polyglutamate expansion are the most common type and account for 36-82% of SCA families. The clinical presentation is possibly related to gain of function of the protein where polyglutamate expansion occurs and is highly dependent on the size of repeats. In general, disease progression is faster in SCAs caused by polyglutamate expansion as compared to that in SCAs with other mutations. Despite sharing the common repeats, there is some degree of specificity in clinical features of each polyglutamate SCAs. This might be the result of the variability of proteins carrying the polyglutamate expansion.
Instability of CAG repeats (dynamic mutation) and phenomenon of anticipation
Normal alleles are transmitted without modification to progeny but larger and expanded alleles are unstable. The already large CAG repeats in SCAs further expand during transmission. This is known as dynamic mutation. SCA 6 and SCA 17 are the exceptions where number of CAG repeats remains stable in subsequent generations. ,
Increased number of repeats in progeny and strong negative correlation between size of expansion and age of onset are responsible for the lower age of onset and higher severity of symptoms in subsequent generations (anticipation).  Mean increase of number of repeats are higher during paternal transmission, probably because spermatogenesis continues throughout the life and gonadal mosaicism seen in sperms. ,
Cytosine adenine adenine / Cytosine adenine thymine (CAA/CAT) interruptions in CAG repeats make the transmission into progeny relatively stable. In SCAs 1 and 2, pathological alleles almost always lose the internal CAA/CAT interruptions. This makes them more vulnerable to expansion in progeny and explains robust "anticipation" observed in SCAs 1 and 2. On the other hand, SCA 17 does not lose CAA/CAT interruptions in CAG repeats and hence number of repeats does not change during transmission. SCA 6 has small size of repeats and they also remain stable during transmission. This stability explains the lack of anticipation in SCA 17 and SCA 6. In rare families of SCA 17, where alleles did not have CAA/CAT, there were increased number of CAG repeats in progeny and thus anticipation. 
Threshold of pathogenicity with expanded alleles
Normal alleles carry a variable number of CAG repeats but always below a particular threshold.  The threshold values of CAG repeats are different for different SCAs [Table 1]. Pathogenic alleles have number of CAG repeats above those threshold values. Uninterrupted expanded CAG alleles are more favored to be pathogenic. Intermediate-sized repeats, not enough to cause disease, may further expand in next generation and become pathogenic. Thus, intermediate alleles can be the reservoir of the pathogenic expansion and can explain lack of family history in some cases of SCAs.
Effect of expansion size on clinical presentation of individual polyglutamate ataxia
- SCA 1: Hyper-reflexia is more common in small-to medium-sized repeats. Frequency of ophthalmoplegia, amyotrophy, sphincter disturbance, and dysphagia increases with the increase in the number of repeats.
- SCA 2: Postural tremors are common with smaller repeats. Ataxia and decreased reflexes are associated with medium-sized to larger repeats. Chorea and dementia are more common with large repeats and fasciculation, myokymia, myoclonus, and dystonia with still larger repeats.
- SCA3: Axonal neuropathy and dopamine responsive parkinsonism are associated with smaller repeats. Ataxia and gaze-evoked nystagmus are associated with medium to large repeats. Frequency of dystonia and pyramidal sign increase with larger repeats.
- SCA 6: Episodic ataxia can be seen with small repeats. Pure cerebellar ataxia is common with medium to large repeats. Mild sensory neuropathy may be an additional finding with larger repeats.
- SCA 7: Cerebellar ataxia without visual loss is seen with smaller repeats. Ataxia with macular degeneration is associated with medium-sized repeats. Visual loss can precede the onset of ataxia by years with large repeats. Frequency of ophthalmoplegia and Babinski sign increases with increase in number of repeats. 
- SCA 17: Frequency of dementia and spasticity increases with increase in number of repeats.
- DRPLA: Larger repeats present with early onset disease and a phenotype characterized by progressive myoclonus, epilepsy, and dementia. Shorter repeats have late onset disease with high frequency of choreoathetosis and psychiatric manifestations.
Pattern of neurodegeneration in polyglutamate ataxia
They all show extensive cerebellar degeneration, where dendritic atrophy is followed by loss of Purkinje cells. But some characteristic patterns can be recognized: SCAs 1, 2, and 7 have Olivo-ponto-cerebellar type of degeneration; SCAs 2 and 3 have pronounced basal ganglionic involvement; SCA 3 shows degeneration of anterior horn cells and spino-cerebellar tracts; and SCA 7 is characterized by associated retinal degeneration. Patients with SCA 17 have global brain atrophy. All SCAs except SCA 6 have significant brain stem degeneration.
Newer insights into pathogenesis of polyglutamate SCA
Most accepted view is the toxic gain of function at protein level results from CAG expansion. Expansion promotes a misfolding of disease protein resulting in aggregation and formation of microscopic inclusions. Role of inclusions in pathogenesis has been debated. These inclusions seem to be merely a marker of misfolding and accumulation. In some studies, inclusions have been linked to survival rather than cell death and were considered a protective response to the presence of accumulated abnormal protein. There are evidences to suggest that small oligomers of mutant protein produced during earlier steps in aggregation pathway may be toxic.  The larger fibrillar complex produced further downstream may contain the mutant protein packaged into an inert milieu. Following overlapping mechanisms are considered important for polyglutamate toxicity.
Disturbance of global protein homeostasis
Expression of mutant polyglutamate protein puts a continuous burden on the pathways that efficiently fold and degrade the misfolded proteins. , This might induce global misfolding of proteins. This chronic abnormality of global protein homeostasis has deleterious effects on neurons. The cellular pathways to handle abnormal polyglutamates are molecular chaperones, ubiquitin proteasomal degradation pathway, and autophagy. Their individual roles in causation of polyglutamate diseases are still unclear.
Aberrant interaction of polyglutamate protein with other nuclear proteins might lead to their functional depletion.  Transcription factors are important nuclear proteins affected by this mechanism. This might lead to global transcriptional dysregulation of nuclear proteins. On the other hand, some polyglutamate proteins are directly involved in transcription. For example, SCA 7 protein (ataxin 7) is a part of STAGA protein complex and SCA 17 protein is the basal transcriptional factor, TATA-binding protein.
Specific mechanism for some individual SCA
The serine residue of ataxin 1 (SCA 1 protein) helps to associate this protein with transcriptional repressor, capicua. Carboxy terminal of ataxin 1 also functions as nuclear localization factor.  Thus, interaction of ataxin 1 with other nuclear protein requires serine residua and carboxy terminal. A serine-mutated form of ataxin 1 has been shown to be non-toxic even in the presence of large polyglutamate expansion.
Retinoid-related Orphan Receptors- alpha, a transcriptional factor, is important for cerebellar development. Mutant ataxin 1 interacts with Retinoid-related Orphan Receptors and mature the disease progression.  If mutant ataxin 1 is not expressed even after the window of cerebellar development has passed, degeneration is substantially reduced. This suggests that early developmental events influence later neurodegeneration in adults.
SCA 3 protein (ataxin-3) is a ubiquitin chain-binding protein. It has an intrinsic activity to suppress its own polyglutamate toxicity.  This explains why required repeat length to produce disease is much larger (at least 55 residua) in SCA 3 than the repeat length in other polyglutamate diseases.
SCA 6 is the only polyglutamate disease caused by mutation in a membrane protein (Voltage-gated calcium channel alpha 1 a subunit).  The fact that small expansion has shown to produce episodic ataxia brings SCA 6 closer to channelopathies. Expansion may lead to channel dysfunction in SCA 6. But abnormal accumulation of protein is also seen in SCA 6, as in other polyglutamate SCAs.
Recently, it was shown that selective expression of polyglutamate disease protein Ataxin 7 in glial cells of cerebellum leads to degeneration of neighboring Purkinje cells.  Similar non-neuronal involvement is being sought in other SCAs.
Non-coding repeat SCA
Techniques that recognize large polyglutamate (like IC2 antibody SCA) found no evidence of unrecognized disease causing genes and it is unlikely that a new polyglutamate ataxia will be discovered. Naturally, this has shifted focus to other mechanisms. Majority of newly identified forms of SCAs have either non-coding repeat expansion or mutation in other genes. Expansions of non-coding region of gene, also known as micro-satellite expansions, are found in SCAs 8, 10, and 12. They are associated with RNA gain of function mutation. Myotonia dystrophica, Fragile X-associated Tremor Ataxia Syndrome (FXTAS), and Huntington's disease like 2 (HDL 2) are other dominantly inherited neurological conditions that have non-coding expansion with the gain of function mutation. On the other hand, FA is an AR condition that has non-coding expansion with loss of function mutation.
Non-coding mutations are rare in Caucasians. SCA 10 has been reported from families in Mexican/Brazilian families and SCA 12 has been reported almost exclusively in Indian families. Recent findings of SCA 8 expansion in the carriers of other SCA mutation or even in healthy individuals have generated lot of interest.
SCA 8 has χΨτoσinε τηΨμinε guαninε (CTG) expansion located at 3' end of a non-coding mRNA and pathogenic threshold is approximately 110 repeats. , It is transmitted as AD with reduced penetrance (not all individuals with expansion develop disease). Factors that may contribute to this reduced penetrance are variable interruptions in CTG expansion and variations in the size of χΨτoσinε τηΨμinε αδεninε (CTA) tracts that precede the CTG expansion. The mechanism of toxicity of this CTG repeat is largely unknown but possibly the expansion alters KLH1 1 (Kelch-like gene 1) expression. This gene acts as actin-binding protein.
SCA 8 is almost exclusively expressed in the Central nervous system (CNS) and the disease is characterized by degeneration of Purkinje cells, inferior olive, and nigral neurons together with peri-aqueductal gliosis. Patients with SCA 8 present with slowly progressive cerebellar degeneration characterized by limb and gait ataxia, nystagmus, and dysarthria.
It was initially characterized by pure cerebellar degeneration with seizures. But polyneuropathy, pyramidal signs, cognitive, and psychiatric impairment have been observed in recently reported families. SCA 10 is caused by a huge ATTCT expansion in an intron of ATXN (Ataxin) 10 gene. The encoded protein, Ataxin 10, is highly expressed in brain and may promote G protein signaling leading to neurite formation in neural cells. , Till date, the mutation has been limited to American Indian ancestry.
It is characterized by action tremors in upper limbs, slowly progressive ataxia, hyper-reflexia, parkinsonism, and dementia. CAG repeat expansion at 5' end of PPP2R2B (protein phosphatase 2, regulatory subunit B, beta) gene has been detected in SCA 12 families.  Pathogenesis is not yet elucidated. SCA 12 is almost restricted to families in North India.
Huntington's disease like 2
It is a related disorder where there is CTG expansion in junctophilin 3 gene and depending upon alternative splicing, it is located in the coding portion of gene (intron), or as a part of 3' UTR (Untranslated region). Huntington's disease like 2 (HDL 2) is clinically characterized by abnormal movements, dementia, and psychiatric abnormality. The mechanism of pathogenesis is likely related to RNA gain of function.
Fragile X-associated tremor ataxia syndrome
It is another related disorder where there is cytosine guanine guanine (CGG) repeat pre-mutation (length is less than 200 but more than 55) at FMR 1 (fragile X mental retardation 1) gene. Mechanism of pathogenesis is related to RNA gain of function. It presents with late onset, progressive intentional tremor and gait instability, gradual cognitive deterioration, varying degree of memory loss, and dys-executive symptoms. A repeat length of more than 200 at FMR 1 gene results in Fragile X syndrome. This is the most common inherited cause of mental retardation and autism. RNA loss of function is implicated in Fragile X syndrome.
SCA caused by conventional mutation
Conventional mutations have been implicated in pathogenesis of SCAs 5, 13, 14, 27, 31, and 36.
It presents with early onset slowly progressive ataxia with occasional bulbar signs. Family of Abraham Lincoln is a famous example of this ataxia. There is missense mutation in SPTB (Spectrin beta chain, erythrocyte) N2 gene at chromosome 11p13.  The gene is responsible for organelle stability and membrane protein dynamics of neurons.
It presents with childhood onset ataxia with cognitive delay and short stature. There is missense mutation in KCNC3 gene encoding voltage-gated potassium channel (Kv3.3), which is highly represented in cerebellum.  The mutation presumably changes the fast-spiking cerebellar neurons.
It is caused by various missense, deletion, and splice site mutation in PRKCG gene encoding protein kinase C gamma.  This protein is highly expressed in Purkinje cells. The clinical feature can be varied. Most patients have late onset pure cerebellar ataxia with mild extrapyramidal features. Individual case with facial myokymia, eye movement abnormalities, axial myoclonus, dystonia, and vibratory loss has been reported. Non-progressive ataxia with multi-focal myoclonus was reported in one patient.
It is clinically characterized by slowly progressive ataxia, tremors, impaired cognition, behavioral outburst, and orofacial dyskinesia. Mutations in the FGF 14 gene have been found in SCA 27.  Pathogenesis is supposed to be based on the novel role of FGF 14 in spatial learning and synaptic plasticity.
It is caused by the pentanucleotide (TGGAA) n repeat insertion. It is clinically characterized by gait disturbance, dysarthria, hypotonia, abnormal fine finger movements, and mild hearing loss.
It is caused by the expansion of a hexanucleotide guαninε guαninε χΨτoσinε χΨτoσinε τηΨμinε guαninε (GGCCTG) repeat in intron 1 of the nucleolar protein 56 gene. The age at onset of ataxia was 53.1 ± 3.4 years, with the most frequent symptoms being truncal ataxia (100% of patients), ataxic dysarthria (100%), limb ataxia (93%), and hyper-reflexia (79%). Tongue fasciculation and subsequent atrophy were found in 71% of cases, particularly in those of long duration. 
Clinical approach to patient with suspected inherited ataxia
Polyglutamate SCAs generally present with progressive ataxia with oculomotor, pyramidal, extrapyramidal, and other neurological features in varying combinations. Gait instability is the usual first sign in majority of patients. But psychiatric alteration or dementia in SCA 17, dystonia in SCA 1, and visual alteration in SCA 7 (with larger repeats) can precede ataxia by years.
Neurological examination for objective signs of cerebellar impairment (impaired tandem walk, truncal ataxia, finger-nose test, and eye signs) is the essential primary step in a suspected case of inherited ataxia. All suspected patients should have detailed clinical history with information regarding age of onset, sex, mode of onset, family history, and pedigree analysis. Associated features such as pyramidal tact signs, extrapyramidal signs, eye movement abnormalities, visual impairment, hearing deficit, autonomic dysfunction, behavioral, and cognitive sub-normalities are helpful in differential diagnosis [Table 2] and categorization of particular type of SCA. Some of the clinical clues point toward the diagnosis of a particular SCA and thus can help to focus the genetic testing:
- SCA 1 and 2: Neuronopathy.
- SCA 2: Higher frequency of hyporeflexia, reduced saccadic velocity, postural tremor, and dementia.
- SCAs 3 and 7: Neuronopathy and dying back axonopathy.
- SCA 6: Generally pure cerebellar ataxia.
- SCA 7: Macular degeneration leading to progressive blindness.
- SCA 17 and DRPLA: Presence of chorea, psychiatric abnormalities, and dementia.
Clinical overlap with other neurodegenerative diseases
SCA 2 and SCA 3 can present with dopa responsive Parkinsonism and late onset cases of SCA 3 can be mistaken with PD. SCA 3 can also present as dopa responsive dystonia. SCA 17 can present with dementia and chorea and thus mimics HD.  Adult onset DRPLA has psychiatric features and choreoathetosis and can also be mistaken as HD.  All patients of HD like illness with negative genetic test should be tested for SCA17 and DRPLA. SCAs 18 and 25 have progressive motor sensory neuropathy and can mimic Hereditary Motor Sensory Neuropathy.
Conditions mimicking SCA
Considering the great degree of variability in the phenotype of SCA, multiple other conditions may be mistaken as SCA. A brief list of such conditions is produced in [Table 2]. Some of the AR conditions may mimic SCA, especially if there is introduction of two independent mutant alleles in the same family.
SCA - Indian perspective
Clinical identification of SCA cases was reportedly done first time in India in the 1970s by Wadia and Sami as a group of AD ataxias characterized by slowed saccades.  Subsequent research and genetic analysis confirmed the phenotype of those cases to be consistent with mutation at SCA 2 gene locus. SCA 2 type has been regarded as the most prevalent variety in India.  Unlike other studies, Sinha et al. reported that slow saccades are not universal or exclusive for SCA 2. 
Literature review reveals wide genotypic variation for SCA for the diverse ethnic population in India. In a study at institutional setting in eastern India by Basu et al., the calculated highest frequencies of SCAs identified by CAG repeats in respective gene loci were 17.5% and 10.5% for SCA 2 and SCA 1, respectively.  Another set of studies among the Bengali community from eastern India showed predominance of SCA 3 variety. , A higher prevalence of SCA 1 was noted in an ethnic Tamil population of Southern India.  Bahl et al. observed that about 16% of diagnosed dominant ataxias in a tertiary care center in North India were SCA 12.  Interestingly, they noticed that all the SCA 12 belonged to an endogamous population, which originated in Agroha (state of Haryana, India). A recent communication reported detection of rare SCA 7 from ethnic tribe of Assam.  In a recent study from Western India, Khadilkar et al. reported 14 consecutive index cases of SCA and found that SCA 2 (10/14) was the commonest.  The authors proposed a useful algorithm for genetic tests for diagnosis of SCAs in India depending on the patient's geographic origin. A comprehensive neurological care and databases being in need, further multi-centric outreach programs and planned interventions might help to appreciate the magnitude of SCA in India.
| Conclusion|| |
SCAs are diverse condition having cerebellar and brain stem degeneration as common features. With the detection of new gene loci, number of SCAs continues to grow. There are some clinical pointers that help to focus in genetic test. According to recent genetic and molecular findings, the SCAs can be grouped into ataxias related to polyglutamate toxicity, ataxias due to expansion of non-coding regions, and ataxias due to conventional mutations. Link between the molecular mechanisms and cerebellar degeneration is still tenuous. Further understanding of mechanisms might lead to treatment directed to prevent cerebellar degeneration in cases of SCAs.
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[Table 1], [Table 2]