Spinocerebellar ataxia (SCA) is a clinically heterogeneous group of neurodegenerative disorders characterized by progressive degeneration of the cerebellum and its associated connections. Genetic defects causing SCA include trinucleotide repeat expansions in the coding and non-coding regions of the genes, gene rearrangements, and conventional mutations. Various non-ataxic manifestations, such as dementia, peripheral neuropathy, and movement disorders (MDs) are described in SCA. MDs are the most common non-ataxic manifestations of SCA, and their prevalence and type vary according to the underlying genetic defects as well as the geographical and ethnic differences. In addition to the size of the repeat expansions, genetic modifiers contribute to the phenotypic pleiotropy of SCA. When present in association with ataxia, MDs may provide an important diagnostic clue for genotyping. However, patients with SCA presenting with MDs can be a diagnostic challenge when cerebellar ataxia is subtle or absent. Certain MDs may be more frequent in particular SCA subtypes compared to others. Similarly, MD may be an infrequent but pertinent manifestation in specific subtypes of SCA. Knowledge about MDs in SCA can help clinicians choose the genetic tests appropriately. Our paper comprehensively reviews the spectrum of MDs in SCA, and attempt to guide clinicians in choosing appropriate genetic tests for SCA in patients presenting with isolated or prominent MDs.
Keywords: dystonia, ethnicity, parkinsonism, tremor, trinucleotide repeat disorders
|How to cite this URL:|
Radhakrishnan DM, Pillai KS, Das A, Rajan R, Srivastava A. Unraveling movement disorders in spinocerebellar ataxia. Ann Mov Disord [Epub ahead of print] [cited 2022 Aug 18]. Available from: https://www.aomd.in/preprintarticle.asp?id=352656
| Introduction|| |
Spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal dominant inherited disorders of the cerebellum and its connections., While SCA3 is the most common SCA subtype observed worldwide, SCA2 is the most frequent subtype observed in India., To date, 48 SCAs have been identified. They are named using the prefix SCA, followed by the number that represents the order in which the genetic mutation was identified.,, The most commonly occurring SCAs (SCA1, 2, 3, 6, 7, 17, and dentatorubral-pallidoluysian atrophy-DRPLA) are caused by CAG trinucleotide repeat expansions, which encode polyglutamine, resulting in a toxic polyglutamine protein., SCA8, 10, 12, 31, 36, and 37 are caused by trinucleotide repeat expansions in the non-coding region, while conventional point mutations or deletions in the coding region cause other SCAs.,,, Patients with SCA can experience many non-ataxic manifestations including dementia, movement disorders (MDs), and peripheral neuropathy. The major determinant of the phenotypic variation of SCAs is the size of CAG repeat expansions; similar CAG repeat numbers can have varied manifestations. The other factors that play a major role in affecting SCA phenotypes include ethnicity, interruptions in repeat expansions, and undefined genetic modifiers. Although most of the non-ataxic features overlap among SCA subtypes, the presence of certain clinical features may provide important diagnostic clues to specific SCA subtypes.
MDs are common non-cerebellar manifestations of SCA and are described in almost all SCA subtypes with varied frequency., Both hyper and hypokinetic MDs are reported in SCAs, and they may precede the onset of ataxia by many years., The diagnosis of SCA can be challenging when MD is the only presenting manifestation or the most prominent symptom during the course of the disease. However, the occurrence of certain MDs can indicate specific subtypes of SCA and help in identifying appropriate genetic tests.,,
In this review, we have described the spectrum of non-ataxic MDs in SCA. We have attempted to identify the MDs specific to each of the common SCA subtypes. In addition, we have reviewed the factors influencing the presence and prevalence of MDs in each SCA. Finally, we have briefly discussed the pathophysiology of MDs in SCA and the screening of SCA mutations in patients whom MDs are the sole or prominent manifestation.
| Materials and Methods|| |
We performed a literature search of online databases such as Pubmed, MEDLINE, and EMBASE in August 2021. All the articles containing descriptions of the clinical features of genetically proven SCA were screened. These included letters to editor, case reports, case series, observational studies, systematic reviews, and review articles. In addition, we used MD terms such as Parkinsonism More Details, dystonia, chorea, myoclonus, and tremor to search the database. Additional articles were obtained from the reference lists of the relevant articles.
Making Sense of MD in SCA
MDs are a well-known manifestation of SCA. Except for tics, which are unusual, all types of MDs can be observed in patients with SCA. In a systematic review by Rossi et al., the estimated prevalence of MDs in SCA was 4% at disease onset. MD was the presenting symptom in 29% patients, either in isolation or combined with ataxia. More than one-third of the patients had two or more MDs during the overall disease course. This implies that even if MD is present at disease onset in only 4% of the cases, it remains a prominent symptom during the disease course, requiring an expert evaluation in 29% of the cases. After postural or intention tremor of the upper limbs, which can be a part of the cerebellar syndrome, parkinsonism was the most common MD observed at onset, followed by dystonia. In addition, parkinsonism was the most frequent MD reported in patients without ataxia during the overall disease course.
The frequency of MDs in SCA can vary with geographical location and ethnicity. In a Brazilian SCA study of 378 patients from 169 families, the frequency of MDs was highest in SCA3. Dystonia was the most common MD observed in 5.5% of the cohort, mostly in SCA3. Similarly, a Korean study reported the highest frequency of extrapyramidal signs (EPS) in patients with SCA3 (53%), followed by SCA2 (14%). An Indian study observed one or more EPS in 48% patients with genetically proven SCA; the frequency of EPS was 60.7% for SCA2, 52.9% for SCA3, and 37.5% for SCA1. A study from north India found MD in at least 43% of their SCA cohort during the disease course. Action tremor of the hands were the most common MD observed, predominantly in patients with SCA12. Patients with MD developed ataxia at a later age than those without MD; however, there was no correlation between the severity of ataxia and MD. In this particular study, the majority (81%) of SCA12 cases were from the Agrawal community that shared the same ethnic origin.
It is noteworthy that certain MDs are common in some SCA subtypes, and although certain MDs may be infrequent, they are important clinical features in specific SCAs ([Table 1]). Similarly, a few SCA subtypes can typically have MD as the presenting symptom, such as action tremor of the hands in SCA12. In the following section, we briefly discuss the common MDs encountered in SCA. For each MD, we describe the SCA subtypes that should be considered. The approach based on the type of MD, most prominent clinical picture, age of onset, ethnicity, and resemblance to various non-SCA conditions have been summarized in the [Table 2][Table 3][Table 4][Table 5]. [Figure 1] illustrates the approach for MDs associated with SCA with respect to the body parts that are most prominently affected.
|Figure 1: Approach for MDs associated with SCA based on the body part most prominently affected|
Abbreviations: BS, Blepharospasm; CD, Cervical dystonia; FG, Facial grimacing; LD, limb dystonia; MD, Movement disorder; OMD, Oromandibular dystonia; OT, Orthostatic tremor; PT, Postural tremor; SCA, spinocerebellar ataxia; TD, Truncal dystonia; WC, Writer’s cramp
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Parkinsonism in SCA
Parkinsonism is a well-recognized feature in many SCA subtypes including, SCA2, 3, 17, 12, 6, and 8. The prevalence and associated clinical features vary with ethnicity and family history,, ([Table 1]). SCA2 is the most common subtypes associated with parkinsonism worldwide. The parkinsonian phenotype of SCA2 and SCA17 is particularly common in the Asian population, while SCA3 with parkinsonism is more frequent in the African population.,,,,,, Approximately, 5% of the patients with SCA2 and SCA3 and 10% of the patients with SCA17 may present with some form of parkinsonism during the disease course. The most frequent parkinsonian features described in patients with SCA are rigidity and bradykinesia, followed by rest tremor., The clinical spectrum may vary from limb rigidity in combination with marked ataxia to phenotypes mimicking idiopathic Parkinson’s disease (IPD) and atypical parkinsonism syndromes such as multiple system atrophy (MSA-P and MSA-C) and progressive supranuclear palsy (PSP).,, This clinical presentation is often complicated by variable responses to dopamine replacement therapy (DRT), treatment-related motor complications, and abnormalities of nigrostriatal pathways in functional imaging.,,,, In patients with parkinsonism, the presence of ataxia and response to DRT may be inversely related. The disruption of nigrostriatal pathways can partly explain the response to DRT and motor complications in these patients. Brain magnetic resonance imaging has shown cerebellar or brainstem atrophy in one-third of the patients with isolated parkinsonism. The screening of SCA2 and SCA3 is recommended in Asian patients presenting with early-onset parkinsonism and autosomal dominant parkinsonism.,
Parkinsonism in SCA2
SCA2 contributes to 0.4–2.2% of sporadic parkinsonism and approximately 9% of familial parkinsonism in the Asian population.,,, Parkinsonism in SCA2 may remain isolated without ataxia, even after decades of follow-up, and it may resemble IPD.,,, Compared to the cerebellar variant, the parkinsonian phenotype of SCA2 had a lower CAG repeat size (33–43) and a later mean age at onset.,,, Another important determining factor for the parkinsonian phenotype was the CAA interruptions within the expanded CAG repeat. The combined CAG/CAA repeat expansions were absent in the cerebellar phenotype of SCA2.,, Interruptions of CAG repeat expansions (CAA, CGG, and CCG) stabilize the repeat size expansions across the generations and may be responsible for sporadic cases of SCA2 with low penetrance.,,
Parkinsonism in SCA3
Parkinsonism has been described as a prominent feature in many subphenotypes of SCA3.,,,, SCA3 was originally classified into three main subphenotypes: Type 1 (Joseph type) with early onset pyramidal signs, extrapyramidal features such as parkinsonism and dystonia, and cerebellar ataxia; Type 2 (Thomas type) with cerebellar ataxia and pyramidal signs; and Type 3 (Machado type) with late onset of ataxia, anterior horn cell degeneration, and peripheral neuropathy., A fourth subtype of SCA3, indistinguishable from IPD, has been suggested by some authors., This phenotype has been previously described in African–American families with autosomal dominant parkinsonism.,, Parkinsonism in subphenotype 4 was variably associated with other neurological features, such as ataxia and peripheral neuropathy. In addition, subphenotype 7 features akinetic-rigid parkinsonism, cerebellar ataxia, and severe spasticity. SCA3 is not an uncommon cause of parkinsonism in the Asian population.,,,, In a recent Chinese study of 68 patients with genetically proven SCA3, the frequency of rigidity was as high as 47.1%; 16% of the cohort had rest tremor. Similarly, in a Taiwanese study, 21.1% of the patients with genetically confirmed SCA had parkinsonism; SCA3 was the most common subtype featuring parkinsonism, followed by SCA2. Most patients had an akinetic-rigid phenotype and almost half of them responded favorably to L-Dopa. Some patients with SCA3 and parkinsonism were reported to carry sequence variations in the glucocerebrosidase (GBA) gene. Similar to SCA2, the parkinsonian variant of SCA3 was associated with an intermediate number of CAG (58–73) repeat expansions and older age at onset.,,
Parkinsonism in SCA17 and other subtypes
The parkinsonism dominant SCA17 closely resembles IPD and is one of the genetic causes of sporadic cases of parkinsonism in Asia., Therefore, screening of SCA17 may be considered in Asian PD patients. Parkinsonism in SCA17 is associated with a shorter CAG repeat size expansion (43–49). The low penetrance of the TATA-binding protein (TBP) gene may be responsible for the sporadic cases of SCA17. Similar to SCA2 and SCA3, sporadic cases of SCA17 can mimic MSA when associated with parkinsonism and autonomic dysfunction., A Korean study observed mutations in SCA genes in 7.3% of the patients with clinically diagnosed MSA, and SCA17 comprised more than half of the mutation-positive cases. Therefore, genetic testing for SCA may be recommended for patients with MSA, particularly for those with cerebellar dysfunction. As discussed in the previous section, SCA12 is particularly common in the northern part of India and frequently features parkinsonism., A recent Indian study reported a high frequency of parkinsonism (>50%) in a genetically confirmed cohort of SCA12. Parkinsonism was also found in SCA12 patients from American Kindred. Both SCA6 and SCA8 may infrequently present with parkinsonism; the reported phenotypes vary from classical PD-like presentation to parkinsonism mimicking MSA and PSP.,
Dystonia in SCA
Dystonia has been described in many SCA subtypes ([Table 3]), but it is more frequent in SCA2, SCA3, and SCA17.,,,, Although less frequent, dystonia may be a relevant feature in SCA6, 12, 14, and 1. Both focal and generalized dystonia have been reported in patients with SCA. Upper limb dystonia, including writer’s cramp, has been reported in approximately half of the patients with SCA, while cervical dystonia is observed in one-third of the patients., Furthermore, dystonia involving the lower limbs, upper or lower cranium, larynx, or trunk is reported at variable frequencies. In many subtypes of SCA, dystonia may be the presenting manifestation. For example, cervical dystonia in SCA1, 2, and 17; foot dystonia in SCA17; writer’s cramp in SCA1, 2, 3, 6, 7, and 14; and spasmodic dysphonia in SCA12.,,,,,,,,, The probable mechanism of the development of dystonia is discussed in the "Pathophysiology of MD in SCA" section. The presence of dystonia was associated with severity of ataxia but not with the rate of progression of ataxia in SCA1, SCA2, and SCA3. In contrast, the presence of dystonia was predictive of the slow progression of ataxia in SCA6.
Dystonia in SCA2
The prevalence of dystonia in SCA2 varies between 14% and 17%, although one study has reported the prevalence to be as high as 61%., The frequency of cervical dystonia in SCA2 appears to be higher than previously reported. Adult-onset lower cranial dystonia, particularly jaw and tongue dystonia, and orofacial dyskinesia are well-recognized features in SCA2. Their presence in patients with inherited cerebellar ataxia indicates the diagnosis of SCA2.,, Postural trunk dystonia has been described in one SCA2 patient with long-standing ataxia. In addition, dystonia in SCA2 is associated with large CAG repeat size expansions, although observations from studies have been variable.,
Dystonia in SCA3
The estimated prevalence of dystonia in SCA3 varies from 3.7% to 33% in different studies.,,, Dystonia is a predominant feature in the Joseph type of SCA3, and its presence is associated with a large CAG amplification and young age at onset.,, A Dopa-responsive dystonia phenotype has been described in SCA3 patients with low CAG expansion. The possibility of SCA3 should be considered in an adult presenting with the Dopa-responsive dystonia phenotype and positive family history of ataxia.
Dystonia in SCA17 and other subtypes
Dystonia is described in approximately 5% of the patients with SCA17, particularly in those with large repeat expansions. The frequency of dystonia in SCA17 was as high as 53% in some series. The dystonia phenotype represents a subset of SCA6 with additional basal ganglia involvement. Ikeuchi and colleagues observed dystonia in 15% of the patients with SCA6; dystonia was more common in patients with a long disease duration. Dystonia is a minor feature in SCA12 and develops late in the disease course. However, dystonia may be prominent at onset in some patients with SCA12 and may be the sole presenting manifestation. Various types of dystonia have been reported in SCA12, including cervical dystonia, foot dystonia, hand dystonia, axial dystonia, and laryngeal dystonia.,, Compared to a western SCA12 cohort, facial myokymia and axial dystonia are were frequently observed in patients of Indian origin.,
Tremor in SCA
Previous studies had proposed tremor as the most common MD in SCA. Most of the tremor encountered in SCA patients, such as postural and intention tremors of the extremities and head tremor, are part of the cerebellar syndrome. Postural or kinetic (intention) tremor are reported in almost all SCA subtypes, and the presence of these tremors are not suggestive of any specific subtype. However, rest tremor indicates parkinsonism and the occurrence of palatal tremor indicates SCA20 or SCA7., Action (postural/intention) tremor of the upper limbs are typically present at onset in some subtypes of SCA, including SCA12, 8, 15–16, and 27.
Tremor in SCA12
Action tremor of the upper limbs are the presenting symptom in approximately 65% of the patients with SCA12, and they precede the onset of ataxia by many years. The amplitude and distribution of tremor may increase over the years to involve the head and neck. SCA12 is an important cause of familial tremor in patients of Indian ethnicity. Choudhury et al. reported tremor as the initial presentation in 90% of their SCA12 cohort, and the majority of the patients were descendants of the endogamous Agrawal community. In addition to action tremors of the hands, the authors reported tremor involving other body parts in these patients, including head and voice tremor, lingual and orofacial tremor, and trunk tremor. Radhakrishnan et al. observed action tremor of the hands at onset in 92% of the patients with SCA12, and in approximately 54% patients tremor preceded the onset of ataxia. Furthermore, majority of the SCA12 patients (81%) belonged to the Agrawal community. Prominent neck tremor was reported in more than one-third of the patients with SCA12. Tremor at onset predicts SCA12, especially in patients belonging to the Agrawal community and genetic testing for SCA12 should be considered even in the absence of ataxia.
Tremor in SCA3
In their study of 72 patients with SCA3, Bonnet et al. observed two distinct tremor types: 1) a “fast” (6.5–8 Hz) action, postural or tremor in orthostatism (early symptom), which became slow after a decade of follow-up, with associated parkinsonism and 2) a “slow” rest, action and intention tremor of 3–4 Hz, involving the distal and proximal extremities and axial tremor in orthostatism. The “slow” tremor of the limbs and tremor in orthostatism responded to L-Dopa with the development of dyskinesia and fluctuations. The presence of L-Dopa-responsive postural or action tremor of the limbs, when associated with a slow tremor in orthostatism (<14–18 Hz), suggests the diagnosis of SCA3 in young patients.
Tremor in SCA27 and other subtypes
Almost 70% of the patients with SCA27 may present with postural tremor of the upper limbs in childhood. Head tremor is observed in approximately 27% patients during the disease course; ataxia develops in the late teens;.,, In addition, action tremor of the upper limbs are a presenting feature of SCA14 (8%) and SCA8 (25%)., However, it is likely that some patients had a high-frequency, myoclonus-resembling tremor. Action tremor of the hands and head have been described in almost 14% of SCA15/16 patients at onset. Furthermore, tremor is a prominent clinical feature in patients with SCA2, and it is reported in almost 50% of the patients during the disease course. There are occasional reports of subthalamic–thalamic deep brain stimulation being performed for SCA patients with severe postural tremor.,
Myoclonus in SCA
Many SCA subtypes ([Tables 1] and ) feature myoclonus, but it is most commonly observed in SCA2, SCA14, and DRPLA.,,, Myoclonus can be a less frequent but relevant clinical feature in SCA7, 8, 17, 19, 3, and 1., The myoclonus in SCA may be appendicular or axial or positive or negative. In addition, it may be of cortical, brainstem, or spinal origin. In a series of 526 SCA patients from Europe, myoclonus was most frequent in those with SCA2 (13.7%) compared to other subtypes (SCA1, 3, and 6) that were evaluated. Myoclonus in SCA2 appears late in the disease course, and patients with myoclonus carry a large CAG repeat size expansion than those without., In the original Japanese SCA14 family, five out of nine patients presented with axial myoclonus and had an early age at onset. Myoclonus was the initial symptom in two Dutch families, as well., In addition to axial myoclonus, positive and negative myoclonus of the arms and action myoclonus of the limbs have been reported in patients with SCA14., SCA14 can present with multifocal myoclonus resembling the Ramsay–Hunt syndrome (progressive myoclonic ataxia), and it should be considered in the differential diagnosis of progressive myoclonic ataxia. SCA14 may present with a myoclonus–dystonia phenotype. In patients with the myoclonus–dystonia phenotype with negative DYT-11, genetic testing for SCA14 is suggested, particularly, when there is a family history of ataxia or cerebellar atrophy in neuroimaging.
Chorea in SCA
Chorea is frequently reported in SCA17 and DRPLA; it is a rare feature in other SCA subtypes ([Tables 1] and ).,,, The reported prevalence of chorea in SCA17 ranges between 20% and 66%.,, Both focal and generalized chorea have been reported in SCA. The clinical presentation of SCA17 mimics Huntington’s disease (HD), particularly, when associated with cognitive and behavioral symptoms; it is referred to as Huntington’s disease-like disease Type 4 (HDL4). Patients with HD-like phenotypes had a short CAG (43–49) repeat expansion or interruptions within the expanded CAG/CAA repeat. These expansions are found to have a low penetrance; therefore, they lead to sporadic cases of SCA17., The combination of chorea and ataxia suggests the diagnosis of SCA17. Screening for SCA17 is recommended even in patients presenting with isolated chorea in the absence of a HTT mutation. In addition, DRPLA also present with chorea and mimic HD-like disorders and has onset in early adulthood (>20 years).Recently, Kaur et al. reported SCA12 CAG expansion in two Indian choreatic patients with HD-like presentation. The mechanism of development of chorea is discussed in the Pathophysiology of MD in SCA section.
Other MDs in SCA
Compared to the general population, restless legs syndrome is reported at a higher frequency (5–15% vs. 33%) in the SCA population (SCA1, 2, 3, and 6), independent of the peripheral neuropathy., A favorable response to L-Dopa in these patients suggests underlying dopaminergic dysfunction. Stiff-person syndrome is reported in one sporadic case of SCA1 and another familial case of SCA3., SCA should be considered in the differential diagnosis of stiff-person syndrome in patients with negative autoimmune workup, particularly when there is a positive family history for ataxia or cerebellar atrophy in neuroimaging. Other uncommon MDs reported in SCA include orofacial dyskinesia (SCA2), prominent perioral twitches/facial myokymia (SCA2, 12), generalized myokymia (SCA3), akathisia (SCA3), gait apraxia (SCA10), tics (SCA17 and 25, DRPLA), palatal tremor and spasmodic-like dysphonia (SCA20), and paroxysmal nonkinesigenic dyskinesia (SCA27).,,,,,
Pathophysiology of MD in SCA
Degeneration of the cerebellum as well as the extra-cerebellar structures can be responsible for MDs in SCA. The cerebellar pathology itself can lead to the development of tremor, dystonia, and myoclonus in SCA patients. However, in most of the SCAs, MDs occur when degeneration progresses beyond the cerebellum. Dysfunction of the other parts of motor system, particularly, the cortico-basal ganglia–thalamic–cerebellar circuitry, plays a key role in the pathogenesis of MDs., The probable explanation for dystonia in SCA is the loss of integrity of the cerebellothalamocortical and basal ganglia-thalamocortical circuits. Neuronal loss in the basal ganglia-thalamocortical loop might be responsible for the development of chorea in SCA patients. The neuropathological evidence shows involvement of the substantia nigra, pallidum, caudate, putamen, and motor cortex in patients with SCAs, accounting for various MDs; for example, substantia nigra degeneration for the PD phenotype (SCA2, SCA3, and SCA17), globus pallidus and putamen involvement for dystonia and parkinsonism (SCA1, 2, 3, and 17), and caudate nucleus involvement for chorea (SCA1 and SCA17).,, Volumetric magnetic resonance imaging analysis has shown atrophy of the putamen and caudate in SCA1 and SCA3.11C-Raclopride positron emission tomography scans have shown postsynaptic D2 receptor loss in SCA1, SCA2, and SCA3, which explains L-Dopa responsiveness., Involvement of the ventral anterior and ventrolateral thalamic nuclei, disrupting the re-entrant motor cerebellothalamocortical and basal ganglia-thalamocortical circuits, have been implicated in the pathophysiology of bradykinesia and postural instability in SCA2 and SCA3. The existing neuropathological evidence proposes the affection of the cortico-basal ganglia–cerebellar connectome for the wide repertoire of MDs in SCA.
Screening of SCAs based on MDs
Parkinsonism is the most frequent MD in SCA, followed by dystonia. A quick screening based on the predominant MD type in SCA patients can indicate its subtype ([Table 1]).
| Conclusion|| |
MDs are common in SCA and have variable prevalence globally. In addition to the geographical location, ethnicity, and founder effect, genetic modifiers play a key role in the phenotypic diversity of SCA. MDs can precede or follow the onset of ataxia in patients with SCA; they may be the presenting symptoms or the sole manifestations of SCA. MDs in patients with SCA can help in differentiating between the different SCA subtypes and judiciously utilizing the available genetic tests.
Divya M. Radhakrishnan: Literature search, data acquisition, manuscript preparation
Kanchana S. Pillai: Literature search, data acquisition, manuscript preparation
Animesh Das: Literature search, manuscript preparation
Roopa Rajan: Manuscript editing and review
Achal K. Srivastava: Concept, manuscript editing and review
Ethical compliance statement
We confirm that the approval of an institutional review board was not required for this work. We have read the journal’s position on issues involved in the ethical publication and affirm that this work is consistent with those guidelines.
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Conflicts of interest
There are no conflicts of interest.
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Achal K Srivastava,
Department of Neurology, Room number 60, Ground floor, Neurosciences Center, All India Institute of Medical Sciences, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]