Spinocerebellar ataxia type 3 (SCA3) …

Kanae J Nagao MBBS FRACP

Movement Disorders

Updated 03.06.2024
Released 07.22.1996
Expires For CME 03.06.2027

Spinocerebellar ataxia type 3

Author: Kanae J Nagao MBBS FRACP

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Editor: Robert Fekete MD

Spinocerebellar ataxia type 3

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Introduction

Overview

Spinocerebellar ataxia type 3 (also called Machado-Joseph disease, MJD/SCA3) is the most common spinocerebellar ataxia subtype worldwide and is an autosomal dominant triplicate nucleotide repeat expansion disorder (76; 119; 97). It has a heterogeneous presentation encompassing a wide range of motor and nonmotor symptoms. Currently, there are no disease-modifying therapies to treat spinocerebellar ataxia type 3. However, there is increasing recognition of shared pathogenic mechanisms between spinocerebellar ataxia type 3 and other neurodegenerative disorders, which raises the possibility of utilizing therapies such as antisense oligonucleotide infusions that have shown success in spinal muscular atrophy.

Key points

	• Spinocerebellar ataxia type 3 is the most commonly inherited autosomal dominant ataxia.
	• It is mediated by an expanded triplicate nucleotide repeat that encodes for mutant ataxin-3 protein.
	• Ataxia is the most common symptom at onset, but clinical presentation is heterogeneous and includes motor and nonmotor symptoms.
	• There are no known disease-modifying treatments, but RNA-based therapies show promise in spinocerebellar ataxia type 3 animal models.

Historical note and terminology

Since its initial description more than six names have been associated with MJD/SCA3. In 1972, two separate reports in two distinct Massachusetts families of Azorean descent were reported. The term "Machado disease" was used to describe the condition after the family described by Nakano and colleagues (90; 149). In 1976, the Joseph family, also of Azorean descent but living in California, was reported with a phenotypically different spinocerebellar disorder (107). Further investigations in the Azores, Portuguese-settled islands in the eastern Atlantic Ocean, supported the concept that Joseph disease and Machado disease reflected different phenotypic expressions of the same genetic disorder (21). Over the years, the eponyms "Machado," "Joseph," "Machado-Joseph," "Joseph-Machado," "Machado-Thomas-Joseph," and "Azorean" disease have all been used interchangeably to refer to this disorder.

The spinocerebellar ataxia nomenclature was developed in the 1990s to classify autosomal dominant progressive cerebellar syndromes following the development of diagnostic genetic tests. The affected gene loci were numbered in the order that they were discovered (76). In 1994, a cytosine-adenine-guanine (CAG) nonsense repeat on the long arm of chromosome 14 was identified as spinocerebellar ataxia type 3 (53) and was found in other spinocerebellar ataxia families without Portuguese ancestry. Interestingly, this same genetic abnormality was also found in patients with Machado-Joseph disease, indicating that this should be considered the same disease despite significant phenotypic variability (80).

Clinical manifestations

Presentation and course

	• Gait ataxia is the most common presenting symptom.
	• MJD/SCA3 has a heterogeneous phenotype including sensory or motor neuropathies, upper motor neuron signs, abnormalities in extraocular movements, dystonias, and parkinsonism.
	• Nonmotor symptoms such as sleep disorders and autonomic dysfunction are often present and may precede the onset of ataxia.

Mean age of onset is approximately 32 to 37 years (51; 49), with a wide range between 4 to 78 years (73; 17). In addition to progressive ataxia secondary to cerebellar degeneration, other regions such as the pyramidal system, basal ganglia, and oculomotor and motor neurons are also affected, resulting in a heterogeneous syndrome of both motor and nonmotor symptoms (Table 1) (21; 06; 99). Age of disease onset, number of CAG repeats, and disease duration influence disease phenotype (118). Larger repeat expansions result in an earlier age of onset and primarily manifest with spasticity and dystonia (mean onset 24 years; mean CAG repeat 76), whereas longer disease duration, older age of onset, and smaller repeat expansions are associated with peripheral neuropathy (mean onset 46.8 years; mean CAG repeat 72.2) (74; 113).

Table 1. Prevalence of Motor and Nonmotor Symptoms and Signs in MJD/SCA3

	Prevalence (%)	Reference
Gait ataxia	96.2	(91)
Dystonia	7.1 – 28	(113; 38; 93; 91)
Parkinsonism	6.6 – 12	(38; 89; 91)
Dysarthria	89.1	(91)
Dysphagia	17.1	(91)
Peripheral neuropathy	54 – 84	(38; 67)
Fasciculation	11.9 – 37	(113; 91)
Cognitive dysfunction	1 - 19.3	(113; 114; 91; 71)
Depression	13 – 69	(114; 68; 77)
Bladder dysfunction	40 – 64	(113; 38; 153)
Constipation	40	(153)
Fatigue	61 - 63.5	(40; 77)
Orthostatic hypotension	4 – 25	(38; 132)
Pain	47	(37)
Cramps	80 – 82	(52; 39)

Motor presentation

Ataxia. Gait ataxia is the most common presenting symptom (151) but is rarely seen in isolation (155). Limb incoordination, intentional tremor, scanning speech, dysphagia, and truncal ataxia are typically observed (23). Loss of ambulation generally occurs within 5 to 10 years of onset (130), but cases with preserved ambulation for more than 30 years have been documented (04). The severity of ataxia is influenced by disease duration, age of onset, and CAG repeat expansion (113). Standardized scales such as the Scale for the Assessment and Rating of Ataxia (SARA) (115) or the International Cooperative Ataxia Rating Scale (ICARS) (116) can objectively quantify ataxia symptoms and are often used for monitoring disease progression. A prospective longitudinal study of Ataxin-3 (atxn-3) mutation carriers showed that SARA scores start increasing in the premanifest stage but rise at a greater rate once ataxia becomes clinically apparent (defined as SARA score of 3 or above) (50).

Gait impairment

Machado-Joseph disease

Dystonia. Dystonia may present as generalized, focal/segmental, or task-specific, and can be progressive, often seen in those with larger repeat expansions and younger age of onset (93; 144). Often, dystonia may be severe, painful, and not associated with a sensory trick (93).

Dystonia

Machado-Joseph disease

Parkinsonism. Parkinsonism (bradykinesia, rigidity, rest tremor) can be responsive to levodopa and may precede the onset of ataxia by up to 10 years (13; 143). Multiple system atrophy-cerebellar subtype has a similar presentation to MJD/SCA3 with the presence of parkinsonism and cerebellar and autonomic dysfunction (143). Genetic testing can be utilized to distinguish between the two conditions.

Pyramidal dysfunction/spasticity. Pyramidal symptoms are frequently present, manifesting as spasticity, hyperreflexia, and positive Babinski reflexes (113). These symptoms typically manifest in patients with earlier age of onset and larger CAG expansions (74; 113). Patients with MJD/SCA3 can present with spastic paraplegia with or without ataxia, and should, therefore, be considered in the differential diagnosis of hereditary spastic paraplegia (42; 145).

Oculomotor. The presence and severity of oculomotor abnormalities correlate with disease progression (129) and may present in premanifest patients (105; 150). In a Chinese cohort of 12 molecularly confirmed premanifest patients with MJD/SCA3, there was a higher frequency and amplitude of square wave jerks, greater antisaccade error rate, slower upward saccades, and lower mean vertical smooth pursuit gain compared to healthy controls (150). The predominant type of oculomotor abnormality is also useful in differentiating between spinocerebellar ataxia subtypes. Fixation abnormalities such as square wave jerks and oscillations are more commonly found in patients with MJD/SCA3 (64% of 11 patients in a cross-sectional study), whereas static and head-shaking vertical nystagmus are highly suggestive of spinocerebellar ataxia type 6 (67% to 83% of 12 patients). The absence of gaze-evoked nystagmus and saccadic dysmetria is predictive of spinocerebellar ataxia type 2 (56). Patients with MJD/SCA3 can also have progressive external ophthalmoparesis or pseudo-exophthalmos with lid retraction and “bulging eyes” (66; 91).

Ophthalmoparesis in Machado-Joseph disease

This patient with Machado-Joseph disease has difficulty with conjugate eye movements. Note masklike face.

Neuromuscular. Peripheral nerve involvement manifests as amyotrophy, weakness, fasciculations, sensory disturbance, and areflexia and is associated with longer disease duration and older age of onset (40 to 60 years) (74; 118; 58; 113). In a series of 42 patients with MJD/SCA3, peripheral neuropathy was typically associated with fewer than 73 CAG repeats (118). The most common etiology is a mixed demyelinating and axonal sensorimotor neuropathy (58; 67). Myokymia has also been described; particularly involving the cheek and tongue but may also occur in lower limb muscles (05).

Nonmotor presentation

Nonmotor symptoms are prevalent and appear to increase with disease duration. In a cohort of 68 MJD/SCA3 patients with a mean disease duration of 5.6 years, the mean total number of nonmotor symptoms was 2.72 (155) whereas the mean was 5.2 in another cohort of 139 MJD/SAC3 patients with a longer mean disease duration of 11.6 years (113). Higher numbers of nonmotor symptoms are associated with worse ataxia and longer CAG repeat length (113).

Sleep disorders. The various disorders associated with sleep are rapid eye movement sleep behavior disorder (15% to 59%), restless legs syndrome/periodic limb movements during sleep (20.7% to 55%), excessive daytime sleepiness (29.2% to 40.9%), insomnia (37.7%), obstructive sleep apnea (22.6%), non-REM parasomnias (40%), and excessive fragmentary myoclonus (50%) (98). Sleep disorders are frequently present, even in the premanifest stage, as found in the largest cross-sectional study to date (31).

Mood disorders. Between 13% to 69% of patients with MDJ/SCA3 have depression (114; 77), and more report associated sleep disturbances and suicidal ideation compared to other spinocerebellar ataxia subtypes (114; 68). The presence of depressive symptoms significantly contributes to difficulty in performing daily activities, greater fatigue, and poorer quality of life, independent of ataxia severity (68; 77). Apathy, anxiety, and poor regulation of affect are also common (10; 71).

Cognitive impairment. The cognitive profile of MJD/SCA3 is inconsistent across studies. Impairments in attention, verbal fluency, verbal memory, visuospatial function, processing speed, and executive dysfunction have been described (10; 134; 57). However, a systematic review found relative preservation of visuospatial function, attention, and processing (154). Memory retrieval rather than encoding appears to be selectively compromised compared to healthy controls (134; 154). Degeneration with disruption of the cerebello-thalamo-frontal cortical network is proposed to underly the observed cognitive deficits (134). No significant relationship has been found between cognitive performance and CAG repeat length or age of onset (70; 134; 71). However, a small cross-sectional study used the Cerebellar Cognitive Affective Syndrome Scale (CCAS-S) to demonstrate an inverse correlation of cognitive performance with disease duration and SARA score and increasing cognitive impairment as walking speed slowed (71). Changes in cognition as measured by the CCAS-S are already evident in premanifest carriers (08).

Autonomic disorders. Prominent autonomic dysfunction can make it difficult to differentiate MJD/SCA3 from multiple system atrophy-cerebellar subtype at times; family history can be particularly helpful in these cases. The most common autonomic complaints are urinary dysfunction (nocturia, urinary retention), abnormalities in perspiration, and cold intolerance (38). Autonomic dysfunction most frequently presents in patients with parkinsonian and polyneuropathic phenotypes (38) and is probably due to a combination of central and peripherally mediated impairment in sympathetic response (38; 153; 132). Involvement of Onuf nucleus, which plays a major role in the micturition reflex, and voluntary continence likely contribute to urinary dysfunction (124). Abnormal heart rate response to postural changes has also been documented (60) but the prevalence of objectively defined orthostatic hypotension varies widely across studies (4% to 25%) (38; 132). No correlation has been demonstrated between autonomic dysfunction and SARA score, CAG repeat expansion size, or age of onset (38; 132).

Pain. Chronic pain is present in almost 50% of patients and is most often musculoskeletal in etiology but can be neuropathic, secondary to dystonia, or mixed (37). Almost 90% of a cohort of 33 patients with MJD/SCA3 in a cross-sectional study reported daily pain (37).

Cramps. Cramps are found in approximately 80% of patients with MJD/SCA3, a higher prevalence than seen in patients with other causes of peripheral excitability (52; 39). Although cramps usually develop later in disease (mean 9 years after symptom onset), they may occasionally be the presenting symptom (39). A distinguishing feature of MJD/SCA3-associated cramps is the greater involvement of upper limbs when present early in disease (52; 39).

Fatigue. Fatigue is highly prevalent in MJD/SCA3 (61% to 63.5%) and more severe than in other common spinocerebellar ataxias (1, 2, 6, 7, 10) (88). It is associated with greater rates of depression and excessive daytime sleepiness (40; 77). Fatigue has no correlation with the severity of ataxia, suggesting that it is multifactorial in etiology (77). There are conflicting data regarding its association with longer disease duration (40; 77).

Others. Olfactory dysfunction and reduction in body mass index are other features that may be observed (11; 110).

Prognosis and complications

A prospective 2-year multicenter study of 139 patients with MJD/SCA3 (EUROSCA study) demonstrated that SARA scores increased by 1.61+/-0.12 annually and were paralleled by an increase in nonmotor symptoms (49). The rate of progression was influenced by disease duration, but unlike previous studies, no correlation was found with age of onset or CAG repeat length (49). The 10-year survival rate was 73% (95% confidence interval [CI] 65%-82%) (28). In a different study involving 412 affected individuals, mean longevity was 63.96 years (95% CI 62.09 - 65.83) compared to a mean of 78.61 years in 413 unaffected individuals (95% CI 74.75 - 82.47; p < 0.001) (54). Shorter survival length correlated with more rapid progression and greater ataxia severity, presence of dystonia, earlier age at onset, and larger CAG repeat length, but not with increasing numbers of nonmotor symptoms (54; 28; 27). The most common cause of mortality was respiratory in etiology (28).

Clinical vignette

A 53-year-old Cambodian-born man who had immigrated to the United States toward the end of the Vietnam War described a 5-year history of progressive ataxia manifest primarily by gait ataxia. He was unaware of any family history, but he had not seen his family in over 20 years. His exam revealed normal mental function, nystagmus but full eye movements, mild limb ataxia, and moderately severe gait ataxia. Although the family history was negative, he tested positive for spinocerebellar ataxia type 3 with a CAG repeat number of 59 on one allele and 22 on the other.

Biological basis

	• The genetic basis of MJD/SCA3 is a cytosine-adenine-guanine triplicate nucleotide repeat on chromosome 14q32.1, which encodes for mutant ataxin-3 protein.
	•Intranuclear aggregation of mutant ataxin-3 mediates clinical phenotypic expression.

Etiology and pathogenesis

Genetics. The pathogenic mutation in MJD/SCA3 is a trinucleotide repeat expansion (CAG) located in the 10th exon of chromosome 14q32.1 (53), which leads to an abnormally long polyglutamine (polyQ) tract in the encoded protein, ataxin-3.

Ataxin-3 is predominantly a cytoplasmic protein that is expressed ubiquitously throughout the brain and somatic tissue (111; 139). Current knowledge suggests atxn-3 has a role in the clearance of misfolded proteins, participating in the chaperone system, the ubiquitin-proteasome system, and aggregation-autophagy (14; 147; 35; 148; 121; 122; 65; 94). Other functions include gene transcription regulation through modulating histone deacetylases (156).

Triplet repeat expansions are a shared mechanism of several spinocerebellar ataxias (1, 2, 6, 7, 17), Huntington disease, and spinomuscular atrophy. Most MJD/SCA3 cases are heterozygotes; however, homozygous cases have been described and tend to present with younger onset and demonstrate rapid progression (61; 17). Lang and colleagues described a homozygote presenting at age 16 who progressed to a severe generalized dystonia phenotype over only 4 years (61). In another homozygous case, a 4-year-old girl inherited two expanded alleles (67, 72) from consanguineous parents and became bed-bound and nonverbal by the age of 11 (17). This rapid progression occurred despite inheriting CAG repeat expansion lengths that were similar to both parents, one of whom was asymptomatic (mother 67; father 69) (17).

Normal alleles have a CAG repeat range of 12 to 47 (74; 126; 82) and expanded alleles typically have 61 or more repeats with complete penetrance (53; 79; 82). In rare instances, there is an intermediate repeat length of 47 to 61, which leads to elevated risk with incomplete penetrance (133; 142). Expanded CAG repeats are relatively unstable and there is anticipation whereby the following generation inherits an increased number of repeats and an earlier age of disease onset (16; 74). Some studies have shown greater instability in CAG repeat expansion lengths with paternal transmission (79; 47) whereas other studies have found no significant difference between maternal and paternal transmission (16). The size of the CAG repeat expansion explains 55% of the variability in age of onset and shows an inverse correlation (74; 24). Other factors that influence age at onset are other (CAG)n-containing genes (ATXN2, ATXN1, and HTT), geographic origin, and mitochondrial DNA haplogroups (136; 24; 25; 104). Single-nucleotide polymorphisms of calpain and calpastatin genes may also modulate the onset age of MJD/SCA3 and affect disease progression, although further studies are required (78).

Neuropathology. There is no clear pathological hallmark of MJD/SCA3; however, gray matter is more affected than white matter and despite ubiquitous atxn-3 expression, degeneration is selective for neuronal subpopulations (109). Gray matter degeneration involves the cerebellum, thalamus, basal ganglia, and brain stem nuclei, primarily affecting the dopaminergic, cholinergic, and noradrenergic-mediated pathways (109). Anterior horn cells and Clarke column in the spinal cord are also involved (152). The cerebellar cortex is relatively spared, and the cerebellar peduncle and dentate nucleus are more affected compared to several other spinocerebellar ataxias (111; 152). White matter degeneration is restricted to the cerebellum, spinal cord, and brainstem (109). Peripheral nerve analyses reveal axonal degeneration followed by sprouting of nerve endings and repeated degeneration, leading to fiber-type muscle grouping and atrophy (128).

Pathophysiology. The exact pathogenic mechanism of the polyQ expansion is incompletely understood (81). Mutant atxn-3 form intranuclear aggregates and transgenic mouse models have demonstrated that intranuclear localization is important for phenotypic expression of MJD/SCA3 (07). It is still unclear if the inclusions are themselves pathogenic. Only certain neuronal populations are vulnerable to atxn-3-mediated degeneration (111; 81) and one hypothesis for selectivity is that atxn-3 expression may be subject to differential posttranslational modifications across neuronal subpopulations (81). Proposed pathogenic mechanisms mediated by mutant atxn-3 are primary toxic gain of function, aggregation-induced toxicity, disruption of cellular protein clearance, and toxicity from protein breakdown products (18; 112; 44; 85; 65; 103). Oxidative stress, mitochondrial dysfunction, dysfunctional brain cholesterol metabolism, and altered calcium signaling are also believed to contribute to the development of MJD/SCA3 (81; 92).

Diagnostic workup

	• Diagnosis of MJD/SCA3 is made by a serum molecular gene test.
	• MRI is a useful supportive investigation. Characteristic structural changes can help differentiate between disorders that share a similar clinical phenotype.
	• Serum neurofilament light chain shows promise as an early biomarker for diagnosis and monitoring of MJD/SCA3.

If the family history is unknown or the presentation is atypical, then diagnostic studies to evaluate other possible diagnoses must be undertaken in an orderly manner, including a brain MRI that may provide clues to an alternative diagnosis. In addition to excluding space-occupying lesions, strokes, and demyelinating lesions, brain MRI can show characteristic disease patterns. For example, pantothenate kinase deficiency often has an "eye-of-the-tiger" sign (with iron accumulation in the basal ganglia) (117), and patients with multiple system atrophy can demonstrate atrophy of the olivo-ponto-cerebellar tracts with a cruciform pontine T2 hyperintensity (“hot-cross bun sign”) (120). However, these findings are not always present and are not disease-specific. For example, the hot cross bun sign has been found in several spinocerebellar ataxia subtypes (62).

Brain imaging studies demonstrate a caudal-rostral progression of atrophy in MJA/SCA3 (106). Structural changes are already present in premanifest patients, with atrophy of the midbrain, substantia nigra, and spinal cord, as well as microstructural white matter changes in cerebral and cerebellar peduncles (106; 55). There is growing interest in diffusion tensor imaging (DTI) to detect early microstructural changes. Significant DTI differences have consistently been found compared to healthy controls in the corticospinal tract and superior and inferior cerebellar peduncles (84; 96; 102).

Degeneration patterns on brain MRI can reliably differentiate spinocerebellar ataxia subtypes early in the disease (45). The motor regions of the cerebellar cortex are selectively more affected in patients with MJD/SCA3 compared to other spinocerebellar ataxias, and, interestingly, patients with MJD/SCA3 had relatively greater motor impairment for the same degree of objective cerebellar degeneration (45).

MRI can also be useful for monitoring disease progression. A linear T2-weighted hyperintensity of the lateral margin of the internal capsule and pontine cross-like hyperintensity were found in all six cases of molecularly confirmed patients with MJD/SCA3 in a longitudinal imaging study and correlated with disease duration (46).

Dentatorubral-pallidoluysian atrophy (DRPLA), Huntington disease, spinocerebellar ataxia types 1, 2, 3, 6, 7, and Friedreich ataxia can all be evaluated through commercially available laboratory gene panel testing. Antibodies against intracellular and cell surface antigens (eg, Hu, Yo) may be positive in paraneoplastic cerebellar degeneration and are important to identify, as treating the underlying malignancy early can improve ataxia (19). Reversible/treatable etiologies of ataxia should be excluded with vitamin E levels, celiac serology, thyroid antibodies, connective tissue disease screening, and anti-GAD antibodies.

Currently, there are no validated biomarkers for diagnosis or monitoring MJD/SCA3, but serum neurofilament light chain (sNfL) is promising. In a cross-sectional Chinese study, sNfL levels correlated with SARA and INAS scores in manifest and premanifest subjects, even after adjusting for age and CAG repeat size (101). A meta-analysis also found that sNfL was elevated in the premanifest stage and showed a positive correlation with disease progression (100). sNfl levels start rising as early as 13 years prior to onset of ataxia in the premanifest stage (36), and a metaanalysis demonstrated a positive correlation with disease progression, including with SARA scores and INAS count (100; 137).

Spectral domain optical coherence tomography (SD-OCT) has also been proposed as a tool to monitor MJD/SCA3. A small retrospective review demonstrated that decline in SARA scores were associated with change in macular volume and ganglion cell complex thickness (15).

Management

	• The mainstay of treatment is currently symptomatic management.
	• RNA-based therapies and therapies targeting serotonin pathways, cholesterol metabolism, and chaperone systems show promise as future disease-modifying therapies.
	• Modulation of cerebello-thalamo-cortical pathways through electrical stimulation is under investigation.

After diagnosis, it is important to provide genetic counseling for the patient and immediate family members (23). Predictive testing is available for asymptomatic carriers and prenatal diagnosis can also be offered (23). Although there are no disease-modifying therapies, symptomatic treatments can have an enormous impact on improving quality of life.

Symptomatic therapies. The cornerstones of treatment of degenerative cerebellar ataxia are rehabilitation services such as physical, occupational, and speech/swallow therapies, as well as ongoing participation in an exercise program (23; 48; 26).

L-dopa has been reported to improve parkinsonian symptoms in some patients (130); however, those primarily experiencing dystonia have varied responses. In a blinded trial of 21 patients, L-dopa did not demonstrate a statistically significant improvement in dystonia (93). However, of those who responded, almost half demonstrated a large magnitude of benefit based on blinded assessment (93), suggesting that L-dopa should be offered to patients with symptoms of both parkinsonism and dystonia. Botulinum toxin can also be utilized to treat focal dystonia (140; 93).

Pain is often multifactorial and the treating physician should try to identify if the etiology is musculoskeletal, neuropathic, secondary to dystonia, or mixed. This will assist in the selection of optimal treatment. Cramps, muscle spasms, and dystonia may be treated with mexiletine, carbamazepine, baclofen, or tizanidine (52; 39). Neuropathic pain can be treated with tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors, gabapentin, or pregabalin (43).

Fatigue treatment is divided into pharmacological (methylphenidate, dextroamphetamine, modafinil, and amantadine) and nonpharmacological interventions (patient and caregiver education, behavioral modification, physical activity) (64).

Repetitive transcranial magnetic stimulation (rTMS) of the cerebellum is a promising noninvasive stimulation method. In a sham-controlled study of 20 patients with mixed spinocerebellar ataxias, rTMS led to short-term improvement in ataxia (75). This positive outcome was further supported by a single-center prospective study of 44 participants with spinocerebellar ataxia type 3 who were randomized to sham or low-frequency rTMS (125). The participants in the interventional arm scored significantly better than the sham arm on ataxia rating scales and rTMS was well tolerated, with the only adverse effect of nausea occurring at a similar frequency to the sham group.

Deep brain stimulation using subthalamic nuclei and globus pallidus targets has been trialed in case series with mixed success for parkinsonism and dystonia (01; 02). A mixed ataxia population of five participants, enriched for response to rTMS were randomized to either sham or bilateral deep brain stimulation of the dentate nuclei in a cross-over trial. No significant benefit in ataxia or quality of life was demonstrated. However, the power of the study was limited as only two participants had spinocerebellar ataxia type 3 (22).

Similarly, a randomized, sham-controlled study of direct transcranial current stimulation of the cerebellum in 20 patients with mild to moderate spinocerebellar ataxia type 3 failed to show significant short-term improvements in ataxia and did not successfully modulate the cerebello-thalamo-cortical pathway (72).

Disease-modifying therapies. Although no disease-modifying therapy is currently available, several experimental and repurposed therapeutics targeting different cellular pathways are undergoing preclinical in vitro and in vivo studies.

Following the success of antisense oligonucleotide-based therapy in spinal muscular atrophy (86), more interest has been generated in the potential efficacy of RNA-based therapies in MJD/SCA3 (59; 81). The inherent challenge is developing an agent that is selective for mutant atxn-3 alleles while sparing wild type because nondiscriminate reduction of all atxn-3 may be deleterious in the long term (20).

Antisense oligonucleotide therapies have reduced both mutant atxn-3 levels and pathological intracellular aggregates in transgenic mouse models and in vitro studies (87; 138; 83; 59). In mouse models, this has correlated with clinical motor improvement and has been well tolerated, with a duration of effect of more than 3 months (83).

Other potential therapeutic mechanisms include augmentation of protein clearance pathways, upregulation of antioxidant responses, and enhancement of mitochondrial function (32; 146). Modulation of the chaperone system to promote folding of misfolded atxn-3 is one proposed method to reduce aggregation with minimal impact on normal atxn-3 function (20). Another novel mechanism is the enhancement of CYP46A1 expression to correct dysfunction in brain cholesterol metabolism. In mouse models, atxn-3 aggregates were reduced, and motor phenotype was improved by this mechanism (92).

The role of neurotransmitters, such as adenosine and serotonin in MJD/SCA3 pathogenesis, is also under investigation through trials of repurposed medications such as selective serotonin reuptake inhibitors (135). Citalopram has been shown in vivo in mice and C elegans SCA3/MJD models to suppress the aggregation of mutant atxn-3 and mitigate neuronal degeneration (135). Furthermore, this has been associated with improvement in motor phenotype in transgenic MJD/SCA3 mouse models (135; 34).

Other repurposed medications include valproic acid, which led to improvement in gait and ataxia over 12 weeks in 36 patients with SCA3/MJD in a randomized, double-blind, placebo-controlled study (63) and varenicline, which improved gait and stance over 8 weeks (157).

Finally, a successful feasibility study shows promise for the use of clustered regularly interspaced short palindromic repeats (CRISPR) for gene editing in induced pluripotent stem cells in spinocerebellar ataxia type 3 patients. The CRISPR-nuclease 9 (Cas 9) targets the expanded polyQ encoding region in atxn-3 for excision (95). This potential treatment overcomes the limitations of other genetic therapies, which produce only temporary downregulation of gene expression (95).

Outcomes

Patients with MJD/SCA3 may potentially be more sensitive to the side effects of botulinum toxin injections for dystonia (140; 93). In a case series of 10 MJD/SCA3 patients with focal dystonia, 30% developed adverse effects such as diplopia and ptosis, and one patient required nasogastric feeding for dysphagia (93). Additionally, Tuite and Lang describe prolonged duration of dysphagia over several months in two patients following botulinum toxin injection for cervical dystonia (140).

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Kanae J Nagao MBBS FRACP

Dr. Nagao of Royal Melbourne Hospital has no relevant financial relationships to disclose.
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Editor

Robert Fekete MD

Dr. Fekete of New York Medical College received consultation fees from Acadia Pharmaceutical, Acorda, Adamas/Supernus Pharmaceuticals, Amneal/Impax, Kyowa Kirin, Lundbeck Inc., Neurocrine Inc., and Teva Pharmaceutical, Inc.
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Former Authors

Anelyssa D'Abreu MD
Joseph H Friedman MD
Neepa Patel MD

Patient Profile

Age range of presentation: 2 to 65+ years
Sex preponderance: male=female
Heredity: heredity typical

heredity may be a factor

autosomal dominant
Population groups selectively affected: Azoreans
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Primary cerebellar degeneration: 334.2
ICD-10: Hereditary ataxia, unspecified: G11.9
OMIM: Machado-Joseph disease: #109150

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Spinocerebellar ataxia type 3

Associated Disorders

Gait ataxia

Differential Diagnosis

dentatorubral-pallidoluysian atrophy
Huntington disease
other spinocerebellar ataxias (types 1, 2, 4, 5, 6, 7)
neurodegeneration with brain iron accumulation
Friedreich ataxia
- multiple system atrophy-cerebellar type
- vitamin E deficiency
- gluten ataxia
- paraneoplastic cerebellar degeneration
- anti-GAD
- Hashimoto disease
- systemic lupus erythematosus
- Parkinson disease
- multiple sclerosis
- demyelination

Also Relevant

Ataxia
Autosomal dominant hereditary ataxias
Childhood movement disorders
Hereditary spastic paraplegia
Molecular diagnosis of neurogenetic disorders
- Multiple system atrophy
- Spasticity

Clinical Categories

Movement Disorders

	• There is no therapy to prevent or delay symptom onset in those carrying the mutated ataxin-3 gene.
	• There are several methods of preventing transmission to offspring.

Spinocerebellar ataxia type 3

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Prevalence of Motor and Nonmotor Symptoms and Signs in MJD/SCA3

Motor presentation

Nonmotor presentation

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Associated or underlying disorders

Diagnostic workup

Management

Outcomes

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Questions or Comment?

Also in This Category

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Sleep and cerebral degenerative disorders

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