Machado–Joseph Disease (SCA3) and CAG-Expansion Spinocerebellar Ataxias

ATXN3-related spinocerebellar ataxia type 3 and the other autosomal dominant polyglutamine ataxias: SCA1 (ATXN1), SCA2 (ATXN2), SCA6 (CACNA1A), SCA7 (ATXN7), SCA17 (TBP), and dentatorubral-pallidoluysian atrophy (ATN1).

Literature and regulatory information updated: 6 October 2026.

0. Initial Reference Table

1. Introduction

Machado–Joseph disease is a paradigm of hereditary neurodegeneration whose clinical history preceded molecular understanding by two decades. In the 1970s, three US groups independently described autosomal dominant neurological disorders in families of Azorean ancestry who had emigrated to the United States. In 1972, Nakano, Dawson and Spence published the “Machado disease”, a hereditary ataxia in descendants of William Machado, a native of São Miguel Island living in Massachusetts [16]. In the same year, Woods and Schaumburg described a “nigro-spino-dentate degeneration with nuclear ophthalmoplegia” in the Thomas family, which they considered partially treatable [17]. In 1976, Rosenberg and colleagues reported an “autosomal dominant striatonigral degeneration” in a family of Portuguese origin with more than 329 people across eight generations (the Joseph family). The phenotype included parkinsonian rigidity, spasticity, spastic dysarthria and oculomotor abnormalities, and the authors considered it distinct from Machado disease and nigro-spino-dentate degeneration [18].

The unification of these descriptions resulted from Portuguese work. In 1978, Coutinho and Andrade studied 40 patients from 15 Azorean families and concluded that ataxia, ophthalmoplegia, pyramidal signs, dystonia, rigidity and distal atrophy were variable expressions of a single genetic disease, proposing that the American entities were variants of the same disorder [19]. In 1980, Lima and Coutinho established clinical diagnostic criteria based on a non-Azorean Portuguese family [20]. The designation “Machado–Joseph disease” became associated with the Azorean origin of the index families, while the acronym SCA3 arose from mapping, initially thought to be independent, of a dominant ataxia to the same region of chromosome 14 [1]. In 1994, Kawaguchi and colleagues identified a novel gene containing CAG repeats at 14q32.1, with 13 to 36 repeats in unaffected individuals and 68 to 79 in patients, including all affected members of a family with clinical and pathological MJD [21]. It then became clear that MJD and SCA3 were the same disorder, caused by a CAG expansion in the gene now called ATXN3 [1].

MJD belongs to the polyglutamine disease group, which includes Huntington disease, spinal and bulbar muscular atrophy, spinocerebellar ataxias (SCAs) 1, 2, 3, 6, 7 and 17, and dentatorubral-pallidoluysian atrophy (DRPLA) [11]. These entities share a mechanistic principle (translation of an expanded CAG repeat into a glutamine tract), an inverse correlation between repeat length and age at onset, varying degrees of anticipation, and failure of conventional panel or exome sequencing to detect the expansion [11, 22]. They differ, however, in distinguishing features (retinopathy in SCA7, slow saccades and hyporeflexia in SCA2, pure late-onset cerebellar ataxia in SCA6, and a Huntington disease-like phenotype in SCA17 and DRPLA), repeat stability and geographic distribution, justifying both an integrated approach and dedicated subsections for each disorder [11, 22].

The current clinical importance of MJD rests on three facts. First, it is the most common SCA worldwide and has high-prevalence founder foci in Portuguese-speaking populations, particularly the Azores, the Tagus Valley and southern Brazil [1, 2, 8]. Second, natural-history cohorts in Europe, North America, Brazil and Asia have generated measures of progression and biomarkers that support the design of pre-ataxic trials [23, 24]. Third, the first regulatory submission of a medicine for an SCA (troriluzole) was rejected by the FDA in November 2025, making it essential to distinguish rigorously between randomised trial results, comparisons with external controls and sponsor communications [9, 25]. Friedreich ataxia is addressed here only as a differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. The ATXN3 gene and ataxin-3

The ATXN3 gene is located at 14q32.12 and encodes ataxin-3, a deubiquitinating enzyme widely expressed in the brain and other tissues and present in both the cytoplasm and nucleus [1]. The normal protein binds and shortens long polyubiquitin chains, participates in protein quality control, transcriptional repression as a histone-binding protein, autophagy (through deubiquitination and stabilisation of BECN1), and regulation of mTORC1 signalling [3]. The initially described genomic structure comprises 11 exons, with the CAG tract in exon 10; additional exons (6a and 9a) and multiple splice variants have since been described [2]. In neurons, ataxin-3 is predominantly cytoplasmic but shuttles between the nucleus and cytoplasm and tends to accumulate in the nucleus in disease, where it forms intranuclear inclusions [1].

2.2. Pathogenic mechanism

The mechanism is a gain of function: expansion of the CAG repeat produces a long polyglutamine tract that makes ataxin-3 prone to aggregation and abnormal localisation [1]. MJD shares this principle with other polyglutamine SCAs, although each host protein modulates toxicity through its own interactions [1]. Neurodegeneration is widespread and not limited to the cerebellum, brainstem and basal ganglia; the cerebral cortex is relatively spared, deep cerebellar nuclei (particularly the dentate nucleus) are affected, and Purkinje cells and inferior olivary neurons are relatively preserved, distinguishing MJD from SCA1, SCA2 and SCA6 [1, 26]. Neuropathological studies describe neuronal loss in the dentate nucleus, pons, substantia nigra, thalamus, globus pallidus, anterior horns and Clarke’s column of the spinal cord, vestibular nuclei and numerous cranial motor nuclei, together with reduced brain weight and depigmentation of the substantia nigra [2].

2.3. Alleles, repeat ranges and discrepancies between sources

GeneReviews classifies alleles with 12 to 44 repeats as normal (93.5% have fewer than 31), regards alleles between the normal range and the full-penetrance range as intermediate (the smallest unstable allele described had 45 repeats), and places full penetrance at approximately 60 to 87 repeats, without a well-defined lower boundary [1]. The methodological table in the same chapter gives a pathogenic range of approximately 60 to 97, while its variant table gives 60 to 86; these internal discrepancies reflect the rarity of extreme alleles and do not change clinical interpretation [1]. The review by Bettencourt and Lima places mutated alleles consensually between 61 and 87 repeats [2]. A proposal based on the Han Chinese population, cited by GeneGuidance, defines normal as ≤44, intermediate as 45–49 and expanded as ≥50; in the Portuguese predictive testing programme, an allele with 51 repeats, found in a patient with a second allele of 71 and in two asymptomatic relatives, did not appear to be associated with disease [3, 27, 28]. These discrepancies lie precisely in the counselling-critical range (45 to approximately 60), so a result within this range should be reported with the corresponding uncertainty.

Rare intermediate alleles from 45 to approximately 60 repeats may have variable expression and may present, for example, as isolated restless legs syndrome. An asymptomatic 66-year-old with 68 repeats has been described, illustrating that a firm threshold for reduced penetrance has not been established [1].

2.4. Instability, anticipation and somatic mosaicism

The expanded repeat is unstable during transmission: expansions are more common than contractions, producing anticipation; paternal bias exists but is less marked than in Huntington disease [1]. Sperm cells generally have longer repeats than leukocytes from the same individual [1]. In the cohort of all families from Rio Grande do Sul (159 families, 3,725 individuals alive in 2015), median instability was greater in paternal transmissions, correlated with anticipation (r = 0.38) and, weakly, with parental age at conception; expansion carriers represented 65.6% of genotyped siblings, indicating transmission distortion in favour of the expanded allele in that cohort [8]. Somatic instability appears in PCR and Southern blot assays as “smears” containing alleles of several sizes [1]. In an amplicon-sequencing study of Azorean patients, somatic expansion in blood depended mainly on age and, more modestly, on repeat length; it was greater in buccal DNA than in blood, associated with the adjacent variant rs12895357, and revealed systematic sizing errors by conventional fragment-length analysis [29].

2.5. Mutational origin

Haplotype studies indicate at least two independent mutational events: one ancestral event of Asian origin, estimated to date to approximately 5,800 years ago, and a more recent event, approximately 1,400 years ago, expressed in the Portuguese population [1, 2]. In Azorean families, the ACA haplotype predominates in families from Flores Island and the GGC haplotype in those from São Miguel; both are present in mainland Portugal. Approximately 72% of families worldwide share the ACA haplotype [2]. Most disease outside Asia is thought to result from Portuguese emigration [1].

2.6. Other polyglutamine ataxias: genes, alleles and mechanisms

GeneGuidance and the EMQN consensus differ from GeneReviews on SCA17 thresholds: EMQN considers up to 42 normal and 43–48 uncertain, whereas GeneReviews considers 41–48 reduced-penetrance alleles. Alleles with 41 or 42 repeats should therefore be reported as of uncertain significance, not as normal [3, 33]. In SCA1, an assay that does not assess CAT interruptions cannot classify alleles with 36 to 44 repeats [3, 26].

2.7. HGVS nomenclature and normalisation

Repeat expansions are sequence variants, and their HGVS description depends on the transcript, version and repeat alignment. GeneReviews chapters often use transcripts predating MANE (Matched Annotation from NCBI and EMBL-EBI), and ClinVar normalises repeats on the MANE transcript using 3′ alignment, so the number in square brackets may describe only the pure CAG segment rather than the total count reported by clinical laboratories [4, 35]. The following table reproduces notations as they appear in the sources, without manual conversion between numbering systems.

In practice, the report should state the gene, transcript with version, total repeat count for each allele (and, where relevant, the presence of CAT or CAA interruptions), method, sizing margin of error, allele class with explicitly cited ranges, and limitations [1, 14]. When historical literature uses a different numbering system, both may be cited, but the exact correspondence should be obtained from a normalisation tool or the laboratory rather than calculated manually.

2.8. Allelic disorders and associations

No ATXN3 allelic phenotypes are known apart from MJD; OMIM records an association with susceptibility to late-onset Parkinson’s disease, which is not a Mendelian relationship [1, 3]. Large structural changes in the 14q32 region appear in ClinVar as pathogenic copy-number variants through other mechanisms and should not be confused with MJD [35]. In CACNA1A, point variants and deletions cause episodic ataxia type 2, familial hemiplegic migraine type 1, progressive SCA6-like ataxia and early-onset epileptic encephalopathy [31]. In ATXN2, intermediate alleles are associated with ALS risk [30]. Variants in a 16-amino-acid segment of exon 7 of ATN1 cause a neurodevelopmental disorder distinct from DRPLA, and mosaic tetrasomy 12p (Pallister–Killian syndrome) includes this gene [34].

3. Clinical Spectrum and System-Specific Manifestations

3.1. Onset and presentation

Age at onset of MJD varies widely, most often from the second to the fifth decade; the mean was 37 years in a large Azorean cohort and 36 years in a Brazilian series, with mean survival of 21 years after onset [1]. The review by Bettencourt and Lima gives a mean of approximately 40 years, with a range of 4 to 70 years, and reports gait ataxia as the first symptom in 92.4% and diplopia in 7.6% of cases in a Portuguese series [2]. Initial complaints include gait difficulty, speech changes, loss of dexterity, and vestibular and oculomotor symptoms; a sense of instability when turning the head may be an early manifestation of vestibular dysfunction, and subtle balance changes usually precede hand incoordination [1]. In the general assessment of ataxia, early symptoms may be intermittent, more apparent at the end of the day, with fatigue or after alcohol intake, and may lead to investigations for peripheral vestibulopathy, essential tremor, parkinsonism or ALS [11].

3.2. System-specific manifestations (MJD)

The minor signs with greatest specificity include progressive external ophthalmoplegia, dystonia, action-induced facial and lingual fasciculations, and bulging eyes (lid retraction), although neither a fixed gaze nor perioral fasciculations is exclusive to SCA3 [1, 2]. Vocal cord paralysis has been reported but is not considered a characteristic feature [1].

3.3. Clinical types

Coutinho and Andrade systematised three types: type 1 (“Joseph type”), with early onset (mean 24.3 years) and rapid progression, marked pyramidal and extrapyramidal signs, including dystonia; type 2 (“Thomas type”), with intermediate onset (mean 40.5 years), cerebellar ataxia and progressive external ophthalmoplegia, with or without pyramidal signs, which may progress to type 1 or 3 after 5 to 10 years; and type 3 (“Machado type”), with later onset (mean 46.8 years), ataxia, ophthalmoplegia and peripheral changes [2]. Some authors also describe a parkinsonian type 4 with mild cerebellar impairment and neuropathy or distal amyotrophy, and a possible type 5 with spastic paraplegia without ataxia [2]. GeneReviews emphasises that assigning a patient to a subtype has little clinical value because the types overlap, coexist in the same family, and one may evolve into another [1]. A familial Parkinson’s disease phenocopy should prompt consideration of SCA3, particularly in people of African ancestry [1].

3.4. Progression

Walking becomes progressively difficult, requiring walking aids and eventually a wheelchair 10 to 15 years after onset [1]. Brainstem signs develop (temporal and facial atrophy, action-induced perioral jerks, vestibular symptoms, tongue atrophy and fasciculations, dysphagia and ineffective cough), along with peripheral polyneuropathy with distal sensory and ankle-reflex loss, and postural changes while sitting [1]. In advanced disease, patients are generally wheelchair-bound, with severe dysarthria and dysphagia, facial and temporal atrophy, weak cough, dystonic postures, ophthalmoparesis and, sometimes, blepharospasm [1]. Death results from pulmonary complications and cachexia 6 to 29 years after onset [1]. In the EUROSCA European study, involving 462 patients followed for a median of 49 months, the annual increase in the SARA (Scale for the Assessment and Rating of Ataxia, 0–40) score was 1.56 in SCA3, 2.11 in SCA1, 1.49 in SCA2 and 0.80 in SCA6; the number of non-ataxic signs reached a plateau in SCA1, 2 and 3 [23].

3.5. Imaging and neurophysiology

Magnetic resonance imaging (MRI) typically shows pontocerebellar atrophy with enlargement of the fourth ventricle; clinical severity correlated with total brainstem atrophy in a European natural-history study [1]. MR spectroscopy detects early neurochemical changes [1]. Nerve conduction studies often show sensory and motor involvement [1]. In a multicentre analysis of 322 carriers, atrophy followed a uniform sequence, beginning in the caudal brainstem with substantial white-matter involvement; staging based on this sequence predicted SARA progression better than isolated volumetric measurements [36].

3.6. SCA1

SCA1 typically begins in the third or fourth decade with ataxia, dysarthria and progressive bulbar deterioration. Early signs include brisk reflexes, hypermetric saccades, nystagmus and mild dysphagia; later findings include slow saccades, upward-gaze paresis, muscle atrophy, proprioceptive loss, executive dysfunction, chorea and dystonia [26]. Mixed sensorimotor polyneuropathy occurs in 82%, extrapyramidal signs in 37.5%, and cognitive dysfunction is more extensive and progresses more rapidly than in SCA2, SCA3 and SCA6 [26]. Time from onset to death ranges from 10 to 30 years; juvenile forms (onset before age 13) progress more rapidly and lead to death before age 16, with severe brainstem dysfunction [26]. Respiratory failure is the main cause of death [26].

3.7. SCA2

SCA2 usually presents in the fourth decade, with a disease duration of 10 to 15 years. It is characterised by slowly progressive ataxia with early slow saccades, nystagmus, ophthalmoparesis, tremor, cramps, progressive hyporeflexia and, in some patients, levodopa-responsive parkinsonism [30]. In the original Holguín series in Cuba, more than 50% developed kinetic or postural tremor, hypotonia, hyporeflexia and slow saccades progressing to supranuclear ophthalmoplegia [30]. Dystonia or chorea (38%) and dementia (37%) were reported in a North American series [30]. Repeats longer than 45 are almost always associated with onset before age 20, and very large expansions may cause severe childhood disease [30].

3.8. SCA6

SCA6 is a pure, slowly progressive adult-onset cerebellar ataxia (age range 19 to 73 years; mean 43–52 years), beginning with gait instability in approximately 90% and dysarthria in the remainder [31]. Gaze-evoked horizontal nystagmus occurs in 70%–100%, vertical nystagmus (often downbeat) in 65%–83%, diplopia in approximately 50%, pyramidal signs in 40%–50%, and dystonia or blepharospasm in fewer than 25% [31]. Cognition is generally preserved, life expectancy is not reduced, onset may be episodic, and severity increases during pregnancy [31].

3.9. SCA7

SCA7 combines progressive cerebellar ataxia with cone-rod retinal dystrophy and loss of central vision, a blue-yellow (tritan-axis) colour defect, macular changes, paracentral scotoma and an electroretinogram showing early cone involvement [32]. In adolescent-onset disease, visual loss precedes ataxia and may lead to blindness in less than a decade; in adult-onset disease, ataxia precedes visual loss, and after the fifth decade there may be no relevant visual impairment [32]. Infantile forms feature growth failure, loss of motor milestones, hypotonia, dysphagia and heart failure, with death within months, sometimes before the carrier parent develops symptoms [32, 37].

3.10. SCA17

SCA17 (also known as Huntington disease-like 4) is characterised by ataxia (95%), dementia (~90%) and involuntary movements (~70%), including chorea and dystonia, with frequent psychiatric symptoms, pyramidal signs and rigidity [33]. Onset ranges from 3 to 75 years (mean 34.6), and all carriers of full-penetrance alleles develop neurological or psychiatric symptoms by age 50 [33]. The correlation between repeat length and age at onset is weaker than in other polyglutamine disorders [33].

3.11. DRPLA

DRPLA has five or six cardinal features: ataxia, cognitive decline, myoclonus, chorea, epilepsy and psychiatric manifestations [34]. Onset ranges from 0 to 72 years (mean 31.5), mean disease duration is 8 years, and mean age at death is 49 years [34]. Before age 20 (usually ≥65 repeats), progressive myoclonic epilepsy with developmental delay and intellectual deterioration predominates; after age 20 (<65 repeats), ataxia, choreoathetosis, dementia and psychiatric changes predominate and may mask ataxia and mimic Huntington disease [34, 38]. MRI shows cerebellar and pontine tegmental atrophy and, in later-onset forms, paravermian cerebellar white-matter lesions [34].

4. Clinical Recognition and Red Flags

Recognition begins with progressive adult-onset ataxia and a family history consistent with dominant transmission, but absence of a family history does not exclude the diagnosis because relatives’ disease may have gone unrecognised, a relative may have died early, a parent may have late onset, or an intermediate allele may have expanded [1]. Abele and colleagues found a 13% probability of SCA1, SCA2, SCA3, SCA6, SCA7, SCA17 or Friedreich ataxia in adults with sporadic ataxia [22]. Up to 40% of adults with late-onset ataxia and no family history remain without a genetic cause after a complete evaluation [11]. The clinical history should include a three-generation pedigree, consanguinity, ethnic origin (for example, Azorean, Cuban, Japanese or Mexican ancestry), onset and disability stage, visual loss, cognitive impairment and non-neurological manifestations [11, 22].

Comparison of phenotypic frequencies summarises the differences: slow saccades occur in 71%–92% of SCA2, 50% of SCA1, 10% of SCA3 and 0%–6% of SCA6; pyramidal involvement in 70% of SCA1 and SCA3; peripheral neuropathy in 44%–94% (SCA2), 100% (SCA1), 80% (SCA3) and 16%–44% (SCA6); and intellectual disability in 31%–37% of SCA2, 20% of SCA1, 5% of SCA3 and 0% of SCA6 [30]. These percentages come from older series, do not replace molecular testing, and show sufficient overlap to make clinical subtype diagnosis often impossible [1, 30].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no formal clinical criteria for the SCAs. MJD is diagnosed in a proband with suggestive findings and a heterozygous CAG expansion in ATXN3 identified by molecular testing [1]. Suggestive findings are progressive cerebellar ataxia variably associated with pyramidal signs, dystonic-rigid syndrome, peripheral amyotrophy with generalised areflexia, progressive external ophthalmoplegia, faciolingual fasciculations and bulging eyes, in a context consistent with dominant inheritance [1].

5.2. Methods and test limitations

The proportion of probands with MJD detected by targeted analysis is 100%, because the expansion is the only known mechanism; this figure describes detection of the causal variant type, not the clinical sensitivity of a panel in a patient with ataxia of unknown cause [1]. Exact sizing has no demonstrated clinical utility beyond allele classification [1]. Somatic and germline instability make repeat length an approximate, tissue-dependent measure [1, 29]. Research results should be confirmed in an accredited laboratory before being reported [13].

5.3. Algorithms

For a dominant family history, the 2014 EFNS/ENS consensus recommends initial screening for SCA1, 2, 3, 6, 7 and 17 (level B) and also DRPLA in Asian patients. In the absence of a family history, it also recommends screening for the most common dominant and recessive ataxias; complete evaluation for recessive ataxias when onset is before age 45; testing for an FMR1 premutation when onset is after age 45; and considering multiple system atrophy in sporadic cases after age 30 [12]. The Oxford Desk Reference describes a stepwise strategy, testing the most common types first [22]. The 2025 North American recommendations, developed by a multidisciplinary panel that selected 68 articles, reverse the stepwise logic: initial testing should be as comprehensive as possible, include the most relevant genes and reliably detect repeat expansions, with genome sequencing suggested as first-line. In people with a known family history and compatible neurological assessment, genetic testing should be the first investigation; reanalysis should be considered after at least two years or a clinical change, and DNA storage should be offered to symptomatic patients with a negative result or who decline testing [15]. The divergence reflects the period and availability of technology: where genome sequencing with validated repeat analysis is unavailable, a targeted repeat-expansion panel remains the most direct route for a dominant phenotype.

Before molecular testing, evaluation includes brain MRI, nerve conduction studies, ophthalmological assessment with electroretinography, electrocardiogram and echocardiogram (particularly relevant to Friedreich ataxia), and, according to context, vitamin E, alpha-fetoprotein, cholesterol, albumin and metabolic studies [22]. Antigliadin antibodies are positive in 10%–15% of patients with ataxia, but it is not established whether they are a cause or consequence [22]. The Saudubray textbook lists metabolic causes of chronic, episodic or myoclonic ataxia, identifying treatable causes such as cerebrotendinous xanthomatosis, vitamin E deficiency, abetalipoproteinaemia and GLUT1 deficiency [41].

5.4. Evaluation after diagnosis (MJD)

GeneReviews recommends a neurological assessment using a standardised scale (SARA, ICARS—International Cooperative Ataxia Rating Scale—or BARS—Brief Ataxia Rating Scale); assessment for upper and lower motor neuron and extrapyramidal signs; brain or spinal MRI to exclude coincident pathology; ophthalmological examination (acuity, nystagmus, saccades, gaze limitation, ptosis); speech and swallowing assessment, including aspiration risk; respiratory function tests if symptomatic; autonomic and bladder assessment (with possible urodynamic studies); polysomnography; pain characterisation (with possible electromyography or regional MRI); cognitive assessment using the CCAS (cerebellar cognitive affective syndrome) scale; genetic counselling; and assessment of family and social needs [1]. In SCA7, add best-corrected visual acuity, colour vision testing, full-field electroretinography and optical coherence tomography [32]; in juvenile DRPLA, obtain a baseline electroencephalogram before antiepileptic treatment, a myoclonus scale and a developmental assessment [34].

5.5. Research biomarkers

In the European ESMI cohort (291 carriers and 121 controls from 14 centres in five European countries and the United States), plasma neurofilament light chain (NfL) became abnormal approximately 21.5 years before ataxia onset, medullary volume loss was the earliest MRI change (−4.7 years), and pontine volume was the most responsive marker of change, outperforming SARA [24]. These data are intended for trial design and research staging; they do not replace genetic testing or establish individual clinical thresholds [24].

6. Differential Diagnosis

The differential diagnosis of MJD largely overlaps with that of hereditary and acquired ataxias, and clinical distinction between dominant SCAs is often impossible [1]. Dystonia and parkinsonism responsive to levodopa or dopamine agonists may lead to confusion with dopa-responsive dystonia or Parkinson’s disease, although almost all patients with parkinsonian signs also have some cerebellar sign [1]. Some families with predominantly pyramidal involvement mimic hereditary spastic paraplegia [1]. Multifactorial and acquired causes of ataxia are four to five times more common than hereditary causes and may confound the family history [11].

For the grouped entities, the differential is specific. In SCA7, retinal degeneration distinguishes it from other SCAs; the differential includes cone-rod dystrophy due to CRX, Leber hereditary optic neuropathy, Costeff syndrome and Wolfram syndrome [32]. In SCA17, the differential includes DRPLA (ataxia and myoclonus), Huntington disease (prominent chorea), C9orf72-related ALS/frontotemporal dementia, Huntington disease-like 1 and 2, chorea-acanthocytosis, McLeod syndrome, benign hereditary chorea, familial Creutzfeldt–Jakob disease, early-onset familial Alzheimer disease and frontotemporal dementia with parkinsonism [33, 42]. In adult-onset DRPLA, early ataxia and brainstem atrophy (especially pontine tegmentum) favour DRPLA, while caudate atrophy favours Huntington disease; testing for both is often necessary. In juvenile DRPLA, the differential is that of progressive myoclonic epilepsies (neuronal ceroid lipofuscinoses, Unverricht–Lundborg disease, Lafora disease, MERRF, sialidosis, Gaucher disease type 3, among others) [34, 43]. SCA2 and SCA6 are included in the differential of sporadic adult-onset ataxia and multiple system atrophy, while SCA2 is also considered in levodopa-responsive parkinsonism and ALS [30, 31]. In dystonia with a dominant family history or other neurological signs, consider Huntington disease, SCA, DRPLA and Gerstmann–Sträussler disease [44].

7. Treatment and Risk-Management Strategies

7.1. Principles

There is no treatment that delays or stops progression of MJD or the other polyglutamine SCAs; the aim is to maximise function and reduce complications through a multidisciplinary team (neurology, physical medicine and rehabilitation, physiotherapy, occupational therapy, speech and language therapy, nutrition, orthopaedics, urology, psychology and social work) [1, 11]. Ataxia UK guidelines emphasise that many symptomatic interventions are extrapolated from other neurological disorders, such as multiple sclerosis, and that most recommendations are good-practice points rather than trial-based evidence [13].

7.2. Rehabilitation and non-pharmacological measures

Physiotherapy (balance and gait training, strengthening; in SCA1, coordination training should take priority over strengthening) and occupational therapy maintain mobility and independence, while intensive inpatient rehabilitation may improve ataxia and function in degenerative ataxias [1, 26]. The American Academy of Neurology (AAN) systematic review concluded that four weeks of inpatient rehabilitation probably improves ataxia and function (one class I study) [45]. The EFNS/ENS consensus considers the evidence class II for physiotherapy and class III for occupational therapy [12]. Neither exercise nor physiotherapy has been shown to slow progression, but activity should be maintained [1]. Assistive devices (canes, walkers, powered wheelchairs, weighted cutlery, dressing hooks), home adaptations (grab bars, raised toilets, ramps), weight management and speech therapy with alternative communication methods are part of the plan [1]. In MJD, occupational therapy also improved depression scores in an open-label Brazilian trial [1].

7.3. Symptomatic treatment by manifestation (MJD)

7.4. Medicines with trial evidence and trial or label doses

None of the following medicines has an approved indication for SCA in the European Union or the United States; doses shown are from product labels (for the approved indication) or cited trials, and use for ataxia is off-label.

Interpretation of these trials should account for three limitations. Trials are small, short and often include mixed populations (SCA and Friedreich ataxia); a response defined as a reduction of at least one SARA point, in a patient progressing by approximately 1.5 points per year, mainly measures symptomatic effect rather than modification of disease course [23, 46]. ATRIL, the first riluzole trial in a single genotype, did not confirm benefit in SCA2 [47]. The AAN review supporting some of these conclusions is currently classified as withdrawn in PubMed and is therefore cited as a historical synthesis, not as current guidance [45].

7.5. Troriluzole: trials and regulatory status

Troriluzole (BHV-4157) is a riluzole tripeptide prodrug. The 8-week phase 2b/3 trial (dose 140 mg once daily) did not differ from placebo on SARA. The phase 3 BHV4157-206 trial (NCT03701399) randomised adults with SCA1, 2, 3, 6, 7, 8 and 10 to troriluzole (140 mg for the first 4 weeks, then 200 mg once daily) or placebo for 48 weeks, with f-SARA (a modified four-item functional scale, 0–16) as the primary outcome [9, 53]. The primary endpoint was not met: in the registry, the least-squares mean difference was −0.06 (95% CI −0.47 to 0.34; p = 0.76) in the overall population, and the sponsor attributed the result to lower-than-expected progression in the placebo group [9, 53]. In a genotype subgroup analysis described by the sponsor as post hoc, with descriptive p values, patients with SCA3 (41% of participants) had a difference of −0.56 (95% CI −1.11 to −0.01; p = 0.045) [9, 53]. Falls were recorded as adverse events in 13/108 treated patients and 24/109 receiving placebo, and headache in 13/108 and 8/109; serious adverse events occurred in 6/108 and 8/109 [53].

The BHV4157-206-RWE study (NCT06529146) compared patients treated for up to 3 years in the trial and open-label extension with external controls from the CRC-SCA (United States) and EUROSCA natural-history cohorts, matched using an adjusted indirect comparison; the sponsor reported favourable f-SARA differences at 1, 2 and 3 years [9, 54]. This was a non-randomised comparison with external controls, subject to selection, follow-up and assessment bias; its results are reported in sponsor communications and the registry, not in a peer-reviewed publication consulted for this article.

7.6. Riluzole: regulatory status of the molecule

7.7. Therapies under investigation

ATXN3 silencing with antisense oligonucleotides (ASOs) ameliorated disease in mouse models [1]. The phase 1 trial of intrathecal ASO BIIB132 (Biogen) in adults with SCA3 (NCT05160558) was terminated by sponsor decision after enrolling 8 participants [56]. VO659 (Vico Therapeutics), an intrathecal ASO targeting CAG repeats, is in an open-label phase 1/2a trial in SCA1, SCA3 and Huntington disease (NCT05822908; doses 10 to 60 mg; 68 participants planned; primary completion estimated in 2028); in February 2026, the sponsor reported administration of a twice-yearly regimen [57]. The STRIDES trial of intravenous trehalose (SLS-005; 0.5 or 0.75 g/kg weekly) in SCA was terminated for financial reasons after 23 participants, with no published efficacy data [58]. In neuromodulation, a Chinese randomised trial of transcranial alternating current stimulation (70 Hz, 2 mA, 40 minutes daily for 2 weeks) in 80 patients with SCA3 reported a primary response in 80% vs 10% with sham stimulation; another trial of cerebellar intermittent theta-burst stimulation for 3 weeks in 38 patients reported an ICARS improvement of 2.67 points after treatment and 4.11 at 3 months [59, 60]. These trials are single-centre and short-term and do not establish sustained benefit. The 2026 reviews of trials in trinucleotide-repeat disorders emphasise repeated phase II and III failures and the need for target-engagement biomarkers, allele-specific treatments and inclusion at early stages [61, 62].

7.8. Disorder-specific treatment in other entities

In SCA6, acetazolamide may eliminate episodes of ataxia without changing progression; diphenhydramine, baclofen and gabapentin may reduce vertigo and oscillopsia; 4-aminopyridine has literature support for vestibular symptoms and nystagmus; clonazepam treats REM sleep disorder unless it worsens morning imbalance; and positive airway pressure treats apnoea [31]. Acetazolamide and dalfampridine (the only aminopyridine approved by the FDA, for walking in multiple sclerosis) are not indicated for ataxia, so such use is off-label [3]. In SCA7, medicines most often used for ataxic symptoms are amantadine, buspirone and riluzole, with variable response; spasticity is treated with baclofen, tizanidine, gabapentin, clonazepam, dantrolene or diazepam; and visual loss with low-vision aids [32]. In SCA17, psychiatric symptoms are treated with psychotropic medicines, seizures with antiepileptics, and dystonia with botulinum toxin; adverse effects are common and may require dose reduction or discontinuation [33]. In juvenile DRPLA, myoclonus may respond to carbamazepine, phenytoin or levetiracetam, and generalised seizures to sodium valproate, perampanel or zonisamide; in adult DRPLA, choreoathetosis and dystonia may respond to tetrabenazine, risperidone, bromazepam or gabapentin, and psychosis to quetiapine [34].

7.9. Agents and circumstances to avoid; special populations

Avoid alcohol, sedative or hypnotic medicines that worsen incoordination, neurotoxic agents (isoniazid, high-dose vitamin B6, phenytoin in SCA1), and activities with a risk of falling, such as operating machinery or working at heights [26, 30, 31]. General anaesthesia requires caution in MJD (combined epidural-spinal anaesthesia has been reported) and increases the risk of intra- and postoperative seizures in DRPLA [1, 34]. SCA6 may worsen during pregnancy, and balance-support measures should be reinforced; in DRPLA, antiepileptic treatment decisions should be made before conception because untreated epilepsy also poses a risk, and human data on riluzole are limited [31, 34]. Driving should be assessed periodically by professionals [31]. For children with juvenile forms (SCA7, SCA2, SCA1, DRPLA), the plan includes individualised educational support and palliative care when appropriate [34].

8. Reproductive Options and Family Counselling

8.1. Risks

All disorders in this article are autosomal dominant: each child of a carrier has a 50% chance of inheriting the expansion [1]. Most probands have an affected parent, but may have inherited an expansion from an unaffected parent with an intermediate allele [1]. If neither parent has the expansion in leukocytes, sibling risk is low but greater than the population risk because of possible germline mosaicism; in SCA17, this risk was estimated at 1% [1, 33]. If the parents have not been tested and are clinically unaffected, siblings remain at increased risk [1]. An apparently negative family history is confirmed only by molecular testing of the parents; non-medical explanations (alternative paternity or maternity, undisclosed adoption) may also be considered [1]. In SCA17, approximately 38% of cases are simplex, and the proportion of de novo expansions is unknown [33].

8.2. Predictive testing

Predictive testing of at-risk adults is possible once the expansion has been identified in an affected relative, but does not predict age at onset, severity, symptom type or rate of progression [1]. For disorders in which a result does not change surveillance or treatment, such as Huntington disease and the SCAs, the Oxford Desk Reference describes a staged programme with at least three consultations over several months, a support person chosen by the consultee, and discussion of natural history, implications of a high-risk result, family implications and financial and insurance consequences [63]. The 2025 North American recommendations advise genetic counselling for all asymptomatic people with a family history, assessment of psychological status, informed consent, decision-making capacity, absence of coercion, discussion of legal protections, post-test counselling regardless of result, and the presence of a support person when results are disclosed [15]. In the Azores, among 46 people who completed the presymptomatic testing programme, depression and anxiety scores did not change one year after result disclosure, in carriers or non-carriers; overall uptake was 20.7% and reached 35.8% on Flores Island, where the disease was a source of stigma [1, 64].

8.3. Minors

Predictive testing of asymptomatic minors is considered inappropriate for adult-onset disorders without beneficial early intervention, because it limits the child’s future autonomy without a compensating benefit [1]. Ataxia UK allows case-by-case consideration, and the 2025 North American recommendations limit testing to symptomatic minors assessed by a paediatric neurologist experienced in ataxia; asymptomatic minors may be tested only if an approved childhood treatment exists [13, 15]. In a family with an established diagnosis, a symptomatic child may be tested at any age [1].

8.4. Reproductive options

The ideal time to determine risk and discuss prenatal diagnosis or preimplantation genetic testing is before pregnancy, and counselling should be offered to affected or at-risk young adults [1]. Prenatal diagnosis and preimplantation testing are possible once the familial expansion has been identified; views on prenatal diagnosis may differ among professionals and within families [1]. The North American recommendations state that fetal testing should not be performed if it would not change pregnancy management and that people wishing to test a pregnancy should be referred for genetic counselling before or early in gestation [15]. DNA storage from affected patients should be considered [22, 31]. In sporadic adult-onset ataxia without an identified cause after investigation, risk to offspring is unknown; an empirical risk of 5% is often used, without strong supporting data [22].

8.5. Psychosocial aspects

In interviews with 25 people recruited through a Portuguese patient association, reasons for declining presymptomatic testing included lack of expected clinical benefit, anticipated psychological burden, prioritising day-to-day life, and family conflict between wanting to know and preferring not to know [65]. In São Miguel, a qualitative study of 28 participants described intense stigma in the past and a current trend towards greater openness, attributed in part to the role of the local patient association [66]. Depressive symptoms are common in patients and relatives and should be assessed at each visit [1].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Global frequency

Estimated prevalence of all SCAs combined ranges from 0.3 to 2.0 per 100,000 [2]. Precise population prevalence data for MJD are unavailable, but it is considered the most common SCA worldwide, accounting for 20%–50% of SCA families [1]. Orphanet, as cited by GeneGuidance, records a global prevalence of 1.5/100,000 (category 1–9/100,000), with 1.0/100,000 in Portugal and 5.5/100,000 in Japan; these values are derived from estimates and studies using different methods and are not directly comparable [3, 5].

These proportions measure the genetic composition of referred family series, not population prevalence.

9.2. Portugal and the Azores

A population-based Portuguese national survey conducted between 1994 and 2004, with active collaboration from general practitioners and examination by a single neurology team, identified 1,336 patients with hereditary cerebellar ataxia or spastic paraplegia in a population of 10.3 million (12.9/100,000). Hereditary cerebellar ataxias had a prevalence of 8.9/100,000 (5.6 dominant), with MJD most common (3.1/100,000), followed by Friedreich ataxia (1.0) and ataxia with oculomotor apraxia (0.4); no genetic cause was identified in 39.7% [7]. According to the review by Bettencourt and Lima, MJD is relatively rare on the mainland (approximately 1/100,000), except for a small area of the Tagus Valley (approximately 1/1,000), and reaches the highest prevalence worldwide in the Azores, on Flores Island (1/239) [2]. For the archipelago as a whole, the Azorean follow-up cohort reports 39 per 100,000 inhabitants; this cohort, comprising 20 pre-ataxic carriers and 52 patients at baseline, is part of the European ESMI initiative [6]. In Portugal, DRPLA is the second most common dominant ataxia (0.33/100,000), sharing the same haplotype as Japanese families, a relevant point for Portuguese diagnostic panels [34].

9.3. Brazil and South America

SCA3 accounts for 69%–92% of Brazilian SCA families [1]. In Rio Grande do Sul, the registry of all known families (159 families, 94% of the registry; 625 symptomatic patients in 2015) estimated a minimum prevalence of 6/100,000 [8]. In a series of 412 patients from 82 families, mean survival was 63.96 years (95% CI 62.09–65.83), compared with 78.61 years in 413 unaffected relatives, and survival after onset was 21.18 years [67]. A 2025 South American systematic review and meta-analysis included 2,111 patients (2,026 in Brazil), with a mean of 21.90 repeats in the normal allele, 74.65 in the expanded allele and age at onset of 34.90 years. Expansion length explained 62% of the variability in age at onset, but its effect varied by geographic origin (Peruvian patients appeared to have earlier onset than predicted); ACA, CCG and AGA haplotypes were reported in Brazilian patients, reinforcing the link with Luso-Azorean origin [68]. DRPLA was identified in 0.2%–0.92% of Brazilian ataxia cohorts [34].

9.4. United States, Europe and other founder populations

In the United States and Canada, SCA3 is among the most common SCAs (21%–25% of families); in a Los Angeles ataxia clinic with diverse ethnic composition, SCA3 accounted for 23% of autosomal dominant cerebellar ataxias, SCA2 for 13% and SCA1 for 6% [1, 30]. The parkinsonian SCA3 phenotype has been reported as more common in patients of African ancestry [1]. Outside Lusophone populations, six Yemeni Jewish families in Israel share an extended haplotype consistent with a recent common ancestor; in one Yemeni family, many homozygotes did not have more severe disease than heterozygotes in other families [1, 69]. The highest prevalence outside the Azores was reported in remote Aboriginal communities in Australia’s Top End, where families on Groote Eylandt provided a distinct model for maintaining mobility [70]. For other entities, notable foci include SCA2 in Holguín (Cuba), where the disease was first characterised; SCA2 as the most common ADCA in Korea; SCA1 as virtually the only ADCA in eastern Siberia and absent in Koreans; an SCA7 focus in Veracruz (Mexico), with more than 150 patients due to a colonial founder effect, and its concentration in northern Europeans and Africans; SCA6 in 31% of families in Japan, 13% in Germany and 12% in the United States; and DRPLA at 0.2–0.7/100,000 in Japan (9.7% of dominant ataxias, the third most common), 11.4% in South Wales series, and 1%–3.3% in Spain and Italy [26, 30–32, 34]. SCA17 has a minimum prevalence of 0.16/100,000 in northeast England and 0.047/100,000 in Japan, with fewer than 100 families described, probably an underestimate because of phenotypes resembling Huntington disease [33].

9.5. Gaps

No recent population prevalence estimates for SCA3 in Brazil as a whole or in the United States were found in the sources consulted; clinical series measure the composition of referred cohorts and should not be converted into national prevalence. The absence of data in the consulted sources does not demonstrate that no studies have been published.

10. Illustrative Clinical Case

10.1. Parkinsonian MJD phenotype in two Azorean families

Bettencourt and colleagues described two unrelated patients with parkinsonian triad (tremor, bradykinesia and rigidity) in a series of 70 Azorean patients with confirmed MJD, one from a São Miguel family and the other from Graciosa Island [71]. Patient 1, aged 40, noticed slowness of movement at age 30; examination showed hypomimia and marked bradykinesia, with a good response to levodopa, which she continued for 8 years. She was then admitted because of neurological deterioration and depression. She had prominent parkinsonian syndrome with on–off fluctuations, cerebellar dysarthria and incoordination, axial and upper-limb dystonia, restricted upward gaze with nystagmus, generalised hyperreflexia, bilateral Babinski signs and marked gait ataxia [71]. Her mother also had a parkinsonian phenotype: gait and fine-movement difficulties began at age 34; at age 36 she had bradykinesia, amimia and bilateral hypertonia without tremor or incoordination, with a purely parkinsonian gait, and achieved a normal neurological examination on 300 mg levodopa with 75 mg of the decarboxylase inhibitor. Twelve years later, she remained on levodopa, with extreme dyskinesias, profound depression, moderate ataxia, cerebellar dysarthria and marked limitation of upward gaze [71]. The maternal grandfather developed gait ataxia at age 63, followed by dysarthria, diplopia and dysphagia, peroneal atrophy with areflexia and, four years later, resting tremor and rigidity [71]. The family pedigree is available in figure 1 of the original article (Figure 1).

Patient 2, aged 38, had a left-hand tremor since age 33; at age 35 he had mild tremor of the left hand and leg, left cogwheel rigidity, mild ataxia, hyperreflexia and a right Babinski sign, with a consistent response to levodopa and normal MRI; his father and three affected siblings had no extrapyramidal signs (Figure 2) [71]. Both patients had an expanded allele of 72 CAG repeats (normal alleles of 14 and 29); no mutations were found in the PARK2, LRRK2, PINK1 or DJ-1 genes, nor the mitochondrial variant T4336C (historical notation, = NC_012920.1:m.4336T>C in MT-TQ, classified as benign in ClinVar, VCV000009615) [35]; DJ-1 and APOE polymorphisms were observed, which the authors proposed as possible modifiers, an unconfirmed hypothesis [71].

10.2. Lessons from the case

The case illustrates four points of this article. The same repeat count (72) was associated with different phenotypes, confirming that expansion length explains only part of the variability [1, 71]. Levodopa-responsive parkinsonism may precede cerebellar signs by years and lead to an initial diagnosis of Parkinson’s disease [1, 71]. Familial clustering of parkinsonian phenotypes suggests a contribution from modifiers, but the reported polymorphisms are research hypotheses and do not justify additional testing in clinical practice. The prolonged levodopa response reported reflects individual patients and is not a dosing recommendation; GeneReviews only indicates levodopa or a dopamine agonist for parkinsonism in MJD [1].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

MJD progresses continuously; walking aids are needed 10 to 15 years after onset, and death occurs 6 to 29 years after onset due to pulmonary complications and cachexia [1]. In the southern Brazilian cohort, survival after onset was 21.18 years, and mean age at death was approximately 15 years lower than in unaffected relatives; earlier onset and longer repeats predicted shorter survival [67]. Across hereditary ataxias, falls causing head trauma or femoral neck fracture, aspiration and infections are common causes of morbidity and mortality, and survival rarely exceeds 25 years after onset [11]. The annual SARA progression of 1.56 points in SCA3 allows estimation of group trajectories, but not individual progression [23]. In ESMI, younger age and lower medullary volume predicted more rapid clinical progression [24]. Among the other entities, SCA6 does not reduce life expectancy, juvenile SCA1 and SCA7 progress over a few years, and mean DRPLA duration is 8 years [26, 31, 32, 34].

11.2. Surveillance

No published surveillance guidelines are available for hereditary ataxias overall; the intervals above are expert recommendations from GeneReviews chapters [11]. During transition from paediatric to adult care (juvenile forms of SCA2, SCA7 and DRPLA), continuity of the multidisciplinary team and educational and social support should be ensured [34].

11.3. Networks and resources

In Europe, the relevant reference network is ERN-RND, which brings together 64 specialised centres and 4 affiliated partners in 24 countries and includes a cerebellar ataxia and hereditary spastic paraplegia group, with case discussions through the CPMS system [10]. Registries and natural-history cohorts (EUROSCA, ESMI, CRC-SCA, READISCA) support trial preparation [1, 23, 24]. Patient organisations listed by GeneReviews include the National Ataxia Foundation (United States), the Ataxia MJD Research Project, Ataxia UK, euro-ATAXIA (European federation), FEDAES (Spain), AISA (Italy) and the CoRDS registry [1, 11]. In Brazil, the Brazilian Association for Hereditary and Acquired Ataxias (ABAHE) provides information and support and maintains a national patient registry [72].

12. Summary and Concluding Remarks

Machado–Joseph disease is the most common dominant spinocerebellar ataxia worldwide and is closely linked to the history of Portuguese-speaking populations: it was described in Azorean families who emigrated to the United States, unified by Portuguese neurologists and linked to two mutational events; it reaches its highest prevalence worldwide on Flores Island and has foci in the Tagus Valley and southern Brazil. The cause is a CAG expansion in ATXN3 that produces ataxin-3 with an expanded polyglutamine tract. Diagnosis requires targeted repeat analysis or genome methods validated for expansions; a negative panel or exome result does not exclude the disease. Allele ranges differ between sources in the 45–60-repeat region, and reports should specify transcript, count, method and limitations.

The clinical picture combines cerebellar ataxia with pyramidal, extrapyramidal, peripheral and oculomotor signs; different phenotypes may occur within the same family, and annual SARA progression is approximately 1.5 points. Other polyglutamine ataxias are distinguished by guiding signs (retinopathy in SCA7, slow saccades in SCA2, pure late-onset ataxia in SCA6, and a Huntington-like phenotype in SCA17 and DRPLA) and by differing degrees of anticipation. Treatment remains multidisciplinary and symptomatic; riluzole, valproate and varenicline have limited evidence and are used off-label, lithium was negative in SCA3, and riluzole was negative in SCA2. Troriluzole did not meet the primary endpoint in a randomised trial, received an FDA complete response letter in November 2025 and had its European application withdrawn. Antisense oligonucleotides, natural-history cohorts and biomarkers (neurofilaments, brainstem volumetry) define the next generation of trials, potentially in the pre-ataxic phase. Genetic counselling, including staged predictive testing, protection of minors and reproductive options, remains central and should be offered before pregnancy.

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