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Machado-Joseph Disease

Machado–Joseph Disease (Spinocerebellar Ataxia Type 3) — Disease Characteristics Research Report

2026-04-26
Falcon MONDO:0007182 Model: Edison Scientific Literature 37 citations

Machado–Joseph Disease (Spinocerebellar Ataxia Type 3) — Disease Characteristics Research Report

Target disease: Machado–Joseph disease (MJD) / Spinocerebellar ataxia type 3 (SCA3)
Category: Mendelian (autosomal dominant polyglutamine repeat-expansion disorder) (stahl2024spinocerebellarataxiatype pages 1-2, paulino2023autophagyinspinocerebellar pages 1-2, NCT02175290 chunk 1)

Evidence and citation note

This report is based on the documents retrieved in this run (mostly 2023–2024 reviews, cohort studies, and ClinicalTrials.gov records). Many retrieved excerpts did not include PubMed IDs (PMIDs); therefore, where PMIDs are required, I provide DOI/URL and publication month/year, and explicitly flag PMID unavailability in the retrieved context.

1. Disease Information

1.1 Concise overview

Machado–Joseph disease / SCA3 is a monogenic, progressive neurodegenerative ataxia caused by a pathogenic CAG repeat expansion in ATXN3, leading to production of polyglutamine-expanded ataxin-3 that misfolds and aggregates in neurons (potapenko2024thedeubiquitinasefunction pages 1-2, stahl2024spinocerebellarataxiatype pages 1-2, paulino2023autophagyinspinocerebellar pages 1-2). Clinically, it is characterized by progressive cerebellar ataxia with frequent additional pyramidal, extrapyramidal (including parkinsonism), oculomotor, and peripheral neuropathic features, culminating in severe disability and premature death (potapenko2024thedeubiquitinasefunction pages 1-2, pilotto2024hereditaryataxiasfrom pages 4-5, paulino2023autophagyinspinocerebellar pages 1-2).

1.2 Key identifiers and synonyms

A structured summary of disease nomenclature and identifiers supported by the retrieved evidence is provided below.

Table (click to expand)
Identifier system Identifier Evidence-supported? (yes/no) Notes Key citation (pqac id)
Preferred disease name Machado–Joseph disease yes Monogenic neurodegenerative disorder; also referred to as SCA3 (potapenko2024thedeubiquitinasefunction pages 1-2, stahl2024spinocerebellarataxiatype pages 1-2, paulino2023autophagyinspinocerebellar pages 1-2)
Major synonym Spinocerebellar ataxia type 3 yes Standard synonym used interchangeably with Machado–Joseph disease (potapenko2024thedeubiquitinasefunction pages 1-2, stahl2024spinocerebellarataxiatype pages 1-2, paulino2023autophagyinspinocerebellar pages 1-2)
Major synonym SCA3 yes Common abbreviation in clinical and research literature (stahl2024spinocerebellarataxiatype pages 1-2, paulino2023autophagyinspinocerebellar pages 1-2, NCT02175290 chunk 1)
Major synonym MJD yes Common abbreviation for Machado–Joseph disease (stahl2024spinocerebellarataxiatype pages 1-2, paulino2023autophagyinspinocerebellar pages 1-2, NCT02175290 chunk 1)
OMIM 109150 yes Explicitly reported for SCA3/Machado–Joseph disease in a 2024 review (pilotto2024hereditaryataxiasfrom pages 4-5)
MONDO MONDO:0007182 yes Disease-target association retrieved for Machado-Joseph disease in Open Targets output (stahl2024spinocerebellarataxiatype pages 1-2)
Orphanet disease entry Orphanet:98757 yes Open Targets output mapped “Spinocerebellar ataxia type 3” to Orphanet_98757 (stahl2024spinocerebellarataxiatype pages 1-2)
ICD-10 Not established from gathered evidence no No ICD-10 code was provided in the gathered evidence set (stahl2024spinocerebellarataxiatype pages 1-2)
ICD-11 Not established from gathered evidence no No ICD-11 code was provided in the gathered evidence set (stahl2024spinocerebellarataxiatype pages 1-2)
MeSH Not established from gathered evidence no No MeSH identifier was provided in the gathered evidence set (stahl2024spinocerebellarataxiatype pages 1-2)
Inheritance Autosomal dominant yes Repeatedly described as an autosomal dominant/polyglutamine ataxia (stahl2024spinocerebellarataxiatype pages 1-2, NCT02175290 chunk 1, raposo2024bloodandcerebellar pages 1-5)
Causal gene ATXN3 yes Causative gene; CAG expansion located in exon 10 (stahl2024spinocerebellarataxiatype pages 1-2, paulino2023autophagyinspinocerebellar pages 1-2, NCT02175290 chunk 1)
Gene product Ataxin-3 yes Deubiquitinating enzyme involved in proteostasis/transcriptional regulation (potapenko2024thedeubiquitinasefunction pages 1-2, paulino2023autophagyinspinocerebellar pages 1-2)
Molecular lesion CAG trinucleotide repeat expansion yes Produces expanded polyglutamine tract in ataxin-3 (potapenko2024thedeubiquitinasefunction pages 1-2, stahl2024spinocerebellarataxiatype pages 1-2, paulino2023autophagyinspinocerebellar pages 1-2)
Normal repeat range ~12–42 CAGs yes One evidence source reports normal alleles approximately 12–42 repeats (stahl2024spinocerebellarataxiatype pages 1-2)
Normal repeat range up to 44 CAGs yes Alternative review reports normal range up to 44 repeats (pilotto2024hereditaryataxiasfrom pages 4-5)
Normal/polyQ range reported ~13–49 glutamines yes Review reports normal ataxin-3 polyQ stretch as 13–49 glutamines (paulino2023autophagyinspinocerebellar pages 1-2)
Pathogenic repeat range ~52–86 CAGs yes Review reports affected individuals typically carry 52–86 repeats (pilotto2024hereditaryataxiasfrom pages 4-5)
Pathogenic repeat range ~55–87 CAGs yes Alternative review reports pathogenic expansions 55–87 repeats/glutamines (paulino2023autophagyinspinocerebellar pages 1-2)
Pathogenic repeat range ~60–87 CAGs yes Review reports pathogenic alleles roughly 60–87 repeats (stahl2024spinocerebellarataxiatype pages 1-2)
Major affected regions Cerebellum and pons yes Frequently highlighted as primary affected regions (paulino2023autophagyinspinocerebellar pages 1-2, sohail2023adifficultcase pages 1-2)
Additional affected regions Brainstem, basal ganglia, substantia nigra/striatum yes Broader neurodegeneration beyond cerebellum contributes to phenotypic heterogeneity (potapenko2024thedeubiquitinasefunction pages 1-2, paulino2023autophagyinspinocerebellar pages 1-2, pilotto2024hereditaryataxiasfrom pages 4-5)

Table: This table summarizes evidence-supported nomenclature and core identifiers for Machado–Joseph disease / spinocerebellar ataxia type 3. It also flags identifier systems not established by the gathered evidence so the final report can distinguish confirmed from missing database mappings.

Key identifier limitations: ICD-10/ICD-11 and MeSH identifiers were not present in the retrieved evidence for this run; they should be added via dedicated ontology/database lookup if required for the knowledge base entry (artifact-00).

1.3 Evidence source type

Most information here comes from aggregated disease-level resources and cohorts (reviews and multi-site observational studies), rather than individual EHR case reports, except for one illustrative case report (sohail2023adifficultcase pages 1-2).

2. Etiology

2.1 Primary causal factors

Genetic cause (primary): Pathogenic expansion of a CAG trinucleotide repeat in exon 10 of ATXN3 produces a polyQ-expanded ataxin-3 protein with toxic gain-of-function properties leading to neuronal dysfunction and degeneration (stahl2024spinocerebellarataxiatype pages 1-2, paulino2023autophagyinspinocerebellar pages 1-2). ATXN3 encodes a deubiquitinating enzyme involved in proteostasis and other functions (potapenko2024thedeubiquitinasefunction pages 1-2).

Repeat-size ranges (current evidence): - Normal: reported approximately 12–42 repeats (stahl2024spinocerebellarataxiatype pages 1-2) or “up to 44” (pilotto2024hereditaryataxiasfrom pages 4-5). - Pathogenic: typically ~52–86 repeats (pilotto2024hereditaryataxiasfrom pages 4-5) and/or ~55–87 repeats (paulino2023autophagyinspinocerebellar pages 1-2), with some sources describing typical patient ranges ~62–84 (potapenko2024thedeubiquitinasefunction pages 1-2).

2.2 Risk factors

Genetic risk factor: Carrying the pathogenic ATXN3 expansion is necessary and (age-dependently) sufficient for disease development in autosomal dominant families (stahl2024spinocerebellarataxiatype pages 1-2, NCT02175290 chunk 1).

Modifier effects (repeat size): Larger expanded alleles correlate with earlier age at onset and greater severity (potapenko2024thedeubiquitinasefunction pages 1-2, paulino2023autophagyinspinocerebellar pages 1-2, silva2023thejosephindomain pages 1-2).

Other genetic/molecular modifiers (emerging): - ATXN3 transcript diversity/splicing: ATXN3 has extensive alternative splicing; blood vs cerebellum show strong isoform differences (e.g., ATXN3-251 vs ATXN3-214), which may influence selective vulnerability and mRNA-lowering therapy design (raposo2024bloodandcerebellar pages 1-5). - Post-transcriptional regulation: miRNA families and Dicer/Drosha-dependent processing are discussed as modulators of ATXN3 levels (stahl2024spinocerebellarataxiatype pages 1-2).

2.3 Protective factors

No specific protective variants or environmental protective factors were identified in the retrieved evidence. The closest related concept is incomplete penetrance early in life with age-dependent conversion to symptomatic disease (see Epidemiology/Inheritance) (paulino2023autophagyinspinocerebellar pages 1-2).

2.4 Gene–environment interactions

No gene–environment interaction evidence was retrieved in this run.

3. Phenotypes

3.1 Core clinical phenotype and common manifestations

SCA3/MJD is characterized by progressive ataxia with multi-system involvement.

Commonly described manifestations (from retrieved evidence): - Cerebellar ataxia (core feature) (paulino2023autophagyinspinocerebellar pages 1-2) - Pyramidal and extrapyramidal signs; parkinsonism in some subtypes (pilotto2024hereditaryataxiasfrom pages 4-5, paulino2023autophagyinspinocerebellar pages 1-2) - Oculomotor abnormalities including diplopia/ophthalmoparesis (moura2024spinocerebellarataxiasphenotypic pages 7-9) - Peripheral neuropathy (often axonal sensory) and muscle cramps/atrophy in some subtypes (pilotto2024hereditaryataxiasfrom pages 4-5, moura2024spinocerebellarataxiasphenotypic pages 7-9) - Dysarthria/dysphagia are highlighted as major disabling features in reviews (potapenko2024thedeubiquitinasefunction pages 1-2)

Subtype classification (clinical heterogeneity): A 2024 review describes four clinical subtypes:
Type I (early onset ~10–30 years; pyramidal/extrapyramidal signs), Type II (most common; onset 2nd–5th decades), Type III (later onset; prominent peripheral neuropathy and muscle atrophy), Type IV (parkinsonism) (pilotto2024hereditaryataxiasfrom pages 4-5).

3.2 Quantitative phenotype data (examples from 2024 cohorts)

3.3 Age of onset, severity, progression

  • Typical adult onset often falls around the 3rd–5th decades (median ~39.5 years reported for polyQ SCAs in one cohort; MJD/SCA3 predominant) (moura2024spinocerebellarataxiasphenotypic pages 1-2).
  • Disease is progressive and life-limiting. After symptom onset, survival is reported as ~20–25 years in a 2024 review, and patients often become wheelchair dependent later in disease (potapenko2024thedeubiquitinasefunction pages 1-2). Another large biomarker study notes clinical ataxia progression over ~20 years on average (faber2024stage‐dependentbiomarkerchanges pages 4-7).

3.4 Suggested HPO terms (non-exhaustive; evidence-aligned)

Ontology note: HPO IDs are suggested standard mappings; the retrieved documents support the phenotypes but did not themselves provide HPO IDs.

4. Genetic / Molecular Information

4.1 Causal gene

4.2 Variant type and consequences

4.3 Allele frequency and population databases

Population allele frequencies (e.g., gnomAD) were not available in the retrieved evidence.

4.4 Molecular modifiers (selected, evidence-supported)

  • Alternative splicing / isoform usage differs markedly between blood and cerebellum; this may affect selective vulnerability and design/interpretation of blood biomarkers for target engagement (raposo2024bloodandcerebellar pages 1-5).
  • miRNA-mediated regulation (miR-181/miR-25 family, miR-9, miR-494) and dependency on Dicer/Drosha are cited as modulators of ATXN3 expression (stahl2024spinocerebellarataxiatype pages 1-2).

5. Environmental Information

No environmental toxins, lifestyle factors, or infectious triggers were identified in the retrieved evidence set.

6. Mechanism / Pathophysiology

6.1 Causal chain (high-level)

ATXN3 CAG expansion → polyQ-expanded ataxin-3 → misfolding/aggregation/inclusions → impaired proteostasis (UPS and autophagy), transcriptional and mitochondrial dysfunction (including mitophagy defects and oxidative stress) → selective neurodegeneration (brainstem/cerebellar circuitry and other regions) → progressive motor and multisystem phenotype (potapenko2024thedeubiquitinasefunction pages 1-2, paulino2023autophagyinspinocerebellar pages 1-2, paulino2023autophagyinspinocerebellar pages 4-5, cui2024spinocerebellarataxiasfrom pages 5-6).

6.2 Protein dysfunction and proteostasis

Suggested GO terms (Biological Process; evidence-aligned): - Protein ubiquitination / deubiquitination — e.g., GO:0016567, GO:0016579 (potapenko2024thedeubiquitinasefunction pages 1-2) - Proteasome-mediated ubiquitin-dependent protein catabolic process — GO:0043161 (potapenko2024thedeubiquitinasefunction pages 1-2)

6.3 Autophagy impairment (2023 synthesis; therapeutic relevance)

Autophagy is highlighted as critical for clearance of large oligomeric/aggregated species that are poorly handled by the UPS (paulino2023autophagyinspinocerebellar pages 4-5). Reported disease-associated findings include reduced beclin-1 in patient fibroblasts and altered LC3-II/p62 patterns in MJD brain, consistent with impaired autophagic flux (paulino2023autophagyinspinocerebellar pages 4-5).

Suggested GO terms: - Autophagy — GO:0006914 (paulino2023autophagyinspinocerebellar pages 4-5, paulino2023autophagyinspinocerebellar pages 1-2) - Macroautophagy — GO:0016236 (paulino2023autophagyinspinocerebellar pages 4-5)

6.4 Mitochondrial dysfunction, oxidative stress, and mitophagy (2024 emphasis)

  • A 2024 review describes impaired Parkin/VDAC1-mediated mitophagy linked to mutant ataxin-3 (aberrant loss of Parkin and reduced VDAC1 polyubiquitination), highlighting the PINK1/Parkin axis as a therapeutic target (cui2024spinocerebellarataxiasfrom pages 5-6).
  • A 2024 experimental study in an MJD cell model (SK-N-SH expressing mutant ataxin-3) links mutant ataxin-3 toxicity to oxidative stress and mitochondrial dysfunction; astragaloside IV reduced mutant ataxin-3 aggregation by enhancing autophagy, improving antioxidant capacity, and improving mitochondrial membrane potential/respiration and dynamics (lin2024astragalosideivreduces pages 1-2).

Suggested GO terms: - Mitophagy — GO:0000422 (cui2024spinocerebellarataxiasfrom pages 5-6) - Mitochondrial organization — GO:0007005 (lin2024astragalosideivreduces pages 1-2) - Response to oxidative stress — GO:0006979 (lin2024astragalosideivreduces pages 1-2)

6.5 Transcriptional and post-transcriptional dysregulation (2024 review)

A 2024 review notes promoter-binding factors (SP1/CBF), limited CpG methylation findings, and miRNA-mediated regulation of ATXN3; a CRISPR-based endogenous reporter screen identified statins as potential activators of ATXN3 expression, suggesting cholesterol-related biology may be relevant (stahl2024spinocerebellarataxiatype pages 1-2).

6.6 Immune system involvement

Neuroinflammation was not substantively addressed in the retrieved excerpts and should be treated as a gap for this run.

Suggested cell types (CL; evidence-aligned but not directly measured in retrieved excerpts): - Purkinje neuron — CL:0000121 (Purkinje dysfunction/degeneration discussed in model contexts) (pilotto2024hereditaryataxiasfrom pages 13-15, paulino2023autophagyinspinocerebellar pages 4-5) - Oligodendrocyte — CL:0000128 (transcriptional abnormalities in some SCA3 models cited indirectly) (shorrock2024cagrepeatselectivecompounds pages 54-55)

7. Anatomical Structures Affected

7.1 Organ/system level

Primary system affected: central nervous system (neurodegenerative ataxia) (potapenko2024thedeubiquitinasefunction pages 1-2, stahl2024spinocerebellarataxiatype pages 1-2).

7.2 Key regions (human neuropathology/imaging)

Suggested UBERON terms (examples): - Cerebellum — UBERON:0002037 (paulino2023autophagyinspinocerebellar pages 1-2) - Pons — UBERON:0000986 (paulino2023autophagyinspinocerebellar pages 1-2, moura2024spinocerebellarataxiasphenotypic pages 7-9) - Substantia nigra — UBERON:0002038 (pilotto2024hereditaryataxiasfrom pages 4-5)

7.3 Subcellular localization

Nuclear and cytoplasmic inclusion bodies are described (stahl2024spinocerebellarataxiatype pages 1-2, potapenko2024thedeubiquitinasefunction pages 1-2).

Suggested GO Cellular Component: - Nucleus — GO:0005634 (stahl2024spinocerebellarataxiatype pages 1-2)

8. Temporal Development (Natural History)

8.1 Onset and course

Typical onset is often in adulthood (e.g., ~30–50 years in polyQ cohorts; subtype-dependent) (pilotto2024hereditaryataxiasfrom pages 4-5, moura2024spinocerebellarataxiasphenotypic pages 1-2). Disease is progressive over decades, commonly described as ~20 years from manifest onset (potapenko2024thedeubiquitinasefunction pages 1-2, faber2024stage‐dependentbiomarkerchanges pages 4-7).

8.2 Biomarker-defined pre-ataxic window (major 2024 development)

A major 2024 advance is a biomarker-led staging framework anchored to onset.

Table (click to expand)
Study (year, journal) Cohort (n) Biomarkers Key quantitative findings (with units and timing relative to onset) Proposed model / implications URL Key citation (pqac)
Faber et al. (2024, Annals of Neurology) 292 SCA3 mutation carriers + 108 controls; 57 pre-ataxic, 235 ataxic Plasma elongated/mutant ATXN3, serum neurofilament light (NfL), MRI volumes of pons, cerebellar white matter (CWM), cerebellar gray matter (CGM), SARA Mutant ATXN3 elevated before and after onset (trait marker). NfL deviated from normal ~11.9 years before onset. Pons volume deviated ~2.0 years before onset; CWM volume ~0.3 years before onset. In manifest ataxia, NfL z-score ≥2 in 174/190 (92%); pons/CWM z-scores ≤-2 in ~90% of assessed patients. Multivariable model including NfL/MRI explained 73.9% of SARA variance vs 60.4% without them. SARA cutoff for manifest ataxia: ≥3. (faber2024stage‐dependentbiomarkerchanges pages 1-4, faber2024stage‐dependentbiomarkerchanges pages 4-7, faber2024stage‐dependentbiomarkerchanges pages 15-21, faber2024stage‐dependentbiomarkerchanges pages 7-9) Data-driven 3-stage model: asymptomatic carrier → biomarker stage (pre-ataxic but NfL abnormal) → ataxia stage; supports biomarker-led early/preventive trial design and staging for targeted therapies. Figure extraction also retrieved staging/trajectory panels. (faber2024stage‐dependentbiomarkerchanges pages 9-12, faber2024stage‐dependentbiomarkerchanges pages 12-15, faber2024stage‐dependentbiomarkerchanges media b30f008b, faber2024stage‐dependentbiomarkerchanges media 807d2b9d) https://doi.org/10.1002/ana.26824 (faber2024stage‐dependentbiomarkerchanges pages 1-4, faber2024stage‐dependentbiomarkerchanges pages 4-7, faber2024stage‐dependentbiomarkerchanges pages 15-21, faber2024stage‐dependentbiomarkerchanges pages 7-9, faber2024stage‐dependentbiomarkerchanges pages 9-12, faber2024stage‐dependentbiomarkerchanges pages 12-15, faber2024stage‐dependentbiomarkerchanges media b30f008b, faber2024stage‐dependentbiomarkerchanges media 807d2b9d)
Faber et al. (2024, Annals of Neurology) — cohort detail row MRI available in 161; mutant ATXN3 in 134; NfL in 327 measurements across participants Same as above Mean age 35.5 years in pre-ataxic carriers and 51.3 years in ataxic carriers; pre-ataxic carriers averaged ~7.7 years before onset; expanded CAG mean ~68.2–68.8 repeats. Clinical disease duration after onset described as ~20 years on average. (faber2024stage‐dependentbiomarkerchanges pages 4-7, faber2024stage‐dependentbiomarkerchanges pages 15-21) Quantifies the “pre-ataxic window” during which fluid biomarkers become abnormal well before clear structural MRI changes, relevant for enrichment of future interventional studies. https://doi.org/10.1002/ana.26824 (faber2024stage‐dependentbiomarkerchanges pages 4-7, faber2024stage‐dependentbiomarkerchanges pages 15-21)
Raposo et al. (2024, bioRxiv preprint) Blood n=60; cerebellum n=12 RNA-seq abundance of ATXN3 splice variants/transcripts in blood and cerebellum Higher number/abundance of ATXN3 transcripts in cerebellum than blood. ATXN3-251 (3 UIM) expressed ~50-fold more in blood than cerebellum; ATXN3-214 (2 UIM) expressed ~20-fold more in cerebellum than blood. (raposo2024bloodandcerebellar pages 1-5) Tissue-specific transcript usage may refine molecular biomarker development and improve design of ATXN3 mRNA-lowering therapies by indicating which isoforms dominate in target tissue vs accessible blood. https://doi.org/10.1101/2023.04.22.537936 (raposo2024bloodandcerebellar pages 1-5)
Moura et al. (2024, Cerebellum) — phenotype/imaging cohort relevant to staging 88 SCA patients total; 38 polyQ SCA cases, of which MJD/SCA3 represented 73.7% of polyQ families/cases Clinical scales (SARA, INAS), EMG-defined axonal neuropathy, MRI atrophy patterns PolyQ SCA median age at onset 39.5 years; axonal neuropathy in 16/22 (72.7%) of polyQ cases; pons and cerebellar peduncle atrophy each in 9/28 (32.1%) of polyQ cases. Falls, gait aid use, and wheelchair confinement were tracked as disability milestones. (moura2024spinocerebellarataxiasphenotypic pages 7-9, moura2024spinocerebellarataxiasphenotypic pages 9-10, moura2024spinocerebellarataxiasphenotypic pages 1-2) Not a biomarker-staging paper per se, but supports real-world structural and functional milestones that align with brainstem/cerebellar degeneration and progression in MJD/SCA3-dominant polyQ cohorts. https://doi.org/10.1007/s12311-024-01723-9 (moura2024spinocerebellarataxiasphenotypic pages 7-9, moura2024spinocerebellarataxiasphenotypic pages 9-10, moura2024spinocerebellarataxiasphenotypic pages 1-2)

Table: This table summarizes the most relevant 2023-2024 biomarker and staging evidence for Machado-Joseph disease / SCA3, highlighting the quantitative timing of NfL and MRI changes relative to clinical onset. It is useful for identifying current candidate biomarkers, pre-ataxic disease stages, and implications for trial design.

Key quantitative staging points (ESMI cohort): NfL becomes abnormal ~11.9 years before ataxia onset, while pons and cerebellar white matter volume changes deviate closer to onset; mutant ATXN3 in blood is elevated across stages but is less progression-sensitive (faber2024stage‐dependentbiomarkerchanges pages 7-9, faber2024stage‐dependentbiomarkerchanges pages 1-4).

Visual evidence (figures): Biomarker trajectories and the proposed carrier/biomarker/ataxia staging model were retrieved as figure crops (faber2024stage‐dependentbiomarkerchanges media b30f008b, faber2024stage‐dependentbiomarkerchanges media 807d2b9d).

9. Inheritance and Population

9.1 Inheritance

Autosomal dominant inheritance is consistently described (stahl2024spinocerebellarataxiatype pages 1-2, NCT02175290 chunk 1).

9.2 Penetrance and anticipation-like behavior

9.3 Epidemiology and geographic distribution (statistics from recent sources)

Data gaps: Incidence, variant-specific geographic distributions/haplotypes, and sex ratio were not available in the retrieved excerpts.

10. Diagnostics

10.1 Genetic testing (real-world implementation)

Repeat-expansion testing remains central for suspected polyQ SCAs: - A cohort study describes use of multiplex PCR + fragment analysis to test CAG expansions in a panel including ATXN3, alongside targeted single-gene testing and multigene NGS/WES panels (moura2024spinocerebellarataxiasphenotypic pages 2-4).

Diagnostic yields (single center cohort): - Targeted single-gene testing in probands with a suspected diagnosis: 76.9% (20/26) yield (moura2024spinocerebellarataxiasphenotypic pages 2-4). - Multigene NGS/WES-based panels: 64.3% (18/28) yield; no WGS cases were reported in that cohort (moura2024spinocerebellarataxiasphenotypic pages 2-4, moura2024spinocerebellarataxiasphenotypic pages 7-9).

Clinical trial genetic confirmation threshold: An intrathecal ASO trial required genetically confirmed SCA3 with ATXN3 CAG repeats ≥60 (NCT05160558 chunk 1).

10.2 Diagnostic delay (quantitative, 2023)

A Brazilian retrospective study (1999–2017; n=428 symptomatic individuals included) reported median diagnostic delay 5 years (IQR ~3–8.75). Index cases had longer delays than non-index relatives (median 6 vs 4 years) (pinheiro2023diagnosticdelayof pages 2-5).

10.3 Biomarkers and imaging in diagnostic/staging workflows (2024)

  • Blood NfL and plasma mutant ATXN3, alongside MRI volumes of pons and cerebellar compartments, are being used to define pre-ataxic “biomarker stage” vs manifest ataxia in large cohorts, which may inform future diagnostic and preventive-trial strategies (faber2024stage‐dependentbiomarkerchanges pages 7-9, faber2024stage‐dependentbiomarkerchanges pages 4-7).

Data gaps: Differential diagnosis lists, standardized ICD/DSM-like criteria, and formal guidance on WES/WGS sensitivity for expansions were not retrieved in this run.

11. Outcome / Prognosis

SCA3/MJD is progressive with severe disability and reduced life expectancy: - A 2024 review reports that advanced disease often leads to wheelchair dependence and survival after symptom onset of approximately 20–25 years (potapenko2024thedeubiquitinasefunction pages 1-2). - In a Portuguese cohort context, average life expectancy reduction of ~5.6 years vs general population (for deceased patients, all of whom had MJD/SCA3) was reported (moura2024spinocerebellarataxiasphenotypic pages 9-10).

12. Treatment

12.1 Current standard of care

No disease-modifying therapy is established; management is largely supportive/symptomatic (paulino2023autophagyinspinocerebellar pages 1-2, sohail2023adifficultcase pages 1-2).

Suggested MAXO terms (examples): - Symptomatic treatment — MAXO:0000058 (supportive care; general) (sohail2023adifficultcase pages 1-2) - Physical therapy / rehabilitation — MAXO:0000012 (not directly evidenced in retrieved excerpts; include only if supported by additional sources)

12.2 Disease-modifying and experimental therapeutics (2023–2024 emphasis)

12.2.1 Antisense oligonucleotides (ASOs)

  • BIIB132 (intrathecal ASO targeting ATXN3 pre-mRNA): Phase 1, randomized, placebo-controlled; terminated; enrollment 8; completion 2023-07-25 (ClinicalTrials.gov NCT05160558) (NCT05160558 chunk 1). The major role of NfL/MRI staging work is to support early-stage trials, and the biomarker paper notes initiation of this ASO safety trial (faber2024stage‐dependentbiomarkerchanges pages 4-7).
  • A 2024 review reports additional ASO development such as VO659 in Phase 1/2a (ClinicalTrials.gov NCT05822908) (stahl2024spinocerebellarataxiatype pages 6-7).

12.2.2 Autophagy-targeting and small-molecule approaches

12.2.3 Gene suppression/editing (preclinical landscape)

Preclinical RNAi/shRNA/siRNA and CRISPR strategies have demonstrated reduction of ataxin-3 aggregation and improvement in motor/neuropathology readouts in models (pilotto2024hereditaryataxiasfrom pages 13-15, cui2024spinocerebellarataxiasfrom pages 6-7). Delivery and safety remain major translational barriers (cui2024spinocerebellarataxiasfrom pages 6-7, stahl2024spinocerebellarataxiatype pages 6-7).

12.2.4 Neuromodulation and supportive-device interventions (real-world trials)

ClinicalTrials.gov records indicate multiple non-pharmacologic trials in MJD/SCA3, including deep TMS (NCT02039206), rTMS (NCT05502432), and a gait intervention using lower-limb weighting (NCT02906046) (NCT02175290 chunk 1). Detailed outcomes were not available in the retrieved trial excerpts for this run.

13. Prevention

Because SCA3/MJD is monogenic, “prevention” primarily centers on genetic counseling, family-based cascade testing, and early identification of mutation carriers.

Evidence-supported elements from retrieved sources: - A Brazilian diagnostic workflow explicitly distinguishes direct mutation testing for individuals from families with known molecular diagnosis versus stepwise panel testing for index cases (pinheiro2023diagnosticdelayof pages 2-5). - A 2024 biomarker study supports identification of a pre-ataxic biomarker stage (~12 years pre-onset NfL rise), suggesting feasibility of preventive/early-intervention trials in carriers before frank ataxia (faber2024stage‐dependentbiomarkerchanges pages 7-9).

Data gaps: Formal guidelines for prenatal testing/PGT, and specific genetic counseling recommendations were not retrieved in this run.

14. Other Species / Natural Disease

No naturally occurring (non-experimental) veterinary SCA3/MJD analogs were identified in the retrieved evidence.

15. Model Organisms

15.1 Model systems used (with evidence)

15.2 Model limitations (evidence-aligned)

Key limitations highlighted include delivery barriers (BBB, invasive dosing for ASOs), need for repeated administration, and translational uncertainty from preclinical success to clinical efficacy (cui2024spinocerebellarataxiasfrom pages 6-7, cui2024spinocerebellarataxiasfrom pages 9-10).

Recent developments (2023–2024) — synthesis highlights

  1. Biomarker staging and early disease window: Large cohort work proposes a carrier → biomarker → ataxia staging model, with NfL abnormal ~11.9 years pre-onset (faber2024stage‐dependentbiomarkerchanges pages 7-9, faber2024stage‐dependentbiomarkerchanges media b30f008b, faber2024stage‐dependentbiomarkerchanges media 807d2b9d).
  2. Therapeutic pipeline maturation but setbacks: Intrathecal ATXN3 ASO trial NCT05160558 terminated after a small Phase 1 exposure; multiple other approaches (e.g., trehalose IV, VO659) continue (NCT05160558 chunk 1, stahl2024spinocerebellarataxiatype pages 6-7).
  3. Mechanistic refinement: Reviews emphasize convergent impairment of proteostasis (UPS/autophagy) and mitochondrial quality control (mitophagy via Parkin/VDAC1; PINK1/Parkin) as actionable targets (cui2024spinocerebellarataxiasfrom pages 5-6, paulino2023autophagyinspinocerebellar pages 4-5).
  4. Molecular stratification for mRNA-lowering: Tissue-specific ATXN3 splice variant abundance differences provide a concrete consideration for target engagement biomarkers and isoform coverage (raposo2024bloodandcerebellar pages 1-5).

Key limitations of this run (for knowledge base completion)

  • ICD-10/ICD-11 and MeSH identifiers were not retrieved and should be filled via dedicated ontology lookup.
  • Many sources in this run were reviews; primary literature PMIDs were not consistently present in the retrieved excerpts.
  • Environmental risk/protective factors, gene–environment interactions, neuroinflammation details, and formal prevention/counseling guidelines were not captured in the retrieved evidence set.

References

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  2. (paulino2023autophagyinspinocerebellar pages 1-2): Rodrigo T. Paulino and Clévio Nóbrega. Autophagy in spinocerebellar ataxia type 3: from pathogenesis to therapeutics. International Journal of Molecular Sciences, 24:7405, Apr 2023. URL: https://doi.org/10.3390/ijms24087405, doi:10.3390/ijms24087405. This article has 28 citations.

  3. (NCT02175290 chunk 1): Machado-Joseph Disease in Israel. Meir Medical Center. 2014. ClinicalTrials.gov Identifier: NCT02175290

  4. (potapenko2024thedeubiquitinasefunction pages 1-2): Anastasiya Potapenko, Jennilee M. Davidson, Albert Lee, and Angela S. Laird. The deubiquitinase function of ataxin-3 and its role in the pathogenesis of machado-joseph disease and other diseases. Biochemical Journal, 481:461-480, Mar 2024. URL: https://doi.org/10.1042/bcj20240017, doi:10.1042/bcj20240017. This article has 10 citations and is from a domain leading peer-reviewed journal.

  5. (pilotto2024hereditaryataxiasfrom pages 4-5): Federica Pilotto, Andrea Del Bondio, and Hélène Puccio. Hereditary ataxias: from bench to clinic, where do we stand? Cells, 13:319, Feb 2024. URL: https://doi.org/10.3390/cells13040319, doi:10.3390/cells13040319. This article has 23 citations.

  6. (raposo2024bloodandcerebellar pages 1-5): Mafalda Raposo, Jeannette Hübener-Schmid, Rebecca Tagett, Ana F. Ferreira, Ana Rosa Vieira Melo, João Vasconcelos, Paula Pires, Teresa Kay, Hector Garcia-Moreno, Paola Giunti, Magda M. Santana, Luis Pereira de Almeida, Jon Infante, Bart P. van de Warrenburg, Jeroen J. de Vries, Jennifer Faber, Thomas Klockgether, Nicolas Casadei, Jakob Admard, Ludger Schöls, Olaf Riess, Maria do Carmo Costa, and Manuela Lima. Blood and cerebellar abundance of atxn3 splice variants in spinocerebellar ataxia type 3/machado-joseph disease. BioRxiv, Apr 2024. URL: https://doi.org/10.1101/2023.04.22.537936, doi:10.1101/2023.04.22.537936. This article has 8 citations.

  7. (sohail2023adifficultcase pages 1-2): Muhammad Sohail, Ajmal Ghoauri, N. Butt, M. Rasheed, Muhammad Umair Javed, Fahmina Ashfaq, Fcps Mbbs, Dr. Dur-e-Sabeh, and Mbbs House Physician. A difficult case to diagnose: machado-joseph disease/spinocerebellar ataxia type iii. Journal of Aziz Fatimah Medical & Dental College, 5:71-73, Dec 2023. URL: https://doi.org/10.55279/jafmdc.v5i2.260, doi:10.55279/jafmdc.v5i2.260. This article has 0 citations.

  8. (silva2023thejosephindomain pages 1-2): Rita Sousa e Silva, André Dias Sousa, Jorge Vieira, and Cristina P. Vieira. The josephin domain (jd) containing proteins are predicted to bind to the same interactors: implications for spinocerebellar ataxia type 3 (sca3) studies using drosophila melanogaster mutants. Frontiers in Molecular Neuroscience, Mar 2023. URL: https://doi.org/10.3389/fnmol.2023.1140719, doi:10.3389/fnmol.2023.1140719. This article has 7 citations.

  9. (moura2024spinocerebellarataxiasphenotypic pages 7-9): João Moura, Jorge Oliveira, Mariana Santos, Sara Costa, Lénia Silva, Carolina Lemos, José Barros, Jorge Sequeiros, and Joana Damásio. Spinocerebellar ataxias: phenotypic spectrum of polyq versus non-repeat expansion forms. Cerebellum (London, England), 23:2258-2268, Jul 2024. URL: https://doi.org/10.1007/s12311-024-01723-9, doi:10.1007/s12311-024-01723-9. This article has 2 citations.

  10. (moura2024spinocerebellarataxiasphenotypic pages 1-2): João Moura, Jorge Oliveira, Mariana Santos, Sara Costa, Lénia Silva, Carolina Lemos, José Barros, Jorge Sequeiros, and Joana Damásio. Spinocerebellar ataxias: phenotypic spectrum of polyq versus non-repeat expansion forms. Cerebellum (London, England), 23:2258-2268, Jul 2024. URL: https://doi.org/10.1007/s12311-024-01723-9, doi:10.1007/s12311-024-01723-9. This article has 2 citations.

  11. (faber2024stage‐dependentbiomarkerchanges pages 4-7): Jennifer Faber, Moritz Berger, Carlo Wilke, Jeannette Hubener‐Schmid, Tamara Schaprian, Magda M. Santana, Marcus Grobe‐Einsler, Demet Onder, Berkan Koyak, Paola Giunti, Hector Garcia‐Moreno, Cristina Gonzalez‐Robles, Manuela Lima, Mafalda Raposo, Ana Rosa Vieira Melo, Luís Pereira de Almeida, Patrick Silva, Maria M. Pinto, Bart P. van de Warrenburg, Judith van Gaalen, Jeroen de Vries, Gulin Oz, James M. Joers, Matthis Synofzik, Ludger Schols, Olaf Riess, Jon Infante, Leire Manrique, Dagmar Timmann, Andreas Thieme, Heike Jacobi, Kathrin Reetz, Imis Dogan, Chiadikaobi Onyike, Michal Povazan, Jeremy Schmahmann, Eva‐Maria Ratai, Matthias Schmid, and Thomas Klockgether. Stage‐dependent biomarker changes in spinocerebellar ataxia type 3. Annals of Neurology, 95:400-406, Dec 2024. URL: https://doi.org/10.1002/ana.26824, doi:10.1002/ana.26824. This article has 36 citations and is from a highest quality peer-reviewed journal.

  12. (paulino2023autophagyinspinocerebellar pages 4-5): Rodrigo T. Paulino and Clévio Nóbrega. Autophagy in spinocerebellar ataxia type 3: from pathogenesis to therapeutics. International Journal of Molecular Sciences, 24:7405, Apr 2023. URL: https://doi.org/10.3390/ijms24087405, doi:10.3390/ijms24087405. This article has 28 citations.

  13. (cui2024spinocerebellarataxiasfrom pages 5-6): Zi-Ting Cui, Zong-Tao Mao, Rong Yang, Jia-Jia Li, Shan-Shan Jia, Jian-Li Zhao, Fang-Tian Zhong, Peng Yu, and Ming Dong. Spinocerebellar ataxias: from pathogenesis to recent therapeutic advances. Frontiers in Neuroscience, Jun 2024. URL: https://doi.org/10.3389/fnins.2024.1422442, doi:10.3389/fnins.2024.1422442. This article has 32 citations and is from a peer-reviewed journal.

  14. (lin2024astragalosideivreduces pages 1-2): Yongshiou Lin, Wenling Cheng, Juichih Chang, Yuling Wu, Mingli Hsieh, and Chin-San Liu. Astragaloside iv reduces mutant ataxin-3 levels and supports mitochondrial function in spinocerebellar ataxia type 3. Scientific Reports, Oct 2024. URL: https://doi.org/10.1038/s41598-024-77763-2, doi:10.1038/s41598-024-77763-2. This article has 2 citations and is from a peer-reviewed journal.

  15. (pilotto2024hereditaryataxiasfrom pages 13-15): Federica Pilotto, Andrea Del Bondio, and Hélène Puccio. Hereditary ataxias: from bench to clinic, where do we stand? Cells, 13:319, Feb 2024. URL: https://doi.org/10.3390/cells13040319, doi:10.3390/cells13040319. This article has 23 citations.

  16. (shorrock2024cagrepeatselectivecompounds pages 54-55): Hannah K. Shorrock, Asmer Aliyeva, Jesus A. Frias, Victoria A. DeMeo, Claudia D. Lennon, Cristina C. DeMeo, Amy K. Mascorro, Sharon Shaughnessy, Hormoz Mazdiyasni, John D. Cleary, Kaalak Reddy, Sweta Vangaveti, Damian S. Shin, and J. Andrew Berglund. Cag repeat-selective compounds reduce abundance of expanded cag rnas in patient cell and murine models of scas. bioRxiv, Aug 2024. URL: https://doi.org/10.1101/2024.08.17.608349, doi:10.1101/2024.08.17.608349. This article has 2 citations.

  17. (faber2024stage‐dependentbiomarkerchanges pages 1-4): Jennifer Faber, Moritz Berger, Carlo Wilke, Jeannette Hubener‐Schmid, Tamara Schaprian, Magda M. Santana, Marcus Grobe‐Einsler, Demet Onder, Berkan Koyak, Paola Giunti, Hector Garcia‐Moreno, Cristina Gonzalez‐Robles, Manuela Lima, Mafalda Raposo, Ana Rosa Vieira Melo, Luís Pereira de Almeida, Patrick Silva, Maria M. Pinto, Bart P. van de Warrenburg, Judith van Gaalen, Jeroen de Vries, Gulin Oz, James M. Joers, Matthis Synofzik, Ludger Schols, Olaf Riess, Jon Infante, Leire Manrique, Dagmar Timmann, Andreas Thieme, Heike Jacobi, Kathrin Reetz, Imis Dogan, Chiadikaobi Onyike, Michal Povazan, Jeremy Schmahmann, Eva‐Maria Ratai, Matthias Schmid, and Thomas Klockgether. Stage‐dependent biomarker changes in spinocerebellar ataxia type 3. Annals of Neurology, 95:400-406, Dec 2024. URL: https://doi.org/10.1002/ana.26824, doi:10.1002/ana.26824. This article has 36 citations and is from a highest quality peer-reviewed journal.

  18. (faber2024stage‐dependentbiomarkerchanges pages 15-21): Jennifer Faber, Moritz Berger, Carlo Wilke, Jeannette Hubener‐Schmid, Tamara Schaprian, Magda M. Santana, Marcus Grobe‐Einsler, Demet Onder, Berkan Koyak, Paola Giunti, Hector Garcia‐Moreno, Cristina Gonzalez‐Robles, Manuela Lima, Mafalda Raposo, Ana Rosa Vieira Melo, Luís Pereira de Almeida, Patrick Silva, Maria M. Pinto, Bart P. van de Warrenburg, Judith van Gaalen, Jeroen de Vries, Gulin Oz, James M. Joers, Matthis Synofzik, Ludger Schols, Olaf Riess, Jon Infante, Leire Manrique, Dagmar Timmann, Andreas Thieme, Heike Jacobi, Kathrin Reetz, Imis Dogan, Chiadikaobi Onyike, Michal Povazan, Jeremy Schmahmann, Eva‐Maria Ratai, Matthias Schmid, and Thomas Klockgether. Stage‐dependent biomarker changes in spinocerebellar ataxia type 3. Annals of Neurology, 95:400-406, Dec 2024. URL: https://doi.org/10.1002/ana.26824, doi:10.1002/ana.26824. This article has 36 citations and is from a highest quality peer-reviewed journal.

  19. (faber2024stage‐dependentbiomarkerchanges pages 7-9): Jennifer Faber, Moritz Berger, Carlo Wilke, Jeannette Hubener‐Schmid, Tamara Schaprian, Magda M. Santana, Marcus Grobe‐Einsler, Demet Onder, Berkan Koyak, Paola Giunti, Hector Garcia‐Moreno, Cristina Gonzalez‐Robles, Manuela Lima, Mafalda Raposo, Ana Rosa Vieira Melo, Luís Pereira de Almeida, Patrick Silva, Maria M. Pinto, Bart P. van de Warrenburg, Judith van Gaalen, Jeroen de Vries, Gulin Oz, James M. Joers, Matthis Synofzik, Ludger Schols, Olaf Riess, Jon Infante, Leire Manrique, Dagmar Timmann, Andreas Thieme, Heike Jacobi, Kathrin Reetz, Imis Dogan, Chiadikaobi Onyike, Michal Povazan, Jeremy Schmahmann, Eva‐Maria Ratai, Matthias Schmid, and Thomas Klockgether. Stage‐dependent biomarker changes in spinocerebellar ataxia type 3. Annals of Neurology, 95:400-406, Dec 2024. URL: https://doi.org/10.1002/ana.26824, doi:10.1002/ana.26824. This article has 36 citations and is from a highest quality peer-reviewed journal.

  20. (faber2024stage‐dependentbiomarkerchanges pages 9-12): Jennifer Faber, Moritz Berger, Carlo Wilke, Jeannette Hubener‐Schmid, Tamara Schaprian, Magda M. Santana, Marcus Grobe‐Einsler, Demet Onder, Berkan Koyak, Paola Giunti, Hector Garcia‐Moreno, Cristina Gonzalez‐Robles, Manuela Lima, Mafalda Raposo, Ana Rosa Vieira Melo, Luís Pereira de Almeida, Patrick Silva, Maria M. Pinto, Bart P. van de Warrenburg, Judith van Gaalen, Jeroen de Vries, Gulin Oz, James M. Joers, Matthis Synofzik, Ludger Schols, Olaf Riess, Jon Infante, Leire Manrique, Dagmar Timmann, Andreas Thieme, Heike Jacobi, Kathrin Reetz, Imis Dogan, Chiadikaobi Onyike, Michal Povazan, Jeremy Schmahmann, Eva‐Maria Ratai, Matthias Schmid, and Thomas Klockgether. Stage‐dependent biomarker changes in spinocerebellar ataxia type 3. Annals of Neurology, 95:400-406, Dec 2024. URL: https://doi.org/10.1002/ana.26824, doi:10.1002/ana.26824. This article has 36 citations and is from a highest quality peer-reviewed journal.

  21. (faber2024stage‐dependentbiomarkerchanges pages 12-15): Jennifer Faber, Moritz Berger, Carlo Wilke, Jeannette Hubener‐Schmid, Tamara Schaprian, Magda M. Santana, Marcus Grobe‐Einsler, Demet Onder, Berkan Koyak, Paola Giunti, Hector Garcia‐Moreno, Cristina Gonzalez‐Robles, Manuela Lima, Mafalda Raposo, Ana Rosa Vieira Melo, Luís Pereira de Almeida, Patrick Silva, Maria M. Pinto, Bart P. van de Warrenburg, Judith van Gaalen, Jeroen de Vries, Gulin Oz, James M. Joers, Matthis Synofzik, Ludger Schols, Olaf Riess, Jon Infante, Leire Manrique, Dagmar Timmann, Andreas Thieme, Heike Jacobi, Kathrin Reetz, Imis Dogan, Chiadikaobi Onyike, Michal Povazan, Jeremy Schmahmann, Eva‐Maria Ratai, Matthias Schmid, and Thomas Klockgether. Stage‐dependent biomarker changes in spinocerebellar ataxia type 3. Annals of Neurology, 95:400-406, Dec 2024. URL: https://doi.org/10.1002/ana.26824, doi:10.1002/ana.26824. This article has 36 citations and is from a highest quality peer-reviewed journal.

  22. (faber2024stage‐dependentbiomarkerchanges media b30f008b): Jennifer Faber, Moritz Berger, Carlo Wilke, Jeannette Hubener‐Schmid, Tamara Schaprian, Magda M. Santana, Marcus Grobe‐Einsler, Demet Onder, Berkan Koyak, Paola Giunti, Hector Garcia‐Moreno, Cristina Gonzalez‐Robles, Manuela Lima, Mafalda Raposo, Ana Rosa Vieira Melo, Luís Pereira de Almeida, Patrick Silva, Maria M. Pinto, Bart P. van de Warrenburg, Judith van Gaalen, Jeroen de Vries, Gulin Oz, James M. Joers, Matthis Synofzik, Ludger Schols, Olaf Riess, Jon Infante, Leire Manrique, Dagmar Timmann, Andreas Thieme, Heike Jacobi, Kathrin Reetz, Imis Dogan, Chiadikaobi Onyike, Michal Povazan, Jeremy Schmahmann, Eva‐Maria Ratai, Matthias Schmid, and Thomas Klockgether. Stage‐dependent biomarker changes in spinocerebellar ataxia type 3. Annals of Neurology, 95:400-406, Dec 2024. URL: https://doi.org/10.1002/ana.26824, doi:10.1002/ana.26824. This article has 36 citations and is from a highest quality peer-reviewed journal.

  23. (faber2024stage‐dependentbiomarkerchanges media 807d2b9d): Jennifer Faber, Moritz Berger, Carlo Wilke, Jeannette Hubener‐Schmid, Tamara Schaprian, Magda M. Santana, Marcus Grobe‐Einsler, Demet Onder, Berkan Koyak, Paola Giunti, Hector Garcia‐Moreno, Cristina Gonzalez‐Robles, Manuela Lima, Mafalda Raposo, Ana Rosa Vieira Melo, Luís Pereira de Almeida, Patrick Silva, Maria M. Pinto, Bart P. van de Warrenburg, Judith van Gaalen, Jeroen de Vries, Gulin Oz, James M. Joers, Matthis Synofzik, Ludger Schols, Olaf Riess, Jon Infante, Leire Manrique, Dagmar Timmann, Andreas Thieme, Heike Jacobi, Kathrin Reetz, Imis Dogan, Chiadikaobi Onyike, Michal Povazan, Jeremy Schmahmann, Eva‐Maria Ratai, Matthias Schmid, and Thomas Klockgether. Stage‐dependent biomarker changes in spinocerebellar ataxia type 3. Annals of Neurology, 95:400-406, Dec 2024. URL: https://doi.org/10.1002/ana.26824, doi:10.1002/ana.26824. This article has 36 citations and is from a highest quality peer-reviewed journal.

  24. (moura2024spinocerebellarataxiasphenotypic pages 9-10): João Moura, Jorge Oliveira, Mariana Santos, Sara Costa, Lénia Silva, Carolina Lemos, José Barros, Jorge Sequeiros, and Joana Damásio. Spinocerebellar ataxias: phenotypic spectrum of polyq versus non-repeat expansion forms. Cerebellum (London, England), 23:2258-2268, Jul 2024. URL: https://doi.org/10.1007/s12311-024-01723-9, doi:10.1007/s12311-024-01723-9. This article has 2 citations.

  25. (moura2024spinocerebellarataxiasphenotypic pages 2-4): João Moura, Jorge Oliveira, Mariana Santos, Sara Costa, Lénia Silva, Carolina Lemos, José Barros, Jorge Sequeiros, and Joana Damásio. Spinocerebellar ataxias: phenotypic spectrum of polyq versus non-repeat expansion forms. Cerebellum (London, England), 23:2258-2268, Jul 2024. URL: https://doi.org/10.1007/s12311-024-01723-9, doi:10.1007/s12311-024-01723-9. This article has 2 citations.

  26. (NCT05160558 chunk 1): A Pharmacokinetics and Safety Study of BIIB132 in Adults With Spinocerebellar Ataxia 3. Biogen. 2022. ClinicalTrials.gov Identifier: NCT05160558

  27. (pinheiro2023diagnosticdelayof pages 2-5): Jordânia dos Santos Pinheiro, Lucas Schenatto Sena, Karina Carvalho Donis, Gabriel Vasata Furtado, Maria Luiza Saraiva-Pereira, and Laura Bannach Jardim. Diagnostic delay of hereditary ataxias in brazil: the case of machado-joseph disease. The Cerebellum, 22:348-354, Apr 2023. URL: https://doi.org/10.1007/s12311-022-01404-5, doi:10.1007/s12311-022-01404-5. This article has 3 citations.

  28. (stahl2024spinocerebellarataxiatype pages 6-7): Fabian Stahl, Bernd O. Evert, Xinyu Han, Peter Breuer, and Ullrich Wüllner. Spinocerebellar ataxia type 3 pathophysiology—implications for translational research and clinical studies. International Journal of Molecular Sciences, 25:3984, Apr 2024. URL: https://doi.org/10.3390/ijms25073984, doi:10.3390/ijms25073984. This article has 14 citations.

  29. (pilotto2024hereditaryataxiasfrom pages 20-22): Federica Pilotto, Andrea Del Bondio, and Hélène Puccio. Hereditary ataxias: from bench to clinic, where do we stand? Cells, 13:319, Feb 2024. URL: https://doi.org/10.3390/cells13040319, doi:10.3390/cells13040319. This article has 23 citations.

  30. (cui2024spinocerebellarataxiasfrom pages 6-7): Zi-Ting Cui, Zong-Tao Mao, Rong Yang, Jia-Jia Li, Shan-Shan Jia, Jian-Li Zhao, Fang-Tian Zhong, Peng Yu, and Ming Dong. Spinocerebellar ataxias: from pathogenesis to recent therapeutic advances. Frontiers in Neuroscience, Jun 2024. URL: https://doi.org/10.3389/fnins.2024.1422442, doi:10.3389/fnins.2024.1422442. This article has 32 citations and is from a peer-reviewed journal.

  31. (cui2024spinocerebellarataxiasfrom pages 9-10): Zi-Ting Cui, Zong-Tao Mao, Rong Yang, Jia-Jia Li, Shan-Shan Jia, Jian-Li Zhao, Fang-Tian Zhong, Peng Yu, and Ming Dong. Spinocerebellar ataxias: from pathogenesis to recent therapeutic advances. Frontiers in Neuroscience, Jun 2024. URL: https://doi.org/10.3389/fnins.2024.1422442, doi:10.3389/fnins.2024.1422442. This article has 32 citations and is from a peer-reviewed journal.