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docs_md/articles/spinocerbellar-ataxia_df64565a-5c8c-4387-879b-b341b655e478.md
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---
title: "Spinocerbellar Ataxia"
docid: "df64565a-5c8c-4387-879b-b341b655e478"
breadcrumbs:
- "Brain"
- "Diagnosis"
- "Pathology-Based Diagnoses"
- "Acquired Toxic/Metabolic/Degenerative Disorders"
- "Dementias and Degenerative Disorders"
- "Spinocerbellar Ataxia"
---
# KEY FACTS
- ## Terminology
- Spinocerebellar ataxia (SCA)
- ## Imaging
- Cerebellum atrophy always, brainstem often
- Supratentorial atrophy variably in volumetric analysis
- Cerebellum & pontine tegmentum (dorsal pons) atrophy in SCA1, SCA3 [Machado-Joseph disease (MJD)], DRPLA
- Cerebellum & pontine base (ventral pons) atrophy in SCA2
- Pontine base:tegmentum distance ratio (BT-ratio) useful
- Cerebellum atrophy purely/predominantly in SCA5, SCA6, SCA11, SCA26, SCA30, SCA31, SCA37
- Superior cerebellar peduncle atrophy in MJD, SCA6, SCA8, DRPLA; severe cerebral atrophy in juvenile-onset DRPLA
- Medulla & upper cervical cord atrophy in SCA3 (MJD); relative lack of cord involvement in SCA6
- Hot cross bun sign in pons in SCA2 & rarely MJD
- Anteroposteriorly oriented pontine midline linear T2-hyperintensity (PMH) in SCA1, SCA2, SCA3 (MJD), DRPLA
- Bilateral bright middle cerebellar peduncle (MCP) sign rarely in SCA2, SCA3 (MJD), SCA6, DRPLA
- Cerebral white matter (WM), brainstem, & thalamic hyperintensities in adult-onset DRPLA
- Cerebral WM signal abnormalities usually absent in juvenile-onset DRPLA
- Periventricular WM changes may be seen in very late stage
- ## Top Differential Diagnoses
- Multiple system atrophy-cerebellar (MSA-C)
- Friedrich ataxia
- Ataxia with oculomotor apraxia types 1 & 2
- Ataxia telangiectasia
- Fragile X-associated tremor/ataxia syndrome (FXTAS)
- Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)
- ## Pathology
- Autosomal dominant ataxia; many SCAs due to PolyQ expansion of coding CAG repeats
- Various other gene loci & proteins in remaining SCAs
- Commonest mutant genes: *ATXN1* (SCA1), *ATXN2* (SCA2), *ATXN3* (SCA3/MJD),*CACNA1A* (SCA6), *ATN1* (DRPLA)
- ## Clinical Issues
- Young to middle-aged patient with slowly progressing cerebellar ataxia & other typical associated symptoms
- ## Diagnostic Checklist
- Atrophy of cerebellum ± brainstem
- Evaluate axial T2WI for characteristic hyperintense signal in SCA types, especially pons, MCP, periventricular WM
# TERMINOLOGY
- ## Abbreviations
- Spinocerebellar ataxia (SCA)
- Polyglutamine repeats (PolyQ)
- Cytosine-adenine-guanine (CAG)
- Machado-Joseph disease (MJD)
- Dentatorubropallidoluysian atrophy (DRPLA)
- Distance ratio of pontine base:tegmentum (BT-ratio)
- ## Synonyms
- MJD = Spinocerebellar ataxia type 3 (SCA3)
- ## Definitions
- Slowly progressive cerebellum and cerebellar interconnection neurodegenerative diseases
- Autosomal dominant ataxia; many SCAs [SCA1, SCA2, SCA3 (MJD), SCA6, SCA7, SCA12, SCA17] due to PolyQ expansion of coding CAG repeats, similar to Huntington disease
- SCA8 shows CTG expansion and complementary CAG repeat
- Various other gene loci and proteins in remaining SCAs
- SCA type number as per order in which disease identified (by linkage analysis initially and gene discovery lately)
- SCA types now 1-40 and beyond; but SCA9, SCA33, and SCA39 not been assigned to specific clinical disorders
- SCA1, SCA2, SCA3, SCA6 relatively common types with SCA3 (MJD) being most common among these worldwide
- DRPLA, CAG repeat PolyQ expansion disorder that resembles SCA, usually discussed along with SCA
# IMAGING
- ## General Features
- ### Best diagnostic clue
- Atrophy of cerebellum ± brainstem
- Atrophy difficult to detect in early stage, careful MR analysis needed
- ### Location
- Cerebellum always, brainstem often, supratentorial structures variably on volumetric analysis
- Early stages of any SCA may show pure cerebellar atrophy and later show brainstem atrophy
- ### Size
- Atrophy of involved structures
- Cerebellum and **pontine tegmentum (dorsal pons)** atrophy: SCA1, SCA3 (MJD), DRPLA
- Cerebellum and **basal pons (ventral pons)** atrophy: SCA2
- Cerebellum atrophy purely/predominantly: SCA5, SCA6, SCA11, SCA26, SCA30, SCA31, SCA37
- Superior cerebellar peduncle (SCP) atrophy mainly in SCA3 (MJD), SCA6, SCA8, DRPLA
- Medulla and upper cervical cord atrophy in SCA3 (MJD); relative lack of cord involvement in SCA6
- Severe cerebral atrophy in juvenile-onset DRPLA
- Pontine **BT-ratio** useful in diagnostic decision tree
- Distance from ventral edge of pons to medial lemniscus (ML): Distance from ML to its dorsal edge
- ### Morphology
- Variable abnormal T2/FLAIR hyperintense signal
- **Hot cross bun sign** (**HCBS**; cruciform ↑ T2 in pons)
- 8.7% overall prevalence in SCA; 25.7% SCA2, 1.3% SCA3 (MJD); extremely rare SCA7, SCA8
- Anteroposteriorly oriented **pontine midline** linear T2-**hyperintensity** (**PMH**) in SCA1, SCA3 (MJD), DRPLA
- Bilateral **bright middle cerebellar peduncle (MCP) sign** rarely in SCA2, SCA3 (MJD), SCA6, DRPLA
- Cerebral white matter (WM), brainstem, and thalamic hyperintensities in adult-onset DRPLA
- Cerebral WM usually normal in juvenile-onset DRPLA
- Periventricular WM changes may occur very late
- ## CT Findings
- Atrophy of involved structures
- ## MR Findings
- **SCA types 1 and 3 (SCA1 and SCA3/MJD)**
- Pontine tegmentum (dorsal pons) atrophy in early stage
- In contrast to multiple system atrophy with predominant cerebellar ataxia (MSA-C)
- Important, more common differential diagnosis
- MSA-C mainly pontine base (ventral pons) atrophy
- Cerebellum and brainstem atrophy prominent later
- PMH in later stage on axial T2WI MR; HCBS in 1.3% MJD
- In contrast to pontine HCBS in MSA-C commonly
- Slightly shrunken neurons of pontine nuclei with preserved cell architecture
- Relatively preserves myelinated transverse pontocerebellar fibers
- Fiber loss seen only in pontine midline where fibers from right and left pontine nuclei cross
- Considered early change of HCBS
- Volumetric MR: Caudate/putamen and temporal lobe atrophy in SCA1
- Volumetric MR: Temporofrontoparietooccipital, limbic, SCP, basal ganglia, thalamus atrophy in MJD
- Medulla/upper cervical cord atrophy, bright MCP in MJD
- Progressive linear ↑ T2 just outside ICs (inner segments of globi pallidi) in SCA3 (MJD)
- **SCA2**
- MR findings **mimicking MSA-C in young** ataxic patient
- Prominent cerebellum and brainstem atrophy, more severe than SCA1 and SCA3
- Pontine atrophy more prominent in pontine base (ventral pons) than tegmentum (dorsal pons)
- Characteristic pontine HCBS in 25%; PMH earlier
- Inconsistently, T2 hyperintensities of basal ganglia
- Rarely, bilateral MCP focal hyperintensities
- Volumetric data shows no cerebral gray matter (GM) or WM atrophy
- **SCA5, SCA6, SCA11, SCA26, SCA30, SCA31, SCA37**
- Pure/predominantly cerebellar atrophy
- **DRPLA**
- Cerebellum, brainstem, SCP atrophy
- Pontine atrophy is more prominent in pontine tegmentum (dorsal pons) than base (ventral pons)
- Rarely, PMH and/or bilateral MCP focal hyperintensities
- **Adult-onset DRPLA**: ↑ T2 cerebral WM, brainstem, thalamus
- **Juvenile-onset DRPLA**: Cerebral WM usually normal
- ↑ T2 periventricular WM in very late stage
- Severe cerebral atrophy in juvenile-onset DRPLA
- **MRS**
- Significantly lower NAA/Cr, Cho/Cr, and NAA/Cho in cerebellar hemispheres/vermis in SCAs, especially SCA2
- MSA-C also shows similar findings
- ## Imaging Recommendations
- ### Best imaging tool
- MR
- ### Protocol advice
- Volumetric 3D T1 MR sequences, such as MPRAGE or SPGR
- Axial T2WI and FLAIR to evaluate ↑ T2 like PMH, HCBS
# DIFFERENTIAL DIAGNOSIS
- [Multiple System Atrophy - Cerebellar](/document/multiple-system-atrophy/4fb9af00-e0bd-4164-8f61-4011ddc8bf9e)
- Most cases sporadic; 6th decade
- Atrophy of pons, cerebellum, and inferior olives
- Pontine atrophy predominantly at its**base (ventral pons)**
- PMH or HCBS in pons on axial T2; bright MCP sometimes
- Due to loss of myelinated transverse pontocerebellar fibers
- MR mimics SCA2 (consider SCA2 in younger patient)
- **SCP spared in MSA-C**; SCP may atrophy in MSA-P, PSP, SCA3/MJD, SCA6, SCA8, DRPLA, Friedrich ataxia, ARSACS
- ## Friedrich Ataxia
- Autosomal recessive ataxic disorder
- Severe spinal cord atrophy with flat posterior aspect
- May show ↑ T2 in spinal cord posterior (fasciculus gracilis and cuneatus) and lateral (pyramidal tracts) columns
- Atrophic dorsal medulla, rostral vermis (culmen, declive), inferomedial cerebellar hemisphere, and SCP
- Conventionally, cerebellar involvement considered rare, but nowadays volumetric MR shows atrophy
- Scoliosis, cardiomyopathy, and stroke due to atrial fibrillation or mural thrombus
- ## Ataxia With Oculomotor Apraxia Types 1 and 2
- **Type 1**: Autosomal recessive, mutation in *APTX* gene
- MR shows cerebellar atrophy, mild brainstem atrophy
- Cortical atrophy in advanced stages
- **Type 2**: Autosomal recessive, mutation in *SETX* gene
- Peripheral neuropathy and ↑ serum α-fetoprotein
- MR shows cerebellar atrophy
- ## Ataxia Telangiectasia
- Autosomal recessive ataxic disorder
- Normal pons; initially cerebellum may also be normal
- MR between 3 and 7 years of age usually shows superior vermian and lateral cerebellar hemispheric atrophy
- Later, diffuse cerebellovermian atrophy, including dentate nuclei and cerebellar peduncles
- Subtle ↑ FLAIR signal of cerebellar cortex after atrophy
- Telangiectasias evident by late childhood and early adult stage using T2*/SWI/postcontrast MR
- Supratentorial WM hyperintensities due to spongiosis surrounding telangiectasias
- ## Fragile X-Associated Tremor/Ataxia Syndrome
- Late-onset X-linked dominant neurodegeneration
- Variable penetrance; males between 50 and 80 years of age
- *FMR1* gene mutation affecting CGG trinucleotide repeats
- Generalized cerebral, cerebellar, and brainstem atrophy
- Periventricular, deep WM and corpus callosum ↑ T2
- Characteristic bilateral MCP focal hyperintensities in 60%
- ## Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay
- Atrophy of anterior cerebellar vermis and SCP 1st
- Cerebellar hemisphere, medulla, and cervical cord later
- Bulky pons and MCP; subtle ↑ T2 in lateral pons and MCP
- Characteristic ↓ T2/FLAIR transverse striations (pontine tigroid hypointensities) in pontine base and tegmentum
- DTI shows interruption of thin pyramidal tracts by these hyperplastic pontocerebellar fibers
- Rim of T2 hyperintensity around thalami
- Straightened spine in radiographs
# PATHOLOGY
- ## General Features
- Autosomal dominant ataxia; many SCAs due to PolyQ expansion of coding CAG repeats
- Various other gene loci and proteins in remaining SCAs
- 60-75% SCA patients only have mutations in known loci
- Expansion of CAG repeats produce toxic gain of function
- PolyQ SCAs, such as other PolyQ disorders, symptoms manifest above particular CAG repeat threshold
- Threshold for symptoms variable for different genes
- Threshold in most SCA types > 36, for SCA3 (MJD) > 50
- Commonest mutant genes: *ATXN1* (SCA1), *ATXN2*(SCA2), *ATXN3* (SCA3/MJD), *CACNA1A* (SCA6), *ATN1* (DRPLA)
- ## Staging, Grading, & Classification
- SCA types currently numbered 1-40 and beyond
- Genetic anticipation: Earlier onset and progressive worsening of phenotype in successive generations
- ## Gross Pathologic & Surgical Features
- Cerebellar atrophy, variable brainstem atrophy, flattening of facial colliculus in MJD
- Neuronal dysfunction and neuronal loss in 10-20 years
- Neurodegeneration of pontine reticulotegmental nucleus in SCA1, SCA2, SCA3
- Nucleus involved in horizontal smooth pursuit eye movements and accuracy of horizontal saccades
# CLINICAL ISSUES
- ## Presentation
- ### Most common signs/symptoms
- Cerebellar ataxia in all SCAs
- ### Other signs/symptoms
- SCA1: Pyramidal signs, peripheral neuropathy
- SCA2: Slow saccades, myoclonus, areflexia
- SCA3/MJD: Slow saccades, persistent stare, extrapyramidal signs, peripheral neuropathy
- SCA6: Nystagmus; mild, can be very late onset
- Juvenile-onset DRPLA: Myoclonus, seizures, behavioral changes, and intellectual deterioration
- Adult-onset DRPLA: Choreoathetosis, delusions, dementia
- ## Demographics
- **SCA3 (MJD)****:**Portuguese Azorean, William **Machado** family in New England 1st to be diagnosed with MJD
- Azorean Californian **Joseph** family also had MJD
- SCAs usually present in middle age
- SCA1, 37 years (range: 5-65); SCA2, 35 years (range: 7-66); SCA3, 37 years (range: 5-66); SCA6, 55 years (range: 31-77)
- Earlier age of onset and more severe disease with increasing number of CAG repeats on expanded alleles
- ## Natural History & Prognosis
- Average SCA disability progression over 1-2 decades
- Wheelchair bound by 10-15 years after symptom onset
- Higher baseline scores on Scale for the Assessment and Rating of Ataxia (SARA) associated with shorter survival
- SCA1 (mean age of death 56 years) more rapid disease progression and shorter survival than SCA2, SCA3, SCA6
- ## Treatment
- No effective or curative treatment
- Zolpidem: Transient improvement in cerebellar symptoms
- Varenicline (partial nicotine agonist): Improvement in some measures of cerebellar dysfunction
- Polyglutamine neurotoxicity suppressed by overexpression of heat shock proteins in animal studies
- Gene silencing with RNA interference promising in SCA mouse model
# DIAGNOSTIC CHECKLIST
- ## Consider
- Young to middle-aged patient with slowly progressing cerebellar ataxia and other typical associated symptoms
- ## Image Interpretation Pearls
- Atrophy of cerebellum ± brainstem
- Evaluate axial T2WI for characteristic hyperintense signal in SCA types, especially pons, MCP, periventricular WM
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