Ataxia: Dominant

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HEREDITARY ATAXIAS: DOMINANT

Spinocerebellar Ataxia (SCA)
1: Ataxin-1; CAG repeat; 6p22
2: Ataxin-2; CAG repeat; 12q24
3: Ataxin-3; CAG repeat; 14q32
4 (Sensory ataxia): 16q22
5: β-III Spectrin; 11q13
6: CACNA1A; CAG repeat; 19p13
7: Ataxin-7; CAG repeat; 3p21
8: ATXN8OS; CTG repeat; 13q21
9: ?
10: ATXN10; ATTCT repeat; 22q13
11: TTBK2; 15q14
12: PPP2R2B; CAG repeat; 5q31
13: KCNC3; 19q13
14: PRKCG; 19q13.4-qter
15 & 16: ITPR1; 3p26
29: 3p26
17: TBP; CAG repeat; 6q27
18: 7q31
19: 1p21-q21
20: 11q12, Duplication
21: 7p21
22: 1p21-1q23
23: PDYN; 20p13
25: 2p15-p21
26: 19p13
27: FGF14; 13q33
28: AFG3L2; 18p11
30: 4q34
31: TGGAA repeat; 16q22
32: 7q32
35: TGM6; 20p13
36: NOP56; 20p13
SCA Unlinked

SCA: Differential features

Other dominant ataxia syndromes
Adult-onset leukodystrophy: 5q31
Branchial myoclonus & Spastic paraparesis: GFAP; 17q21
CAPOS syndrome
Congenital ataxia
Cough, Spasmodic
Deafness & Narcolepsy: DNMT1; 19p13
DRPLA: ATN1; CAG repeat; 12p13
Familial dementia: ITM2B; 13q14
Gillespie: PAX6; 11p13
Glucose transporter 1 deficiency: 1p35
Holmes ataxia
Huntington 2: Junctophilin-3; CAG/CTG repeat; 16q23
Mental retardation: 19q13
Multiple hamartoma syndrome: PTEN; 10q23
Myelocerebellar
Neuronal intranuclear inclusion disease
Nystagmus
Parenchymal degeneration
Prion disease: Prion protein; 20p12
Rigidity & Peripheral Neuropathy
SANDO: POLG1; 15q25
Sensory ataxic neuropathy: 16q22
Sensory-Motor Neuropathy + Ataxia: IFRD1; 7q22
SMEI: SCN1A; 2q24
SPAR
Spastic ataxia syndromes
Thermoanalgesia & loss of fungiform papillae
Tremor, Essential: 3q13
Vanishing white matter
Vermal aplasia
Von Hippel-Lindau Syndrome: VHL protein; 3p26

Episodic ataxias (EA)
EA 1 + Myokymia: KCNA 1; 12p13
EA 2, Paroxysmal: α_1A Ca⁺⁺ channel; 19p13
EA 3 + Vertigo & Tinnitus: 1q42
EA 4 (PATX)
EA5: CACNB4β4; 2q22
EA6 + Migraine & CNS: SLC1A3; 5p13
EA7: 19q13
EA + Choreoathetosis & Spasticity: 1p
Differential diagnosis

Ataxia Syndromes: Other
Recessive
X-linked
Congenital
DNA repair defects
Metabolic disorders
Mitochondrial
Multisystem disorders
Spastic
Acquired

Cajal

Dominant Spinocerebellar Ataxia (SCA): General³⁵

Incidence: ~1 to 5 per 100,000
Average age of onset: 3rd decade
Mutation types
- CAG repeats
  - Coding: SCA1; SCA2; SCA3; SCA6; SCA7; SCA17; DRPLA
  - Non-coding: SCA12
- Other repeats
  - CTG: SCA8
  - ATTCT: SCA10
  - TGGAA: SCA31
  - GGCCTG (Intronic): SCA36
- Other mutations
  - β-III Spectrin: SCA 5
  - TTBK2: SCA 11
  - PPP2R2B: SCA 12
  - KCNC3: SCA 13
  - PRKCG: SCA 14
  - ITPR1: SCA 15 & 16
  - PDYN: SCA 23
  - FGF14: SCA 27
Channel disorders
- Primary
  - SCA6: CACNA1A/Cav2.1; Haploinsufficiency or Gain of function
  - SCA13: KCNC3/Kv3.3; Dominant negative
  - SCA15: ITPR1/IP3 receptor; Dominant negative
  - EA 1: KCNA1/Kv1.1; Dominant negative
  - EA 2: CACNA1A/Cav2.1; Haploinsufficiency
  - EA 5: CACNB4/Cav2.1; Auxiliary subunit; Haploinsufficiency or Dominant negative
  - Severe Myoclonic Epilepsy of Infancy: SCN1A/Nav1.1; Haploinsufficiency
- Secondary
  - SCA27: Na_v1.6
  - SCA5: Ionotropic glutamate receptors
  - DRPLA: Ionotropic glutamate receptors, GABA_A receptors
  - EA 6: Ionotropic glutamate receptors
  - Paraneoplastic cerebellar ataxia: Ca_v2.1

Dominant Spinocerebellar Ataxia (SCA): Differential diagnosis

Age
Polyneuropathy
Syndromes
Other

Dominant SCA syndromes have many overlapping signs: Difficult to distinguish on clinical grounds
Common features to all: Gait ataxia; Dysarthria
Features in some ataxias: Ocular disorders; Extrapyramidal; Peripheral nerve; Intellectual deterioration; Seizures
Features with some predictive value for specific gene defects
- SCA: Clinical syndromes
  - SCA1: Hypermetric saccades; Tendon reflexes increased; Executive dysfunction; Evoked motor potentials with Long conduction times; OPCA
  - SCA2: Slow saccadic velocity; Parkinsonism; Myoclonus or action tremor; Pons atrophy (OPCA); Cuba
  - SCA3/Machado-Joseph: Ophthalmoparesis; Gaze-evoked nystagmus; Prominent spasticity; Polyneuropathy; Brazil & Portugal
  - SCA4: Cerebellar syndrome; Later onset > 40
  - SCA5: Pure cerebellar syndrome; Bulbar signs; Early onset; Slow progression
  - SCA6: Pure cerebellar syndrome; Lack of family history; Late onset > 50
  - SCA7: Pigmentary retinopathy; Hearing loss; Onset in 1st decade
  - SCA8: Cerebellar syndrome; Late spasticity; Mild sensory neuropathy
  - SCA9: Ataxia + Ophthalmoplegia
  - SCA10: Pure cerebellar syndrome ± Seizures, complex partial; Mexico
  - SCA11: Pure cerebellar syndrome; Hyperreflexia; Benign course
  - SCA12: Tremor (Early arm); Hyperreflexia; Dementia; Cortical & Cerebellar atrophy
  - SCA13: Early childhood onset; Mental retardation
  - SCA14: Ataxia; Myoclonus (with early onset); Cognitive decline
  - SCA15: Pure cerebellar; Slow progression
  - SCA15: Head & Hand tremor
  - SCA17: Dysphagia; Intellectual deterioration; Absence seizures; Extrapyramidal signs
  - SCA18: Muscle atrophy; Sensory loss
  - SCA19: Cognitive impairment, mild; Myoclonus
  - SCA20: Palatal tremor; Dysphonia
  - SCA21: Extrapyramidal features
  - SCA22: Pure cerebellar syndrome; Slow progression; Hyporeflexia
  - SCA23: Ataxia; Sensory loss; Pyramidal signs
  - SCA25: Sensory neuropathy; Severe cerebellar atrophy
  - SCA26: Pure cerebellar syndrome
  - SCA27: Tremor; Dyskinesia; Psychiatric episodes
  - SCA28: Ophthalmoplegia
  - SCA30: Pure cerebellar syndrome; Late onset
  - SCA31: Pure cerebellar syndrome; Japanese
  - SCA35: Upper motor neuron signs
  - SCA36: Fasciculations & Muscle wasting; Late onset
  - DRPLA: Myoclonus & Epilepsy (Onset < 20 years); Choreoathetosis, Dementia, Psychosis (Onset > 20 years); OPCA
- NOTE: Friedreich ataxia may present as a late onset, chronic idiopathic ataxia syndrome
Polyneuropathy in SCA: Axonal; Sensory or Sensory-Motor
- SCA1: 42%; More with more CAG repeats
- SCA2: 80%
- SCA3: 54%; More with fewer CAG repeats
- SCA4: Sensory loss
- SCA7: 0%
- SCA8: Mild sensory neuropathy
- SCA12: Subclinical; 80%
- SCA14: Vibratory loss
- SCA27: Mild axonal sensory neuropathy
- SCA18: Motor-Sensory
- SCA25: Sensory neuropathy
- Tendon reflexes reduced or absent: SCA 2, 4, 19, 21, 22, Older adult onset SCA 2
- Also see
  - Ataxia, Rigidity & Peripheral Neuropathy
  - Sensory-Motor Neuropathy + Ataxia

Other typical clinical features¹⁶

SCA SYNDROMES: DIAGNOSTIC TESTING³⁵
Clinical sign	1° Testing	2° Testing
Cerebellar ataxia, Pure	SCA6, SCA5	SCA11, SCA14, SCA15, SCA16, SCA22
Spasticity	SCA3	SCA1, SCA7
Peripheral neuropathy	SCA3, SCA4, SCA18, SCA25	SCA1
Cortical disorders
Dementia	SCA17, DRPLA	SCA2, SCA13, SCA19, SCA21
Psychosis	DRPLA, SCA17	SCA3, SCA27 (Episodic)
Epilepsy	SCA10, DRPLA	SCA17
Movement disorders
Chorea	DRPLA, SCA17	SCA1 (Late stage)
Myoclonus	DRPLA	SCA2, SCA19
Tremor	SCA2, SCA8, SCA12	SCA15, SCA21, SCA27
Parkinsonism	SCA3, SCA9, SCA12	SCA2, SCA21
Dystonia	SCA3	SCA17
Ocular disorders
Ophthalmoplegia	SCA3, SCA2, SCA1, SCA9
Slow saccades	SCA2	SCA1, SCA3, SCA7, SCA17
Pigmentary retinopathy	SCA7

Age at onset
- Young adult: SCA 1, 2, 3, 21
- Older adult: SCA 6, 35, 36:
- Childhood: SCA 2, 7, 13, SCA27, DRPLA, 25
Anticipation
- Some SCA: 1, 2, 3, 6, 7, 8, 10, 12, 17, 22 & DRPLA
- More prominent in SCA 7 & DRPLA
Normal lifespan: SCA 6, 11
Eye
- Slow saccades
  - Early/prominent: SCA 2, 7
  - Late: SCA 1, 3, 28
  - Very rarely: SCA 6
- Downbeat nystagmus: SCA 6; EA 2
- Maculopathy: SCA 7
Palatal tremor: SCA 20
Motor neuron & Fasciculations: SCA 3, 36
UMN signs
- Common: SCA 1, 3, 7, 9, 12, 35
- Some: SCA 6, 8
- Rarely: SCA 2
Extrapyramidal
- Akinesia/rigidity/dystonia: SCA 3, SCA9, 21; SCA 12 (Akinesia)
- Chorea Early/prominent: DRPLA; Rarely SCA 2
- Dyskinesia: SCA 27
- Myoclonus
  - Common: SCA 2, 14
  - Occasional: SCA 1, 3, 6, 7, 19
- Dysphonia: SCA 20
- Torticollis: SCA 35
Head or Hand tremor: SCA 12, 15, 19, 27
Cortical
- Mental retardation: SCA 13, 21
- Cognitive defects: SCA 1, 2, 3, 12, 13, 19, 21
- Seizures
  - Adult: SCA 10
  - Childhood onset: DRPLA, SCA 7
- Dementia
  - Common: DRPLA; SCA17
  - Early onset patients: SCA 2, 7
  - Oldest patients: SCA 12
Pontine involvement: SCA 1, 2, 3

Dominant Spinocerebellar Ataxia (SCA): Symptomatic Classification

ADCA I
- Cerebellar syndrome + Other CNS (Pyramidal, Extrapyramidal, Ophthalmoplegia, & Dementia)
- SCA1; SCA2; SCA3; SCA4; SCA8; SCA9; SCA12; SCA17; SCA27; SCA28, SCA35
ADCA II
- Cerebellar syndrome + Pigmentary maculopathy
- SCA7
ADCA III
- "Pure" cerebellar syndrome ± Mild pyramidal signs
- SCA5; SCA6; SCA10; SCA11; SCA14; SCA15; SCA22; SCA26; SCA30; SCA NLa
Other
- SCA13, SCA36

Dominant Spinocerebellar Ataxia (SCA): CAG repeat disorders

Ataxias: SCA1; SCA2; SCA3; SCA6; SCA7; SCA12; SCA17; DRPLA

Clinical correlations with CAG repeat expansion size

CAG REPEAT EXPANSION SIZE
Small	Medium	Large

SCA1

Ataxia
Reflexes increased

Spasticity

SCA2

Tremor: Postural

Ataxia
Reflexes reduced

Ataxia; Chorea;
Dementia

SCA3

Neuropathy
(Axonal)

Ataxia; Nystagmus

SCA6

Ataxia: Episodic

Ataxia

SCA7

Ataxia

Ataxia
Macular degeneration

Visual loss
before ataxia

Spinocerebellar Ataxia 1 (SCA 1)

(ADCA I)
l Ataxin-1 (ATXN1)

; Chromosome 6p22.3; Dominant

Epidemiology
- 10% worldwide
- Most frequent in South Africa (41%)
- Also common in: Japan, India, Italy Australia
- Uncommon in: Portugal, Brazil, Central Japan
Genetic features
- Extra CAG trinucleotide repeats in reading frame
  - Normal: 6 to 39 repeats
  - Intermediate: 40 repeats
  - Disease: 41 to 83 repeats
  - Disease-associated 39 to 44 CAG repeat sequences have no CAT interruptions
- Lack of CAT interruptions in CAG repeats
  - Makes gene unstable: ? Predisposes to
    - New mutations into disease range
    - Enlargement of disease range repeats
  - Causes disease in patients with marginal numbers of CAG repeats (39 to 44)
- Increased number of CAG repeats: Correlations
  - Greater Disease severity
  - Earlier onset
  - No change in rapidity of progression
- Homozygotes: Disease severity corresponds to size of larger allele
- Anticipation: Paternal > Maternal; ~ 10 years/Generation
Ataxin-1 protein
- ? Function
- Cell localization
  - Neurons: Predominantly nuclear
  - Systemic: Cytoplasmic
  - SCA-1: Prominent in nuclear inclusions in Purkinje cells
- Mutant gene is translated into ataxin protein with more glutamines in repeat seguence
- Degradation
  - Normal: Via ubiquitin & proteasomes
  - SCA-1 disease: Reduced degradation of mutant ataxin-1 with more CAG repeats
- Region-specific interaction protein
  - Leucine-rich acidic nuclear protein (LANP): Purkinje cells
Clinical features: Variable
- Frequency: 6% to 27 % of dominant ataxias; Varies among different populations
- Onset
  - Age: 4 to 74 yrs; Average = 4th decade
  - Anticipation in families
- Ophthalmologic
  - Gaze paresis: 50%
  - Slow/Absent saccades: 100%
  - ± Nystagmus
  - Suggests pontine disease
  - Most prominent later in disease course
- Ataxia: Pancerebellar
  - Trunk > Limbs
  - Dysarthria
  - Gait
  - EOM
- Bulbar dysfunction: Vocal cord paralysis & Stridor
- Extrapyramidal: Later in disease course
  - Dystonia
  - Choreiform hyperkinesia
- Spinal: Spasticity
  - Lower extremities: 75%
  - Tendon reflexes: Increased; Present at knee
  - Plantar responses: Extensor
- Stiffperson-like syndrome: Occasional patient
- Polyneuropathy⁴⁶
  - Type: Axonal loss; Neuronopathy in some
  - Frequency: 42%; Higher with more CAG repeats
  - Age: 26 to 45 years
  - Sensory or sensory-motor
  - Proprioceptive loss
- Cognitive impairment
  - Mild: 50%
  - Dementia: Unusual
- Course
  - Disabled: 5 years after onset
  - Bedridden: 10 years after onset
  - Death: 10 to 20 years after onset
Laboratory testing
- Motor evoked potentials: Slow peripheral & central motor conduction velocities
- MRI: Pontine & cerebellar atrophy
Pathology
- CNS
  - Cerebellum: Especially connections
    - Dentate nucleus
    - Spinocerebellar tract
    - Inferior olive
    - Also: Purkinje cells
  - Spinal cord
    - Clarke's nucleus & Spinocerebellar tract degeneration
    - Anterior horn
    - Posterior columns
  - Brainstem: Substantia nigra; Red nucleus; Olivopontocerebellar system
  - Other: Globus pallidus externa
  - Mouse models: Symptomatolgy occurs before cell loss in CNS
- Cellular
  - Intranuclear inclusions
    - Stain for polyglutamine ataxin-1 & ubiquitin
    - Mainly in regions most affected by disease
    - Interact with leucine-rich acidic nuclear protein (LANP), ubiquitin, HSP-40 chaperone
    - Visible nuclear aggregates not required for initiation of pathogenesis
  - Mouse model
    - Early loss of Purkinje cell dendritic spines & branches
    - Later heterotopias
Links: GeneTests

SCA 2

¹ (ADCA I)
l Ataxin-2 (ATXN2)

; Chromosome 12q24.12; Dominant

Epidemiology
- Frequency: Somewhat common dominant cerebellar ataxia (13% to 18%)
- Common in: US, Spain, India, Mexico, South Africa, Italy, Cuba
- Uncommon in: Brazil, Finland, Japan
Genetic features⁵⁰
- Mutation: Expanded CAG trinucleotide repeat sequence
  - Normal CAG repeat length
    - 14 to 30 repeats
    - Most common size = 22
    - Alleles with CAA interruptions
      - Commonly present
      - May be reservoir of mutable alleles: Prone to expansion in subsequent generations; Lead to full disease mutations
  - Indeterminate
    - Repeat length: 31 or 32
    - Often contain CAA interruptions
    - ALS susceptibility or ALS, Dominant (ALS 13 )
      - Associated with 27-39 repeats: Most often interrupted
      - Found in: Sporadic (1.1% to 3%) & Unexplained hereditary ALS (2.2%)
      - No correlation of repeat length with onset age or survival
      - No relation to expansions in other polyQ disease genes
  - Disease
    - Repeat range: 33 to 77 (Most common size = 37)
    - Repeat length unstable within families
    - 33 repeats associated with very late onset (9th decade) ataxia
  - Repeat features
    - Normal repeats: Usually have CAA interruptions
    - Elongated CAG sequence: May be perfect or have interruptions
    - Sporadic SCA 2: May have interrupted 34-CAG repeat allele (2 patients reported)
    - Location of CAG repeats: Coding region of gene
  - Intergenerational expansions
    - Common with paternal > maternal transmission
    - Paternal anticipation of onset up to 26 years
ATXN2 protein
- 1,313 amino acids (~150 kDa)
- Location: Ubiquitously expressed in brain & systemic tissue
  - Highest levels: Ependyma & Choroid plexus
  - High: Cerebellar Purkinje cells, Substantia nigra large neurons & Trochlear nuclei
  - Increased levels: Age & SCA2
- Interacts with itself & 1 other cerebellar protein
- Subcellular localization
  - Golgi apparatus
  - Ataxin-2 with expanded glutamine repeat²⁸
    - Disrupts (disperses) Golgi apparatus
    - Induces cell death without nuclear aggregates
- Mouse knockout: Hyperphagia; Obesity
Clinical-Genetic correlations
- Longer CAG repeat sequence
  - Earlier onset: Childhood with longest repeats
  - Myoclonus; Dystonia; Myokymia
  - More rapid progression
  - Maximal saccade velocity slower
  - Somewhat more effect when (CAG)_n repeat in retinoic acid-induced 1 gene also long
- ? Other signs related to disease duration
  - Reduced DTRs
  - Oculomotor dysfunction: Slow saccades 100%; Gaze paresis 50%
  - Sphincter disturbance
  - ± Cognitive deficit
Clinical features
- Clinical overlap with SCA 1 & 3; Intrafamilial variability
  - More frequent slow saccades, tremor & titubation, myoclonus, & hyporeflexia
- Onset
  - Variable age
    - Symptomatic: Range 6 to 67; 40% < 25 yrs
    - May be presymptomatic features from birth
  - Anticipation in families: Average = 20 years
- Prognosis
  - Earlier onset (< 20 years): Faster progression; Dementia & Chorea
  - Female: Shortened survival
- Ataxia: Tremor (Postural & Action); Dysarthria; Gait
- Polyneuropathy⁴⁶
  - Age: 18 to 62 years
  - Frequency: 80%; Increases with age
  - Lower extremity
  - Sensory loss: Vibratory sense reduced
  - Tendon reflexes: Reduced
  - NCV: Sensory ganglionopathy
  - Nerve pathology: Axonal loss
- Motor
  - Fasciculations & Amyotrophy (20%)
  - Upper motor neuron: Upgoing toes (20%)
  - Proximal leg weakness (20%)
  - Dysphagia (49%)
  - Rapidly progressive motor neuron disease: Reported in 3 patients⁵¹
- Ocular
  - Slow saccades: 100%
    - Maximal velocity: Slower with longer glutamine repeat sequences
  - Gaze paresis 50%
  - Ophthalmoparesis (40%)
  - Supranuclear paresis
  - Patterns suggest pontine pathology
- Bladder dysfunction (40%)
- Parkinsonism
  - Occasionally presenting or dominant feature in family
  - May be L-DOPA responsive
- No visual loss
- Presymptomatic patients
  - Motor performance defects common
  - Slow saccade velocity
MRI: Pontine & cerebellar atrophy
Pathology
- Brainstem: Most prominent
  - Pontine nuclei
  - Inferior olive
- Basal ganglia: Substantia nigra
- Cerebellum
  - Purkinje cells
  - White matter
- Cerebral & White matter abnormalities
- Spinal cord
  - Clarke's nucleus ± Spinocerebellar tract degeneration
  - Sensory: Posterior columns; Dorsal root ganglia
  - Corticospinal tract
  - Anterior horn: Loss of motor neurons
- Cellular aggregates
  - Cytoplasmic: Most prominent
    - Differs from other SCA disorders
    - Increased perinuclear staining for ataxin-2
  - Nuclear: Not prominent; Some brainstem neurons
Links: GeneTests

SCA 3 (Machado-Joseph)

(ADCA I)
l Ataxin-3 (ATXN3; MJD gene)

; Chromosome 14q32.12; Dominant

Epidemiology
- Most common worldwide: 20% to 50% of SCA
- Common in many countries: 85% of SCA in Brazil
- Uncommon in: India, Mexico, Italy, South Africa, Finland
Genotype-Phenotype Corrleations
- CAG trinucleotide repeats
  - Normal range: 12 to 40
  - Disease: 51 to 86
- More CAG repeats
  - Earlier onset
  - More rapid progression
  - Types I & II syndromes
- More intergenerational instability of the CAG repeat length with
  - Male parent
  - GGG (vs CGG) polymorphism at 3' end of ACG in normal allele
  - CGG polymorphism at 3' end of ACG in 90% of SCA alleles
- Male parent: Transmits mutant allele 73% of time
- Paternal > maternal anticipation
- Repeats tend to enlarge with successive generations, but may contract
- Homozygotes have more severe syndrome than heterozygotes
Protein
- Cytoplasmic: In neuronal soma & processes
- Nuclear inclusions: Only in disease (50%)
- Pathological ataxin-3
  - Conformationally altered ataxin-3 bound to nuclear matrix
  - Exposed polyglutamine domain
Clinical features: General
- Frequency: Common dominantly inherited ataxia; 23% to 36% of SCA
- Between families
  - Variable disorders: Several allelic clinical syndromes
  - Most syndromes include cerebellar signs
- Within families: Tends to be consistent syndrome
- Anticipation: Common
- Ocular
  - Ophthalmoparesis
    - Impaired vestibulo-ocular reflex gain
    - Suggests vestibular nerve or nuclei involvement
  - Square wave jerks
  - Normal saccade velocity
Clinical syndromes
- SCA 3 (Type III): Spinocerebellar ataxia ± Dementia; Up to 200 CAG repeats
  - Clinical
    - Ataxia
    - Spasticity: Severe
    - Polyneuropathy: Sensory > Motor
      - Frequency
        
        Overall: 54%
        
        Increases with age
        
        More in type II syndrome patients
        
        No relation to number of CAG repeats
      - Age: 32 to 65 years
      - Sensory loss: Temperature discrimination reduced
      - Autonomic dysfunction: Occasional; Orthostatic hypotension
      - NCV⁴⁶
        
        Axonal neuropathy (70%)
        
        Distal predominant
        Symmetric
        
        CMAP & SNAP amplitudes: Small
        
        Neuronopathy (30%): Motor or Sensory
      - Pathology²⁵
        
        Axonal loss: Distal; Especially large myelinated axons
        
        Regeneration
        
        Degeneration: Some patients
        Hypomyelination: Mild
    - Diplopia
    - Stiffperson-like syndrome: Occasional patient
    - Few dystonic features
  - Pathology: Spinopontine atrophy
  - Epidemiology: German & Dutch-African descent
- Machado-Joseph
  - Originally described features
    - Descent: Azorean-Portuguese & others
    - Clinical: Ataxia, Extrapyramidal signs & Bulging eyes
  - Type I: Earliest onset (5 to 30 yo)
    - Longer CAG repeats
    - Dystonia; Spasticity; Facial & Lingual Fasciculations; Bulging Eyes
  - Type II: Intermediate onset (36 yo) & clinical features
    - Polyneuropathy common
  - Type III: Later onset (40 yo)
    - Cerebellar signs; Peripheral neuropathy; Ophthalmoplegia
  - Type IV: Oldest onset (38-47 yo)
    - Fewest CAG repeats
    - Parkinsonism
    - Neuropathy: Fasciculations; Sensory loss
    - Responsive to L-dopa
  - Type V: Spastic paraparesis
    - Japanese families
- Distinctive features in some patients
  - Sleep disorders
    - Restless legs syndrome
    - Periodic leg movements in sleep
    - Respond to dopaminergic stimulation
  - Impaired temperature discrimination: All limbs, trunk & face
  - Pseudoexophthalmos: Bulging eyes due by lid retraction
  - Faciolingual myokymia
  - Dystonia
- DRPLA variant: with ophthalmologic signs
MRI: Enlarged 4th ventricle
Pathology
- Basal ganglia: Prominent
  - Globus pallidus interna (Medial)
  - Subthalamic nucleus
  - Substantia nigra
  - Red nucleus
- Cerebellar connections: Prominent
  - Dentate nucleus
  - Spinocerebellar tract
  - Pontine nuclei
  - Inferior olive spared
- Brainstem: Cranial nerve nuclei
- Spinal cord: Mild
  - Clarke's nucleus
  - Anterior horn
  - Posterior column
- Cellular
  - Intranuclear inclusions
    - Stain for polyglutamine ataxin-3 & ubiquitin
    - Mainly in regions most affected by disease
  - White matter axons
    - Aggregates in affected fiber tracts: Ubiquitinated; p62+
Links: GeneTests

SCA 4 (Sensory ataxic neuropathy 2)

l Chromosome 16q22.1; Dominant

Clinical: Sensory ataxic neuropathy

SCA 5³³

(ADCA III)
l β-Spectrin, nonerythrocytic, 2 (β-III Spectrin; SPTBN2)

; Chromosome 11q13.2; Dominant

Epidemiology
- US: 1 family descended from paternal grandparents of Abraham Lincoln
- Europe: Germany; France
Genetics⁴⁴
- Mutations: Inframe deletions; Missense (Leu253Pro)
Protein
- Normal
  - Highly expressed in Purkinje cells
  - Associated with Golgi & vesicles
  - Binds to dynactin subunit ARP1
- Mutant: Loses ability to stabilize GluRδ2 & glutamate transporter EAAT4 at plasma membrane
Frequency: Rare
Onset
- Range 15 to 50 years
- Mean 33 years
- Anticipation: Probable
Clinical
- Ocular
  - Nystagmus: Downbeat, not suppressed by fixation
  - Impaired smooth pursuit
- Ataxia: Stance, Gait & Limbs.
- Dysarthria
- Other features in some families
  - Facial myokymia
  - Gaze palsy: Horizontal
  - Vibration sense impaired
Laboratory
- MRI
  - Atrophy of cerebellar vermis & hemispheres
  - Sparing of supratentorial & brainstem structures
- Nerve conduction: Normal

SCA 6

(ADCA III)
l Calcium channel, voltage dependent, P/Q type, α_1A subunit (CACNA1A; CaV_2.1)

; Chromosome 19p13.2; Dominant

Epidemiology
- 13% to 15% worldwide
- Common in: Germany, Taiwan, Australia, US & Japan (Northern), Netherlands
- Uncommon in: Spain, Italy, India, Mexico, Finland
Genetics
- SCA6 mutations: CAG trinucleotide repeats
  - Number of CAG repeat ranges
    - Normal: 4 to 18 or 20
    - SCA6 disease
      - 20 to 31
      - # of repeats is smallest # producing SCA syndrome
  - Intergenerational stability in number of repeats
    - ? Factors other than repeat size cause anticipation
- Allelic with
  - Episodic ataxia 2: Gene truncations
  - Hemiplegic migraine ± Coma: Missense mutations
  - Ataxia, Congenital
    - Congenital ataxia, Mental retardation, Dyskinesia, Recurrent Coma: IIe712Val; R1350Q
    - Early onset ataxia: Global delay; Nystagmus; Thr666Met (Also associated with hemiplegic migraine)
  - Epilepsy ± Migraine: R1820stop
- Frequency: 10% to 30% of dominant cerebellar ataxias
- Age of onset:
  - Earlier (~ 30 years)
    - More repeats (25 to 27)
    - Homozygosity or compound heterozygosity (Some patients)
  - Later (~ 40 to 50 years) with fewer repeats (21 to 24)
  - Some intrafamilial variation
- Family history: Dominant 73%; Sporadic 27%
- Mouse defect
  - Tottering & leaner
  - Seizures & cerebellar ataxia
CACNA1A protein
- P/Q type calcium channel subunit
- Interacts with synaptotagmin
- Also see
Clinical
- Cerebellar features
  - Onset age
    - Adult: 19 to > 55 years; 60% > 50 years
    - Variable within families without change in expansion size
  - Episodic early in course in some patients: Sensation of instability with turning
  - Dysarthria
  - Ataxia: Trunk > Limb
  - Hypermetria: Increased after hyperventilation
  - Progression
    - Usually slow: Over 20 to 30 years to severe disability
    - Occasionally rapid: Wheelchair within 5 years of onset
- Ophthalmologic disorders
  - Nystagmus
    - Downbeating
    - Gaze evoked; All directions
    - Rebound
  - Impaired: Vestibulo-Ocular reflex; Optokinetic nystagmus (OKN); Smooth pursuit
  - Normal: Saccade velocities; Vestibulo-ocular reflex gain
  - Consistent with pure cerebellar pathology
- Brainstem
  - Vestibular: Sense of imbalance with head movement
  - Dysphagia: Late (10 to 20 years)
- Sensory neuropathy
  - Mild loss of vibration & proprioception
- Extrapyramidal: Nigrostriatal dysfunction
  - Bradykinesia
  - Parkinsonism
  - Dystonia
  - Frequency: Occasional
- ? Dementia: Frontal lobe signs
MRI
- Cerebellar atrophy (Sagittal MRI): Vermis and Hemispheres
- Brainstem atrophy (Mild)(Transaxial MRI): Pons; Middle cerebellar peduncle
- Red nucleus: Slight atrophy
Pathology: Localized to cerebellum & connections
- Cerebellar cortex
  - Cellular
    - Loss of Purkinje cells; Proliferation of Bergmann glia
    - No intranuclear inclusions
  - Location: Superior vermis > Hemispheres
- Inferior olivary complex: Mild
- Dentate nucleus: Mild
Links: GeneTests
Hemiplegic migraine²⁰: Different mutation types from SCA6
- Genetics
  - Usually related to missense mutations
  - ~90% of patients with both hemiplegic migraine & cerebellar signs have mutations
  - Mutations with pure hemiplegic migraine often different from patients with cerebellar signs
  - Specific mutations
    - T666M: High frequency of hemiplegic migraine (98%), Severe attacks + Coma (50%), Nystagmus (86%)
    - R583Q: Ataxia (81%) without nystagmus
    - D715E: Lowest frequency of attacks of hemiplegic migraine (64%); ? Tremor
- Clinical
  - Onset Age: Mean 12 years; Range 6 to 86 years
  - Duration of hemiparesis: Days
  - Triggers: Emotional; Head trauma
  - Hemiparesis always associated with other symptoms: Sensory; Visual; Language
  - 33% with severe attacks: Coma; Severe hemiparesis
  - Complete recovery

SCA 7

(ADCA II)
l Ataxin-7 (ATXN7)

; Chromosome 3p14.1; Dominant

Epidemiology
- 3% to 5% worldwide
- Common in South Africa, Sweden, Finland & Mexico
Genetic features
- Expanded CAG, glutamine, DNA repeat sequence
  - Disease: 37 to > 200 repeats
  - Normal: 4 to 27 repeats; Most common length 10 repeats
  - Gonadal instability high with repeats in disease range
    - Paternal transmission: Large CAG repeat expansions
      - Typical: 15±20 repeat expansion in offspring
      - Some very large expansions: > 200
      - Under-representation of male transmission: Many sperm with very large expanded alleles, ? Lethal
    - Maternal transmission: 5±5 repeat expansion
    - Gonadal mosaicism
  - Intermediate range: 28 to 36 repeats
    - Non-symptomatic
    - Rare in general population
    - Increased frequency in SCA7 families
    - May randomly expand into disease range: Especially with paternal transmission
    - De novo expansion of CAG repeats from intermediate to disease range: Also in Huntington's
- Clinical-Genetic correlations
  - 38 to 43 CAG repeats: Asymptomatic young carriers, Mildly symptomatic when older
  - 54 to 55 repeats: Adolescent onset; Full syndrome
  - Longer repeat length (> 200): Childhood onset (18 to 36 months); Fatal course ~ 2 years
Protein: Ataxin-7
- Nuclear localization: Matrix, Nucleolar & Diffuse
- 130 to 140 kD protein
- Subunit of GCN5 histone acetyltransferase-containing complexes
- Ataxin-7 binding protein: Cbl-associated protein (CAP; SH3D5)
- Overexpression of mutant ataxin-7 in cells
  - Inclusion formation: Fibrillar; Contain caspase-3
  - Abnormal protein folding: Increased heat-shock proteins & proteasome subunits
  - Inhibits function of cone-rod homeobox protein (CRX) in photoreceptors
Clinical features
- Onset
  - Age
    - Range: 1 month to 76 years; Average ~ 20 years
    - Anticipation
      - Clinical features: Younger onset & more severe phenotype
      - More common and greater with paternal inheritance
      - Infantile onset: Very large repeat expansion; Paternal inheritance
  - Retinal degeneration: Visual loss; Especially with > 60 CAG repeats
  - Ataxia: Especially with < 60 CAG repeats
- Typical clinical syndrome
  - Ataxia
    - Truncal instability
    - Limb: Dysmetria
    - Dysarthria
    - Dysphagia
  - Retinal degeneration
    - Often initial symptom with > 59 repeats
    - Macular degeneration
    - Blue-Yellow color blindness: Early
    - Visual loss: Decreased acuity 83%; Blindness 28%
    - Optic atrophy 69%: More nasal
    - Pigmentary retinopathy 43%
    - Onset
      - Early onset cases: Up to 9 years before ataxia
      - Late onset cases: Up to 25 years after ataxia
  - Ophthalmoplegia (70%)
    - Supranuclear
    - Slow saccades
    - Ptosis
  - Pyramidal signs: Spasticity; Tendon reflexes brisk
  - Hearing loss
  - Extrapyramidal
    - Cranio-cervical dystonia: Some families
    - Parkinsonian features
  - Progression
    - Time course: Slow, over decades
    - Degree: Disability often severe
  - No peripheral nerve pathology
- Infantile syndrome²¹
  - Repeat expansion
    - Large (> 200)
    - Greatly increased size from parent to child: 4- to 9-fold
  - Inheritance: Paternal
  - Onset: Congenital or 1st months
  - Extraneural features
    - Cardiac: Patent ductus arteriosus; Cardiac failure
    - Microcephaly
    - Capillary leak syndrome
    - Hepatomegaly
    - Hemangiomas
  - Neural
    - CNS: Hypotonia; Developmental delay
    - Eye: Visual loss; Nystagmus; Retinal pigment disorders
  - Course: Fatal over 2 to 3 years
MRI: Atrophy
- Pons
- Medulla oblongata
- Cerebellar vermis
- Hemispheres
Pathology: Diffuse CNS involvement
- Prominent in cerebellum & connections
  - Purkinje cells
  - Inferior olive
  - Dentate nucleus
- Basal ganglia
  - Subthalamic nucleus
  - Substantia nigra
- Other
  - Cerebral atrophy
  - Anterior horn cells: Loss from medial group
  - Long tracts: Reduced axons in Posterior; Spinocerebellar; Pyramidal
- Cellular pathology: Intranuclear inclusions
  - Neuronal
  - Most frequent in inferior olivary (IO) complex
  - May occur in sites without severe neuronal loss
  - Ubiquitination: Variable ® 60% in IO, < 1% in cerebral cortex
  - Do not contain LANP
  - Protein may also accumulate in cytoplasm
- Mitochondria: Abnormalities in some patients
  - Morphologic change in muscle or liver
  - Reduced Complex IV activity
- Retina
  - Outer nuclear layer: Atrophic
  - Photoreceptors: Reduced or absent
  - Retinal pigment epithelium: Abnormal
Mouse model
- Over expression of mutant, but not normal, Ataxin-7 causes disease
Links: GeneTests

SCA 8

⁹
l ATXN8OS; CTG repeat expansion; Chromosome 13q21.33; Dominant (Usually)

Epidemiology
- 3% worldwide
- Common in Finnish population
- Uncommon in India, Mexico & Japan
- Penetrance with CTG expansion mutation: Incomplete
- Homozygosity: Increases penetrance
Genetics: SCA8 associated with enlarged CTG repeat
- Normal CTG repeat: Spanned by 2 genes expressed in opposite directions
  - Ataxin 8 opposite strand (ATXN8OS)
    - Produces noncoding CUG expansion RNA
  - Ataxin 8 (ATXN8)
    - Encodes nearly pure polyglutamine expansion protein in CAG direction
    - Present in intranuclear inclusions
- Enlarged CTG repeat
  - Similar to CTG mutation in myotonic dystrophy
  - CTG repeat repeat location: 3' Untranslated region of transcribed RNA
  - Transcript location: Brain & Lung (low levels)
  - CTG repeat length: Tetramodal
    - 15 to 21 (19%)
    - 22 to 37 CTG repeats (80%): 24 CTG most common
    - 40 to 91 CTG repeats: 0.7%
    - > 100 CTG repeats
      - SCA 8 patients: Usually 100 to 155 CTG repeats; Range 80 to 800
      - Psychiatric patients: 1.5%
      - Normals: 0.7%
      - Very large CTG expansions (> 800) found in occasional normals
    - Somatic mosaicism in number of CTG repeats: Even in normals
    - Intergenerational transmission of normal CTG alleles: Prominent instability in size
  - Transmission of CTG alleles: Prominent instability; Maternal anticipation more prominent
    - Paternal: Repeat length expansion or contraction (-86 to +16)
    - Maternal: Repeat length expansion more common (-11 to +600)
  - Other disease expansions in transcribed but untranslated DNA
    - DM1 (CTG)
    - DM2/PROMM (CCTG)
    - SCA10 (ATTCT)
- Enlarged CTG repeat: Clinical correlations
  - Not specific for SCA8
    - Enlarged CTG repeat occurs in normal SCA8 family members
    - Enlarged CTG repeat occurs in normal & disease control populations
  - SCA8 families
    - Disease range
      - Varies among families
      - Lower threshold 80 to 107
      - Upper range ~ 300
    - Affected SCA8 family members usually inherit CTG expansion from mother
    - Mean CTG repeat expansion length longer in affected famioly members
    - No correlation between CTG repeat size & onset age or progression rate
SCA8: Clinical features¹⁵
- General phenotype
  - Uniform in families
  - Variable in sporadic cases with expanded CTG repeats
- Onset
  - Mean: 40 to 50 years
  - Range: Congenital to 73
  - Incomplete penetrance
- Cerebellar signs
  - Eye movement disorders: Impaired smooth pursuit (100%); Horizontal nystagmus (67%)
  - Ataxia (100%): Trunk, Limb & Gait
  - Dysarthria (100%)
- Sensory neuropathy
  - Vibratory sense: Reduced in 25%
  - Electrophysiology: Small SNAPs
- Upper motor neuron: Severely affected individuals
  - Spastic dysarthria
  - Reflexes: Tendon increased; Extensor plantar
- Progression
  - Slow
  - Ambulation aids needed: After > 20 years of disease
  - Some patients non-ambulatory: By 4th or 5th decades
  - Severity correlates with repeat length & age
- Congenital onset SCA8 patient
  - Severe cerebellar signs in first year
  - Walked (with aid) at 5 years
  - Myoclonic epilepsy at 3 years
  - Mental retardation
SCA 8: Laboratory
- MRI: Cerebellar vermis & hemisphere atrophy

SCA 9

(ADCA I)
l Chromosome ?; Dominant

Epidemiology: American-English family
Clinical
- Onset
  - Age: Adult
  - Gait imbalance
- Ataxia (100%)
- Ophthalmoplegia (100%)
- Other
  - Optic atrophy
  - Dysarthria
  - Pyramidal tract signs
  - Weakness
  - Extrapyramidal: Parkinsonian
    - Shuffling gait
    - Bradykinesia
    - Cogwheel rigidity,
    - Bradylalia,
    - Tremor: Resting 2-6/sec
  - Posterior column
Laboratory
- MRI: Cerebellar atrophy

SCA 10

(ADCA III) ¹⁰
l Ataxin 10 (ATXN10; SCA 10 gene; E46L)

; Chromosome 22q13.31; Dominant

Genetics: Pentanucleotide repeat ATTCT in SCA 10 gene
- Location: Intron 9
- Normal range
  - 10 to 22 repeats
  - Interruptions present in some larger (≥ 17) normal alleles
- Intermediate range: 280 repeats with variable penetrance
- Disease range
  - 800 to 4,500 repeats
  - Interruptions
    - Present in some, but not all, repeat expansions
    - May be disease modifier
- Changes in ATTCT expansion: Intergenerational & other
  - Unstable repeat length may expand or contract
  - Instability greater for paternal than maternal transmission
  - Clinically anticipation may be associated with intergenerational contraction rather than expansion of ATTCT repeat
  - Mosaicism
    - Somatic instability
    - Blood leukocytes, lymphoblastoid cells, buccal cells & sperm have variable repeat sizes
  - Little change in length of expanded ATTCT repeat over time
  - Clinical appearance of anticipation may not correlate with changes in repeat length
- Clinical: Larger number of repeats correlates with younger onset age of SCA 10
- Allelic with: Nephronophthisis
  - Mutation: Recessive, Splice site
  - Clinical
    - Renal disease: Joubert syndrome-like
    - CNS: No lesions described
- Other disease expansions in transcribed but untranslated DNA
  - DM1 (CTG)
  - DM2/PROMM (CCTG)
  - SCA8 (CTG)
SCA 10 protein
- Expressed widely in brain
Epidemiology: Mexican & Brazilian families
Anticipation
- Marked: Up to 20 years
- Especially with paternal inheritance
Clinical: Predominantly cerebellar
- Onset
  - Age: 10 to 40 years
  - Gait disorder
- Cerebellar
  - Ataxia: Gait & Limb
  - Dysarthria
  - Eye: Nystagmus, gaze evoked; Fragmented pursuit
- Seizures
  - Complex partial ± Generalization
  - At onset or later in disease course
  - Frequency: 20% to 80% in different families
- Personality changes: Flat affect & apathy; Occasional; 1 family
- Progression
  - Wheelchair needed in some patients
  - Seizures contribute to mortality
Laboratory
- MRI: Cerebellar atrophy
- EMG/NCV: Normal

SCA 11¹¹ (ADCA III)

l tau tubulin kinase 2 (TTBK2)

; Chromosome 15q15.2; Dominant

Epidemiology: 2 British families
Mutations
- Stop, frameshift insertion or deletion
- Conserved, serine-rich region of protein
TTBK2 protein
- Ubiquitous expression
- High in: Purkinje & granule cells; Hippocampus, midbrain & substantia nigra
- Casein kinase (CK1) group
- Transport (Microtubule regulator)
Clinical
- Onset age: 25 ± 8 years
- Cerebellar
  - Ataxia course: Slowly progressive
  - Gait disorder: 100%
  - Ocular: Saccadic pursuit; Nystagmus (Horizontal > Vertical) (100%)
  - Dysarthria (100%)
  - Limb ataxia (93%)
- Other
  - Hyperreflexia (100%)
  - No extrapyramidal, weakness, or sensory signs
- Disease course
  - Slow progression
  - Disease duration: Decades
  - Life expectancy: Normal
Laboratory
- Nerve conduction: Normal
- MRI: Isolated cerebellar atrophy
Cerebellar pathology
- Atrophy
- Purkinje & Granule cell loss
- Neurofibrillary tangles, neuropil threads & tau-positive neurites

SCA 12¹²

l Protein phosphatase 2, regulatory subunit B, β (PPP2R2B)

; Chromosome 5q32; Dominant

Genetics
- CAG repeat in 5' untranslated region of gene: ? Upstream of transcription start site
- Normal repeat size: 7 to 32
- Expanded CAG repeat size: 55 to 93
- Expanded CAG Repeat sequence uninterrupted
- Minor instability in repeat size over generations: -1 to +2
Protein phosphatase 2A (PP2A) protein
- Serine/threonine phosphatase
- PPP2R2B: Brain-specific regulatory subunit of PP2A
- Regulatory processes
  - Cell growth, cycle progression & division
  - Muscle contraction
  - Gene transcription
  - PP2A dephosphorylation activity for
    - Tau
    - Vimentin
  - Apoptosis
Epidemiology
- German family
- Common in India: 7% of ADCA
Clinical: Variable phenotype
- Onset
  - Age: 8 to 55 years; Mean in 4th decade
  - Signs: Arm tremor, or Gait ataxia & Dysarthria
- Cerebellar (100%)
  - Tremor: Arm & head
  - Ataxia: Gait; Extremities; Dysarthria
  - Eye movement disorders (33%): Slow saccades; Broken pursuit; Nystagmus
- Other CNS
  - Tendon reflexes: Increased (80%)
  - Extrapyramidal: Paucity of movement; Axial dystonia
  - Dementia: In oldest patients
- Peripheral nervous system
  - Facial myokymia (33%)
  - Polyneuropathy (80%)
    - Often subclinical
    - Sensory, or Sensory motor
    - NCV: Axonal loss
Laboratory
- MRI or CT: Cortical & cerebellar atrophy

SCA 13¹³

l Potassium channel, voltage-gated, shaw-related subfamily, member 3 (KCNC3)

; Chromosome 19q13.33; Dominant

Epidemiology
- French & Philipino families
- Females in 88% (7 of 8)
Genetics: Missense mutations
- Phe448Leu: More severe phenotype
- Arg420His
KCNC3 protein
Onset
- Age: Early Childhood, usual; 5th decade in 1 patient
- Signs: Motor & Mental Developmental delay
- No anticipation
Clinical features
- Ataxia
  - Legs > Arms
  - Dysarthria (88%)
  - Nystagmus, horizontal (75%)
- Motor dysfunction
  - Delayed development
  - Poor running
  - Inability to walk (4th to 6th decade)
- Tendon reflexes: Increased
- Mental retardation: Some families
  - With more severe phenotypes
  - IQ 62 to 76
- Progression: Slow
MRI: Cerebellar & Pontine atrophy

SCA 14¹⁴

l Protein kinase Cγ (PRKCG)

; Chromosome 19q13.42; Dominant

Mutations: Missense³⁹
- Exons 4, 5, 10, 18
- Conserved residues in C1, cysteine-rich region of Exon 4
  - H101Y, C114Y; Gly118Asp, S119P; G123R; G123E; G128D
- Catalytic domain of the enzyme
  - G360S; F643L
- Other: V692G; Inframe deletion; Splice site
PKCγ protein
- Serine/threonine kinase
- Expression high in brain, especially cerebellar cortex, & spinal cord
- Translocates between plasma membrane and cytosol during its activation cycle
- Binds to DAG & Zinc
- Mutated protein
  - May have dominant negative effect, interacting with aprataxin
  - Degraded by autophagy
- Nonsense mutation in PKCγ in agu rats: Parkinsonian-like disorder, recessive
Epidemiology
- Families: Japanese, English-Dutch, French (1.5%)
- Not identified in German families
- Sporadic patient identified
- Some patients with mutation may be asymptomatic
Onset
- Age
  - Range: 10 to 59 years
  - Mean 31 to 40 years
  - Variable within families
  - No relation between age of onset & severity
- Signs
  - Gait disorder
  - Tremor in younger onset patients
Clinical features
- Ataxia
  - Gait disorder: All patents
  - Legs > Arms
  - Dysarthria
  - Pure ataxia with later onset
- Movement disorders
  - Myoclonus
    - Most common with onset < 27 years
    - Axial or Limbs
  - Tremor: Extremities & Head
  - Rippling of small hand muscles
- Tendon reflexes: Increased at ankles
- Cognition
  - Usual: Normal
  - Impaired: Some family members (33%)
- Some family members with
  - Dystonia
  - Peripheral neuropathy: Reduced vibration sense
- Progression: Slow; Most have continued walking with falls
Laboratory
- MRI: Cerebellar atrophy, Vermis ± Hemispheres
- Pathology
  - Reduced staining for PKCγ & ataxin 1 in Purkinje cells
  - Staining for calbindin preserved

SCA 15¹⁶

l Inositol 1,4,5-triphosphate receptor, type 1 (ITPR1)

; Chromosome 3p26.1; Dominant

Epidemiology: Australian, French & Japanese families; 1% of AD SCA
Genetics
- Mutations
  - Large deletions: Most common
    - Heterozygous deletions of 5� parts of ITPR1 gene
    - Deletions may extend into neighboring gene SUMF1
  - Missense: V494I
- Same locus as SCA 16
ITPR1 protein
- Intracellular IP3-gated calcium channel
- Modulates intracellular calcium signaling
- High expression in Cerebellar Purkinje cells
- Mutant
  - Reduced levels of ITPR1 in cells
  - Probable disease mechanism: Haploinsufficiency
Clinical
- Onset: Mean 26 to 35 years; Range 10 to 66 years
- Pure cerebellar ataxia: Often mild
  - Gait disorder 71%
  - Limb ataxia 86%
  - Dysarthria
  - Ocular: Nystagmus, gaze evoked; Dysmetric saccades
  - Tremor: Upper limb
  - Dysphagia: Late in course
- Other features: Some patients
  - Pyramidal signs
  - Cognitive dysfunction: Mild
- Slow progression: Patients usually remain ambulatory
Laboratory
- MRI Cerebellum: Superior (Dorsal) vermis atrophy; Sparing of hemispheres & tonsils; May be diffuse
- Nerve conduction velocities: Normal
Variants
- SCA 29
  l Chromosome 3p26; Dominant
  - Epidemiology: Japanese family
  - Clinical
    - Ataxia
    - Tremor
    - Myoclonus
- CLA4: Congenital nonprogressive ataxia
  l Chromosome 3pter; Dominant
  - Clinical
    - Cerebellar
      - Gait ataxia
      - Some patients: Dysarthria, Dysmetria, Dysdiadochokinesia, Nystagmus
    - Cognitive disability
    - Dystonia: Some patients
  - Imaging: Cerebellar hypoplasia
- SCA 16¹⁷
  - Japanese family
  - Genetics: Mutations
    - Deletion of exons 1 to 48
    - Missense: P1059L
  - Clinical
    - Onset
      - Age: Range 20 to 66 years; Mean 40 years
      - Gait ataxia; Dysarthria; Head Tremor
      - No anticipation
    - Cerebellar ataxia (100%)
      - Gait disorder
      - Limb ataxia
      - Speech: Dysarthria
      - Eyes: Impaired smooth pursuit; Nystagmus
    - Head tremor (15%): Regular; Rotatory
    - Strength: Normal
    - Progression: Slow; Variable
  - Laboratory
    - MRI: Cerebellar atrophy; No brainstem changes
    - NCV: Normal
- Mouse disorder (opt): Ataxia with Spontaneous itpr1 mutation

SCA 17: Ataxia with intellectual deterioration¹⁸

l TATA box-binding protein (TBP)

; Chromosome 6q27; Dominant

Nosology
- ? Same disorder as OPCA V
- Huntington disease-like 4
Epidemiology: French, Japanese, Italian & German families; 1 sporadic patient
Genetics
- Normal CAG sequences
  - Length: 25-42 repeats
- Expanded CAG repeat sequences
  - Length: 43 to 66 repeats
  - Types
    - Simple: Long stretches of pure CAG repeats
    - Imperfect: Many CAA interruptions
  - Lengths of expansions in different generations of same family
    - May be constant
    - Occasional large variation
    - Variation with
      - Simple CAG repeats: More instability; Expansions & Deletions
      - CAA interruptions: More stable; Deletions more common
- Intermediate CAG length with incomplete penetrance: 43 to 48 repeats
- No meiotic instability
Clinical
- General: Complex & variable phenotype
- Onset
  - Age
    - Range: 1st to 7th decade
    - Mean: 3rd decade
    - Younger with more repeats
  - Ataxia: Gait
  - Other CNS: Dementia; Psychiatric disorders; Parkinsonism
  - May be rapid
- CNS features: Variable
  - Cerebellar (100%)
    - Ataxia: Limb & Trunk; Gait
    - Bulbar: Dysarthria; Dysphagia
    - Correlate with disease duration
  - Upper motor neuron (50%)
    - Hyperreflexia
    - Extensor plantar responses
  - Dysphagia
  - Cortical: Intellectual deterioration (80%)
    - Types: Dementia; Psychiatric disorders; Mutism
    - Often occurs early in disease course
  - Seizures
    - Atypical absence; Some families
    - Grand mal: Severe cases
    - May be associated with more severe long-term disability
  - Extrapyramidal signs
    - Dystonia
      - Signs: Blepharospasm, Torticollis, Writer's cramp, Foot dystonia
      - Huntington-like phenotype
    - Chorea
    - Parkinsonism
  - Ocular
    - Nystagmus: Gaze evoked, Downbeat, Rebound
    - Saccades: Hypometric; Normal velocity
    - Smooth pursuit initiation & maintenance: Impaired
    - Increased with disease duration
- Endocrine: Hypogonadotropic hypogonadism (Occasional)
Laboratory
- MRI: Cerebellar atrophy; Cerebral atrophy, mild
- NCV: No peripheral neuropathy
- EMG: Distal denervation in legs (30%)
Pathology²⁹
- Cerebellum: Absent Purkinje cells; Rarified inner granule cell layer
- Neuronal intranuclear inclusions
  - Pannuclear & Coarsely granular
  - Larger than in SCA2 & SCA3
  - Abundant in dorsomedian thalamic nucleus
- Similar distribution of changes to SCA 6

SCA 18: Ataxia with sensory disorder and neurogenic muscular atrophy

l Chromosome 7q22-q32; Dominant

Epidemiology: 1 American family of Irish ancestry
Onset
- Age: 13 to 27 years
- Symptoms: Gait difficulty, especially in the dark
Clinical
- Expressivity: Variable severity of symptoms
- Sensory loss: 100%
  - Panmodal
  - Romberg positive
- Tendon reflexes: Reduced or Absent
- Ataxia
  - Gait ataxia: 100%
  - Coordination decreased: Dysdiadochokinesia
  - Dysmetria
  - Head tremor
  - Dysarthria
  - Nystagmus: Some patients
- Pyramidal tract
  - Extensor plantar responses: Some patients
- Weakness: 70%
  - Proximal or Distal
  - Arms or Legs
  - Muscle atrophy
- Hearing loss: 20%
- Cognition: Normal
- Course
  - Progression: Slow
  - Disability: Wheelchair at later ages
  - Lifespan: Normal
Laboratory
- Nerve conduction studies: Sensory axonal neuropathy
- EMG: Denervation
- Muscle biopsy: Neurogenic atrophy
- Brain MRI: Cerebellar atrophy, Mild

SCA 19: Ataxia with cognitive impairment²⁴

l Chromosome 1p21-q21; Dominant

Epidemiology: Dutch family
Genetics
- ? Anticipation
- Locus similar to SCA 22
Onset: 20 to 45 years
Clinical
- Ataxia: Mild; Gait disorder & falling; Saccadic EOM
- Tremor: Postural
- Cognitive impairment: Mild; Disturbed abstract reasoning
- Myoclonus (30%): Spinal or Cortical
- Tendon reflexes: Reduced (60%); Increased (20%)
- Sensation: Reduced vibration & joint position
Laboratory
- Transcranial magnetic stimulation: Slightly increased central conduction times
- NCV: Usually normal; Occasional mild reduction
- MRI: Marked atrophy of cerebellar hemispheres; Mild vermal & cerebral atrophy

SCA 20: Ataxia with Dysphonia & Dentate calcification³⁴

l Chromosome 11q12; Dominant

Genetics
- 260-kb duplication at 11q12
- Contiguous gene duplication syndrome: Region contains ≥ 12 genes
Epidemiology: Anglo-Celtic family in Southeastern Australia
Onset
- Age: 19 to 64 years; Mean 46 years; 10 years younger in 2nd generation
- Dysphonia
Clinical
- Bulbar
  - Dysphonia
  - Spasmodic cough
- Ataxia
  - Gait
  - Arms: Ballistic tracking more than ramp (finger:nose)
  - Ocular: Hypometric saccades on horizontal & downgaze
- Palatal tremor
- Bradykinesia: Slow index finger tapping
- Progression: Slow
Laboratory
- CT: Dentate calcification
- MRI: Pan-cerebellar atrophy; Low dentate signal
- Nerve conduction studies: Normal

SCA 21: Ataxia with extrapyramidal features²³

l Chromosome 7p21.3-p15.1; Dominant

Epidemiology: French family
Onset age
- Mean 17 years; Range 6 to 30 years
- Probable anticipation
Clinical
- Cerebellar
  - Gait disorder (100%)
  - Limb ataxia (85%)
  - Dysarthria (85%)
- Extrapyramidal
  - Akinesia (80%)
  - Rigidity (30%): No response to L-DOPA
  - Tremor (60%)
- Cognitive defect: Mild to Severe; Some patients
- Tendon reflexes: Reduced in 90%
- Course: Slow progression
MRI: Cerebellar atrophy; Normal brainstem & basal ganglia

SCA 22: Pure cerebellar ataxia²⁷

l Chromosome 1p21-q21; Dominant

Epidemiology: Chinese Han family
Genetics: Locus similar to SCA 19
Onset age: 10 to 46 years; Anticipation mean of 10 years
Clinical: Pure cerebellar disorder
- Ataxia: 100%; Trunk; Gait; Appendicular
- Bulbar: Dysarthria; Scannning speech; Dysphagia
- Ocular
  - Intermittent microsaccadic pursuits
  - Normal saccadic velocity
  - Gaze-directed horizontal nystagmus: 67%
- Hyporeflexia: 89%
- Normal mentation
- Course: slowly progressive
Laboratory
- MRI: Cerebellar atrophy, homogeneous; Normal brainstem
- EMG & NCV: Normal
- Somatosensory & auditory brainstem evoked potentials: Abnormal

SCA 23

³⁷
l Prodynorphin (PDYN)

; Chromosome 20p13; Dominant & Sporadic

Epidemiology: Dutch families
Mutations
- Missense: R138S; L211S; R212W; R215C
PDYN protein
- Precursor protein for opioid neuropeptides: α-neoendorphin, Dyn A & Dyn B
- Ligands for κ-opioid receptor (OPRK1)
- High levels in Purkinje cells
- Secreted
- Dyn A: May induce neurodegeneration
  - Nonopioid mechanism
  - May involve glutamate receptors & acid-sensing ion channels
- Mutations: Higher levels of DynA produced
Clinical
- Onset
  - Age: Mean 50 years;/ Range 43 to 73 years
  - Cerebellar: Gait & Speech disorders
- Cerebellar
  - Gait ataxia
  - Speech disorder (60%)
  - Limbs: Ataxia
  - Ocular: Slow saccades; Ocular dysmetria
- Tremor: Head & Limbs
- Sensory loss (60%): Vibration; Legs, distal
- Pyramidal signs
  - Hyperreflexia (80%)
  - Toes: Upgoing
  - (40%)
- Other CNS: Memory loss in some patients
- Course: Slowly progressive over decades
Laboratory
- MRI
  - Cerebellar atrophy
  - White matter lesions
- Pathology
  - Atrophy: Cerebellum; Brainstem; Spinal cord
  - Cell loss: Purkinje; Dentate; Inferior olive

SCA 25: Spinocerebellar ataxia & Sensory neuropathy³⁰

l Chromosome 2p21-p13; Dominant

Epidemiology
- Southern French family
- Incomplete penetrance
Onset
- Age
  - Usual: Childhood
  - Range: 17 months to 39 years
  - No anticipation
- Clinical
  - Ataxia
  - Vomiting & Gastrointestinal features
Clinical: Variable among family members
- Cerebellar
  - Ataxia
  - Eye movements
    - Nystagmus: Some patients
    - Movement speed: Slow
  - Hypotonia
  - Gait: Difficulty running; Wheelchair use
  - No dysarthria
- Sensory neuropathy
  - Vibration loss at ankles (100%)
  - Pain loss: Some patients
  - Gastric pain: Episodic
  - May be most prominent feature
- Tendon reflexes: Absent at ankles; Reduced elsewhere in some
Laboratory
- NCV: SNAPs absent; Motor velocity normal
- MRI: Global cerebellar atrophy, severe; Normal brainstem

SCA 26⁴¹

: Pure cerebellar ataxia
l Chromosome 19p13.3; Dominant

Epidemiology: Norwegian (North Dakota) family
Clinical
- Onset age
  - 26 to 60 years
  - No anticipation
- Ataxia
  - Trunk
  - Limbs: Arms & Legs
  - Dysarthria
  - Visual pursuit
    - Movements: Irregular vertical & horizontal
    - Nystagmus: Some patients
- Normal
  - Intellegence
  - Strength
  - Sensation
  - Pyramidal
- Course: Slowly progressive
Laboratory
- MRI: Cerebellar atrophy

SCA 27: SCA with Tremor & Dyskinesia²⁶ (ADCA I)

l Fibroblast growth factor 14 (FGF14)

; Chromosome 13q33.1; Dominant

Epidemiology: Dutch family
Genetics
- Mutation: F145S; Produces reduced protein stability
- ? Association with SCA8 at 13q21
FGF-14 protein
- Subfamily: FGF Homologous Factors (FHF)
- Expressed primarily in nervous system
- Intracellular
- Interacts with voltage gated Na⁺ channels
Onset
- Childhood
- Tremor
Clinical
- Tremor: Limbs & Head; Exacerbated by emotional stress & exercise
- Ataxia
  - Limbs: Arms > legs; Onset in late teens
  - Gait: Onset 27 to 40 years
  - Cranial nerves: Dysarthria; Nystagmus
- Dyskinesia: Orofacial
- Sensation: Reduced vibration at ankles in some patients
- Psychiatric episodes (50%): Aggression; Depression
- Cognitive defect
- Progression
  - Normal life expectancy
  - Difficulty or inability to walk by 7th or 8th decade
  - No anticipation
Laboratory
- MRI: Cerebellum normal or atrophic
- Nerve conduction tests: Mild axonal peripheral neuropathy
Fgf14-knockout mice
- Ataxic gait
- Widened stance
- Lack of forefoot-hindfoot correspondence
- Paroxysmal hyperkinetic dyskinesia

SCA 28: SCA with Ophthalmoparesis & Hyperreflexia⁴³ (ADCA I)

l ATPase family gene 3-like 2 (AFG3L2)

; Chromosome 18p11.21; Dominant

Epidemiology: Multiple families; 3% of SCA
Genetics⁴⁹
- Mutations
  - Missense
  - N432T; S674L; E691K; A694E; R702Q
  - Location: Commonly in proteolytic domain
- No anticipation
- Variant syndrome: Spastic Ataxia, Myoclonic epilepsy with Neuropathy, Recessive (SPAX5)
AFG3L2 protein⁴⁹
- Cellular location: Mitochondrial inner membrane
- High expression: Purkinje cells; Deep cerebellar nuclei; Motor neurons
- Zinc ligand
- Actions & Functions
  - m-AAA Protease complex
  - Metalloproteinase
  - Interacts with: Paraplegin & itself
  - ?? Related to OPA1 processing
- Mutation mechanism
  - Dominant negative most likely
  - Mitochondrial respiratory defect: Reduced COX activity & protein levels in yeast
  - Impaired AFG3L2 proteolytic activity
  - No effect on OPA1 processing
Clinical
- Onset
  - Age: Range 12 to 36 years; Mean 19 years
  - Cerebellar: Standing imbalance; Gait incoordination
- Cerebellar
  - Gait ataxia
  - Limb ataxia
  - Dysarthria
  - Progression: Slow; Walking aid or Wheelchair in 8th decade
  - Variable severity
- Eye
  - Nystagmus: Gaze evoked; Early in disease course
  - Ophthalmoparesis (80%)
    - Late
    - Mild to Severe
  - Ptosis: Later in disease course
  - Slow saccades (60%): Late
- Upper motor neuron
  - Hyperreflexia in legs (80%)
  - Extensor plantar response (50%)
  - Spasticity: Legs > Arms
- Cognitive: Normal
- Myoclonic epilepsy: Some patients
Laboratory
- Brain MRI
  - Cerebellar atrophy: May be present in patients with normal exam
- NCV: Normal
- Muscle biopsy
  - Morphology: Normal morphology
  - Mitochondrial oxidative enzymes: Normal

Variant syndrome: Spastic Ataxia with Myoclonic Epilepsy & Neuropathy (SPAX5) ⁵⁵
l Recessive
- Genetics
  - AFG3L2 mutations: Homozygous Y616C
  - Allelic with: SCA 28
- Clinical
  - Onset
    - Age: Early 1st decade
    - Spastic gait
  - Myoclonic epilepsy
  - Neuropathy
    - Weakness: Distal; Legs > Arms
    - Axonal
  - Upper motor neuron: Spasticity; Tendon reflexes increased
  - Cerebellar: Ataxia; Dysarthria
  - Eye
    - Oculomotor apraxia: Some patients
    - Ptosis
  - Dystonia: Some patients
  - Cognition: Normal
- Laboratory
  - NCV: Sensory & Motor axon loss in legs
  - EMG: Denervation
  - MRI: Cerebellar atrophy
  - Mitochondrial
    - Cytochrome c oxidase: Mildly reduced
    - mtDNA content: Mildly reduced
    - Muscle lipid: Increased
  - EEG: Slowing; Spike-Wave

SCA 30: Pure cerebellar ataxia⁴⁷ (ADCA III)

l Chromosome 4q34.3-q35.1; Dominant

Epidemiology: 1 Australian family of Anglo-Celtic origin
Genetics: Candidate gene ODZ3
Clinical
- Onset: Mid- to late-life
- Ataxia
  - Dysarthria
  - Appemndicular
  - Gait
  - Saccades: Hypermetric
  - Nystagmus: Gaze-evoked in 1 patient
- Pyramidal signs: Minor; Brisk tendon reflexes in legs
- Sensory: Normal
- Peripheral nerves: Normal
- Progression: Slow
Laboratory
- Vestibuloocular reflex gain: Normal
- MRI: Atrophy of superior & dorsal cerebellar vermis; Cerebellar hemisphere mild atrophy

SCA 31: Pure cerebellar ataxia⁵² (ADCA III)

l Brain-Expressed, Associated with NEDD4 (BEAN)

; Penta-nucleotide (TGGAA)n repeat insertion; Chromosome 16q21; Dominant

Nosology: Syndrome previously called SCA4 in Japanese
Epidemiology
- ADCA III: Japanese families with late onset pure cerebellar syndrome
- 3rd most common SCA in Japan (After SCA3 & SCA6)
- Rare in Caucasians
Genetics
- Insertion composition
  - Preceding four nucleotides: "TCAC"
  - Penta-nucleotide & 1 deca-nucleotide, repeat components
    - (TGGAA)n
      - Most likely pathogenic
      - Segregates with phenotype
    - Other repeat sequences
      - (TAAAA)n: Common in humans generally
      - (TAGAA)n: Japanese
      - (GAAAA)n: Caucasians
      - (TAACA)n: Caucasians
      - (TACAA)n: Caucasians
      - (TGAAA)n: Caucasians
      - (TAAAATAGAA)n
- Insertion point
  - 3'-tail of an AluSx
  - Introns of 2 genes transcribed in opposite directions
    - BEAN
    - Thymidine kinase 2 (TK2)
- Insertion length
  - Variable: 2.5�3.8 kb
  - Longer length correlates with: Earlier onset age
  - May vary within a family
- Transcription product: UGGAA
  - Binds to SFRS1 & SFRS9
  - Transcribed in direction of BEAN
  - Form RNA foci
- Repeat sequence related to satellite sequence in centromeric heterochromatin
  - Other heterochromatin insertion: DFNB10
- Founder effect: All Japanese families with same haplotype
- Normal
  - Usual: No inserted repeats
  - Inserted repeats, with no TGGAA sequences, in 0.2%
  - Repeats not present in SCA4
- Mutation in PLEKHG4
  - Present in many, but not all, patients
  - Previously reported as primary disease-causing mutation
- Nucleotide change (AB473217) at 65,114,245 in chromosome 16: Also present in SCA31
Clinical
- Onset
  - Age
    - Range: 45 to 72 years
    - Mean = 56-61
    - Mild anticipation reported
    - Earlier in homozygote
  - Gait ataxia
- Ataxia: Japanese families with pure cerebellar syndrome
  - Gait disturbance: 100%; Proximal > Distal
  - Limb: Dysmetria
  - Dysarthria: 50% to 100%
  - Later: Abnormal fine finger movements
  - Hypotonia
  - Saccadic pursuit: 57%
  - Progression: Over decades to wheelchair
- Hearing loss: Mild
- No ophthalmoplegia
Laboratory
- MRI: Cerebellar atrophy
- Pathology
  - Cerebellum
    - Atrophy
    - Loss of Purkinje cells
    - (UAAAAUAGAA)n RNA foci in 30%�50% of Purkinje cell nuclei

SCA-32: Cerebellar ataxia with Azospermia and Mental Impariment (ADCA I)

l Chromosome 7q32-q33; Dominant

Epidemiology: Chinese family
Clinical
- Onset age: Adult; Variable, especially females
- Ataxia
- Cognitive impairment: Especially with disease onset < 40 years
- Azospermia: Infertile males
MRI: Cerebellar atrophy
Testicular biopsy: Absent germ cells and progenitors

SCA-35: Cerebellar ataxia with Upper motor neuron features (ADCA I)

⁵³
l Protein-glutamine gamma-glutamyltransferase 6 (TGM6)

; Chromosome 20p13; Dominant

Epidemiology: 2 Chinese families
Genetics
- Mutations: Missense; L517W, D327G
TGM6 protein
- Nosology: Transglutaminase 6
- Transglutaminase family
- Cerebral transglutaminases
  - Ca⁺⁺-dependent enzymes
  - Catalyse covalent attachment of glutaminyl residues & other amine-bearing compounds & lysyl residues
  - Activity increased in Parkinson�s, Huntington�s & Alzheimer�s diseases + Supranuclear palsy
- TGM6: Expressed by Purkinje cells
- Gluten ataxia: TGM6 deposits in cerebellum
Clinical
- Onset age: 5th decade
- Cerebellar
  - Ataxia: Arms; Legs; Gait; Ocular dysmetria
  - Dysarthria
  - Nystagmus: None
  - Saccades: Slow in few patients
- Upper motor neuron
  - Pseudobulbar palsy
  - Tendon reflexes: Brisk
  - Ankle tone increased: 40%
  - Plantar reflex: Extensor in 40%
- Sensory: Positiion sense reduced in 30%
- Spasmodic torticollis: 40%
- Progression
  - Moderate
  - Wheelchair: Common after 2 decades
Laboratory
- MRI: Cerebellar atrophy

SCA-36: Cerebellar ataxia with Motor neuron involvement

⁵⁴
l Nuclear Protein 56 (NOP56; NOL5A)

; Chromosome 20p13; Dominant

Epidemiology
- 9 Japanese families
- Costa da Morte ataxia
Genetics
- Mutations
  - Large expansion of Intronic GGCCTG repeat: 1500-2500
  - Phe265Leu
- Mutation mechanisms
  - RNA gain of function
  - MicroRNA MIR1292 suppression
  - Not haploinsufficiency
NOP56 protein
- Location: Nucleus & Cytoplasm
- Required for 60S ribosomal subunit biogenesis
- Interacts with NOP1 & NOP58
Clinical
- Onset
  - Age: 5th & 6th decades; No anticipation
  - Ataxia
- Ataxia
  - Gait
  - Limbs
  - Dysarthria
- Motor
  - Muscle atrophy: Tongue & Proximal
  - Fasciculations: Limbs, Trunk & Tongue
  - Later in disease course
- Tendon reflexes: Increased
- No spasticity
- Course: Slow progression
Laboratory
- MRI: Cerebellar atrophy
- NCV: Normal
- EMG: Denervation

SCA (Unlinked)¹¹ (ADCA III): No chromosomal linkage
l Chromosome ?; Dominant

Epidemiology
- British family
- Onset: 38 years
- Disease duration: Decades
- Life expectancy: Normal
Clinical
- Cerebellar
  - Ataxia course: Slowly progressive
  - Gait change: 100%
  - Ocular: Saccadic pursuit; Nystagmus (Horizontal) (40%)
  - Dysarthria (80%)
  - Limb ataxia (100%)
- Other: No extrapyramidal, pyramidal, weakness, or sensory signs
Laboratory
- MRI: Cerebellar atrophy

Dentatorubral-Pallidoluysian Atrophy (DRPLA)

⁴⁸
l Atrophin-1 (DRPLA gene; ATN1)

; Chromosome 12p13.31; Dominant

Epidemiology: Common in Japan & Portugal
Mutation: CAG repeat expansion
- Disease size: 49 - 88
- Normal: < 26
- Intermediate size: 37 to 48
DRPLA protein
- Location: Nuronal cytoplasm
- Phosphoprotein
- Truncated protein with excess repeats in nuclear & perinuclear regions
Genotype-Phenotype Correlations
- Homozygotes have more severe syndrome than heterozygotes
- Parental sex
  - Paternal transmission: Usually increases repeat length by 5 or more
  - Maternal transmission: Decrease repeat length or increase < 5
- Repeat length
  - Longer: Younger onset; Myoclonus epilepsy
  - Shorter: Older onset; Ataxia & Chorea
- Repeat length in brain > by several repeats than in other tissues
- Homozygous intermediate-length repeats: Spastic-ataxia syndrome
Clinical features
- Onset age
  - Range: 1 to 67 years; Mean 31/li>
  - Infantile onset: Few patients
  - Correlation with repeat length
  - Anticipation: Intergenerational reduction of 19 years
  - Younger onset (< 20 years): Myoclonic epilepsy common
  - Older onset: Ataxia, Dementia, Chorea or Psychiatric disturbance
- Myoclonus Epilepsy
- Ataxia
- Chorea
- Dementia
- Myelopathy: Homozygotes for DRPLA genes with intermediate # (40 or 41) of repeats
Variants
- Haw River Syndrome
  - Epidemiology: Original family from North Carolina, US
  - Genetics: Allelic with DRPLA
  - Clinical
    - Onset: 15 to 30 years
    - Seizures, not myoclonic
    - Chorea
    - Dementia
  - Pathology
    - Subcortical demyelination
    - Neuroaxonal dystrophy
- Spastic ataxia syndrome
  - Genetics
    - Inheritance: Recessive
    - Mutation: Homozygous DRPLA genes with intermediate # (40 or 41) of CAG repeats
  - Clinical: Spastic ataxia syndrome
    - Onset: 3rd or 4th decade
    - Motor: Spastic paraplegia
    - Vibratory loss: Lower extremities
    - Ataxia: Truncal

Ataxia with Spasmodic Cough⁴⁵

Epidemiology: Portuguese families
Onset
- Age: 25 to 55 years; Mean 35 years
- Cough: Before ataxia by 5 to 38 years
Clinical
- Cough
  - Occurs in bursts: Minutes
  - Often no clear precipitating factor
  - Never during sleep
  - May be associated with sneezing
  - May be aborted by drinking cold water
  - Less prominent after onset of ataxia
- Ataxia
  - Onset: 40 to 65 years
  - Gait imbalance
  - Dysarthria
  - Course: Progressive but benign
- Ocular
  - Downbeat nystagmus
  - Diplopia
- Tendon reflexes: Often brisk
- Peripheral neuropathy: Present in few patients; Mild
MRI
- Cerebellar atrophy: With disease progression
- Normal branistem

Holmes ataxia

Pure ataxia syndrome
Very slowly progressive
Also see: Recessive ataxia

Cerebelloparenchymal degeneration (CPD I)

Clinical features
- Onset: Late; 5th or 6th decade
- Gait disorder
- Dysarthria
- Dementia
Pathology: Loss of Purkinje cells; Normal pontine nuclei

Cerebellar vermal aplasia

Non-progressive from birth
Truncal ataxia; Limb dysmetria; Nystagmus
Female predominance

Prion disease
l Prion protein

; Chromosome 20p13

Disease mechanism: Proteinase K resistant form PrP27-30 accumulates in CNS
Gerstmann-Straüssler-Schienker
- Mutations: Pro102Leu; Ala117Val
- Clinical features
  - Onset
    - Age: 3rd to 7th decades
    - Ataxia
  - Other: 2 to 10 years later
    - Long tract signs
    - Dementia
Creutzfeldt-Jakob
- Frequency in CJD: 10% to 20%
- Mutations: Glu200Lys & other missense; Extra octapeptide coding repeats
- Clinical features
  - Ataxia
  - Dementia: Subcortical
  - Rigidity
  - Polyneuropathy
    - Pathology: Demyelination & axonal loss
    - NCV: Mildly prolonged F-waves & slowed conduction velocities
Variant: Familial Fatal Insomnia

l Creutzfeldt-Jakob: Sporadic

Epidemiology
- Frequency in CJD: 80% to 90%
- Predisposing genotype: Homozygous Met129 in prion protein
- Atypical features: More frequent with
  - Sporadic with homozygous prion Val129
  - Familial CJD
Onset: Mean 6th decade; Range 16 to 82 years
CNS features
- Dementia
- Ataxia
- Visual loss
- Myoclonus
- EEG: Periodic sharp wave complexes (PSWC) in 62%
- Progression: Over months
- Other
  - Seizures
  - Deafness: Sensorineural
Polyneuropathy³⁸
- Clinical (20%)
  - Muscle atrophy: Distal or Diffuse
  - Spontaneous activity: Fasciculations
  - Tendon reflexes: Usually present
- Electrophysiology: Mild changes (86%)
  - Sensory: Distal axonal loss (80%)
  - Motor: Denervation
    - Distal muscles (50%)
    - Proximal denervation: Occasional
- Pathology: Motor neuron loss in ventral horn in some patients
Laboratory
- 14-3-3 assay: Positive in CSF in 93%
- CSF tau
Other acquired prion disease: Kuru
Differential diagnosis: Morvan

CAPOS syndrome

l Dominant vs. Mitochondrial Inheritance

Cerebellar ataxia
- Onset < 5 years: Episodic ataxia with fever
- Later fixed
Areflexia without polyneuropathy
Pes cavus
Optic atrophy
Sensorineural hearing loss

Vertical and Horizontal Nystagmus
l Autosomal; Not linked to Chromosome 19

Nystagmus:
- Similar to SCA6 & EA2
- Downbeating
- Gaze evoked; All directions
- Rebound
- Impaired: Vestibulo-Ocular reflex; OKN; Smooth pursuit
MRI: Mild cerebellar vermian atrophy

Multiple hamartoma syndrome (Cowden; Lhermitte-Duclos)

l Phosphatase & Tensin homolog (PTEN)

; Chromosome 10q23.31; Dominant

PTEN
- Regulates neuronal soma size & cell growth
- May inhibit cell migration
- Expressed in skin, thyroid & CNS
- Phosphoinositide phosphatase: Similar function to myotubularin
Epidemiology: Female predominance
Clinical
- Systemic
  - Hamartomas: Skin; Mucous membranes; Thyroid; Breast; GI
  - Face: Verrucous lesions; Trichilemmomas; Furrowed tongue
  - Endocrine: Thyroid; Gynecomastia
  - GU: Hydrocele; Varicocele
- Neurological
  - Progressive ataxia
  - Mental retardation
  - Increased intracranial pressure
  - Seizures
  - Megalencephaly
  - Cerebellar pathology: Gangliocytoma; Granule cell hypertrophy
- Associated neoplasms
  - Bannayan-Riley-Ruvalcaba
  - Dysplastic cerebellar gangliocytoma
  - Breast cancer
  - Merkel cell (Primary neuroendocrine) skin carcinoma
  - Renal cell adenocarcinoma
  - Juvenile polyposis syndrome
- Scoliosis
PTEN disruption in mouse Schwann cells: Tomaculous neuropathy ⁵⁷
Also see: Cowden-like syndromes : SDHB & SDHD mutations

Cerebellar ataxia, Deafness & Narcolepsy (ADCA-DN)

⁵⁶
l DNA methyltransferase 1 (DNMT1)

; Chromosome 19p13.2; Dominant

Epidemiology: Swedish, US & Italian families
Genetics
- Mutations: Exon 21; Missense; Ala570Val, Val606Phe
- Allelic with: HSN 1E
DNMT1 protein
Onset age
- Range: Childhood to 5th decade
- Usual: 4th decade
Clinical
- Early features
  - Cerebellar ataxia (100%)
  - Deafness: Sensorineural (100%)
  - Sleep disorders
    - Narcolepsy (80%)
    - Excessive daytime sleepiness
    - Cataplexy
    - REM sleep disorder
    - No sleep paralysis or hypnagogic hallucination
- Signs developing with disease progression
  - Eye: Optic atrophy
  - Cognitive: Psychiatric symptoms, Depression & Dementia
  - Upper motor neuron signs: Limbs & Bulbar
  - Sensory loss: Mild
  - Some patients: Diabetes; Leg lymphedema
- Death: 5th to 6th decade
Laboratory
- Muscle biopsy
  - Lipid: Increased
  - COX- muscle fibers: Occasional
  - Mitochondrial: Reduced ATP production; Normal oxidative enzyme activites
- MRI: Cerebellar & Cerebral atrophy
- CSF
  - Hypocretin-1: Low or Absent
  - Tau: High
- HLA-DQB1*06:02 negative

Von Hippel-Lindau Syndrome

l VHL protein

; Chromosome 3p25.3; Dominant

Cerebellar hemangioblastoma: May be sporadic
Other CNS
- Spinal cord hemangioma
- Subarachnoid hemorrhage
Pheochromocytoma
- Hypercalcemia
- Hypokalemia
- Hyperreninemic hyperaldosteronism
Other neoplasms: Liver; Renal Pancreas; Pulmonary; Retinal; Epididymal

Myelocerebellar Disorder

l Autosomal Dominant

Clinical
- Ataxia
  - Onset: Early childhood to Young adult
  - Gait disorder
  - Nystagmus
  - Dysmetria
- Long tract signs: Motor
  - Tendon reflexes: Increased
  - Babinski: Positive
- Sensory loss: Vibratory sensation Reduced in legs
- Course
  - Progressive ataxia
  - Death in childhood in some due to hematologic disorders
Laboratory
- Hematologic
  - Pancytopenia
  - Hypoplastic anemia
  - Acute myelomonocytic leukemia
  - Anemia: Childhood onset
  - Reduced Bone marrow mitotic activity
- Chromosomal
  - Monosomy 7 mosaicism
  - Sensitivity to bleomycin
- CT scan: Cerebellar atrophy
- Electrophysiology: Reduced nerve conduction velocities

Cerebellar ataxia with Mental retardation¹³
l Chromosome 19q13.31; Dominant

Epidemiology: 1 French family
Onset: Childhood 83%; No anticipation
Cerebellar
- Ataxia: Mild to Severe
- Nystagmus
Tendon reflexes: Increased
Mental retardation: Mild

Hereditary ataxia with thermoanalgesia & loss of fungiform papillae

Branchial myoclonus with Spastic paraparesis & Cerebellar ataxia

Familial essential tremor

l Dominant; Chromosome 3q13

Spinocerebellar ataxia with Rigidity & Peripheral neuropathy

l Dominant

Ataxia: Late onset
Extrapyramidal: Rigidity; Bradykinesia; Dysarthria
Spasticity
Muscle atrophy
Peripheral neuropathy: ? Demyelinating

Glucose transporter 1 deficiency syndrome

l SLC2A1

; Chromosome 1p34.2; Dominant or Sporadic

SLC2A1 protein
- Function: Glucose transporter across blood-brain barrier
- Location: Erythrocytes; Brain endothelial cells
Clinical
- Infantile seizures: Increased by fasting
- Delayed development
- Microcephaly: Acquired
- Ataxia: Some patients (R126H missense mutation)
Laboratory
- Blood glucose: Normal
- CSF glucose: Low
- CSF Lactate: Low-to-normal

Familial Dementia
l Integral membrane protein 2B (ITM2B)

; Chromosome 13q14.2; Dominant

Gene mutations: Point mutation; Duplication
ITM2B
- Membrane protein
- Expressed in brain & other tissues
Clinical disorders
- Dementia, familial British
  - Onset: 40 to 60 years
  - Dementia
  - Spasticity
  - Ataxia
- Dementia, familial Danish
  - Ataxia
  - Dementia
  - Hearing loss
  - Cataracts
Pathology
- Congophilic angiopathy: CNS & Systemic

Episodic Ataxias

EA 1 + Myokymia: KCNA 1; 12p13
EA 2, Paroxysmal: α_1A Ca⁺⁺ channel; 19p13
EA 3 + Vertigo & Tinnitus: 1q42
EA 4 (PATX)
EA5: CACNB4β4; 2q22
EA6 + Migraine & CNS: SLC1A3; 5p13
EA7: 19q13
EA + Choreoathetosis & Spasticity (CSE): 1p
PDHA1: Xp22

Differential diagnosis

Episodic ataxias: Differential diagnosis
Type	Onset age (yrs)	Attack duration	Symptoms	Interictal features	Triggers
EA1	< 20	Minutes	Muscle spasms	Seizures, Myokymia	Exertion; Posture Δ, Stress; Startle
EA2	< 20	Hours	Vertigo, Weakness	Ataxia, Nystagmus	Exertion; Stress; Alcohol
EA3	< 20	Minutes	Vertigo, Tinnitus, Headache	None	Kinesigenic
EA4	20-50	Hours	Vertigo, Diplopia	Nystagmus, Smooth pursuit Δ
EA5	20-60	Hours	Vertigo	Nystagmus, Ataxia
EA6	< 10	Hours	Cognitive impairment	Seizures, Ataxia	Fever
EA7	< 20	Hours	Vertigo, Weakness	None	Exertion; Excitement
CSE	2 to 15	20 minutes	Chorea; Ataxia; Headache	Spasticity	Alcohol, Fatigue, Stress, Exercise

EA 1: Episodic Ataxia / Myokymia Syndrome

l Potassium Voltage-Gated Channel (KCNA 1)

; Chromosome 12p13.32; Dominant

Genetics: Mutations
- Usual: Missense, Point
- One nonsense
- Allelic with
  - Hypomagnesemia, N255D mutation, Dominant
  - Variant syndromes
KCNA 1 protein
- Forms Kv1.1 channels in PNS & CNS
- Mutations cause altered neuronal excitability
Onset: Childhood to 2nd decade
Clinical features
- Phenotype may vary within families⁴⁰
- Episodes: Ataxia
  - Duration
    - Brief: Attacks last minutes
  - Provoked by
    - Abrupt postural change
    - Emotion
    - Vestibular stimulation
  - Ataxia
    - During attacks
    - No nystagmus
    - No fixed ataxia between episodes
  - Other symptoms
    - Dizziness without vertigo
    - Visual blurring
  - Choreoathetotic movements: May occur during attacks
  - Episodes occur in most but not all patients with KCNA1 mutations
- Neuromyotonia (Continuous spontaneous muscle fiber activity)
  - Severity: Mild to Constant & severe
  - Hand posture: Like carpopedal spasm
  - Course: Occcurs during & between episodes of ataxia
  - Constant neuromyotonia associated with
    - Increased tone
    - Muscle hypertrophy
    - Skeletal deformities
- Other associations
  - Seizures
  - Skeletal deformities: Associated with more severe neuromyotonia
    - Short stature
    - Kyphoscolosis
- Muscle
  - Variable fiber size
  - Type I predominance
  - PAS stain: Glycogen depletion
- Treatment: Phenytoin, Carbamazepine, Not Acetazolamide
Variant syndrome: Neuromyotonia & Stiffness
- Mutation: Phe249Leu
- Onset: Variable age with neuromyotonia
  - Acute in childhood: Neuromyotonia & Stiffness
  - Milder in adults: Limb stiffness
- Stiffness: Generalized or in Extremities; Episodic
- Hyperhidrosis: Some patients
Variant syndrome: Chronic neuromyotonia with disappearance of ataxia
- Mutation: L305F
Variant syndrome: Severe neuromyotonia & skeletal deformities
- No prominent Episodic Ataxia
- Mutation: Thr226Arg
Variant syndrome: Episodic Ataxia + Paroxysmal Dyspnea
- Mutation: In-frame three-nucleotide deletion: Predicts elimination of Phe at position 250
- Onset: Age 1 to 14 years
- Clinical
  - Attack frequency: Daily to Weekly
  - Triggers: Deep breathing; Stress/anxiety; Exercise; Caffeine
  - Attack features: Difficulty inhaling; Limb stiffening; Weakness; Slurred speech
  - Treatment: ?? Acetazolamide
Variant syndrome: Fixed ataxia
- Mutation
  - Val408Leu
  - Mutation effect: Increases ability of channel to inactivate
- Clinical
  - Cerebellar dysfunction: Persistent
  - Cognitive delay
  - Myokymia
  - Epilepsy
- CNS: Cerebellar atrophy
Variant syndrome: Hypomagnesemia
- Brazilian family
- Genetics: N255D mutation; Dominant
- Clinical
  - Muscle cramps
  - Tetanic episodes
  - Tremor
  - Weakness
- Plasma Mg⁺⁺ levels: 0.40 mmol/L (Normal = 0.70-0.95)

EA 2: Hereditary Paroxysmal Cerebellar Ataxia

l α_1A Calcium channel, voltage dependent (CACNA1A)

; Chromosome 19p13.2; Dominant

CACNA1A Genetics
- Most common: Point mutations or small deletions
  - Nonsense: Lead to disruption of the reading frame; R1281X; R1549X
  - Missense: C287Y; G293R; F1406C; F1493S; R1666H; E1761K
  - CAG repeat: 2 families
  - Large deletions: 3 families
- Mutation locations: Distributed throughout gene
- De novo mutations: 25%
- Allelic with
  - SCA6: Trinucleotide repeat mutations
  - Familial hemiplegic migraine
- Mutations with severe baseline ataxia: C287Y; G293R
CACNA1A protein (Ca_v2.1)
- Voltage dependent Calcium channel
- Mutant CACNA1A protein²²
  - Loss of function
  - Dominant negative effects: Some mutations
  - Association with more severe baseline ataxia
    - Deficienct plasma membrane targeting
    - Misfolded channel protein
Clinical features³²
- Onset: Early childhood to Teens; < 20 years
- Ataxia: Episodic
  - Triggers
    - Physical exertion
    - Emotional stress
    - Heat
  - Attack duration
    - Often last 1/2 to 6 hours
    - > 10 minutes
  - Nystagmus
  - Truncal instability
  - Dysarthria
  - Associated symptoms
    - Vertigo (50%)
    - Nausea
    - Vomiting
    - Headache
  - Generalized weakness (50%)
- Interictal cerebellar signs
  - Nystagmus
    - Downbeating
    - Gaze evoked; All directions
    - Rebound
    - Impaired: Vestibulo-Ocular reflex; OKN; Smooth pursuit
  - Ataxia: Static
    - Mild changes may persist between attacks
    - More severe ataxia between atacks with some mutations
    - Progressive: Over years
- Motor: Myasthenic weakness¹⁹
  - Distribution: Generalized
  - Fatigue
  - Weakness may occur during spells
  - Weakness may precede onset of episodic ataxia
- Other features
  - Dystonia: Neck or Arms; May accompany episodes
  - Seizures
  - Hemiplegic episodes: 10%
- Treatment
  - Acetazolamide: 75%
  - 4-aminopyridine (5 mg tid): K⁺ channel blockade³⁶
  - ? Pyridostigmine
Neuromuscular junction³¹
- Single fiber EMG: Presynaptic failure
  - Jitter & Blocking: Improve with increased stimulation frequency
- Microelectrode studies
  - End plate potential: Reduced; Sensitive to N-type blockade with ω-conotoxin
  - Quantal content: Reduced
- Ultrastructural studies
  - Nerve terminals: Small
  - Postsynaptic membranes: Normal or mildly overdeveloped
- NCV & EMG: Often normal
Brain MRI: Cerebellar atrophy

Episodic ataxia 3

: With vertigo & tinnitus
l Chromosome 1q42; Dominant

Epidemiology: Canadian Mennonite family
Clinical
- Onset age: 1 to 42 years
- Myokymia: Interictal; 50%
- Attacks
  - Duration: 1 minute to 6 hours
  - Provocation: Kinesigenic
  - Ataxia, Vestibular
  - Vertigo: Illusion of rotation of environment
  - Tinnitus
  - Headache
  - Eye: Visual blurring; Diplopia
Treatment: Acetazolamide

Episodic ataxia 4 (EA4; PATX)

l Dominant

Epidemiology: North Carolina families
Onset: 3rd to 6th decade
Clinical
- Episodes: Vertigo; Diplopia; Ataxia
- Ataxia: Slowly progressive
- Ocular: Defective slow pursuit
- No myokymia
- No response to acetazolamide

Episodic ataxia 5 (EA5)

l CACNB4β4

; Chromosome 2q23.3; Dominant

CACNB4β4 protein
Clinical syndromes
- Ataxia
  - Genetics
    - Mutation: C104F
    - Incomplete penetrance
  - Epidemiology
    - French-Canadian family
    - Onset: 3rd or 4th decade
  - Clinical: Similar to EA2
    - Episodic ataxia
      - Attack duration: Hours; Ocasionally weeks
      - Treatment: Acetazolamide
    - Interictal Ataxia
      - Imbalance of gait
      - Truncal
      - Dysarthria: Mild
    - Nystagmus
      - Interictal
      - Downbeat: Spontaneous
      - Gaze-evoked
- Seizures
  - Mutation: C104F
  - German family
  - Generalized epilepsy
  - Praxis-induced seizures
- Juvenile myoclonic epilepsy
  - Mutation: Arg482X
  - Clinical
    - Bilateral myoclonic jerks of shoulders & arms: No loss of consciousness
    - Sporadic absence seizures
    - Generalized tonic-clonic seizures
Mouse disease
- Autosomal recessive
- lethargic
- Ataxia, severe
- Motor abnormalities, focal
- Periods of behavioral immobility
  - Accompanied by bilaterally synchronous, generalized cortical spike-wave discharges
- Physiology: Reduced excitatory synaptic transmission in somatosensory thalamic neurons

EA6: Episodic ataxia + Seizures, Migraine & Alternating hemiplegia

⁴²
l SLC1A3 (EAAT1 protein)

; Chromosome 5p13.2; Dominant

Epidemiology: Sporadic patient
Genetics: Missense; 1047C to G; Pro to Arg
EAAT1 protein
- Glial glutamate transporter ( GLAST)
- Expressed primarily in caudal brainstem & cerebellum
- Mutation
  - Reduced capacity for glutamate uptake
  - Dominant negative effect when polymerized with other EAAT1
Clinical
- Onset
  - Age: Early childhood
  - Episodic hypotonia
- Motor: Delayed milestones
- Ataxia
  - Episodes: Onset 6 months
  - Trigger: Febrile illness
  - Duration: 2 to 4 days
  - Between episodes: Mild truncal ataxia
- Migraine
- Episodic CNS
  - Hemiplegia: Alternating
  - Visual field loss: Hemianopia
  - Seizures
  - Coma
- EOM: Symmetric impairment of
  - Smooth pursuit
  - Optokinetic nystagmus
  - Fixation-suppression of VOR
- Other features between episodes
  - Mental retardation: Mild
  - Tendon reflexes: Increased
MRI
- Cerebellar atrophy, mild
- FLAIR hyperintensity during episodes
EEG: Seizures

Episodic ataxia 7 (EA7)

l Chromosome 19q13; Dominant

Epidemiology: 1 American family
Onset: < 20 years
Ataxic episodes
- Ataxia: Gait disorder; Dysarthria
- Weakness
- Triggers: Exercise; Excitement
- Vertigo: Some patients
- Duration: Hours to days
- Frequency
  - Monthly to every few years
  - Decreases with age
Interictal: No findings

Episodic ataxia with paroxysmal choreoathetosis & spasticity (Dystonia-9; DYT9; CSE)

l Chromosome 1p; Dominant

Epidemiology: German family
Clinical features
- Onset: 2 to 15 years
- Episodes
  - Ataxia
  - Involuntary movements & dystonia of extremities
  - Paresthesias: Perioral & legs
  - Headache
  - Duration: 20 minutes
  - Frequency: 2x per day to 2x per year
  - Precipitating factors: Alcohol, Fatigue, Emotional stress, Physical exercise
- Spastic paraplegia: Persistent between episodes in some
- Treatment: Acetazolamide
Laboratory
- EEG: Slowing

Return to Neuromuscular Syndromes
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Return to Neuromuscular Home Page

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