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: ZFHX3; GGC repeat; 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; 19q13.33
14: PRKCG; 19q13.42
15, 16, 29: ITPR1; 3p26
17: TBP; CAG repeat; 6q27
18: 7q31
19: KCND3; 1p13
20: 11q12, Duplication
21: TMEM240; 1p36
22: KCND3; 1p13
23: PDYN; 20p13
25: PNPT1; 2p16
26: EEF2; 19p13
27: FGF14; 13q33
28: AFG3L2; 18p11
30: 4q34
31: TGGAA repeat; 16q22
32: 7q32
34: ELOVL4; 6q14
35: TGM6; 20p13
36: NOP56; 20p13
37: DAB1; 1p32
38: ELOVL5; 6p12
39: 11q21
40: CCDC88C; 14q32
41: TRPC3; 4q27
42: CACNA1G; 17q21
43: MME; 3q25
44: GRM1; 6q24
45: FAT2; 5q32
46: PLD3; 19q13
47: PUM1; 1p35
48: STUB1; 16p13
49: SAM9DL; 7q21
50: NPTX1; 17q25
51: THAP11: 16q22
SLC1A3; 5p13

SCA: Differential features

Dominant ataxia syndromes, Other
Ataxia + Epilepsy: KCNA2; 1p13
CANPMR: CAMTA1; 1p36
CAPOS: ATP1A3; 19q13
Cerebral Palsy
CIAT: SCN8A
Congenital ataxia
Cough, Spasmodic
Deafness & Narcolepsy: DNMT1; 19p13
DRPLA: ATN1; CAG repeat; 12p13
DYT28: KMT2B; 19q13
Familial dementia: ITM2B; 13q14
Gillespie: PAX6; 11p13
HADDS: EBF3; 10q26
HADDTS: CTBP1; 4p16
Hemiplegia, alternating: 1; 2
Holmes ataxia
Huntington 2: JPH3; CAG/CTG repeat; 16q23
Leukodystrophy
Adult-onset: Lamin B1; 5q23
H-ABC (HLD6): TUBB4A; 19p13
Multiple hamartoma syndrome: PTEN; 10q23
Myasthenia + CNS: SNAP25b; 20p12
Myelocerebellar: SAMD9L; 7q21
Myoclonic epilepsy
KCNA2; 1p13
MEAK: KCNC1; 11p15
Myoclonus
Cortical: NOL3; 16q22
Branchial & Spasticity: GFAP; 17q21
Episodic ataxia + Epilepsy: SCN2A; 2q24
Neurodevelopmental
Ataxia+: CAPRIN1; 11p13
NEDLAS: GRIK2; 6q16
Neuronal intranuclear inclusion disease
Nystagmus
Parenchymal degeneration
Peripheral Neuropathy
CMT 1F: NFL
Rigidity
Saccades slow + Orthostatism
SANDO: POLG1; 15q25
Sensory ataxia: 16q22
Sensory-Motor: IFRD1; 7q22
Thermoanalgesia & Fungiform papillae loss
Prion disease: Prion protein; 20p12
Seizures
GLUT1DS2: SLC2A1; 1p35
MRD55: NUS1; 6q22
SMEI (Dravet; EIEE6): SCN1A; 2q24
SPAR
Spastic ataxia syndromes
Tremor, Essential: 3q13
TUBA4A
Vanishing white matter
Vermal aplasia
Von Hippel-Lindau: VHL protein; 3p26

Episodic ataxias (EA): Usually Dominant
EA1 + Myokymia: KCNA 1; 12p13
EA2, Paroxysmal: α_1A Ca⁺⁺ channel; 19p13
EA3 + Vertigo & Tinnitus: 1q42
EA4 (PATX)
EA5: CACNB4β4; 2q22
EA6 + Migraine & CNS: SLC1A3; 5p13
EA7: 19q13
EA8: ? UBR4; 1p36
EA9: FGF14; 13q33
EA: SCN8A; 12q13
CAPOS: ATP1A3; 19q13
Other
+ Choreoathetosis & Spasticity: SLC2A1; 1p34
+ Epilepsy & Myoclonus: SCN2A; 2q24
+ Optic atrophy & Hearing loss: ATP1A3; 19q13
INNFD: NALCN; 13q23
+ Seizures & Dyskinesias: PRRT2; 16p11
+ Movements & Spasticity: SLC2A1; 1p34
Recessive
LBSL: DARS2; 1125
Joubert 5: CEP290; 12q21
PDHA1: Xp22
Differential diagnosis

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

Cajal

Dominant Spinocerebellar Ataxia (SCA): General ³⁵

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
  - ATTTC insertion (Non-coding): SCA37
- 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
  - SCA19 & SCA22: KCND3/Kv4.3
  - 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 ⁶⁴

Age
Polyneuropathy
Syndromes
Other

Dominant SCA syndromes have
- Many overlapping signs: Difficult to distinguish on clinical grounds
Common features to most
- Gait ataxia
- Dysarthria
- Eyes: Saccadic pursuit
Features in some ataxias
Features with some predictive value for specific gene defects
- SCA: Clinical syndromes
  - SCA1: Saccades hypermetric; Spasticity; Executive dysfunction; Evoked motor potentials with Long conduction times; OPCA
  - SCA2: Saccadic velocity slow; Parkinsonism; Myoclonus; Action tremor; Pons atrophy (OPCA); Cuba; No gaze evoked mystagmus
  - SCA3/Machado-Joseph: Saccadic dysmetria, intrusions & oscillations; Ophthalmoparesis; Gaze-evoked nystagmus; Spasticity; Polyneuropathy; Brazil & Portugal
  - SCA4: Sensory loss; Later onset > 40
  - SCA5: Pure cerebellar syndrome; Bulbar signs; Early onset; Slow progression
  - SCA6: Pure cerebellar syndrome; Saccadic dysmetria; No family history; Late onset > 50; Nystagmus - Gaze evoked, Downbeat & Perverted head-shaking
  - SCA7: Pigmentary retinopathy; Hearing loss; Onset in 1st decade
  - SCA8: Cerebellar; Cognitive & Psychiatric; Spasticity; Sensory neuropathy, Mild
  - 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
  - SCA16: 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: Cognitive disorders; Extrapyramidal features
  - SCA22: Pure cerebellar syndrome; Slow progression; Hyporeflexia
  - SCA23: Ataxia; Sensory loss; Pyramidal signs
  - SCA25: Sensory neuropathy; Cerebellar atrophy, Severe
  - SCA26: Pure cerebellar syndrome
  - SCA27: Tremor; Dyskinesia; Psychiatric episodes
  - SCA28: Ophthalmoplegia; Hyperreflexia
  - SCA30: Pure cerebellar syndrome; Late onset
  - SCA31: Pure cerebellar syndrome; Japanese
  - SCA32: Cognitive deficits; Azoospermia
  - SCA34: Erythrokeratoderma
  - SCA35: Upper motor neuron signs; torticollis
  - SCA36: Fasciculations & Muscle wasting (Motor neuron); Late onset
  - SCA37: Vertical eye movements abnormal; Late onset
  - SCA38: Ataxia ± Neuropathy
  - SCA39: Spastic Ataxia
  - SCA40: Spastic Ataxia
  - SCA41: Ataxia
  - SCA42: Ataxia ± Spasticity & Myokymia
  - SCA43: Ataxia + Polyneuropathy
  - SCA44: Ataxia
  - SCA45: Ataxia
  - SCA46: Sensory ataxia
  - 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, Urinary dysfunction
- SCA4: Sensory loss
- SCA6: Sensory, Mild
- SCA7: 0%
- SCA8: Sensory, Mild
- SCA12: Subclinical; 80%
- SCA14: Vibratory loss
- SCA18: Motor-Sensory
- SCA25: Sensory
- SCA27: Sensory, Mild, Axonal
- SCA38: Sensory ± Motor
- SCA43: Sensory > Motor
- 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: IFRD1; 7q22
  - Saccades slow + Orthostatism
  - SANDO: POLG1; 15q25
  - Sensory ataxia: 16q22
  - Thermoanalgesia & Fungiform papillae loss
  - Prion disease

Other typical clinical features ¹⁶

Age at onset
- Young adult: SCA 1, 2, 3, 21
- Older adult: SCA 6, 35, 36; 37
- Childhood: SCA 2, 7, 13, 27, DRPLA, 25
Anticipation
- Some SCA: 1, 2, 3, 6, 7, 8, 10, 12, 17, 22, DRPLA
- More prominent in SCA 7 & DRPLA
Ataxia
- Truncal: SCA 1; 2; 6; 14; 28; 31; 36
Tremor
- Head or Hand: SCA 8, 12, 15-16, 19, 27
- Palatal: SCA 20
Normal lifespan: SCA 6, 11

Eye ⁶⁰
- Slow saccades
  - Early/prominent: SCA 2, 7
  - Late: SCA 1, 3, 28
  - Very rarely: SCA 6
- Nystagmus
  - Downbeat: SCA 6; EA 2
  - Head-shaking: SCA 6
  - Gaze evoked: SCA 1, 3, 6; Not 2
- Vertical eye movements abnormal: SCA 6; 26; 30; 37
- Maculopathy (Visual loss): SCA 7
- Pseudoexophthalmos: SCA 1, 2, 3
- Ptosis: SCA 7, 28
- Oculomotor apraxia: Saccades slow + Orthostatism; Recessive
Motor
- Motor neuron & Fasciculations: SCA 3, 36
- Cramps: 2,3
UMN signs
- Common: SCA 1, 3, 7, 9, 12, 35
- Some: SCA 6, 8
- Rarely: SCA 2
- Spastic ataxias

Extrapyramidal
- Akinesia/rigidity/dystonia: SCA 3, 9, 17, 21; 12 (Akinesia)
- Chorea Early/prominent: DRPLA, 17, 27; Rarely SCA 2
- Dyskinesia: SCA 27
- Myoclonus
  - Common: SCA 2, 14
  - Occasional: SCA 1, 3, 6, 7, 19
- Dysphonia: SCA 20
- Torticollis: SCA 35
Cortical
- Mental retardation: SCA 13, 21; 27
- Cognitive defects: SCA 1, 2, 3, 12, 13, 19, 21
- Seizures
  - Adult: SCA 10
  - Childhood onset: DRPLA, SCA 7
- Dementia
  - Common: DRPLA; SCA 17
  - Early onset patients: SCA 2, 7
  - Oldest patients: SCA 12
Pontine involvement: SCA 1, 2, 3

SCA SYNDROMES: DIAGNOSTIC TESTING ³⁵
Clinical sign	1° Testing	2° Testing
Cerebellar ataxia, Pure	6, 5	11, 14, 15, 16, 22
Spasticity	3	1, 7
Peripheral neuropathy	3, 4, 18, 25	1
Cortical disorders
Dementia	17, DRPLA	2, 13, 19, 21
Psychosis	DRPLA, 17	3, 27 (Episodic)
Epilepsy	10, DRPLA	17
Movement disorders
Chorea	DRPLA, 17	1 (Late stage)
Myoclonus	DRPLA	2, 19
Tremor	2, 8, 12	15, 21, 27
Parkinsonism	3, 9, 12, 17	2, 21
Dystonia	3	17
Ocular disorders
Ophthalmoplegia	3, 2, 1, 9
Nystagmus	1, 3, 6
Slow saccades	2	1, 3, 7, 17
Pigmentary retinopathy	7

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
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)
● 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 34 repeats
  - Intermediate: 35 to 40 repeats
  - Disease
    - General: 41 to 83 repeats
    - Complete penetrance: > 45 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
  - Sporadic ALS ⁸⁵
    - 3x increased frequency of ≥ 32 repeats (7%)
    - More TDP-43 mislocalization from nucleus to cytoplasm
- Homozygotes: Disease severity corresponds to size of larger allele
- Anticipation
  - ~ 10 years/Generation
  - Paternal > Maternal
Ataxin-1 protein
- Functions
  - Transcription
  - RNA metabolism
- 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
- Interactions
  - ATXN1L (BOAT): Transcription; Corepressor
  - CIC: Transcriptional repressor
  - HDAC3: Histone deacetylation, epigenetic repressor
  - LANP: Inhibitor of histone acetyltransferases
  - PQBP-1: Transcription; Splicing
  - RBM17: Splicing
  - RORa/TIP60: Transcriptional activation
  - SMRT/NCOR2: Transcriptional corepressor
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
- Polyneuropathy ⁴⁶
  - 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

(ADCA I) ¹
● Ataxin-2 (ATXN2)

; Chromosome 12q24.12; Dominant

Epidemiology
- Frequency
  - Common (13% to 18%)
  - 2nd most common polyglutamine disorder after SCA3
- Common in: US, Spain, India, Mexico, South Africa, Italy, Cuba
- Uncommon in: Brazil, Finland, Japan
Genetic features ⁵⁰
- 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 ⁶⁸ or ALS, Dominant (ALS 13 )
      - Associated with 27-39 repeats: Most often interrupted; 7x increased frequency (2.7%)
      - Found in
        
        Sporadic ALS (1.1% to 3%) > Controls
        
        Unexplained hereditary ALS (2.2%)
        
        Pathogenic C9orf72 expansion: Clinical with both FTD & ALS
      - PolyQ repeats ≥ 31
        
        Frequency in
        
        sALS: 0.6% to 1.8%
        ALS-FTD: 7%
        Control: 0.4%
        
        Risk factor (Odds ratio)
        
        ALS: 6.3
        
        ALS-FTD: 27.6
        
        FTD: 3.1
        
        Possible ALS associations ⁹³
        
        Survival: 1 year shorter
        Spinal onset
        Cognitive functions: More severe disorder
        
        No correlation: ALS onset age
      - 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
- 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
  - Other genes
    - ATXN7 > 12 CAG repeats: Earlier disease onset
- Allelic disorders
  - Spinocerebellar ataxia 2
  - Amyotrophic lateral sclerosis, susceptibility to, 13, Dominant
  - Parkinson disease, late-onset, susceptibility to, Dominant
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
- Functions: RNA metabolism; Translation
- Contains: Prion-like domain (PrLD)
- Interactions
  - PABP-1: mRNA splicing & Stability
  - A2BP1/Fox1: Splicing
  - DDX6: RNA degradation
  - TDP-43: RNA processing; Transcription
- Subcellular localization
  - Golgi apparatus
  - Ataxin-2 with expanded glutamine repeat ²⁸
    - Disrupts (disperses) Golgi apparatus
    - Induces cell death without nuclear aggregates
- Mouse knockout: Hyperphagia; Obesity
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 71; 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
- Polyneuropathy/Sensory neuronopathy ⁴⁶
  - Age: 18 to 62 years
  - Frequency: 80%; Increases with age
  - Legs > Arms
  - Sensory loss: Vibratory sense reduced
  - Tendon reflexes: Reduced
  - Autonomic: Variable
    - Course: Early or late in disease course; ? More with disease progression
    - Systems: GU; GI; Cardiac; Orthostatic
  - Laboratory
    - Ultrasound: Nerves often small
    - NCV
      - Sensory ganglionopathy: SNAP amplitues reduced before ataxia
      - Axon loss: Often non-length dependent
      - Severity correlates with disability
    - Nerve pathology: Axon loss
- Motor
  - Fasciculations & Amyotrophy (20%)
  - Upper motor neuron: Upgoing toes (20%)
  - Proximal leg weakness (20%)
  - Dysphagia (49%)
  - Rapidly progressive motor neuron disease: 3 patients ⁵¹
  - Muscle cramps
- Ocular
  - Slow saccades: 100%
    - Maximal velocity: Slower with longer glutamine repeat sequences
  - Gaze paresis 50%
  - Ophthalmoparesis (40%)
  - Supranuclear paresis
  - Patterns suggest pontine pathology
  - No gaze-evoked nystagmus or dysmetric saccades
- 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
Laboratory
- 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)
● 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
Genetics
- ATXN3 mutations: CAG trinucleotide repeat
  - Normal range: 12 to 40
  - Disease: 51 to 87
- Clinical-Genetic correlations
  - 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
  - Anticipation
    - Paternal > Maternal
    - Successive generations: Repeats tend to enlarge, but may contract
  - Homozygotes
  - Other genes
    - Earlier onset with more CAG repeats in: ATXN2 (27-29), ATN1 (Longer allele), Huntingtin (HTT) (Shorter allele)
    - Modifier gene: Parkin V380L mutation ¹⁰⁴
Protein ¹⁰⁵
- Cell locations
  - Cytoplasmic: In neuronal soma & processes
  - Nucleus
- Functions
  - Deubiquitinase (DUB): Ubiquitin hydrolase
  - Transcriptional regulator: Chromatin organization
  - DNA repair mechanisms: Maintain genomic stability
  - Proteostasis: UPS, ERAD, Autophagy, Fibrillar aggregates formation
- Interactions
  - p97: Proteasome shuttle protein
  - CBP/PCAF/P300: Histone acetylation
  - HDAC3/NCOR: Histone deacetylation
  - FOXO4: Transcriptional activation
  - TBP: Basal transcription
  - PML: Nuclear bodies
  - BECN1
- Nuclear inclusions: Only in disease (50%)
- Pathological ataxin-3
  - Conformationally altered ataxin-3 bound to nuclear matrix
  - Exposed polyglutamine domain
Clinical syndromes
- 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
    - Saccadic intrusions & oscillations
    - Normal saccade velocity
- 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
      - NCV ⁴⁶
        
        Axonal neuropathy (70%)
        
        Distal predominant
        Symmetric
        
        CMAP & SNAP amplitudes: Small
        
        Distal latencies: Prolonged
        
        Neuronopathy (30%): Motor or Sensory
      - Nerve pathology ²⁵
        
        Axon loss: Distal; Especially large myelinated axons
        
        Regeneration
        
        Degeneration: Some patients
        Myelin sheath: Thin
        Schwann cells: Cytoplasmic ataxin-3 aggregates
    - Diplopia
    - Stiffperson-like syndrome: Occasional patient
    - Few dystonic features
    - Muscle
      - Coexisitng IBM: 4 patients described with onset in 6th or 7th decade ⁹⁶
      - Autophagic vacuolar myopathy: 1 patient ⁹⁷
  - 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
- Ataxin-3 mutation homozygotes
  - Features vs Heterozygotes ⁸⁴
    - Earlier onset age: 20 to 59 years; Mean 16 years younger
    - More severe disease
    - Larger repeat sequences: More severe disease
  - Clinical
    - Ataxia: Gait; Speech
    - Nystagmus
    - Polyneuropathy
MRI
- Cerebellar atrophy: Correlates with disease severity
- 4th ventricle: Enlarged
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
  - Ataxin-3 aggregates: Neuronal nuclei & cytoplasm; Axons of affected fibre tracts
  - 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)

● ZFHX3

; Chromosome 16q22.2-q22.3; Dominant

Clinical: Sensory ataxic neuropathy

SCA 5

(ADCA III) ³³
● 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
- Frequency: Rare
Genetics ⁴⁴
- Mutations: Inframe deletions; Missense (Leu253Pro; Arg480Trp)
- Inheritance: Dominant or de novo mutations
- Allelic disorders
  - Infantile SCA + Psychomotor delay, Recessive (SCAR14)
  - Ataxic Cerebral palsy, de novo Dominant
SPTBN2 Protein
- Normal
  - Highly expressed in Purkinje cells
  - Associated with Golgi & vesicles
  - Binds to dynactin subunit ARP1
  - Excitatory glutamate signaling: Stabilizes glutamate transporter EAAT4 at membrane�s surface
  - Spectrins: Structural components of plasma membrane skeleton
- Mutant: Loses ability to stabilize GluRδ2 & glutamate transporter EAAT4 at plasma membrane
- Spectin & Spectrin disorders
Clinical
- Onset age
  - Range: Congenital to 50 years
  - Mean 33 years
  - Anticipation: Probable
  - Infantile onset: 2 patients (Arg480Trp)
- 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
Variant syndrome Ataxic Cerebral Palsy
- Epidemiology: 1 patient
- SPTBN2 genetics
  - Mutation: R480W
  - Inheritance: de novo; Dominant
  - Associated with: Increased paternal age
- Clinical
  - Onset age: Early childhood
  - Ataxia
  - Intellectual disability
  - Course: Stable
- Brain imaging: Cerebellar hypoplasia

SCA 6

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

; Chromosome 19p13.2; Dominant

Epidemiology
- Frequency: 10% to 30% of dominant cerebellar ataxias
- Common in: Germany, Taiwan, Australia, US & Japan (Northern), Netherlands
- Uncommon in: Spain, Italy, India, Mexico, Finland
Genetics
- Family history: Dominant 73%; Sporadic 27%
- SCA6 mutations: CAG trinucleotide repeats
  - Number of CAG repeat ranges
    - Normal: 4 to 18 or 20
    - SCA6 disease
      - 20 to 33 repeats
      - # of repeats is smallest # producing SCA syndrome
  - Intergenerational stability in number of repeats
    - ? Factors other than repeat size cause anticipation
- Clinical-Genetic correlations
  - CACNA1A CAG repeats: Age of onset
    - Earlier (~ 30 years)
      - More CACNA1A CAG repeats (25 to 27)
      - Homozygosity or Compound heterozygosity (Some patients)
    - Later (~ 40 to 50 years) with fewer repeats (21 to 24)
    - Some intrafamilial variation
  - Homozygotes or Compound heterozygotes ⁷⁶
    - Disease onset: Earlier; 45 to 68 years
    - Disease progression: More rapid; Gait aids needed < 10 years from onset
  - Normal allele: Earlier age onset with longer size repeats
  - Other genes
    - Earlier disease onset with more CAG repeats in: ATXN1 (Larger difference between alleles); ATXN3 (≥ 25 repeats)
- Allelic disorders
- Mouse defect
  - Tottering & leaner
  - Seizures & cerebellar ataxia
CACNA1A protein
- P/Q type calcium channel subunit
- Interacts with
  - Synaptotagmin
  - AT-rich & CA-rich DNA elements
- 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
  
  SCA 6: Cerebellar atrophy on MRI
  - Nystagmus
    - Downbeating
    - Gaze evoked; All directions
    - Rebound
    - Perverted head-shaking
  - Impaired
    - Vestibulo-Ocular reflex
    - Optokinetic nystagmus (OKN)
    - Smooth pursuit: Saccadic
  - 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
  - NCV normal in 79% ⁸⁷
- 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: GeneReviews
Variant syndrome: Hemiplegic migraine ²⁰
- Genetics
  - Different mutation types from SCA6
  - 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 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)
● 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
  - ATXN7
    - 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
  - Other genes
    - Earlier disease onset with more CAG repeats in: ATXN3 (Shorter allele), TBP (Shorter allele)
Protein: Ataxin-7
- Nuclear localization: Matrix, Nucleolar & Diffuse
- 130 to 140 kD protein
- Functions
  - SAGA component
  - Co-activator of RNAPII-driven transcription
- Interactions
  - GCN5: Histone acetylation
  - USP22: Histone deubiquitinase
  - CRX: Transcriptional activation
  - RORa: Transcriptional activation
  - SIRT1: Deacetylase
  - TBP: Basal transcription
- 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
- General: Spastic ataxia +
- Onset
  - Age
    - Range: 1 month to 77 years; Average ~ 20 years; Median 3rd or 4th decade
    - 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 syndrome ²¹
  - 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
● ATXN8OS (SCA8)

; Chromosome 13q21.33; Dominant (Usually)
● ATXN8

; Chromosome 13q21; Dominant (Usually)

Epidemiology
- Ataxia worldwide: 3% to 4%
- Common: Finland
- Uncommon: India, Mexico & Japan

Genetics

General
- SCA8 associated with enlarged CTG repeat
- Involves CTA/CTG repeat expansion in 2 overlapping genes
Overall CTA/CTG repeat lengths: Tetramodal
- 15 to 21 (19%)
- 22 to 37 repeats (80%): 24 CTG most common
- 40 to 91 repeats: 0.7%
- > 91 repeats
Normal CTA/CTG repeat
- 15 to 50 combined (CTA�TAG)_n(CTG�CAG)_n repeats
  - Short polymorphic CTA repeat (1�21 CTAs) precedes major CTG repeat
- Spanned by 2 genes expressed in opposite directions
  - Ataxin 8 opposite strand (ATXN8OS) : CTG direction
    - Produces noncoding CUG expansion RNA
    - Repeat location: 3' untranslated region
  - Ataxin 8 (ATXN8) : CAG direction
    - Encodes: Polyglutamine expansion protein, Nearly pure
    - Present in intranuclear inclusions
    - Repeat location: Open reading frame
Enlarged CTA/CTG repeat
- Similar to CTG mutation in myotonic dystrophy
- CTG repeat: Gene location
  - 3' Untranslated region of transcribed RNA
- Transcript location: Brain & Lung (low levels)
- CTA/CTG repeat length
  - SCA 8 patients
    - Usually 100 to 155 CTA/CTG repeats
    - Range 52 to 1,455
  - SCA 8 families: Asymptomatic expansion carriers
    - Range 50 to 1,000 repeats
  - Psychiatric patients: 1.5%
  - Normals: 0.7%
  - Very large CTA/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: Maternal anticipation more prominent
  - Prominent instability
  - Paternal: Repeat length expansion or contraction (-86 to +16)
  - Maternal: Repeat length expansion more common (-11 to +900)
- Other disease expansions in transcribed but untranslated DNA
  - DM1 (CTG)
  - DM2/PROMM (CCTG)
  - SCA10 (ATTCT)
Enlarged CTA/CTG repeat: Clinical correlations
- Not specific for SCA8: Enlarged repeat occurs in
  - Normal SCA8 family members
  - Normal populations
  - Disease control populations
    - Parkinson
    - Alzheimer
    - SCA6
    - SCA1
- 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
  - CTG repeat expansion correlations
    - Penetrance
      - Incomplete: At all repeat sizes
      - Increased
        
        Longer CTG�CAG expansion sequences
        
        CCG�CGG interruptions in expansion ⁸⁹
        Homozygosity
    - Onset age or Progression rate
      - Expansion length: No correlation
      - More interruptions: Younger onset age

SCA8: Clinical features ¹⁵

General phenotype
- Uniform in families
- Variable in sporadic cases with expanded CTG repeats
- Family history
  - Single occurrence common
    - Frequency: Up to 82%
    - Due to: Reduced penetrance
  - When FH positive
    - Dominant or Recessive patterns
Onset
- Mean: 33 to 50 years
- Range: Congenital to 79 years or Never
- Incomplete penetrance
Cerebellar signs
- Dysarthria (100%)
  - Scanning
  - Speech slowness
  - May be earliest feature
- Eye movement disorders
  - Impaired smooth pursuit (100%)
  - Horizontal nystagmus (67%)
- Ataxia (100%): Gait; Trunk & Limbs, Legs > Arms
- Truncal titubation: With disease progression
- Tremor
Sensory neuropathy
- Vibratory sense: Reduced in 25%
- Electrophysiology: Small SNAPs
Upper motor neuron: 50%
- Spastic dysarthria
- Reflexes: Tendon increased; Extensor plantar
- Sphincter dysfunction 30%
- More in: Severely affected individuals
Cognitive
- Neuropsychiatric 70%: Phobic; Anxiety; Personality Δ
- Executive function: Often abnormal
- Mood lability: Depression
- Memory disorders: Especially non-verbal
Occasional features
- Ophthalmoplegia
- Extrapyramidal: Parkinsonism; Multisystem atrophy
- Childhood onset: Severe
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

SCA 8: Laboratory

MRI: Cerebellar vermis & hemisphere atrophy
Pathology
- Cerebellar Purkinje cells
  - Loss with fibrillary accumulations
  - Somatic sprouts
  - Intracytoplasmic 1C2-positive granular structures
- Other
  - Inferior olivary & Nigral neuron loss
  - Periaqueductal gliosis

Variant: Congenital onset SCA8 patient

Cerebellar signs: Severe in first year
Motor delay: Walked (with aid) at 5 years
Myoclonic epilepsy at 3 years
Mental retardation

SCA8: Cerebellar Atrophy

SCA 9

(ADCA I)
● 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
● Ataxin 10 (ATXN10; SCA 10 gene; E46L)

; Chromosome 22q13.31; Dominant

Epidemiology
- Geographic distribution: Americas, Europe, Asia
- May have shared distant ancestor: All with similar haplotype
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
  - Instability
    - Unstable repeat length may expand or contract
    - Greater for paternal than maternal transmission
    - Occurs in stretches of pure ATTCT motifs, not those with interruptions
    - Interruptions
      - Occur in some pastients
      - Locally stabilize expansion at 5' end
      - May correlate with epileptic seizure phenotype
  - Anticipation: Clinical
    - May relate to 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
Clinical: Cerebellar ± Seizures
- Onset
  - Age: 10 to 40 years
  - Anticipation
    - Marked: Up to 20 years
    - Especially with: Paternal inheritance
  - 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 11 (ADCA III)

¹¹
● 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; Up to 4th decade
- Cerebellar
  - Ataxia course: Slowly progressive
  - Gait disorder: 100%
  - Ocular: Saccadic pursuit; Nystagmus (Horizontal > Vertical) (40% to 100%)
  - Dysarthria (80% to 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 12

¹²
● Protein phosphatase 2, regulatory subunit B, β (PPP2R2B)

; Chromosome 5q32; Dominant

Epidemiology
- German family
- Common in India (Agarwal families): 7% of ADCA
Genetics
- CAG repeat in 5' untranslated region of gene: ? Upstream of transcription start site
- Normal repeat size: 4 to 32
- Expanded CAG repeat size: 40 to 78
- Expanded CAG Repeat sequence properties
  - Common: Uninterrupted
  - Single nucleotide interruptions in CAG/CTG repeat: Uyghur ethnicity; Milder disease
- Minor instability in repeat size over generations: -1 to +2
- Transcription of repeat: Bidirectional; Antisense has CUG repeat
- No definite correlation between repeat size & clinical features
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
Clinical: Variable phenotype
- Onset
  - Age: 8 to 55 years; Mean in 5th decade
  - Signs: Arm tremor, or Gait ataxia & Dysarthria
- Cerebellar (100%)
  - Tremor: Arm & Head; R ≥ L; Voice
  - Ataxia: Gait; Extremities; Dysarthria
  - Eye movement disorders (33%): Slow saccades; Broken pursuit; Nystagmus
- Other CNS
  - Cognitive & Neuropsychiatric syndromes
  - Tendon reflexes: Increased (80%)
  - Extrapyramidal: Paucity of movement; Axial dystonia
  - Dementia: In oldest patients
  - Myoclonus
- Peripheral nervous system
  - Facial myokymia (33%)
  - Polyneuropathy (80%)
    - Often subclinical
    - Sensory, or Sensory motor
    - NCV: Axon loss
Laboratory
- MRI or CT: Cortical & Cerebellar atrophy
- CNS pathology: Purkinje cell loss; Brain atrophy; No polyGln aggregates

SCA 13

¹³
● 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
- Mutations: Missense
  - Phe448Leu: More severe phenotype
  - Arg420His
- Allelic with: Ataxic cerebral palsy
KCNC3 protein
Clinical features
- Onset
  - Age: Early Childhood, usual; 5th decade in 1 patient
  - Signs: Motor & Mental Developmental delay
  - No anticipation
- Ataxia
  - Legs > Arms
  - Dysarthria (88%)
  - Nystagmus, horizontal (75%)
  - Mild to Severe
- 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
- Myoclonus
- Progression: Slow or Static
MRI: Cerebellar & Pontine atrophy
Variant syndrome: Ataxic Cerebral Palsy
- Epidemiology: 1 patient
- KCNC3 genetics
  - Mutation: T428I
  - Inheritance: de novo; Dominant
  - Associated with: Increased paternal age
- Clinical
  - Onset age: Early childhood
  - Ataxia
  - Motor delay
  - Intellectual disability: Mild
  - Course: Stable
- Brain imaging: Normal

SCA 14

¹⁴
● Protein kinase Cγ (PRKCG)

; Chromosome 19q13.42; Dominant or Recessive

Epidemiology
- Frequency: 1.5% to 7.5% of SCA
- Families: Japanese, English-Dutch, French (1.5%)
- Not identified in German families
- Sporadic patient identified
- Some patients with mutation may be asymptomatic
Mutations: Missense ³⁹
- Most mutations: Regulatory C1 domain
- 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 PRKCG
  - G360S; Ala458Thr
  - Complex phenotype
  - Wider age of onset
- Other: F643L, V692G; Inframe deletion; Splice site
- Allelic disorder: Ataxia & Myoclonus, Recessive
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
Clinical features
- 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
- Ataxia
  - Gait disorder: All patents
  - Legs > Arms
  - Dysarthria
  - Pure ataxia with later onset (67%)
- Movement disorders
  - Myoclonus
    - Most common with onset < 27 years
    - Axial or Limbs
    - More with complex phenotypes
  - Tremor: Extremities & Head
  - Rippling: Small hand muscles
  - Parkinsonism: Non-progressive
  - Dystonia: Focal; Task-induced; Head tremor
- Tendon reflexes: Increased at ankles
- Peripheral neuropathy: Some patients
  - Hand muscles: Wasting
  - Reduced vibration sense
  - NCV: Axon loss, length dependent, sensory & motor
  - Muscle biopsy: Denervation
- Pyramidal (25%)
  - Legs
  - Neurogenic bladder
- Cognition
  - Usual: Normal
  - Impaired: Some family members (33%)
- 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
PRKCG variant disorder: Ataxia & Myoclonus, Recessive
- Epidemiology: 1 patient
- Genetics
  - Mutation: Homozygous; 102-bp deletion at termination codon in exon 18
  - Inheritance: Recessive or Dominant with reduced penetrance
  - Heterozygous carriers: Ataxia with onset at age 60, or Normal
- Clinical
  - Onset age: 7 years
  - Ataxia: Progressive
  - Myoclonus: Generalized
- Laboratory
  - Brain MRI: Cerebellar atrophy

SCA 15

¹⁶ ¹⁷
● Inositol 1,4,5-triphosphate receptor, type 1 (ITPR1)

; Chromosome 3p26.1; Dominant

Nosology: SCA16
Epidemiology: Australian, French & Japanese families; 1% of AD SCA
Genetics
- Inheritance: Dominant
- Mutations
  - Large deletions: Most common
    - Deletion of exons 1 to 48
    - Heterozygous deletions of 5� parts of ITPR1 gene
    - Deletions may extend into neighboring gene SUMF1
  - Missense: Ala19Val; Ala86The; V494I; Ala532Thr; P1059L
- Allelic disorders
  - Adult onset
    - SCA15
    - SCA 16
  - Early onset
ITPR1 protein
- Intracellular IP3-gated calcium channel
- Inositol 1,4,5-triphosphate-responsive
- Modulates intracellular calcium signaling
- High expression in Cerebellar Purkinje cells
- ITP as 2nd messenger: Produced in response to activation of mGluR1
- ITPRs: Ca⁺⁺ channels in endoplasmic reticulum
- Mutant protein
  - Reduced levels of ITPR1 in cells
  - Probable disease mechanism: Haploinsufficiency
Clinical
- Onset
  - Age: Range 10 to 66 years; Mean 40 years
  - Ataxia: Gait; Dysarthria; Head Tremor
  - No anticipation
- Ataxia (100%): Often mild
  - Gait disorder 71%
  - Limb ataxia 86%
  - Speech: Dysarthria
  - Ocular
    - Nystagmus, gaze evoked
    - Saccades: Dysmetric
    - Smooth pursuit: Impaired
  - Tremor
    - Upper limb
    - Head (15%): Regular; Rotatory
  - Dysphagia: Late in course
  - Strength: Normal
- Other features: Some patients
  - Pyramidal signs
  - Cognitive dysfunction: Mild
- Course: Variable
  - Slow progression
  - Patients usually remain ambulatory
Laboratory
- MRI
  - Cerebellum
    - Superior (Dorsal) vermis: Atrophy
    - Hemispheres & tonsils: Atrophic or Spared
- Nerve conduction velocities: Normal
ITPR1 variant syndromes
- SCA 29
  ● ITPR1; Chromosome 3p26; Dominant
  - Nosology
    - Congenital nonprogressive cerebellar ataxia (CNPCA)
    - Congenital or Infantile-onset Nonprogressive ataxia
    - CLA4
  - Epidemiology
    - Multiple families
    - 15% of Congenital nonprogressive ataxia
  - Genetics
    - Inheritance: Dominant or Sporadic
    - Mutations
      - Missense
      - T267M, T267R, S277I, T594I, Asn602Asp
      - Heterozygous
  - Clinical
    - Onset age: Congenital or Infant
    - Hypotonia
    - Cerebellar
      - Gait ataxia
      - Tremor
      - Oculomotor apraxia
      - Dysarthria
      - Nystagmus
      - Dysmetria & Dysdiadochokinesia
    - Cognitive disability
    - Dystonia: Some patients
    - Myoclonus
    - Cognition: Mild delay
    - Course: Non-progressive
  - Brain MRI
    - Cerebellar hypoplasia
      - Especially anterior vermia & superior hemispheres
      - May be progressive
    - Pontine tegmentum: Atrophy
- Ataxic Cerebral Palsy
  - Epidemiology: 2 patients
  - ITPR1 genetics
    - Mutations: N602D; S1487D
    - Inheritance: de novo; Dominant
    - Associated with: Increased paternal age
  - Clinical
    - Onset age: Early childhood
    - Ataxia
    - Intellectual disability
    - Course: Stable
  - Brain imaging: Normal
- ITPR1 variant: Gillespie syndrome ⁷¹
  - Epidemiology: 30 patients
  - Genetics
    - Inheritance: Dominant de novo or Recessive
    - Mutations
      - Type: Stop; Deletion; Missense
      - Locatiom: Distal region of ITPR1 transmembrane domain
    - Also see: Gillespie syndrome, Recessive, PAX6 mutations
  - ITPR1 protein
  - Clinical
    - Onset age: < 1 year
    - Hypotonia: Congenital or Infancy
    - Cerebellar ataxia: Non-progressive
    - Intellectual disability
    - Eyes
      - Iris: Hypoplasia
      - Pupils: Fixed; Dilated
    - Cardiac: Pulmonary stenosis
  - Laboratory
    - Brain MRI: Cerebellar atrophy, Progressive
- Mouse disorder (opt): Ataxia with Spontaneous itpr1 mutation
- Dog disorder: Italian Spinone dog with intronic GAA repeat

SCA15: Cerebellar Hemisphere & Vermis Atrophy

SCA 17: Ataxia + Intellectual Deterioration

¹⁸
● TATA box-binding protein (TBP)

; Chromosome 6q27; Dominant

Nosology
- OPCA V
- Huntington disease-like 4
Epidemiology
- French, Japanese, Italian, Indian & German families
- Sporadic patients: Smaller repeat sizes
Genetics
- Normal CAG sequences
  - Length: 25-42 repeats
- > 38 repeats: Increased risk of Multiple system atrophy
- Expanded CAG repeat sequences
  - Length: 41 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
- Allelic disorder: Parkinson disease, susceptibility
TBP protein
- Functions: TFIID component; Basal transcription
- Interactions
  - DNA elements: Promoter regions
  - TFIIB: General transcription
  - XBP1: Transcriptional activation
  - MYOD Transcriptional activation
  - SP1: Transcriptional activation
Clinical
- General: Complex & varied 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: Varied
  - Cerebellar (100%)
    - Ataxia: Limb & Trunk; Gait
    - Bulbar: Dysarthria; Dysphagia
    - Correlate with disease duration
  - Upper motor neuron (50%)
    - Hyperreflexia
    - Extensor plantar responses
    - Spastic paraplegia
  - Dysphagia
  - Cortical
    - Intellectual deterioration (80%)
      - Types: Dementia; Psychiatric disorders; Mutism
      - Often occurs early in disease course
    - Involuntary laughter
  - 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, Atypical
  - 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
- PET scan: Postsynaptic dopaminergic compartment of putamen & caudate nucleus
- NCV: No peripheral neuropathy
- EMG: Distal denervation in legs (30%)
Pathology ²⁹
- 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

● 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: Cerebellar Ataxia + Cognitive impairment

²⁴
● KCND3

; Chromosome 1p13.2; Dominant or de novo

Epidemiology: Multiple families
Genetics
- Mutations: ≥ 30; Missense or In-frame Deletion/Duplication; T352P, M373I, T377M (Recurrent), S390N, R419H
- Loss of function mutations: Transmembrane region
- Gain of function mutations: Cytoplasmic carboxyl-terminal
- Allelic disorders
  - Early onset syndromes: Neurodevelopmental disorder + Epilepsy or Movement disorders + late Ataxia
  - Later onset syndromes: SCA19 (Ataxia, Cognitive decline, Polyneuropathy)
  - SCA22: Pure cerebellar
  - Brugada syndrome 9 : Gain of function mutations; G600R (Recurent)
KCND3
- Kv4.3 channels
- Expressed in: Cerebellum; Heart
- Mutant protein: Retention in endoplasmatic reticulum; Enhanced protein instability
Clinical
- Onset age: 1 to 80 years
- Ataxia: 100%
  - Gait disorder & falling
  - EOM: Saccadic pursuit & dysmetria; Nystagmus in some patients
  - Dysarthria
  - Degree: Often mild
  - Episodic: Some patients
- Tremor: Postural
- CNS: Other
  - Cognitive impairment: Mild; Disturbed abstract reasoning
  - Myoclonus (30%): Spinal or Cortical
  - Spasticity
  - Extra-pyramidal: Parkinsonism-Dystonia
- Tendon reflexes: Reduced (60%); Increased (20%)
- Polyneuropathy (10% to 20%)
  - Sensory loss: Vibration & Joint position
  - Late onset patients
  - NCV: Sensory or Sensorimotor axon loss
- Some patients: Hearing defects
Laboratory
- Transcranial magnetic stimulation: Slightly increased central conduction times
- NCV: Usually normal; Occasional mild NCV decrease
- MRI
  - Cerebellar hemispheres: Marked atrophy
  - Vermal & Cerebral: Mild atrophy
- Pathology
  - Purkinje cell degeneration: Abnormal intracellular accumulation, & reduced levels of, Kv4.3 in soma
  - Basal ganglia: Iron deposition

SCA 22: Cerebellar ataxia, Pure

²⁷
● KCND3

; Chromosome 1p13.2; Dominant

Epidemiology: Diverse ethnic origins
Genetics
- Mutations: Deletion (Inframe); V338E, G345V, T377M
- Allelic disorders
KCND3: Kv4.3 channels
Clinical: Pure cerebellar disorder
- Onset age: 10 to 51 years; Anticipation mean of 10 years
- Ataxia: 100%; Trunk; Gait; Appendicular
- Bulbar: Dysarthria; Scannning speech; Dysphagia
- Ocular
  - Intermittent microsaccadic pursuits
  - Normal saccadic velocity
  - Gaze-directed horizontal nystagmus: 67%
- Tendon reflexes: Decreased or Increased
- Normal mentation
- Course: slowly progressive
Laboratory
- MRI: Cerebellar atrophy, homogeneous; Normal brainstem
- EMG & NCV: Normal
- Somatosensory & auditory brainstem evoked potentials: Abnormal

SCA 20: Ataxia with Dysphonia & Dentate calcification

³⁴
● Chromosome 11q12; Dominant

Epidemiology: Anglo-Celtic family in Southeastern Australia
Genetics
- 260-kb duplication at 11q12
- Contiguous gene duplication syndrome: Region contains ≥ 12 genes
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

Ataxia with Spasmodic Cough ⁴⁵
● Dominant

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
Differential diagnosis: SCA20

SCA 21: Ataxia with Cognitive impairment & Extrapyramidal

²³
● Transmembrane protein 240 (TMEM240)

; Chromosome 1p36.33; Dominant

Epidemiology
- 8 families
- 2% of French SCA
Genetics
- Mutations: Missense (T80M, R116C, E149K, P170L, R171W) & Stop (Y163*)
- T80M: Milder phenotype; No cognitive impairment
TMEM240 protein
- Transmembrane
- CNS: Synaptic membranes
- Present in: Cerebellum, Putamen & Caudate
Clinical
- Onset age
  - Usual: Childhood
  - Range 1 to 61 years
- Cognitive defect (88% of families)
  - Mild to Severe
  - Cognitive & Motor skills: Delayed
  - Mental retardation: IQ 46 to 71
- Motor deficit
  - Onset age 2 to 20 years
  - Clumsiness
- Cerebellar
  - Gait disorder (100%)
  - Limb ataxia (85%)
  - Dysarthria (85%)
  - Tremor
- Extrapyramidal
  - Akinesia (80%)
  - Rigidity (30%): No response to L-DOPA
  - Tremor (60%)
- Tendon reflexes: Reduced or Increased
- Course: Slow progression
Laboratory
- Brain MRI
  - Cerebellar atrophy: Vermis > Hemispheres
  - Normal brainstem & basal ganglia
  - Iron: Increased in red nucleus & pallidum
  - T2 hyperintensities: Pons; White matter
- EEG: Normal
- EMG: Normal

SCA 23

³⁷
● 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 (proton)-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 neuropathy

³⁰
● Polyribonucleotide Nucleotidyltransferase, Mitochondrial 1 (PNPT1; PNPase)

; Chromosome 2p16; Dominant

Epidemiology
- Southern French & Australian families
- Incomplete penetrance
Genetics
- Mutations
  - Heterozygous
  - Splice & Exon skipping
  - Lead to premature stop codons in S1-domain of PNPase
- Allelic disorders
PNPT1 protein
- Mutations: Reduced PNPase levels
Clinical: Varied among family members
- Onset
  - Age
    - Usual: Childhood
    - Range: Few months to > 80 years
    - No anticipation
    - Incomplete penetrance
  - Clinical
    - Ataxia
    - Vomiting & Gastrointestinal features
- Cerebellar
  - Ataxia
  - Eye movements
    - Nystagmus: Some patients
    - Square waves
    - Movement speed: Slow
  - Hypotonia
  - Gait: Difficulty running; Wheelchair use
  - Dysarthria: Some patients
- Sensory neuropathy/neuronopathy
  - 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
- Hearing loss: Some patients
Laboratory
- NCV: SNAPs absent; Motor velocity normal
- MRI: Global cerebellar atrophy, severe; Normal brainstem
- Blood: Elevated type I interferon response

SCA 26

: Pure cerebellar ataxia ⁴¹
● Eukaryotic translation elongation factor 2 (EEF2)

Chromosome 19p13.3; Dominant

Epidemiology: Norwegian (North Dakota) family
Mutation: Missense; Pro596His
EEF2 protein: Translocation step in protein synthesis
- Peptidyl-tRNA moved to next codon on mRNA from acceptor site on ribosome
- Energy provided by hydrolysis of GTP bound to EF2
- Diphtheria & Pseudomonas exotoxin A (PA toxin)
  - Inhibit protein synthesis by catalyzing covalent binding of ADP-ribose moiety of NAD to EEF2
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 27A: SCA + Tremor & Dyskinesia (ADCA I)

²⁶
● Fibroblast growth factor 14 (FGF14)

; Chromosome 13q33.1; Dominant or de novo

Epidemiology: 4% to 8% of adult onset ataxia
Genetics
- Mutations
  - Phe145Ser, Stop mutations
  - Produce reduced protein stability
- Allelic disorders
  - Episodic Ataxia 9 (EA9)
  - SCA27B: Ataxia, Adult onset
FGF-14 protein
- Subfamily: FGF Homologous Factors (FHF)
- Expressed primarily in nervous system
- Intracellular
- Interacts with voltage gated Na⁺ channels
Clinical
- Onset
  - Childhood to 45 years
  - Tremor
- Tremor
  - Limbs & Head
  - Postural
  - Exacerbated by emotional stress & exercise
- Ataxia
  - Limbs: Arms > Legs; Onset in late teens
  - Gait: Onset 27 to 40 years
  - Cranial nerves: Dysarthria; Nystagmus
  - Episodic: May be exacerbated by fever
- 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 variant disorder: Episodic Ataxia 9 (EA9) ⁸³
- Epidemiology: 2 families, 4 patients
- Genetics
  - Inheritance: Dominant
  - Mutations: Stop; Glu147Ter, Tyr162Ter
- Clinical
  - Onset age: 2 to 8 years
  - Ataxia: Episodes
    - Trigger: Fever
    - Duration: Seconds to 7 days
    - Vertigo: Some patients
  - Tremor: Postural; Arms
  - Nystagmus
- Laboratory
FGF14 variant disorder: SCA27B, Adult onset Ataxia ± Episodes ⁹⁵
- Epidemiology: > 120 patients
- Genetics
  - Inheritance: Dominant
  - Mutation: GAA repeat expansion in intron 1
    - Range: 258-637
    - Founder effect in European families
    - Transmission: GAA alleles
      - Expanded in female germline
      - Contracted in male germline: 30% reduced paternal inheritance
  - Mutation effects: Probably haploinsufficiency
  - Clinical correlations: Repeat sizes
    - < 250: Normal
    - 250 to 300: Incomplete penetrance
    - > 300: Fully penetrant; Adult onset ataxia
- Clinical
  - Onset age
    - Mean 55 to 63 years
    - Range 28 to 87
    - Lower with more GAA repeats
  - Ataxia
    - Episodic: Especally at onset; Triggers alcohol & exercise
    - Gait
    - Appendicular
    - Dysarthria
    - Course: Progressive
  - Peripheral neuropathy
    - Mild
    - Ankle reflexes: Reduced in 70%
    - Vibration at ankle: Reduced in 80%
    - Autonomic: Bladder (60%)
  - Eye: Nystagmus, Horizontal or Downbeat
  - Postural tremor
  - Vertigo
  - Treatment: 4-aminopyridine
  - Differential diagnosis: CANVAS
- Laboratory
  - Brain MRI: Cerebellar atrophy
  - Pathology: Purkinje cell loss, especially in vermis
  - Serum Neurofilament light chain: Normal
  - NCV: Sensory-Motor Axon loss
Fgf14-knockout mice
- Ataxic gait
- Widened stance
- Lack of forefoot-hindfoot correspondence
- Paroxysmal hyperkinetic dyskinesia

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

⁴³
● ATPase family gene 3-like 2 (AFG3L2)

; Chromosome 18p11.21; Dominant

Epidemiology: Multiple families; 3% of SCA
Genetics ⁴⁹
- Mutations
  - Missense
  - N432T; Gly671Trp; S674L; E691K; A694E; R702Q
  - Tyr689His: Late onset & Slow progression
  - Location
    - Most cases: Heterozygous mutations in exons 15 & 16
    - Commonly in proteolytic domain
- No anticipation
- Allelic disorders
  - Spastic Ataxia, Myoclonic epilepsy with Neuropathy, Recessive (SPAX5)
  - OPA12: Optic atrophy + Mild intellectual disability, Dominant : Arg468Cys, F175S
AFG3L2 protein ⁴⁹
- Cellular location: Mitochondrial inner membrane (Matrix side)
- High expression: Purkinje cells; Deep cerebellar nuclei; Motor neurons
- Zinc ligand
- Co-localizes with: Paraplegin
- Actions & Functions
  - Metalloproteinase
  - m-AAA Protease complex: Hexamer Isoforms
    - AFG3L2/AFG3L2
    - AFG3L2/Paraplegin
  - Quality control
    - Proteins: Several nuclear- & mitochondrial-encoded
    - Mitochondrial protein folding
  - Complex I, III & IV assembly
  - ?? 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 or COX- muscle fibers
  - Mitochondrial oxidative enzymes: Normal
  - mtDNA deletions: Multiple
  - AFG3L2 protein: Reduced

Variant syndrome: Spastic Ataxia with Myoclonic Epilepsy & Neuropathy (SPAX5) ⁵⁵
- Epidemiology: 9 patients
- Genetics
  - AFG3L2 mutations: Homozygous Y616C, Ala572Thr
  - Inheritance: Recessive
  - Allelic with: SCA 28
- Clinical
  - Onset
    - Age: Infancy to 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
  - Microcephaly
- Laboratory
  - NCV: Sensory & Motor axon loss in legs
  - EMG: Denervation
  - MRI: Cerebellar atrophy; Basal ganglia signal
  - Mitochondrial
    - Cytochrome c oxidase: Mildly reduced
    - mtDNA content: Mildly reduced
    - Muscle lipid: Increased
  - EEG: Slowing; Spike-Wave
  - Serum lactate: High

SCA 30: Pure cerebellar ataxia (ADCA III)

⁴⁷
● 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 ataxia (ADCA III)

⁵²
● 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)

● 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
● Protein-glutamine gamma-glutamyltransferase 6 (TGM6)

; Chromosome 20p13; Dominant

Epidemiology: 14 families
Genetics
- Mutations: Missense & In-frame deletions; D327G & others
- Mis-identification: Original family had L517W that does not always segregate with disease
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; Younger than SCA23 & SCA36
- 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
● Nuclear Protein 56 (NOP56; NOL5A)

; Chromosome 20p13; Dominant

Epidemiology
- > 70 families
- Japan (Asida River)
- Europe: Spain (Costa da Morte ataxia) & France
Genetics
- Mutations
  - Expansions of Intronic GGCCTG repeat: 25 to 2500; Usually > 650
  - Phe265Leu
- Mutation mechanisms
  - RNA gain of function
  - MicroRNA MIR1292 suppression
  - Not haploinsufficiency
- Possible founder effect: Similar haplotyes in many patients
- No relation between repeat size & Disease severity
NOP56 protein
- Location: Nucleus & Cytoplasm
- Interacts with: NOP1 & NOP58
- Functions
  - 60S ribosomal subunit biogenesis, Middle stage
  - Box C/D small nucleolar ribonucleoprotein (snoRNP) particles
    - Core component
    - Stabilises complex
  - Biogenesis of box C/D snoRNAs: U3, U8 and U14 snoRNAs
Clinical
- Onset
  - Age: 39 to 71 years; No anticipation
  - Ataxia
- Ataxia
  - Gait: Truncal ataxia
  - Limbs
  - Dysarthria
  - Tremor: Postural
  - Nystagmus: Some patients
- Motor
  - Muscle atrophy: Tongue & Proximal
  - Fasciculations: Limbs, Trunk & Tongue
  - Later in disease course
- Reflexes
  - Tendon: Increased legs & arms, not jaw
  - Plantar: Flexor
- Cranial
  - Ptosis
  - Hearing loss (60%)
- Cognition: Impaired (24%)
- Sensory: Normal or Vibration reduced
- Course: Slow progression
- Not present: Spasticity; Spasmodic torticollis
Laboratory
- MRI: Cerebellar atrophy, vermis & hemispheres
- NCV: Normal or Reduced SNAP amplitudes
- EMG: Denervation; Fasciculations, Large motor units
- Muscle biopsy
  - Grouped atrophy
  - Hypertrophy
  - Pyknotic nuclear clumps
- CNS Pathology
  - Motor neuron loss: Hypoglossal early
  - Purkinje cell loss
  - NOP56 in neuronal nuclei

SCA 37: Cerebellar ataxia with abnormal Vertical Eye Movements

⁶¹
● Disabled, drosophila, homolog of, 1 (DAB1); Chromosome 1p32.; Dominant

Epidemiology: Spanish & 6 Portuguese families
Genetics
- Mutation: Pentanucleotide ATTTC Repeat Insertion in Non-coding Region
  - Non-pathogenic: [(ATTTT)_7�400]
  - Pathogenic
    - (ATTTT)_60�79(ATTTC)_31�75(ATTTT)_58�90]
    - ATTTC_n: n = 31 to 75
- Insertions are present on distinct haplotype
- Inverse correlation: Insertion size vs Onset age
- Expression of abnormal insertion: Abnormal nuclear RNA accumulation
DAB1 protein
- Expression: Brain
- Reelin signal transducer
- Function: Positioning of cerebellar, hippocampal & cortical neurons during development
Clinical
- Onset
  - Age: Mean 48 years; Range 18 to 64 years
  - Dysarthria
- Ataxia: Falls; Dysarthria
- Dysphagia
- Eye movements
  - Saccades: Hypometric or hypometric, Vertical > Horizontal
  - Vertical pursuit: Abnormal
- Course
  - Slow progression
  - Wheelchair after 10 to 33 years
Laboratory
- MRI: Cerebellar vermal or diffuse atrophy; Brainstem normal
- NCV: Normal

SCA 38 ⁶⁶
● Elongation of very long chain fatty acids-like 5 (ELOVL5)

; Chromosome 6p12.1; Dominant ⁶⁶

Epidemiology: 4 Italian & French families
Genetics
- Mutation: Leu72Val; Gly230Val
ELOVL5 protein
- Function
  - Elongase
    - General: Play roles in elongation of long-chain polyunsaturated fatty acids
    - Other elongase disorders: ELOVL4
  - ELOVL5: Synthesis of polyunsaturated fatty acids of ω3 & ω6 series
- Final products reduced in serum: Arachidonic acid; Docosahexaenoic acid
- High levels in Purkinje cells
- Cell location
  - Normal: Endoplasmic reticulum
  - Mutant protein: Perinuclear
Clinical
- Onset age: 4th to 6th decade
- Ataxia: Gait; Dysarthria
- Eyes: Slow saccades; Nystagmus
- Polyneuropathy (50%)
  - Weakness: Distal in 1 family
  - Sensory loss
  - Axon loss
- Treatment: Docosahexaenoic acid (DHA)
Laboratory
- Brain MRI: Cerebellar vermis atrophy
- Docosahexaenoic acid (DHA) in serum: Low

SCA 39 ⁷⁸
● Chromosome 11q21-11q22.3; Dominant

Epidemiology: 1 French family
Genetics
- Mutation: 7.5-megabasepair duplication (Contains ~44 genes)
Clinical: Spastic ataxia
- Onset age: Early childhood
- Ataxia
  - Dysmetria
  - Dysarthria
  - Eyes: Saccadic pursuit
- Myelopathy
  - Upper motor neuron
    - Spasticity: Legs > Arms
    - Tendon reflexes: Increased
    - Plantar reflex: Upgoing
  - Sensory: Vibration loss in lower body
- Eyes: Horizontal gaze paresis
- Intellect: Mild impairment
- Other
  - Hearing loss
  - Skeletal: Thoracic & Foot deformation
- Course: Slow progression
Laboratory
- Brain MRI
  - Cerebellar atrophy
  - Corpus callosum: Thin
  - Periventricular white matter hyperintensities
  - Similar to: SPG11
- EMG: Denervation
- NCV: Normal
- Auditory evoked brainstem potentials: Prolonged

SCA 40

⁶⁷
● Coiled-coil domain-containing protein 88C (CCDC88C; Daple)

; Chromosome 14q32.11; Dominant

Epidemiology: Hong Kong China family, 2 patients
Genetics
- Mutation: Missense, R464H
- Allelic with: Hydrocephalus, nonsyndromic, Recessive 1 (HYC1)
CCDC88C protein
- c-Jun N-terminal kinase (JNK) pathway: Modulation
- Negative regulator of canonical Wnt signaling pathway
- Location: Cytosol & Perinuclear
Clinical: Spastic ataxia
- Onset age: 5th decade
- Ataxia
  - Trunk: Gait & Stance; Most severe
  - Dysarthria
  - Dysmetria: Arms, Intention tremor
  - Ocular: Dysmetria: Upgaze limited
- Pyramidal
  - Tendon reflexes: Brisk; Ankle clonus
  - Spasticity: Legs > Arms
Laboratory
- MRI
  - White matter: Linear and punctate subcortical T2W hyperintensities
  - Pons: Mild atrophy
  - Cerebellum & Vermis: Atrophy
  - Brain volume: Reduced

SCA 41

⁷⁰
● Transient receptor potential cation channel, subfamily C, Member 3 (TRPC3)

; Chromosome 4q27; Dominant

Epidemiology: 1 patient
Genetics
- Mutation: Arg762His
TRPC3 protein
- TRP proteins
Clinical
- Onset age: 38 years
- Cerebellar: Gait ataxia
Laboratory
- Brain MRI: Cerebellar vermis atrophy
- NCV & EMG: Unremarkable
Animal model: 'moonwalker' (Mwk) mouse

SCA 42

⁶⁹
● Calcium channel, voltage-dependent, T type, alpha-1G subunit (CACNA1G)

; Chromosome 17q21.33; Dominant

Epidemiology: 3 families
Genetics
- Mutation: c.5144G>A, p.Arg1715His
- Mutation location: Voltage sensor S4 segment of domain IV in Ca_v3.1
- CACNA1G: Allelic disorder
  - SCA42 with Neurodegeneration (SCA42ND)
- CACNA1G: Variants
  - Epilepsy, suscptibility
  - Autism, susceptibility
CACNA1G protein (Ca_v 3.1)
- T-type calcium channel
- Expression: High in cerebellum
  - Large neurons with strong ability to generate rebound burst firing after hyperpolarization
- Mutation effects
  - Current-voltage & Steady-state activation curves shifted positively
  - Inactivation curve: Higher slope factor
  - Decreased neuronal excitability
Clinical: Ataxia ± Spasticity
- Onset age: 9 to 78 years
- Cerebellar
  - Ataxia
  - Dysarthria
  - Eye: Saccadic pursuit
- Dysphagia (20%)
- Tendon reflexes: Present
- Myokymia: Face (30%)
- Upper motor neuron
  - Bladder dysfunction (30%)
  - Spastic gait, mild (30%)
  - Plantar response, extensor (20%)
- Sensory loss: Vibration, mild (30%)
Laboratory
- Cerebellar pathology: Purkinje cell loss; Vermis atrophy
CACNA1G variant: SCA42 with Neurodegeneration (SCA42ND)
- Epidemiology: 4 females
- Genetics
  - Inheritance: de novo; Dominant
  - Mutations: A961T; M1531V
- Clinical
  - Onset: Early infancy
  - Hypotonia
  - Psychomotor delay: Intellectual disability; Reduced speech
  - Spasticity
  - Ataxia
  - Oculomotor apraxia
  - Face: Dysmorphism
  - Seizures: 2 patients
- Laboratory
  - Brain imaging: Cerebellar atrophy

SCA 45

● Fat tumor suppressor, Drosophila, homolog of, 2 (FAT2; MEGF1)

; Chromosome 5q33.1; Dominant

Epidemiology: 2 families, 6 patients
Genetics
- Mutation: Misense; Lys3586Asn, Arg3649Gln
FAT2 protein
- Contains epidermal growth factor-like domains
- Expression: Cerebellum
- Role: ? Cell adhesion
Clinical
- Onset age: 40 to 50 years
- Cerebellar
  - Ataxia: Limb & Gait
  - Dysarthria
  - Nystagmus: Downbeat
- Course: Slow progression
Laboratory
- Brain MRI: Cervebellar vermis atrophy; Hemosiderin in mesencephalon

SCA 47 (PADDAS)

● Pumilio, Drosophila, homolog of, 1 (PUM1; KIAA0099)

; Chromosome 1p35.2; Dominant

Epidemiology: 5 families
Genetics
- Mutations: Missense (Thr1035Ser, Arg1147Trp, Arg1139Trp);
PUM1 protein
- Represses translation of mRNAs
- Binds to ATXN1: Negative regulation
Clinical
- Onset age: Early childhood or Adult (4th to 6th decade)
- Ataxia: Dysmetria; Dysarthria
- Child onset
  - Motor
    - Extrapyramidal: Chorea, Ballismus
    - Spasticity
    - Incoordination
  - Eye: Vision loss
  - Skeletal
    - Scoliosis
    - Face: Dysmorphism,
    - Bone mineral density: Low
    - Short stature
Laboratory
- Brain MRI: Cerebellar vermis atrophy

Dentatorubral-Pallidoluysian Atrophy (DRPLA)

⁴⁸
● 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

Holmes ataxia

Ataxia syndrome
- Pure or with Hypogonadism
- Progression: Very slow
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

Leukoencephalopathy: Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum (H-ABC; HLD6)

⁵⁹
● Tubulin, beta-4A (TUBB4A)

; Chromosome 19p13.3; Dominant (Sporadic)

Epidemiology
- > 22 individuals
- Caucasian common
Genetics
- TUBB4A mutations: Missense; Asp249Asn
- Allelic disorders
  - Dystonia 4, torsion, autosomal dominant (DYT4)
  - CNS Hypomyelination, Isolated
  - Spastic paraparesis, Dominant ¹⁰³
TUBB4A protein
- β-Tubulin
- Brain: High expression
Clinical: Spastic Ataxia
- Onset age: Infancy to Childhood
- Development
  - Delay
  - Poor speech
  - Deficiency: Mild to Severe
  - Language & Cognition: Relatively spared early; Decline over time
- Extrapyramidal
  - Dystonia: Unilateral or Bilateral
  - Rigidity
  - Choreoathetosis
  - Opisthotonus
  - Oculogyric crises
- Spastic
  - Tetraplegia
  - Progressive
- Cerebellum
  - Ataxia
  - Unsteady walking, progressive
  - Nystagmus
  - Dysarthria
- Seizures: Some patients
- Eye (Some patients): Oculomotor apraxia; Hypometric saccades; Nystagmus
- Other: Some patients
  - Short stature
  - Microcephaly
  - Hearing loss
- Course
  - Progressive
  - Loss of unsupported walking: 2 to 14 years of age
- Possible treatments: L-dopa; Folinic acid
Brain MRI
- Hypomyelination: Diffuse; Progressive
- Putamen: Small or Absent
- Head of caudate: Reduced size
- Cerebellar atrophy: Especially granular layer

Prion disease
● Prion protein (PRNP)

; Chromosome 20p13; Dominant

Creutzfeldt-Jakob
Familial Fatal Insomnia
Gerstmann-Straüssler-Schienker
Neuropathy: Autonomic & Sensory
Other variants
Prion-like domains

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 & Axon loss
    - NCV
      - F-waves: Mildly prolonged
      - Conduction velocities: Slowed
Variant: Polyneuropathy, Sensory & Autonomic ⁶²
- Epidemiology: 15% of CJD; British, Italian & Japanese families
- PRNP Genetics
  - Mutations: Stop; Y163X, Glu200Lys, 2 bp deletion in codon 178
  - Inheritance: Dominant
- Clinical
  - Onset
    - Age: Early adult; 26 to 55 years
    - Sensory loss
    - Diarrhea or Urinary dysfunction
  - Autonomic failure: Sympathetic & Parasympathetic
    - Diarrhea, chronic
    - Urinary retention
    - Hypotension, postural
    - Impotence
    - Weight loss
    - Vomiting
  - Polyneuropathy
    - Sensory predominant
    - Distal > Proximal
    - Sensory ataxia: Few patients
    - Tendon reflexes: Reduced in Legs
  - Later features in CNS: Onset in 5th or 6th decade
    - Cognitive decline
    - Seizures
  - Course
    - Progression: Slow over decades
    - Death: At 40 to 70 years
- Laboratory
  - Prion protein amyloid: Deposited in many tissues including peripheral nerve, muscle & CNS
  - NCV
    - Axon loss: Sensory > Motor, Length dependent, Legs > Arms
    - Demyelinating features: Rare patient
  - Thermal threshholds: Abnormal
  - Memory: Abnormal
  - CSF: High tau, S100b & 14-3-3 protein
  - Cardiac: Normal
Variant:Familial Fatal Insomnia
- PRNP Genetics
  - Mutations: Asp178Asn + Methionine-encoding codon 129
  - Inheritance: Dominant
- Autonomic features
  - Sympathetic: Increased activity at basal levels & stimulation
  - Hypertension
  - Pyrexia: Evening
  - Impotence
  - Excessive: Sweating, Lacrimation & Salivation
Variants: Other
- Prion disease with protracted course
- Dementia

● 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
Polyneuropathy ³⁸
- 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

Vertical and Horizontal Nystagmus
● 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; CWS1)

● Phosphatase & Tensin homolog (PTEN)

; Chromosome 10q23.31; Dominant

Epidemiology: Female predominance
Allelic disorder: Motor PN + Hamartomas
PTEN
- Regulates neuronal soma size & cell growth
- May inhibit cell migration
- Expressed in skin, thyroid & CNS
- Phosphoinositide (PIP) phosphatase: Similar function to myotubularin
Clinical
- Systemic
  - Hamartomas: Skin; Mucous membranes; Thyroid; Breast; GI
  - Face: Verrucous lesions; Trichilemmomas; Furrowed tongue
  - Endocrine: Thyroid; Gynecomastia
  - GU: Hydrocele; Varicocele
- Neurological
  - Ataxia
    - Progressive
    - Cerebellar pathology: Gangliocytoma; Granule cell hypertrophy
  - Cortical
    - Mental retardation
    - Seizures
    - Megalencephaly
  - Intracranial pressure: Increased
- Associated neoplasms
  - Bannayan-Riley-Ruvalcaba
  - Dysplastic cerebellar gangliocytoma
  - Breast cancer
  - Merkel cell (Primary neuroendocrine) skin carcinoma
  - Renal cell adenocarcinoma
  - Juvenile polyposis syndrome
- Scoliosis
PTEN variant syndrome: Multifocal demyelinating motor neuropathy and hamartoma syndrome ⁸¹
- Epidemiology: 1 patient
- Genetics: de novo Dominant mutation, Phe90Ser
  - Onset: Childhood
  - Motor neuropathy
    - Multifocal
    - Asymmetric
    - Face
    - Oculomotor
    - Tongue
    - Arm: Proximal
    - Leg: Distal
  - Hamartomas: Skin
  - Macrocephaly
  - Autism spectrum disorder
- Laboratory
  - NCV
    - CMAP amplitudes: Asymmetrically reduced
    - Conduction block: Multiple sites
  - EMG: Chronic denervation
  - Brain MRI: Normal
PTEN disruption in mouse Schwann cells: Tomaculous neuropathy ⁵⁷
Also see: Cowden (CWS) syndromes
- CWS2 : SDHB; 1p36.13
- CWS3 : SDHD; 11q23.1
- CWS4 : KLLN ; 10q23.31
- CWS5 : PIK3CA ; 3q26.32
- CWS6 : AKT1 ; 14q32.33
- CWS7 : SEC23B ; 20p11

Cerebellar ataxia, Deafness & Narcolepsy (ADCA-DN)

⁵⁶
● DNA methyltransferase 1 (DNMT1)

; Chromosome 19p13.2; Dominant or De novo

Epidemiology: Swedish, US, Brazilian & Italian families
Genetics
- Mutations: Exon 21; Missense; Ala570Val, Cys596Arg, 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

Cerebellar ataxia, Non-progressive with Mental retardation (CANPMR)

● Calmodulin-binding transcription activator 1 (CAMTA1)

; Chromosome 1p36.31-p36.23; Dominant or de novo

Nosology: Cerebellar dysfunction with variable Cognitive & Behavioral abnormalities (CECBA)
Epidemiology: 17 patients
Genetics
- Mutations: Nonsense; Intragenic deletion or duplication; Few missense
- Allelic disorder: ALS reduced survival, especially with UNC13A^C/C allele
Clinical
- Onset age: Congenital to Teens
- Ataxia
  - Gait
  - Unstable stance
  - Limb: Some patients
- Extrapyramidal: Dystonia; Myoclonus
- Psychomotor development: Delayed; Intellectual disability
- Face: Mild dysmorphism
  - Long
  - Pointed chin
  - Bulbous nose
  - Long philtrum
  - Thick lower lip
Course: Progressive
Laboratory
- MRI: Cerebellar atrophy; Hippocampal & posterior cortical atrophy

Lissencephaly 9 with Complex Brainstem Malformation

⁸²
● Microtubule-actin cross-linking factor 1 (MACF1)

; Chromosome 1p34.3; Dominant, de novo

Epidemiology: 9 patients
Genetics
- Mutations: Missense or In-frame deletions; Zinc-binding residues in GAR domain; de novo
- Allelic disorders
  - Schizophrenia
  - Myasthenia gravis, Congenital
MACF1 protein
- Localized widely in brain
- NMJ
  - Post-synaptic
  - Links Rapsyn to
    - Microtubule- binding proteins: EB1 & MAP1b
    - Actin-associated protein: Vinculin
- Function: Axon extension; NMJ maintenance
Clinical
- Onset: Congenital
- Developmental delay: Global
- Intellectual disability, severe
- Hypotonia: Axial
- Limb spasticity 30%
- Seizures
- Dyskinesia
Laboratory
- Brain malformation
  - Hemispheres: Pachygyria; Lissencephaly; Hippocampus abnormal
  - White matter: Thin
  - Thin anterior commissures & corpus callosum
  - Brainstem: Reduced crossing fibers; Pons hypoplasia
  - Cerebellum: Hypoplasia
MACF1 variant: Myasthenia gravis, Congenital ⁸⁶
- Epidemiology: Serbian & Indian patients
- Genetics
  - Inheritance: Recessive
  - Mutations: Missense; Thr1799Ala, Leu2208Phe, Val1563Met
- Clinical
  - Onset age: 5 years to adult
  - Eyes
    - Ptosis: Asymmetric
    - EOM weakness: Mild, 1 patient
  - Weakness
    - Bulbar: Tongue weak; Dysphagia
    - Neck flexors: Weakness
    - Limb-girdle, mild
- Laboratory
  - RNS: Decrement at 3 Hz
  - EMG: Normal

Neonatal-Onset, Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis ⁷⁹
● Phosphofurin acidic cluster sorting protein 2 (PACS2)

; Chromosome 14q32.33; de novo

Epidemiology: 14 unrelated patients
Genetics
- Mutations: Missense; Heterozygous; (p.Glu209Lys
PACS2 protein
- Nuclear gene expression & pathway traffic regulation
- Bind cargo proteins, sorting adaptors & cellular kinase
Clinical
- Onset age: Neonatal/Early infantile
- CNS
  - Seizures: Difficult to control
  - Speech: Delay
  - Developmental delay: Late walking at 1.5 to 3 years
  - Hypotonia
- Face: Dysmorphism
  - Synophris
  - Hypertelorism
  - Palpebral fissures: Down-slanting
  - Nasal root: Broad
  - Vermillon of upper lip: Thin
  - Wide mouth: Downturned corners
- Eye: Strabismus in some patients
Laboratory
- Brain MRI: Cerebellar dysgenesis
- EEG: Spikes & Seizure activity

Alternating Hemiplegia of Childhood 1 (AHC1)

● ATPase, Na+/K+ Transporting, α2 polypeptide (ATP1A2)

; Chromosome 1q23.2; Dominant

Epidemiology: > 20 patients
Genetics
- Mutations: Thr378Asn; Ser779Asn
- Allelic disorders
  - Familial hemiplegic migraine 2 (FHM2)
  - Migraine, familial basilar
  - Hypokalemic Periodic Paralysis + CNS
  - Alternating hemiplegia of childhood 1
  - Developmental & Epileptic Encephalopathy 98
  - Fetal akinesia, Respiratory insufficiency, Microcephaly, Polymicrogyria & Dysmorphic facies (FARIMPD)
ATP1A2 protein
- ATPase
- α-subunit of Na,K-ATPase: Catalytic subunit
- Expressed in nervous system
Clinical
- Episodes
  - Onset age: 2 years
  - Duration: Minutes to Days
  - Weakness: Hemi- or Quadriplegia lasting
  - Extrapyramidal: Dystonic posturing, Choreoathetoid movements
  - Nystagmus
  - Autonomic changes: Affected limbs; Flushing
  - Possible treatment: Flunarazine
- Progress to
  - Seizures
  - Cognitive impairment
ATP1A2 variant syndrome: Hypokalemic Periodic Paralysis + CNS
- Epidemiology: 1 patient
- Genetics
  - Mutation: Heterozygous; Missense; S779N
  - Inheritance: Dominant, de novo
- ATP1A2 protein
  - Mutation: Produces leak current of H⁺ & Na⁺
- Clinical
  - Onset: < 1 year
  - Seizures
  - Motor milestones: Delayed
  - Weakness Episodes
    - Tetraparesis
    - Bilateral
    - Dysphagia
    - Duration: Hours to Days
    - Precipitants: Infection; Carbohydrate meals; Acetazolamide
    - Treatment: Potassium
- Laboratory
  - Serum CK: 382 to 1793
  - Serum Potassium: Low; 2.4 mM
  - Muscle biopsy: Myopathic; Type I predominance; Necrotic fibers; Internal nuclei
  - EMG: Normal
  - NCV: CMAPs small during atttack
  - Brain MRI: Mesial temporal sclerosis

Alternating hemiplegia of childhood 2 (AHC2)

● ATPase, Na+/K+ Transporting, α3 polypeptide 3 (ATP1A3)

; Chromosome 19q13.2; Dominant

Epidemiology: Multiple families
Genetics
- Mutations: Missense most common; Heterzygous; Many identified; Asp801Asn, Glu815Lys, Ser811Pro, Gly947Arg
- Allelic disorders: CAPOS
ATP1A3
- Expressed in nervous system
- α-subunit of Na,K-ATPase: Catalytic subunit
- Establishes & Maintains electrochemical gradients across plasma membranes
- ATPase
- Transport: Ions & Protons
- Mutations: Normal amounts of protein with reduced, or altered, activity
Clinical
- Episodes
  - Onset age: Infancy
  - Weakness: Quadriparesis
  - Extrapyramidal: Dystonia; Chorea
  - Eye movements: Abnormal
  - Ataxia
- Fixed defects
  - Developmental delay

CAPOS syndrome

● ATPase, Na+/K+ Transporting, α3 polypeptide 3 (ATP1A3)

; Chromosome 19q13.2; Dominant or de novo

Nosology: Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, Sensorineural hearing loss
Epidemiology: 5 families, > 12 patients
Genetics ⁶³
- Mutation: Glu818Lys
- Allelic disorders
ATP1A3
- Na⁺/K⁺ ATPase α3
- ATPase
- Mutation: Probably gain of function
Clinical
- Cerebellar ataxia (100%)
  - Onset
    - Age 3 months to 5 years
    - Episodic ataxia with fever: May persist from 5 years to 3rd decade
  - Later
    - Ataxia: Fixed; Nystagmus
    - Course: Progressive
- Areflexia (100%)
- Pes cavus (40%)
- Optic atrophy (100%)
- Sensorineural hearing loss (100%)
- Episodes also include
  - Sudden onset
  - Reduced consciousness
  - Hypotonia
  - Quadriparesis
- Cognition: Mild deficits
- No dystonia
Laboratory
- Visual evoked potentials: Absent
- EMG: Motor unit loss
- Nerve biopsy: Axon loss
- Muscle: Varied fiber size or Normal
- MRI: Normal
- CSF: Normal
- Mitochondrial oxidative enzymes: Normal
ATP1A3 variant disorder: Spasticity & Intellectual Disability ¹⁰²
- Epidemiology: 9 patients
- Genetics
  - Mutation: Pro775Leu
  - Inheritance: Dominant or de novo; No family history of similar disorders
  - Mutation effects on ATP1A3 function
    - Leakage of sodium ions & protons into cells
    - Impaired sodium binding/occlusion kinetics → States with fewer bound ions
- Clinical
  - Onset age: Childhood
  - Pyramidal features
    - Spasticity: Diplegia > Quadriplegia
    - Tendon reflexes: Increased in most
    - Course: Progressive or Static
  - Cortical
    - Intellectual disability
    - Developmental disorders
  - Obesity
  - Movement disorders: Some patients
  - Episodic features: 2 patients
- Laboratory
  - Brain MRI: Usually normal

Von Hippel-Lindau Syndrome

● 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

Familial Cortical Myoclonus ⁵⁸
● Nucleolar protein 3 (NOL3; ARC)

; Chromosome 16q22.1; Dominant

Epidemiology: Canadian Mennonite family
Genetics
- Mutation: E21Q
NOL3 protein
- Expressed in heart, skeletal muscle & brain
Clinical
- Onset age: 2nd to 7th decade
- Myoclonus
  - Exacerbation by: Action; Touch; Fatigue; Sleep deprivation; Emotion; Hunger
  - Less with: Frequent small meals
- Falling: Sudden
- Insomnia
- Ataxia: Later in course; Limb & Gait
- Course: Progressive; Wheelchair confinement
- Normal: Cognition; Long tracts; No seizures
- Treatment: Clonazepam; Valproate
Laboratory
- SSEP: Giant cortical potentials
- EEG: Normal

Myelocerebellar Disorder (Ataxia-Pancytopenia; ATXPC)

⁷²
● Sterile alpha motif domain-containing protein 9-like (SAMD9L)

; Chromosome 7q21.2; Dominant or de novo

Epidemiology: 85 patients, 36 families
Genetics
- Mutations
  - Missense
    - c.2640C>A (p.His880Gln), Arg986Cys, c.3587G>C (p.Cys1196Ser)
    - Gain of function
  - Deletions: More severe disease
- Chromosomal
  - Monosomy 7 mosaicism
  - Sensitivity to bleomycin
- Allelic disorders
  - Somatic mutations: Hepatocellular carcinoma
  - Monosomy 7 Myelodysplasia & Leukemia syndrome 1
  - SAMD9L-associated autoinflammatory disease (SAAD)
    - Mutations: Truncating in NOD domain
    - Subcutaneous fat: Inflammation
  - SCA49
SAMD9L protein
- Expressed in
  - Adult & Fetal tissues
  - Purkinje cell soma
- Role in
  - Cell proliferation: ? Tumor suppressor
  - Mitochondrial function
- Type-I interferon responsive gene
  - Anti-viral response
  - SAMD9L mRNA: Marked increase after interferon-β stimulation
- Possible disease mechanism ⁸⁸
  - Interferon-induced translational repressor
  - Activity is unchecked by loss of C-terminal domains
    - C-terminal domains normally sense virus infection
- Paralogous gene: SAMD9
Clinical: Spastic ataxia
- General: Autoinflammatory disorder
- Onset age: 3 months to 62 years
- Ataxia
  - Gait disorder: More in 4th to 7th decades
  - Nystagmus: Most frequent
  - Dysmetria
  - Dysarthria
- Long tract signs: Motor
  - Legs: Spasticity
  - Tendon reflexes: Increased; May be reduced at ankles
  - Plantar reflexes: Extensor
- Polyneuropathy
  - Sensory loss
    - Panmodal
    - Legs > Arms
  - Weakness: Symmetric; Proximal & Distal
- Conjunctiva: Telangectasias
- Course
  - Progressive ataxia
  - Death
    - Childhood
    - Some due to leukemia
Laboratory
- Hematologic
  - Common: Thrombocytopenia & Red cell macrocytosis, mild
  - Immunodeficiency: Especially B-cell, Pancytopenia
  - Hypoplastic anemia
  - Leukemia: Acute myelomonocytic (4%)
  - Anemia: Childhood onset
  - Bone marrow mitotic activity: Reduced
  - Course: May be intermittent
- Retinal nerve fiber layer: Thin
- Brain MRI or CT scan
  - Cerebellar atrophy, especially midline
  - White matter: Periventricular, lesions
- Electrophysiology
  - Reduced nerve conduction velocities
  - Motor & Sensory CV: 25 to 36 M/s
  - Sural SNAP: May be absent
- Cerebellum pathology
  - Purkinje > Granule cell loss
  - White matter change
SAM9DL variant: SCA49 ⁹¹
- Epidemiology: 1 family
- Genetics
  - Mutation: Ser626Leu
  - Inheritance: Dominant
- Clinical
  - Onset ages: 12 to 60 years
  - Gait disorder
  - Ataxia: Dysmetria
  - Nystagmus: Gaze evoked
  - Tendon reflexes: Increased
  - Course: Progressive
- Laboratory
  - Brain MRI: Cerebellar atrophy; Myelin Δ
  - Nerve conduction: Abnormal sensory
Ataxia-Pancytopenia differential diagnosis
- Dyskeratosis congenita (DC): Hoyeraal-Hreidarsson syndrome (HHS)
- X-linked sideroblastic anemia & Ataxia (XLSA/A)

Ataxia with Slow ocular saccades, Neuropathy & Orthostatism

⁶⁵
● Dominant

Epidemiology: 2 Swedish familes, > 20 patients
Clinical
- Onset ages: 16 to 47 years
- Ataxia: Gait, Limb, Dysarthria
- Ocular
  - Horizontal saccades: Slow or Hypometric
  - Ocular motor apraxia
- Polyneuropathy
  - Sensory loss: Pan-modal
  - Muscle wasting: Some patients
  - Tendon reflexes: Absent
- Autonomic: Orthostatic hypotension, Diarrhea
- Extrapyramidal: Mild
  - Head tremor
  - Dystonia
  - Grimacing
- Course: Slow progression
Laboratory
- MRI: Cerebellar atrophy
- NCV: Axon loss, Sensory & Motor

SCA50: Ataxia

⁹⁰
● Neuronal Pentraxin 1 (NPTX1)

; Chromosome 17q25.3; Dominant or de novo

Epidemiology: 8 families, 19 patients
Genetics
- Mutations: Missense; R143L, E327G, Gln370Arg, G389R
NPTX1 protein
- Secreted
- Mutations: Endoplasmic reticulum stress & altered morphology
Clinical
- Onset age: 2 to 71 years
- Ataxia: Trunk; Limb
- Tremor (50%)
- Eye: Nystagmus; Saccadic pursuit; Oculomotor apraxia
- Myoclonus: Some patients
- Cognitive: Normal or Mild impairmant
Laboratory
- Brain MRI: Cerebellar atrophy, especially vermis

SCA51: Ataxia

⁹⁹
● Thap domain containing protein 11 (THAP11; Ronin)

; Chromosome 16q22.1; Dominant

Epidemiology: 2 families; 24 patients
Genetics
- Mutation: CAG repeat
  - Size: Disease 45 to 100; Control 20 to 38, Most commmon 28 or 29
  - Pure CAG repeats: Disease 32 to 87; Control 4 to 16
  - Quality: Reduced interruptions to 3; control 5 to 6
  - Location: Exon 1
  - Longer repeats: Earlier disease onset
- Allelic disorder
  - Methylmalonic aciduria & Homocystinuria of cblL type (MAHCL)
THAP11 protein
- Location: Nucleus
- Regulates: Cell cycle, proliferation, transcription & cobalamin metabolism
- Cofactor: Host cell factor 1 (HCF1)
- Disease mechanism: PolyQ toxicity
Clinical
- Onset age
  - Median 34
  - Range 4 to 51
  - Anticipation: 4th generation onset mean = 8 years
- Ataxia
  - Gait
  - Saccades: Slow
- Upper motor neuron signs (20%)
- Course: Progressive
- Age at death: Mean 40, Range 15 to 61
Laboratory
- Brain MRI: Atrophy, Cerebral & Cerebellar
- NCS/EMG: Normal
- Fibroblasts: THAP11 & p62 aggregates

Familial Dementia with Amyloid angiopathy & Spastic Ataxia
● 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

Paroxysmal Disorders: Seizures; Dyskinesias; Ataxia, episodic & Hemiplegic migraine

● Proline-rich transmembrane protein 2 (PRRT2)

; Chromosome 16p11.2; Dominant

Genetics: Allelic disorders
- Convulsions, familial infantile, with paroxysmal choreoathetosis
- Episodic kinesigenic dyskinesia 1
- Seizures, benign familial infantile, 2
- Episodic ataxia (0.5%)
- Hemiplegic migraine (0.5%)
Clinical
- Common syndrome: Paroxysmal kinesigenic dyskinesia (PKD) ± Infantile convulsions

Hypotonia, Ataxia & Delayed Development (HADDS)

⁷⁵
● Early B-Cell factor 3; EBF3 (EBF3; COE3)

; Chromosome 10q26.3; Dominant or Sporadic

Epidemiology: > 30 patients
Genetics
- Mutations: Slice site, Missense, Stop, Gene deletion
EBF3 protein
- EBF transcription factor Collier/Olf/EBF (COE) family
- Transcriptionally repressed by ARX
- Late neural differentiation
- Ebf3 haploinsufficiency in mice: Abnormal GABAergic interneuron migration & projection
Clinical
- Intellectual disability
- Speech delay
- Ataxia (80%)
- Hypotonia: Truncal
- Pain: Insensitivity
- Facial dysmorphism: Long face; Deep forehead; High nasal bridge; Chin short & broad
- Strabismus
- GU
  - Micropenis
  - Cryptorchidism
  - Neurogenic bladder
  - Vesicoureteric reflux
Laboratory
- Brain MRI: Normal or Cerebellar & Vermis atrophy

Hypotonia, Ataxia, Developmental-Delay, Tooth-enamel defects (HADDTS)

⁹⁸
● C-Terminal-Binding protein 1 (CTBP1)

; Chromosome 4p16.3; Dominant or de novo

Epidemiology: 14 patients
Genetics
- Mutations: Missense; Arg331Trp, Arg342Trp
CTBP1 protein
- Transcriptional co-repressor: Gene-regulation during development
- Scaffolding- protein
  - Recruits chromatin-modifying-enzymes to areas of genome
  - Coordinates gene-expression programs
- Regulates gene-expression during development, apoptosis, oncogenesis
- Interacts with: Myogenin promoter; Calpain-3
- CTBP1 inactivation: Blocks late-stage muscle- differentiation
Clinical
- Onset age: Early childhood
- Hypotonia
- Weakness
  - Proximal limb
  - Trunk
  - Pulmonary
  - Slow progression
- Ataxia
  - Gait
  - Limb
  - Oculomotor apraxia (AOA)
- CNS Development
  - Delay
  - Intellectual disability
- Dysphagia
- Tooth-enamel defects: Soft; Discoloration
- Skeletal: Scoliosis; Joint contractures
Laboratory
- Brain MRI: Cerebellar atrophy
- EMG: Myopathic
- Serum CK: 400 to 500
- Muscle MRI: Posterior thigh; Most leg muscles
- Muscle pathology
  - Fiber sizes: Varied; Nuclear clumps; Hypertrophy; Type 1 smaller
  - Necrosis: Scattered fibers
  - Internal architecture: Irregular; core-like structures
  - COX- fibers
  - Vacuoles
  - Endomysial connective tissue: Increased
  - OXPHOS: Normal or Reduced complexes I & IV
  - Ultrastructure: Focal myofibrillar rarefaction; Vacuoles; Mitochondrial &Delta:

Progressive Myoclonus epilepsy + Ataxia (EPM7; MEAK)

⁷⁷
● Potassium channel, voltage-gated, Shaw-related subfamily, member 1 (KCNC1)

; Chromosome 11p15.1; Sporadic or Dominant

Epidemiology: > 20 patients
Genetics
- Mutation: Recurrent de novo Arg320His
- Mutation mechanism: Dominant-negative loss-of-function
- Mutation rate: 1 per 5,700,000 conceptions
KCNC1 protein
Clinical
- General
  - Resembles Unverricht-Lundborg disease
  - Homogeneous phenotype
  - Varied severity
- Onset age: 3 to 15 years (Median 9.5)
- Myoclonus
  - Action induced
  - Can result in falls
  - Progressively severe
  - Worse: Morning; Stress; Menses
- Tonic-clonic seizures
- Ataxia (95%)
- Course:
- Cognitive decline (50%)
- Course
  - Fever & Pregnancy: Transient clinical improvement
  - Wheelchair-bound by late teens
  - Early death: Not observed
- Treatment: Anti-epileptic drugs
Laboratory
- EEG: Generalized spike & polyspike wave discharges; Photosensitivity
- Myoclonus: Cortical: Co-activation of agonist & antagonist muscles
- MRI: Cerebellar atrophy, symmetric & progressive; Corpus callosum prominent
- Mutant channel function: Improves (Left-shift) with higher temperatures

Mental retardation, autosomal dominant 55, + Seizures (MRD55)

¹⁰⁰
● NUS1 Dehydrodolichyl diphosphate synthase subunit (NUS1)

; Chromosome 6q22.1; Dominant or de novo

Epidemiology: > 10 patients
Genetics
- Mutations: Deletion; Duplication; Insertion; Missense
- Allelic disorders
  - Congenital disorder of glycosylation, Type Iaa : Missense mutation, Recessive
  - Diabetes susceptibility: Japan
  - 6q22 deletion
  - Myoclonic Epilepsy, Recessive
NUS1 protein
- Precursor of membrane receptor for N terminus of Nogo-B (NgBR)
- Functions: Dolichol synthesis & Protein glycosylation
- Stabilizes Dehydrodolichyl-diphosphate synthase (DHDDS) complex in Endoplasmic reticulum
- Similar clinical syndromes caused by: DHDDS mutations
Clinical (MEAID)
- Onset age: Months to 13 years
- Global developmental delay: Intellectual disability, Speech delay
- Seizures: Tonic-Clonic, Myoclonic & Absence; Onset 1 to 41 years
- Ataxia: Gait
- Extrapyramidal: Tremor; Parkinsonism; Dystonia; Limb myoclonus
- Normal: EOM; DTRs; Sensation
Laboratory
- Brain imaging: Normal or Cerebellar atrophy, mild
- Dyslipidemia & Diabetes: Some patients

Dystonia 28 (DYT28)

● Lysine-specific methyltransferase 2B (KMT2B)

; Chromosome 19q13.12; Dominant or de novo

Epidemiology: > 100 patients
Genetics
- Mutations: Stop, Splice, Missense
- Penetrance: Incomplete
KMT2B protein
- Histone methyl transferase
- Gene activation
Clinical
- Onset age: Childhood > Adult
- Dystonia: Generalized
- Myoclonus
- Ataxia: Some patients
- Neuropathy
- Spasticity: Gait disorder; DTRs brisk
- Seizures
- Neurodevelopmental delay
- Eye: Myopia; Optic atrophy; Pursuit fragmented
- Face: Dysmorphic; Microcephaly
- Course: Progressive
Laboratory
- Brain MRI: Globus pallidus lesions
- NCV: Sensory Axon loss

Neurodevelopmental disorder + Impaired language & Ataxia ± Seizures (NEDLAS)

● Glutamate receptor, Ionotropic, Kainate 2 (GRIK2)

; Chromosome 6q16.3; Dominant or de novo

Epidemiology: 11 patients
Genetics
- Mutations
  - Missense: Ala657Thr; Thr660Lys; Thr660Arg
- Allelic disorder
  - Intellectual developmental disorder, autosomal recessive 6
  - Huntington disease: Polymorphism
GRIK2 protein
- Kainate receptor subunit GluK2
- Transmembrane channel
- Activated by: Glutamate
- Excitability of mossy fiber axons
Clinical
- Onset: Infancy
- Hypotonia, axial
- Developmental delay
- Language development: Poor
- Gait: Delayed walking; Ataxia
- Behavioral abnormalities
- Seizures: More severe disease
Laboratory
- Brain imaging: Hypomyelination; Corpus callosum thin

Ataxia, Early onset + Neurodevelopmental Disorder & Neuropathy ⁹⁴
● Cell cycle associated protein 1 (CAPRIN1)

; Chromosome 11p13; Dominant, de novo

Epidemiology: 4 patients
Genetics
- Mutation: Missense; Pro512Leu (c.1535C>T)
- Allelic associations (Haploinsufficiency)
  - Autism spectrum disorder (ASD)
  - Neurodevelopmental disorder + Language impairment, ADHD, ASD
CAPRIN1 protein
- Expression: Ubiquitous; Higher with cell turnover
- RNA-binding protein (RBP)
- Regulates transport &[; translation of mRNAs of synaptic proteins
- Contains: Prion-like domain (PrLD)
- Component of: Stress granules, Cytoplasmic assemblies of RBPs; Stalled mRNAs
- Interactions: ATXN2; GEMIN5
- Mutated protein: Aggregation propensity increased
Clinical
- Onset age: Early childhood
- Developmental delay
- Ataxia: Trunk; Limbs; Tremor
- Bulbar: Dysarthria; Dysphagia
- Cognitive decline
- Muscle weakness: Proximal
- Tendon reflexes: Reduced
- Scoliosis
- Course: Progressive
Laboratory
- NCV: Sensory-Motor Axonal neuropathy
- Muscle pathology: Muscle fiber atrophy
- Nerve pathology: Axon loss
- Brain MRI: Cerebral & Cerebellar atrophy
- SSEP: Reduced in legs

Dominant Ataxia, Other

Hereditary ataxia with thermoanalgesia & loss of fungiform papillae
Branchial myoclonus with Spastic paraparesis & Cerebellar ataxia
Essential tremor, Familial
● Dopamine receptor D3 (DRD3) ; Chromosome 3q13.31; Dominant
Spinocerebellar ataxia with Rigidity & Peripheral neuropathy
● Dominant
- Ataxia: Late onset
- Extrapyramidal: Rigidity; Bradykinesia; Dysarthria
- Spasticity
- Muscle atrophy
- Peripheral neuropathy: ? Demyelinating

Episodic Ataxias ⁷³

Episodic ataxias: Differential diagnosis
Type	Onset age (yrs)	Attack duration	Symptoms	Interictal features	Triggers
EA1: KCNA1	< 20	Minutes	Muscle spasms	Seizures, Myokymia	Exertion; Posture Δ, Stress; Startle
EA2: CACNA1A	< 20	Hours	Vertigo, Weakness	Ataxia, Nystagmus	Exertion; Stress; Alcohol
EA3: 1q42	< 20	Minutes	Vertigo, Tinnitus, Headache	None	Kinesigenic
EA4: ?	20-50	Hours	Vertigo, Diplopia	Nystagmus, Smooth pursuit Δ
EA5: CACNB4	20-60	Hours	Vertigo	Nystagmus, Ataxia
EA6: EAAT1	< 10	Hours	Cognitive impairment	Seizures, Ataxia	Fever
EA7: 19q13	< 20	Hours	Vertigo, Weakness	None	Exertion; Excitement
EA8: 1p36	< 2	Mins to Hrs	Ataxia, Weakness	Tremor	Tiredness; Stress
EA9: FGF14	2 to 8	Mins to Days	Ataxia	Tremor, Nystagmus	Fever; Stress
EA: SCN8A	10	2 to 3 Days	Ataxia; Diplopia	None	Fever
CSE: GLUT1	2 to 15	20 minutes	Chorea; Ataxia; Headache	Spasticity	Alcohol, Fatigue, Stress, Exercise
EA: SCN2A	< 1 yr	Mins to Hrs	Ataxia; Dysarthria	Seizures
EA: CEP290	46 yrs	Mins to Hrs	Ataxia; Dysarthria; Diplopia	Seizures
SCA19: KCND3			Ataxia	Seizures; Cognitive; PN

EA 1: Episodic Ataxia / Myokymia Syndrome

● Potassium Voltage-Gated Channel (KCNA 1)

; Chromosome 12p13.32; Dominant

Genetics
- > 25 Mutations
- Mutation types: Missense, Point; One nonsense
- Allelic disorders
  - Hypomagnesemia, Dominant
  - Epilepsy: Mutations in S1/S2 helices & Pore domain; PVP motif
  - KCNA1 Variant syndromes
  - Paroxysmal Kinesigenic Dyskinesia: N255K & L319R mutations
KCNA 1 protein
- Forms K_v1.1 channels in PNS & CNS
- Mutations cause
  - Altered neuronal excitability
  - Loss of K_v1.1 channel function: Some mutations
Clinical features
- Phenotype may vary within families ⁴⁰
- Onset
  - Age: Childhood to 2nd decade
  - Myokymia may precede Ataxia
- Episodes: Ataxia
  - Duration
    - Brief: Attacks last seconds to minutes
  - Most frequent during adolescence
  - Provoked by
    - Abrupt postural change
    - Emotion & Anxiety
    - Vestibular stimulation
    - Exercise
  - Ataxia
    - During attacks
    - Cerebellar dysfunction: Especially midline; No nystagmus
    - Between episodes: No fixed ataxia
  - Other symptoms
    - Onset: Shock or click in head
    - Dizziness without vertigo
    - Visual blurring
    - Anxiety
  - Choreoathetotic movements: May occur during attacks
  - Episodes occur in most but not all patients with KCNA1 mutations
- Neuromyotonia (Continuous spontaneous muscle fiber activity)
  - Mutations: S2 helix (T226K, A242P) & S2�S3 intracellular linker (P244H)
  - Clinical
    - Present in most EA1 patients
    - Severity: Mild to Constant & severe
    - Distribution: Especially in face & small hand muscles
    - Cramps
    - Hand posture: Like carpopedal spasm
    - Course: Occcurs during & between episodes of ataxia
    - Constant neuromyotonia associated with
      - Increased tone
      - Muscle hypertrophy
      - Skeletal deformities
- Other associations
  - Spasticity: Legs
  - Seizures
  - Skeletal deformities: Associated with more severe neuromyotonia
    - Short stature
    - Kyphoscolosis
  - Hearing loss
  - Hyperthermia: C185W & F249C mutations
- Treatments: Phenytoin, Carbamazepine (600 to 800 mg/day), Oxcarbazepine, Not Acetazolamide
Laboratory
- Muscle
  - Variable fiber size
  - Type I predominance
  - PAS stain: Glycogen depletion
- Nerve conduction studies: Sensory & Motor normal
Variant syndrome: Neuromyotonia & Stiffness
- Mutation: Phe249Leu
- Clinical
  - 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: Neuromyotonia, chronic, with disappearance of ataxia
- Mutation: L305F
Variant syndrome: Neuromyotonia, severe & Skeletal deformities
- No prominent Episodic Ataxia
- Mutation: Thr226Arg
Variant syndrome: Ataxia, Episodic + Paroxysmal Dyspnea
- Genetics
  - Mutation: In-frame three-nucleotide deletion: Predicts elimination of Phe at position 250
- Clinical
  - Onset: Age 1 to 14 years
  - 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: Ataxia, Fixed
- Mutation
  - Val408Leu
  - Mutation effect: Increases ability of channel to inactivate
- Clinical
  - Cerebellar dysfunction: Persistent
  - Cognitive delay
  - Myokymia
  - Epilepsy
- CNS: Cerebellar atrophy
Variant syndrome: Hypomagnesemia ⁸⁰
- Epidemiology: 2 families
- Genetics
  - Inheritance: Dominant
  - Mutations: N255D; Leu328Val
- Clinical
  - Muscle cramps
  - Tetanic episodes
  - Tremor
  - Weakness
- Laboratory
  - Plasma Mg⁺⁺ levels: 0.40 mmol/L (Normal = 0.70-0.95)

EA 2: Hereditary Paroxysmal Cerebellar Ataxia

● α_1A Calcium channel, voltage dependent (CACNA1A)

; Chromosome 19p13.2; Dominant

Epidemiology: Multiple families
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 protein ²²
  - Loss of function
  - Dominant negative effects: Some mutations
  - Association with more severe baseline ataxia
    - Deficienct plasma membrane targeting
    - Misfolded channel protein
Clinical features ³²
- Onset: Early childhood to Teens; < 20 years
- Episodes: Ataxia+
  - Triggers
    - Physical exertion
    - Emotional stress
    - Heat
    - Fatigue
  - Attack duration
    - Often last 1/2 to 6 hours
    - > 10 minutes
  - Cerebellar
    - Nystagmus
    - Truncal instability
    - Dysarthria
  - Associated symptoms
    - Vertigo (50%)
    - Nausea
    - Vomiting
    - Headache
    - Hypotonia
  - Weakness (50%): Generalized
- 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 weakness ¹⁹
  - 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%
  - Migraine
  - Cognitive impariment & Developmental delay: Severe syndromes
- Treatment
  - Acetazolamide: 75%
  - 4-aminopyridine (5 mg tid): K⁺ channel blockade ³⁶
  - ? Pyridostigmine
Laboratory
- Neuromuscular junction ³¹
  - 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
● 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)

● Dominant

Epidemiology: North Carolina families
Clinical
- Onset age: 3rd to 6th decade
- Episodes
  - Precipitants: Sudden head movements; Fatigue; Movement in peripheral vision
  - Features: Vertigo; Diplopia; Ataxia
- Ataxia: Slowly progressive
- Ocular: Defective slow pursuit
- No myokymia
- Treatment: Gabapentin; No response to acetazolamide
Pathology
- Cerebellar atrophy: Purkinje cell loss or damage; Cytoplasmic aggregates

Episodic ataxia 5 (EA5)

● CACNβ4

; Chromosome 2q23.3; Dominant

Epidemiology
- French-Canadian family
- Onset: 3rd or 4th decade
Genetics
- Mutation: Cys104Phe; May be polymorphism
- Incomplete penetrance
CACNβ4 protein
Clinical syndromes
- Ataxia
  - 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
● SLC1A3 (EAAT1)

; Chromosome 5p13.2; Dominant or de novo

Epidemiology: 10 families
Genetics
- Mutations: Missense; Met128Arg, Cys180Ser, Glu219Asp, Pro290Arg, Val393Ile, Arg499Gln
- Allelic disorders
  - Episodic ataxia, late onset
  - Ataxia, Adult onset
EAAT1 protein
- Glial glutamate transporter (GLAST): Clearance of glutamate after synaptic release
- Anion channel: Glutamate-activated, Na⁺ gated
- High glutamate transport rate associated with low chloride conductance
- Expressed primarily in caudal brainstem & cerebellum
- Mutation
  - Reduced capacity for glutamate uptake
  - Dominant negative effect when polymerized with other EAAT1
Clinical
- Onset
  - Age: Infant to Adult
  - Episodic hypotonia
- Motor: Delayed milestones
- Ataxia
  - Episodes: Onset 6 months
  - Triggers: Febrile illness; Stress
  - Duration: Hours to 4 days
  - Between episodes: Mild truncal ataxia; May be progressive
- Episodic
  - Migraine
  - Hemiplegia: Alternating
  - Visual field loss: Hemianopia
  - Seizures
  - Coma
  - Sensory: Photophobia; Phonophobia
  - Vertigo
- EOM
  - Diplopia
  - Symmetric impairment of
    - Smooth pursuit
    - Optokinetic nystagmus
    - Fixation-suppression of VOR
- Other features between episodes
  - Mental retardation: Mild
  - Tendon reflexes: Increased
Laboratory
- MRI
  - Cerebellar atrophy, mild
  - FLAIR hyperintensity during episodes
- EEG: Seizures
SLC1A3 variant disorder: Episodic ataxia, late onset ⁷⁴
- Epidemiology: 1 Korean family
- Genetics
  - Inheritance: Dominant
  - Mutation: c.1177G>A (V393I)
- Clinical
  - Onset age: 55 years
  - Episodes
    - Episodic ataxia
    - Dizziness
    - Dysarthria
    - Diplopia
    - Triggers: Stress, Heat, Smoking
    - Duration: Hours
  - Interictal
    - Downbeat nystagmus
    - Hypermetric saccades
    - Truncal ataxia, mild
  - Treatments
    - Acetazolamide
    - 3,4 Diaminopyridine
- Laboratory
  - Brain MRI: Normal
SLC1A3 variant disorder: Ataxia, Adult onset
- Epidemiology: 1 family
- Genetics
  - Inheritance: Dominant
  - Mutation: c.1361G>A (Arg454Gln (Arg499Gln))
- Clinical
  - Onset age: 30 years
  - Ataxia: Slowly progressive
  - Bulbar
    - Dysarthria
    - Dysphagia
  - Eyes
    - Ocular pursuit: Jerky
    - Saccades: Hypometric
- Laboratory
  - Brain MRI: Normal

Episodic ataxia 7 (EA7)

● Chromosome 19q13; Dominant

Epidemiology: 1 American family
Clinical
- 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 8 (EA8)

● Ubiquitin protein ligase E3 Component N-Recognin 4 (UBR4)

; Chromosome 1p36.13-p34.3; Dominant

Epidemiology: Irish family & Korean patients
Genetics
- Mutations or VUS: Missense
- Variants may also modify EA2
UBR4 protein
- Interacts with calmodulin
- Calcium sensor
Clinical
- Onset age: 1 to 2 years
- Attacks
  - Unsteady gait
  - Generalized weakness
  - Slurred speech
  - Duration: Minutes to Hours
  - Frequency: 2 per day to Monthly
  - Triggers: Tiredness; Stress; Not kinesiogenic
  - Variable features
    - Periocular twitching
    - Nystagmus
    - Myokymia
    - Dysarthria
    - Intention tremor
    - Migraine
  - Course: Reduced frequency with age & pregnancy
  - No vertigo
- Treatment
  - Clonazepam
  - Acetazolamide response: No
Brain MRI: Normal

Episodic ataxia + Paroxysmal choreoathetosis & Spasticity (Dystonia-9; DYT9; CSE)

● SLC2A1 (GLUT1)

; Chromosome 1p34.2; Dominant

Epidemiology: 4 families
Genetics
- Mutations: Gln46X; R126C; R232C; Glu329Lys
- Allelic disorders
GLUT1 protein
- Glucose transporter: Brain, Placenta, Erythrocytes
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
- Treatments: Acetazolamide; Phenytoin
Laboratory
- EEG: Slowing

Episodic Ataxia + Diplopia ¹⁰¹
● SCN8A

; Chromosome 12q13.13; Dominant (de novo)

Epidemiology: 1 patient
Genetics
- Mutation: Missense; Arg847Gln
- Allelic disorders
SCN8A protein
Clinical
- Onset age: 10 years
- Episodes
  - Diplopia
  - Gait disorder
  - Dysmetria
  - Association: Febrile illness
  - Episode length: 2 to 3 days
- Intelligence: Normal
Laboratory
- EEG ± During episodes: Multifocal epileptiform discharges
- Brain MRI: Normal

Glucose Transporter 1 Deficiency Syndrome 2 (GLUT1DS2)

● SLC2A1 (GLUT1)

; Chromosome 1p34.2; Dominant or Sporadic

Epidemiology: > 15 families
Genetics
- Mutations: Deletion; Missense; Stop
- Allelic disorders
  - Epilepsy, idiopathic generalized, susceptibility to, 12
  - Dystonia 9
  - GLUT1 deficiency syndrome 1, infantile onset, severe
  - GLUT1 deficiency syndrome 2, childhood onset
  - Episodic ataxia + Paroxysmal choreoathetosis & Spasticity
  - Stomatin-deficient cryohydrocytosis with neurologic defects
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: Limb; Dysarthria; May be episodic
- Involuntary movements
Laboratory
- Blood glucose: Normal
- CSF glucose: Low
- CSF Lactate: Low-to-normal

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HEREDITARY ATAXIAS: DOMINANT

Episodic Ataxias 73

Episodic Ataxias ⁷³