ATAXIA

1. Approach to Ataxia
ALOK SAHAY, MD
Assistant Professor – Neurology
University of Cincinnati
3/1/06

2. Definition
literal meaning -without order
clumsiness
loss of co-ordination

3. Genesis
 cerebellum and its connecting pathways
 proprioceptive sensory pathways
 vestibular system

4. Cerebellar Dysfunction: Anatomy
Cerebellar parts Functions Signs
Posterior
(Flocculo-nodular lobe)
Archicerebellum
Body equilibrium
Eye movements
Eye movement disorders:
Nystagmus;
Vestibulo-ocular reflex
(VOR)
Postural and gait dysfunction
Midline
(Vermis; vermis of ant. lobe
pyramid , uvula and
paraflocculus)
Paleocerebellum
Input from spinal cord
Muscle tone
Axial stance and gait
Truncal & gait ataxia
Hemisphere
(middle portion of vermis,
cerebellar hemisphere)
Neocerebellum
Connected with Pons
and cortex through
thalalmus
Planning and initiation
of movements
Regulation of fine limb
movements
Limb ataxia:
Dysmetria,
Dysdiadochokinesis,
"intention" tremor
Dysarthria
Hypotonia

5. Cardinal features - Cerebellar pathology
– Stance and gait
– Poor regulation and coordination of skilled
movements (Dysmetria and dysdiadokinesia)
– Eye movement disturbances
– Altered Muscle tone (Hypotonia)
– Speech (Dysarthria)

6. Core Symptoms
• Difficulty with balance of gait
• Clumsiness of hands
• Dysarthria
• Gaze problems

7. Manifestations- Stance and gait
– Wide based stance & Gait
– Gait- staggering, irregular steps, lateral veering.
– Cerebellar gait -visible or more prominent
– Sudden turn, Abrupt stops , Tandem walking
– Ataxic sensory gait
• brisk leg movements
• legs placed far apart to correct instability
• steps of variable length
• need for carefully watching the ground.
• +ve Romberg's sign .
– Most of the autosomal recessive and dominant ataxias and with a
known genetic defect are characterized by the coexistence of
cerebellar and sensory ataxia

8. Limb coordination
• Asynergia- movements are broken into isolated subsequent steps , lack
easiness/ smoothness
• Dysdiadochokinesia- impaired REM
• Dysmetria. there is an abnormal excursion in movements and errors in
reaching a precise target
• Tests
– finger-to nose, the finger-chase tests for the upper limbs
– heel-to-knee and heel-to-tibia tests for the lower limbs.
• In coordination due to cerebellar disease is associated
– with abnormal speed of the movements
– to an excessive rebound phenomenon when an opposed motion is
suddenly released. ( due to a delay in contraction of the muscles, which
normally would arrest the flexion of the limb)
– Speed of initiating the movement is also slow and there is irregularity
in both acceleration and deceleration of movements

9. Tremor
• kinetic (intention) tremor
• static (postural) tremor may also occur.
• Related to hypotonia.
• In some cases of SCAs- myoclonus or chorea
may be superimpose on postural tremor.

10. Muscle tone
• Hypotonia is a typical cerebellar sign.
• Wider excursion of hands on shaking the arms.
• Obliteration of the space between the volar aspect of the wrist and
the deltoid.on a forced flexion of the arm at the elbow.
• In ataxic patient, the hypotonia is not a constant clinical sign.
– Present in FRDA1 patients, “pure” cerebellar syndromes- SCA6,
10, and 11 subtypes.
– In some other spinocerebellar disorders normal or increased
muscle tone may also be found - SCA3 or MSA.

11. Speech- Dysarthria
• Altered articulation of words
• Abnormal fluency of speech.
• Scanning Dysarthria
• Slurring

12. Ocular Motor Functions
• Smooth pursuit movements
• Saccades
• Certain clinical cerebellar syndromes might have characteristic
patterns
– FRDA1- fixation instability , square wave jerk, consistently
undershoot or overshoot the target during horizontal saccadic eye
movements (saccadic dysmetria)
– ABL -progressive paresis of the medial rectus muscles with
nystagmus of the adducting eye on lateral gaze was observed
– AR ataxias (some ) Oculomotor apraxia
– AD ataxias-
• Fragmentation of smooth pursuit movements,
• Saccadic dysmetria
• Nystagmus
• Saccadic slowing SCA1, SCA2, SCA3, SCA7, and SCA17
• ophthalmoplegia -SCA2 SCA1 and SCA3

13. Classification
Congenital
Hereditary
Autosomal Dominant
Autosomal Recessive
Congenital
DNA repair defects
Metabolic disorders
Mitochondrial
Multisystem disorders
X-linked
Immune
Miller-Fisher
Multiple sclerosis
Paraneoplastic
Infections: CNS
Acute ataxia: Viral
Creutzfeldt-Jakob
Meningitis
Mass lesion
Abscess
Neoplasm
Sarcoid
Paroxysmal
Epilepsy
Febrile
Migraine
Polyneuropathy
Anti-MAG Syndrome
GALOP Syndrome
Sensory Neuropathy
Large fiber Neuropathy
Supratentorial
Gait disorders
Elderly
Extrapyramidal
Hydrocephalus
Systemic
Amyloid
Autoimmune
Endocrine
Hypoparathyroid
Thyroid
GI disorders
Celiac disease; Sprue
Vitamin E malabsorption
Whipple's
Toxins & Drugs
Trauma
Vascular
Vestibular

14. Etiology
• Degenerative – MSA, Progressive myoclonic epilepsy
• Stroke
– cerebellar, thalamic, brainstem, pontomedullary junction, lesions
causing ataxic hemiparesis
• Tumors- Medulloblastoma, Astrocytoma, Ependymoma,
Hemangioblastoma, Metastasis, Meningioma, CP angle schwanoma
• Toxic/ Metabolic-
– Alcohol,
– Hypoxia,
– Hyperammonimias
– Vitamin def. -B1, B12, Thiamine
– Endocrine- hypothyroidism, hypoparathyroidism, hypoglycemia,
– Thallium, bismuth, methyl mercury, methybromide, toulene
– Drugs- PHT, CBZ, Brabiturates, Lithium, Cyclosporine, Methotrexate,
5FU, Serotinin syndrome

15. Etiology
• Paraneoplastic
• Autoimmune
– Anti- GAD antibodies
• Infectious/post-infectious-
– rubella
– H.influenza
– Varicella ( post infectious cerebellitis)
– CJD
• Demyelinating- Multiple sclerosis
• Other-
– Chiari malformation
– Abscess
– Hydrocephalus
– Superficial hemosiderosis
• Ataxias of non cerebellar origin- Peripheral neuropathies

16. Paraneoplastic-
cerebellardegenerations (PCD)
• associated with specific tumor
type antineuronal (anti purkinje
cell antibodies)
• late-onset ataxia and are
characterized by a sub acute
progressive course.
• Even if the cancer is found and
successfuly the disorder may well
not improve because cells are
irreversibly damaged.
• Functional outcome best in anti-
Ri,
• Survival worse with anti-Yo and
anti- Hu, better with anti Tr and
anti Ri
• Most common –
– Gynecological & breast
cancer
– Lung cancer
– Hodgkin's
• Small cell lung cancer
– anti-Hu, anti-Ri ( ANNA-2),
anti-VGCC,anti-
CRMP5/CV2* anti-
amphiphysin
• ovarian cancer
– anti-Yo ( PCA-1), anti-Ri,
anti-CRMP5/CV2
• breast cancer
– anti-Yo, anti-Ri
• Hodgkin’s disease
– anti-Tr and anti-mGluR1
• Testes-
– Anti Ma, Anti-Ta( Ma2)
• Colon-
– Anti-HU

17. Antigliadin antibodies
• Celiac disease or sprue is interesting cause of
ataxia
• Celiac disease is gluten sensitive enteropathy
• Cerebellar degeneration does not get better on
gluten free diet.
• Up to 40% of sporadic ataxias have anti-gliadin
antibodies
• Similar % in genetic ataxias
• Importance is not known.
• Bushara KO,Goebel SU, Shill H,GoldfarbLG,Hallett M (2001) Gluten sensitivityin sporadic and
hereditary cerebellarataxia.Ann Neurol 49:540–543

18. Genetic Ataxias
• Mendelian AR and AD ataxias have a higher frequency than other genetic ataxias.
• Prevalence – 1/50,000 - Friedreich’s ataxia (FRDA1)
• 1/100,000 - Ataxia Telangectasia (AT), dominant SCAs
• AR ataxias
– Multi-system disorders with extra-neural signs and symptoms - FRDA1 and AT
– Main mechanisms - loss of protein function,
• the control of energy output and oxidative stress -FRDA1, AVED, ABL,
possibly Cayman ataxia;
• the control of DNA maintenance and the cell cycle -AT, AOA1 and AOA2,
SCAN
• AD ataxias - restricted to the central nervous system.
– Mutant protein with a longer-than-normal poly glutamine stretch.
– Toxic gain-of-function of the aberrant protein
– Longer expansions-earlier onset, more severe disease in subsequent generations
– Diagnostic pathological feature-OPCA-(most common presentation of SCA+)
• AD episodic ataxias (EA)
– Point mutations in the potassium channel gene, KCNA1,- EA 1
– Point mutations in the CACNL1A4 gene - EA2

19. Hereditary Ataxias: Dominant

Spinocerebellar Ataxias

Adult-onset leukodystrophy

Branchial myoclonus &
Spastic paraparesis

CAPOS syndrome

Deafness & Narcolepsy

DRPLA: DRPLA protein;
CAG repeat;12p13

Episodic ataxia

with Myokymia (EA1):
KCNA 1; 12p13

Paroxysmal (EA2): a1A
Ca++ channel; 19p13

with Choreoathetosis &
Spasticity: 1p

Holmes ataxia

Mental retardation: 19q13
 Multiple hamartoma syndrome:
PTEN; 10q23
 Myelocerebellar Nystagmus
 Parenchymal degeneration
 Prion disease: Prion protein; 20p12
 Spastic ataxia syndromes
 Thermoanalgesia & loss of
fungiform papillae
 Tremor, Essential: 3q13
 Vermal aplasia
 Von Hippel-Lindau Syndrome:
VHL protein; 3p26

20. Hereditary Ataxia: Recessive
 Ataxia Telangectasia:
ATM; 11q22
 Ataxia telangectasia-like:
MRE11; 11q21
 Baltic Myoclonus
(Unverricht-Lundborg):
Cystatin B; 21q22
 Cayman ataxia: 19p13
 Cerebelloparenchymal
disorders (CPD): II, III, IV, V
 Charlevoix-Saguenay -
Spastic Ataxia: Sacsin;
13q12
 Cockayne Syndrome (5)
 Cytochrome c Oxidase I
 Early onset with retained
reflexes (EOCA): 13q12
 Friedreich ataxia: 9q13

Infantile Onset Spinocerebellar
Ataxia: 10q23

Leukoencephalopathy with
vanishing white matter: 3q27

Marinesco-Sjögren

Posterior column + Retinitis
pigmentosa: 1q31

Salla syndrome: SLC17A5;
6q14

Vitamin E deficiency: a-
tocopherol transfer protein;
8q13

Xeroderma pigmentosum

Other Congenital ataxias
• DNA repair defects
• Metabolic,Mitochondrial
• Multisystem disorders

21. Hereditary Ataxia: Metabolic,Congenital &X-linked
METABOLIC
Abetalipoproteinemia
Biotinidase Deficiency
Cerebrotendinous
Xanthomatosis
Gamma-Glutamyl Cysteine
Synthetase
Hartnup
Hyperammonemic
Hypobetalipoproteinemia
L-2 Hydroxyglutaric academia
Maple Syrup Urine Disease
Niemann-Pick, Type C
Recessive ataxias
Refsum Disease
Wilson's Disease
CONGENITAL
Aprosencephaly & cerebellar
dysgenesis
Ataxia-Deafness: X
Ataxia-Mental retardation:
Xq24-q27
Behr syndrome
Carbo.deficient glycopr
Cerebellar ataxia 1 (CLA1)
Cerebellotrigeminaldermal
dysplasia
COACH
Congenital muscular atrophy
Dandy-Walker
Fibroblast GF-3
Gillespie
Hoyeraal-Hreidarsson
Syndrome: Dyskerin; Xq28
Joubert: 9q34
Lissencephaly
X-linked congenital ataxia
1,2
X-LINKED
Arts Syndrome
CLA2
Pyruvate dehydrogenase
E1-a
Sideroblastic anemia

22. Spinocerebellar Ataxia (SCA)
Dominant SCA syndromes have many overlapping
signs: Difficult to distinguish on clinical grounds
Common features to all: Gait ataxia; Dysarthria
Features in some ataxias: Ocular D;
Extrapyramidal; Peripheral nerve; Intellectual D;
Seizures
Features with some predictive value for specific
gene defects

23. Epidemiology
 ADCA- 5/100,000 FA 5/100,000
 Among ADCAs
 SCA 1 - 5.6 %
 SCA 2 - 15.2 %
 SCA 3 - 20.8 %
 SCA 6 - 15.2 %
 SCA 7 - 4.5 %
 -ve F/H - 6.8% + CAG repeats, 5.2% FA*
 apparently recessive- 4.4% +CAG rpts, 11.24% FA
Moseley et al: Neurology 1998; 54,:1408-1421

24. Relationship between ADCAs and SCAs
ADCA type SCA type
I -Cerebellar plus
(Pyramidal, Extra-pyramidal,
Ophthalmoplegia, & Dementia) 1,2,3,4,12,16,17, DRPLA
II Cerebellar + pigmentary
maculopathy 7
III pure cerebellar ± Mild
pyramidal signs 5,6,8,11,14,15,22
Ataxia and epilepsy 10
Early onset with mental retardation 13

25. SCA: Clinical Syndromes
•SCA 1: Hypermetric saccades; ++Tendon reflexes; Evoked motor
potentials Long conduction times
•SCA 2 Slowing saccads; Myoclonus or action tremor
•SCA 3/Machado-Joseph: Gaze-evoked nystagmus; Prominent
spasticity or neuropathy
•SCA 4: Cerebellar syndrome; Sensory neuropathy
•SCA 5: Pure cerebellar syndrome
•SCA 6: Pure cerebellar syndrome; -ve family history; Late onset > 50
•SCA 7: Retinal degeneration; Hearing loss; Onset in 1st decade
•SCA 8: Pure cerebellar syndrome
•SCA 10: Pure cerebellar syndrome ± Seizures
•SCA 11: Pure cerebellar syndrome
•SCA 12: Early arm tremor; Late dementia
•SCA 13: Early childhood onset; Mental retardation
•SCA 14: Ataxia; Myoclonus (with early onset)

26. Polyneuropathy in SCA
Axonal; Sensory or Sensory-Motor
SCA1: 42%; More with ↑ CAG repeats
SCA2: 80%
SCA3: 54%; More with fewer CAG repeats
SCA4: Sensory loss
SCA7: 0%

27. SPINOCEREBELLAR ATAXIA 1 ;SCA 1
SPINOCEREBELLAR ATORHY I
OLIVOPONTOCREBELLAR ATORPHY I; OPCA 1
OPCA I
MENZEL TYPE OPCA
 CLINICAL SYNOPSIS
 Neurological:
 Miscellaneous:
 Labs:
 Gene Map Locus:6p 22-p23 CAG 40-83 ( N 6-40)
 cerebellar ataxia
 chorea
 upper motor neuron signs
 extensor planter, hyperreflexia
 lower bulbar palsies
 gaze paresis 50% , slow saccades 100 %
 scanning and explosive speech
 inco-ordination
 onset third/fourth decade
 earlier onset when inherited from father , anticipation
 axonal neuropathy
 atrophy of cerebellum, pons, olive,lower CN nuclei,
dorsal columns and spinocerebellar tracts
 Reduced aspartic acid in brain
 mutant protein Ataxin- 1, Intranuclear inclusions

28. SPINOCEREBELLAR ATAXIA 2; SCA 2
SPINOCEREBELLAR ATROPHY II
OLIVOPONTOCEREBELLAR ATROPHY, HOLGUIN TYPE
OLIVOPONTOCEREBELLAR ATROPHY 2
SPINOCEREBELLAR ATAXIA, CUBAN TYPE
 CLINICAL SYNOPSIS
 Neurological
 Limbs
 Miscellaneous
 Labs
 Gene Map Locus :12q23-24.1 CAG 34-59 ( N 14-31)
 adult onset progressive cerebellar ataxia
 palatal myoclonus , myokimia
 slow saccadic eye movements 100%
 dysarthria
 ophthalmoparesis 40%, optic atrophy
 pyramidal signs 20%
 peripheral sensory loss, abolished tendon reflexes
 dementia
 extrapyramidal signs in Tunisian kindred
 bladder dysfunction
 no parkinsonian features
 flexion contracture of legs
 onset 2 - 65 yrs, 40% < 25 yrs, anticipation, may be
sporadic
 involvement of cerebellum & inferior. olivary
nuc.,pons,spinal cord Ataxin - 2 , nuclear aggregates

29. SPINOCEREBELLAR ATAXIA 3 ; SCA 3
MACHODO-JOSEPH DIEASE,MJD
AZOREAN NEUROLOGIC DISEASE
NIGROSPINODENTATAL DEGENERATION, SPINOPONTINE AROPHY
 CLINICAL SYNOPSIS
 Neurological:
 Eyes
 Muscle
 Endocrinal
 Miscellaneous
 Labs
 Gene Map Locus : 14q32..1 CAG 56-86 (N -12-38)
 ataxia
 parkinsonian features
 facial and lingual fasciculations
 muscle fasciculations
 loss of leg reflexes
 cerebellar tremors
 extensor planter
 bulging eyes, limited eye movements, nystagmus
 muscle atrophy
 diabetes mellitus
 onset after 40 yr, paternal> maternal anticipation
 I- earlier onset(5-30), II- intermediate(~36 yr),
 III- cerebellar,PN,Optho(>40yr), IV- parkinsonian,
fasciculations, sensory(38-47yr levodopa responsive)
 neuronal loss and gliosis in SN, STN,GP,Dedtate nuclei,
nuclei pontis, vestibular & cranial nerve
nuclei,,post.columns and ant. Horns
 abnormal EOG
 ATAXIN- 3, nuclear/cytoplasmic inclusions

30. SPINOCEREBELLAR ATAXIA 4; SCA 4
SPINOCEREBELLAR ATAXIA WITH SENSORY AXONAL NEUROPATHY
 CLINICAL SYNOPSIS
 Neurological
 Miscellaneous
 Labs
 Gene Map Locus :16q22.1
 late onset spinocerebellar ataxia
 dysarthria 50%
 diminished vibration and joint position sense
 absent ankle jerk reflexes, 100%
 absent knee jerks , 85%
 areflexia , 25%
 extensor planter 20%
 no opthalmoplegia
 onset fourth or fifth decade
 anticipation ?
 MRI cerebellar atrophy
 axonal sensory neuropathy

31. SPINOCEREBELLAR ATAXIA 5; SCA5
 CLINICAL SYNOPSIS
 Neurological
 Miscellaneous
 Gene Map locus ; 11p12-q12
 spinocerebellar ataxia
 dysarthria
 onset 10 -68 yrs
 ?descendents from paternal
grandparents of President
Abraham Lincoln
 one family from NE France
 anticipation probable
 slow course

32. SPINOCEREBELLAR ATAXIA 6; SCA6
 CLINICAL SYNOPSIS
 Neurological
 Miscellaneous
 Labs
 Gene Map Locus: 19p13.1-p13.2 CAG 21-31 ( N 4-20 )
 spinocerebellar ataxia
 frontal lobe signs, dysarthria
 dementia
 mild ophthalmoplegia, down beat & gaze evoked-
nystagmus
 peripheral neuropathy
 sense of imbalance on turning
 seizures
 other conditions associated with 19p13 are :
hemiplegic migraine, familial periodic cerebellar ataxia
 onset ~30 if 25-27 repeats, ~40-50 if 21-24 repeats
 sporadic 27%
 cerebellar atrophy
 α -1A voltage dependent calcium channel ( CACNL1A)
 no inclusion bodies

33. SPINOCEREBELLAR ATAXIA 7: SCA7
OLIVOPONTOCEREBELLAR ATROPHY -III,OPCA 3
OPCA WITH RETINAL DEGENERATION
OPCA WITH MACULAR DEGENERATION & EXTERNAL OPHTHALMOPLEGIA
ADCA, TYPE 2
 CLINICAL SYNOPSIS
 Neurological
 Eyes
 Miscellaneous
 Labs
 Gene Map Locus -3p21.1-p12 CAG 38->200 (N 17)
 cerebellar ataxia
 chorea
 periodic slight head tremor
 pyramidal signs, dysarthria
 brisk deep tendon reflexes
 hearing loss
 variable retinopathy 43%
 visual loss ( VA 83%, blindness 28%), tritan (blue
yellow)
 color blindness
 ophthalmoplegia(70%)
 macular degeneration, optic atrophy( 69%)
 circumpapillary degeneration
 slow saccades
 anticipation , paternal transmission larger repeats
 degeneration of cerebellum, basis pontis, inferior
olive, & retinal ganglion cells , Ataxin-7, intranuclear
inclusions

34. SPINOCEREBELLAR ATAXIA 8: SCA 8
 CLINICAL SYNOPSIS
 Neurological
 Miscellaneous
 Labs
 Gene map locus- 13q21 CTG 100-155
( N 15-91)
 cerebellar signs
 impaired smooth pursuit(100%)
 horizontal nystagmus (67%)
 dysarthria ( 100%)
 ataxia
 Progression slow , maternal
anticipation more prominent
 onset 40-50 yrs
 MRI cerebellar vermis& hemisphere
atrophy

35. SPINOCEREBELLAR ATAXIA 9: SCA 9

36. SPINOCEREBELLAR ATAXIA 10: SCA 10
 CLINICAL SYNOPSIS
 Neurological
 Miscellaneous
 Gene Map locus- 12q13
 predominantly cerebellar
dysfunction
 gait and limb ataia
 dysarthria
 nystagmus
 occassional seizures
 Mexican family
 anticipation marked
especially with paternal
inheritance
 ? Calcium channel

37. SPINOCEREBELLAR ATAXIA 11: SCA 11
 CLINICAL SYNOPSIS
 Neurological
 Miscellaneous
 Labs
 Gene map locus - 15q14-21.3
 cerebellar ataxia 100%
 horizontal > vertical nystagmus
(100%)
 dysarthria (100%)
 Limb ataxia (93%)
 Hyper reflexia(100%)
 no extrapyramidal ,weakness or
sensory signs
 normal life expentancy
 normal nerve conduction
 isolated cerebellar atrophy

38. SPINOCEREBELLAR ATAXIA 12: SCA 12
 CLINICAL SYNOPSIS
 Neurological
 Miscellaneous
 Labs
 Gene map locus 5q31-q33 CAG 66-93
( N-<29 )
 Tremor arm & head
 gait & limb ataxia
 hyperreflexia
 paucity of movements
 eye movement abnormalities
 dementia in oldest patients
 onset 8-55 yr
 German family
 MRI cortical and cerebellar atrophy
 protein phosphatease 2, R2B , brain
specific regulatory subunit of PP2A
involved in regulatory processes

39. SPINOCEREBELLAR ATAXIA 13: SCA 13
 CLINICAL SYNOPSIS
 Neurological
 Miscellaneous
 Labs
 Gene map locus 19q13.3-
q13.4
 Ataxia legs > Arms
 dysarthria
 nystagmus
 motor dysfunction
 poor running
 inability to walk by 4-6th
decade
 hyperreflexia
 mental retardation
 French family
 7/8 females
 onset early childhood
 no anticipation
 MRI pontocerebellar atrophy

40. SPINOCEREBELLAR ATAXIA 14: SCA 14
 CLINICAL SYNOPSIS
 Neurological
 Miscellaneous
 Labs
 Gene map locus-19q13.4-qter
 Ataxia legs >arms
 axial myoclonus( younger in
onset<27 yr)
 tremor in exteremities and
head ( younger onset)
 hyperreflexia
 Japanese family
 ? Anticipation
 MRI Cerebellar atrophy

41. DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY; DRPLA
MYOCLONIC EPILEPSY WITH CHOREOATHETOSIS
NAITO-OYANAGI DISEASE; NOD
ATROPHIN 1, INCLUDED
 CLINICAL SYNOPSIS
 Neurological:
 Miscellaneous:
 Labs:
 Gene Map Locus: 12p13.31 CAG 49-75
(N<24)
 Myoclonus
 epilepsy ( longer repeats)
 Dementia
 Ataxia
 Choreoathetosis
 Onset usually in the 20s and death in the
40s
 commaon in Japan
 Combined degeneration of dentatorubral
and pallidoluysian systems
 DRPLA protein , neuronal cytoplasm

42. EPISODIC ATAXIA, TYPE 1; EA1
PAROXYSMAL ATAXIA WITH NEUROMYOTONIA, HEREDITARY
EPISODIC ATAXIA WITH MYOKYMIA; EAM
ATAXIA, EPISODIC, WITH MYOKYMIA; AEM; AEMK
MYOKYMIA WITH PERIODIC ATAXIA
 CLINICAL SYNOPSIS
 Neurological
 Miscellaneous
 Labs
 Treatment
 Gene Map Locus: 12p13
 Myokymia
 Continuous muscle movement
 Periodic ataxia
 Continuous muscle movement
 Periodic ataxia
 Ataxic attacks provoked by abrupt postural
change, emotional stimulus, and caloric-vestibular
stimulation, startle
 Onset in second decade
 Hand posture resembling carpopedal spasm
 Potassium voltage-gated channel gene mutation
 Continuous spontaneous activity on EMG at rest
 Muscle biopsy consistent with denervation, with
enlargement of muscle fiber
 Phenytoin, not Acetazolamide

43. EPISODIC ATAXIA, TYPE 2; EA2
PERIODIC VESTIBULOCEREBELLAR CEREBELLOPATHY,
HEREDITARY PAROXYSMAL ATAXIA,
FAMILIAL PAROXYSMAL ATAXIA
ACETAZOLAMIDE-RESPONSIVE PAROXYSMAL CEREBELLARATAXIA; APCA
EPISODIC ATAXIA, NYSTAGMUS-ASSOCIATED CEREBELLAR ATAXIA
 CLINICAL SYNOPSIS
 Neurological
 Miscellaneous
 Labs
 Treatment
 Gene Map Locus: 19p13
 Episodic ataxia
 Cerebellar ataxia
 Vertigo
 Diplopia
 Downbeat nystagmus
 Ataxia precipitated by stress or
excitement, not by startle
 attacks last 1/2 to 6 hrs.
 point mutation alpha 1A calcium
voltage dependant channel
 allelic with SCA6 & familial
hemiplegic migraine
 Response to oral acetazolamide

44. CHOREOATHETOSIS/SPASTICITY, EPISODIC; CSE
CHOREOATHETOSIS, PAROXYSMAL, WITH EPISODIC ATAXIA
CHOREOATHETOSIS, KINESIGENIC, WITH EPISODIC ATAXIA AND SPASTICITY
DYSTONIA 9; DYT9
 CLINICAL SYNOPSIS
 Neurological
 Miscellaneous
 Treatment
 Gene Map Locus: 1pNeuro :
 Paroxysmal choreoathetosis.
 Episodic ataxia.
 Spasticity.
 Increased tendon reflexes.
 Pyramidal signs in legs.
 Involuntary movements.
 Dystonic limb posture.
 Imbalance.
 Dysarthria.
 Perioral and leg paresthesias.
Headache.
 Double vision.
 Onset from 2 to 15 years.
 Physical exercise, emotional
stress, lack of sleep, and alcohol
precipitate symptoms.
 acetazolamide

45. Episodic Ataxias
Name Chromos
ome
Mutation Protein Clinical
EA type 1 12p Missense K-channel,
KCNA1
Interictal myokimia eyes, lips and fingers
PHT, Diamox
EA type 2 l9p Missense α-
component
the VDCA
CACNL1A4
Attacks of ataxia, dysarthria, N, V, Diplopia,
osciloscopia minutes to day. Interictal
nystagmus or mild ataxia. Provoked by
exercise and stress not startle. ½ pts have
headache. Diamox, 4 aminopyridinesame gene
as SCA -6 but nature of mutation differs
EA type3 Episodic vestibulo-cerebellar ataxia, Defective
smooth pursuit, gaze evoked nystagmus,
vertigo
EA type4 Vestibular ataxia, vertigo, tinnitis, interictal
myokymia - Diamox
EA with
Paroxysmal
choreoathetosi
s & Spasticity
1p Onset 2-15 yr
Attacks of ataxia, involuntary movements ,
dystonia or extremities , parasthethiasa and
headache 20 minutes 2/day-2/yr alc, fatigue,
stress, exercise- Diamox
EA type 5 2q CACNβ4 One family

46. FRIEDREICH’S ATAXIA
 CLINICAL SYNOPSIS Gene Map Locus: 9q13 GAA 66->1700 ( N< 42)
 Neurological: Cerebellar ataxia
Dysarthria
Nystagmus
Incoordined limb movements
Diminished or absent tendon reflexes
Babinski sign
Impaired position & vibratory sense
Hypoactive knee and ankle jerks
 Cardiac : Hypertrophic cardiomyopathy ,CHF, Muscular subaortic stenosis
 Skel : Pes cavus , Scoliosis, Hammer toe
 Metabolic : Diabetes mellitus
 Lab : Abnormal intranscription of protien FRATAXIN (resposible for Iron
efflux from mitochondria)
Abnormal- motor and sensory nerve conduction, EKG, ECHO,MRI

47. Evaluation
• History & Physical Examination
• Careful family history
• Standard laboratory including lipids and thyroid
• MRI Brain
• Autonomic testing ( Sphincter EMG)
• Genetic testing
• Toxic screen, Vitamin E
• Antibodies- paraneoplastic, antigliadin

48. Clinical History
• Accurate family history
• Look for anticipation- earlier onset , heavier clinical
expression in subsequent generations ( SCA 2,7)- gene
mutated parent is still asymptomatic or died before
developing clinical symptoms.
• Consanguity - recessive
• Age of onset – earlier in AR( exceptions-late onset
FRDA1, infantile cases of SCAs e.g. SCA2, SCA7)
• Origin of families-
– SCA3 - Portugal, Brazil, India, rare in Italy SA
– AVED – Southern Mediterranean
– AOA1 – Portugal, Japan
– Cayman Ataxia- Grand Cayman Island

49. Ataxia Rating Scales
• International Co-operative Ataxia Rating scale
(ICARS)
– Evaluation of efficacy of ataxia treatments
– Semi-quantitative 100 point scale
– 19 items divided in 4 sub-scores
• Posture and gait
• Kinetic functions
• Speech
• Ocular movements
• Trouillas et al. J International Cooperative Ataxia Rating Scale for pharmacological
assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of
the World Federation of Neurology J Neurol Sci. 1997 Feb 12;145(2):205-11

50. DIAGNOSIS
 Recognize progressive ataxia syndrome and associated features
 Oculomotor : slow saccades
 Bulbar : facial, temporal, tongue atrophy, fasciculation, 
cough, dysphagia
 UMN : brisk reflexes, spasticity, Babinski
 Extrapyramidal : bradykinesia, plastic rigidity, dystonias,
chorea
 Cortical : late cognitive decline, myoclonus, seizures
 Visual : macular, retinal lesion, optic atrophy
 Peripheral Nervous System : sensory loss, hypo/areflexia,
muscle atrophy,weakness

51. DIAGNOSIS Continued
 Recognize typical family history
 Exclude non inherited causes of ataxia
 Establish specific biochemical error
 Establish specific gene mutation
• MS, strokes , tumors, alcohol, B12, ANA,
hypothyroid, basal meniningitis,
paraneoplastic Anti-Yo, -Ri, - Hu, Anti-
gliadin antibodies, Toxic screen, Vit E levels
• hyperammonemias, hexose aminodase def
Wilson's, abetalipoprotienemia,
aminoacidurias,
• SCA1,2,3,6,7,8,DRPLA,FA,EA

52. Clues to SCAs
Age at onset: childhood onsetSCA 7, 13, DRPLA Young adult: SCAl, 2, 3, 21older
adult: SCA 6
Prominent anticipation SCA 7, DRPLA
Upper motor neuron signs SCA 1,3, 7,12Some in SCA 6, 8RareinSCA2
Slow saccades Early, prominent: SCA 2,7, 12 Late: SCA 1,3 Rare: SCA6
Extra pyramidal signs Early chorea:DRPLA, Akinetic-rigid, Parkinson: SCA 2, 3,21
Generalized reflexes SCA 2,4, 19 ,21 Late: SCA 3Rare: SCA 1
Visual loss SCA7
Dementia Prominent: SCA 17, DRPLA Early: SCA 2,7 Otherwise: rare
Myoclonus SCA 2, 14
Tremor SCA 12*, 16, 19
Seizures SCA 10

53. INVESTIGATIONS: Reasonable Approach
 CBC, electrolytes,
glucose, BUN, creatinine
 ANA
 Thyroid function tests
 Fasting Total Cholesterol
 Alpha-FP
 Immunoglobulins (IgE,
IgA)
 Drug screen
 Vitamins B12 and E
 Anti -Yo, -Ri, -Hu, -gliadin
antibodies
 MRI
 Electrodiagnostic
• Nerve conduction
velocities
• ECG
• ECHO
• Sphincter EMG
Modified from Hallett 2000

54. Laboratory
• Few recessive forms with biochemical
abnormalities
• ↓ Vitamin A – AVED
• ↓ Vit. E, A, Lipoprotein in ABL ( acanthocytes
with absence apo-B lipoproteins
• AT- ↑ AFP, ↓immunoglobulins
• AOA1- ↑Chol, ↓ Alb
• AOA2 - ↓ AFP
• Late onset ataxia- paraneoplastic antibodies,
antigliadin antibodies

55. Imaging
 CT
 MRI
 PET
 Cerebellum, brainstem atrophy, enlarged IV
ventricle
 Above +  T2 signal putamen, substantia nigra,
inferior olive, pontine & dentate nuclei
 Detects subclinical nigrostriatal dysfunction in
OPCA
 Glucose utilization in cerebellar hemisphere,
frontal, prefrontal area,brainstem

56. Neuro-radiology
• FRDA- cervical spinal cord atrophy, mild cerebellar atrophy
• Predominant vermian atrophy – AR ataxia- AT, AOA1,
AOA2, Cayman Ataxia, SCAN
• Congenital ataxia – cerebellar hypoplasia or vermian aplasia
• Joubert syndrome – absence of cerebellar vermis and “molar
tooth sign” at cerebellar & mid brain junction
• Fragile X associated tremor/ataxia syndrome (FXTAS)-
– mild to moderate cerebral & cerebellar atrophy
– Increases T2 signal in deep white matter of cerebellar hemisphere &
middle cerebellar peduncles
• Cerebellar Atrophy- most common finding
– Pure cerebellar – SCA 6,10,11
– Variable atrophy- cortex , brains tem , striatum, spinal cord – Ataxia
plus

57. MANAGEMENT
 Genetic counseling -- inheritance pattern, risk to
relatives, predictive value, prenatal test , implication
for insurability, employment, relationships,
psychological impact
 OT/PT
 Vision
 Speech therapy
 Bladder management
 Pharmacological Therapy

58. PHARMACOLOGICAL THERAPY
 Serotinin System
 Cholinergic System
 GABA
 Dopamine
 Neuropeptide
 Glutamine
 L 5HT Trouillas 1993
 Lisuride Infusion Heinz et al 1992 improve d
performance 3/4
 Buspirone Lou et al 1995 improved
9/20
 Physostigmine , choline , lecithin
 Isonex, Pyridoxine , Primidone
 Clozapine Parson 1993 improved
psychiatric symptoms
 Levodopa
 TRH, DN-1417
 Amantadine Botez1991,96 ~35 %
improvement in UE Ataxia in 30 pts SCA 1,2,3,5

59. References
1. Nature Genetics 1996;14:237-238
2. SCA1: Hum.Mol.Genet. 1995;4(9):1585-90
3. SCA2: Hum.Mol.Genet.1997;6(5):709-715
4. SCA3: Ann.Neurol. 1996;39(4):490-99; J.Neurol.Sci. 1995;132(1):71-
75
5. SCA4: Am.J.Hum.Genet. 1996;59(2):392-99
6. SCA5: Nat.Genet. 1994;8(3):280-84
7. SCA6: Nat.Genet. 1997;15:62-69; Hum.Mol.Genet. 1997;6(8):1289-
93; Hum.Mol.Genet. 1997;6(8):1283-87
8. SCA7: Am.J.Hum.Genet. 1996;59:1328-36; Nat.Genet. 1997;17:65-70
9. SCA8: Nature Genetics 1999;21:379-384
10. SCA10: Am J Hum Genet 1999;64:594-599
11. SCA11: Am J Hum Genet 1999;65:420-426
12. SCA12: Nature Genet 1999;23: 391-392
13. SCA13: Am J Hum Genet 2000;67 (July)
14. SCA14: Ann Neurol 2000;48:156-163

60. Resources
National Ataxia Foundation
2600 Fernbrook Lane, Suite 119
Minneapolis, MN 55447
Phone: 763-553-0020
Fax: 763-553-0167
E-mail: naf@ataxia.org
Web: www.ataxia.org
Spinocerebellar Ataxia: Making an Informed Choice about Genetic Testing
Web: depts.washington.edu/neurogen/AtaxiaBrochure99.pdf
WE MOVE (Worldwide Education and Awareness for Movement Disorders)
204 E 84th St
New York, NY 10024
Phone: 212-875-8312; 1-800-437-MOV2 , Fax: 212-875-8389
Email: wemove@wemove.org
Web: www.wemove.org
International Network of Ataxia Friends (INTERNAF)
Web: http://internaf.merseyside.org

61. Table 1. Autosomal Dominant Cerebellar Ataxias: Molecular
Genetics
Disease
Name
Locus Gene Protein
Normal
CAG#
Abnormal 1
CAG#
Test
Availability
SCA1 6p23 SCA1 Ataxin 1 6-40 40-83
Clinical
SCA2 12q24.1 SCA2 Ataxin 2 14-31 34-400
Clinical
SCA3 14q21 SCA3 SCA3/ MJD1 12-38 55-86
Clinical
SCA4 16q22.1 SCA4 --- --- ---
Research
SCA5 11 SCA5 --- --- ---
SCA6 19p13.1- p13.2
CACN
AIA
Alpha 1A
voltage dependent calcium
channel
4-20 21-31
SCA7 3p21.1- p12 SCA7 Ataxin 7 7-17 38->200
Clinical
SCA8 13q21 SCA8 ---
(CTG)
15-91
(CTG) 100-
155
Clinical
SCA9
Category not
assigned
SCA10 22q13
SCA1
0
--- --- ---
ResearchSCA11 15q14 -q21
SCA12 5q31
SCA1
2
Protein phosphatase 2A <29 66-93
SCA13 19q13
SCA1
3
--- --- --- Research
DRPLA 12p
CTG-
B37
Atrophin 1 3-36 49-88
Clinical
EA1 12p13
KCNA
-1
KV1.1 --- ---
Research
EA2 19p13.1- 13.2
CACN
AIA
Alpha 1A voltage dependent
calcium channel
--- ---

62. Table 2. Autosomal Dominant Cerebellar Ataxias: Clinical
Features
Diseas
e
Name
Freque
ncy in
ADCA
Average Onset
(Range in
Years)
Average
Duration (Range in
Years)
Distinguishing Features
(All have gait ataxia)
SCA1
6%
(5-27)
4th decade
(<10 to >60)
15
(10-28)
Pyramidal signs,
peripheral neuropathy
SCA2
15%
(13-24)
3rd - 4th
decade
(<10 to >60)
10
(1-30)
Slow saccadic eye movement, peripheral neuropathy,
decreased DTR's, dementia
SCA3
21%
(11-36)
4th decade (10-
70)
10
(1-20)
Pyramidal and extrapyramidal signs; lid retraction,
nystagmus, decreased saccade velocity; amyotrophy
fasciculations, sensory loss
SCA4
Rare
4th - 5th decade
(19-59)
Decades
Sensory axonal
neuropathy
SCA5
Rare
3rd - 4th
decade
(10-68)
>25 Early onset, slow course
SCA6 15%
5th - 6th decade
(19-71)
>25 Sometimes episodic ataxia, very slow progression
SCA7 5%
3rd - 4th
decade
(1/2 - 60)
20
(1-45; early onset
correlates with short
duration)
Visual loss with retinopathy
SCA8 2-5% 39 (18-65) Normal lifespan Brisk DTRs and decreased vibration sense
SCA9 Category
not
assigned
SCA10
Rare 36 9 Occasional seizures
SCA11
Rare 30 (15-70) Normal lifespan Mild, remain ambulatory
SCA12
Rare 33 (8-55)
Early tremor,
late dementia
SCA13 Rare Childhood Unknown Mild mental retardation, short stature
DRPLA
Rare
(USA)
20%
(Japan)
8 - 20 or
40 - 60's
Early onset
correlates with
shorter duration
Chorea, seizures, dementia, myoclonus
EA1
Unknown 1st decade
(2-15)
Attenuates after 20
Myokymia; attacks last seconds to minutes; startle or
exercise induced; no vertigo
EA2
Unknown
3-52 Lifelong
Nystagmus; attacks last minutes to hours; posture change
induced; vertigo; later permanent ataxia

63. Table 3. Examples of Autosomal Recessive Hereditary
Ataxias: Molecular Genetics
Disease Name
Chromosome
Locus
Gen
e
Protein
Test
Availability
Friedreich ataxia
(FRDA)
9q13-q21
FRD
A1
Frataxin
Clinical
Ataxia-telangiectasia
(A-T)
11q22-q23 ATM PI3-kinase Clinical
Ataxia with vitamin E
deficiency
(AVED)
8q13
TTP
A
Alpha- tocopherol transfer
protein
Clinical
IOSCA 10q23-q24 ? ?
None
Marinesco- Sjögren ? ? ?
Spastic ataxia
(ARSACS)
13q11
SAC
S
SACSIN Research

64. Table 4. Examples of Autosomal Recessive Hereditary Ataxias: Clinical Features
Disease Name
Population
Frequency
Onset (Range
in Years)
Duration
(Years)
Distinguishing Features
Friedreich ataxia
(FRDA)
1-2/50,000
1st - 2nd
decade
(4-40)
10 - 30
Hyporeflexia,
Babinski responses,
sensory loss,
cardiomyopathy
Ataxia-
telangiectasia
(A-T)
1/40,000 to
1/100,000
1st decade 10 - 20y
Telangiectasia,
immune deficiency, cancer, chromosomal
instability, increased alpha-fetoprotein
Ataxia with
vitamin E
deficiency
(AVED)
Rare
2-52 years,
usually <20
Decades
Similar to FRDA,
head titubation (28%)
IOSCA
Rare
(Finland)
Infancy Decades
Peripheral neuropathy,
athetosis, optic atrophy, deafness,
ophthalmoplegia
Marinesco-
Sjögren
Rare Infancy Decades
Mental retardation,
cataract, hypotonia, myopathy
Spastic ataxia
(ARSACS)
Decades Childhood
Spasticity,
peripheral neuropathy, retinal striation
IOSCA = Infantile onset spinocerebellar ataxia

65. PATHOGENESIS
 Accumulation of glutamate @ cleft leads to degeneration of
post synaptic neurons
  Glutamate catabolism in brain  glutamate in brain
causing neuronal destruction from over excitation and
degeneration
Plaitakis, et al. 1984
 NMDA receptor mediated toxicity is most unifying
hypothesis
 Role of mutant proteins & inclusion bodies is not known

66. PATHOGENESIS
 Accumulation of glutamate @ cleft leads to degeneration of
post synaptic neurons
  Glutamate catabolism in brain  glutamate in brain
causing neuronal destruction from over excitation and
degeneration
Plaitakis, et al. 1984
 NMDA receptor mediated toxicity is most unifying
hypothesis
 Role of mutant proteins & inclusion bodies is not known

67. RECENT THEORIES
 Botez’98
 Drug cocktail L 5-HT(1000mg) , Amantidine (200mg) ,
Thiamine (50mg)
 ? Role - Remacemide ( NMDA recepter inhibiter in predominantly
cerebellum )
 ? Role - Gabapentin ( Neuroprotective )
 ? Role- Idebenone (Antioxidant )
 Hypothesis of replacement and treatment in SCAs based on
 ↓ CSF 5-HIAA
 NMDA- receptor mediated toxicity
 ↓ CSF Thiamine
 Thiamine Rx ↑ 5-HIAA in pts with↓ CSF -thiamine &
5- HIAA
 Cerebral vulnerability ↑ with ↑ EC glutamate in
thiamine def.
 Pretreatment with NMDA recepter agonist MK-801
partially protects against thiamine induced brain
lesions.

68. Pharmacotherapy
The Cerebellum 2004:3 107-111

69. Diagnostic Approach-
Progressive imbalance
Subramony & Nance : Diagnosis and Management of the inherited ataxias. The Neurologist 1998; 4(6) :327-
338

70. Autosomal recessive ataxias
Mariotti etal. J Neurology (2005) 252: 511 - 518

71. Autosomal Dominant
Mariotti etal. J Neurology (2005) 252: 511 - 518

72. Autosomal Dominant Ataxias
F:ataxiaSpinocerebellar Ataxias.xls

73. A-TAX-IA

74. Cerebellar Dysfunction: Anatomy
Cerebellar lesion Signs
Posterior
(Flocculo-nodular
lobe Archicerebellum)
Eye movement disorders:
Nystagmus; Vestibulo-ocular reflex
(VOR)
Postural and gait dysfunction
Midline
(Vermis;
Paleocerebellum)
Truncal & gait ataxia
Hemisphere
(Neocerebellum)
Limb ataxia: Dysmetria,
Dysdiadochokinesis,
"intention" tremor
Dysarthria
Hypotonia

75. Clinical Manifestations of
Cerebellar Dysfunctions
• Cerebellum- modulates motor functions
• Archicerebellum- ( flocculonodular node)
– Body equilibrium
– Eye movements
• Paleocerebellum( vermis of ant. lobe pyramid , uvula and
paraflocculus)
– Input from spinal cord
– Muscle tone
– Axial stance and gait
• Neocerebellum (middle portion of vermis, cerebellar
hemisphere)
– Connected with pons and cortex through thalalmus
– Planning and initiation of movements
– Regulation of fine limb movements