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Approach to Ataxia
ALOK SAHAY, MD
Assistant Professor – Neurology
University of Cincinnati
3/1/06
Definition
literal meaning -without order
clumsiness
loss of co-ordination
Genesis
 cerebellum and its connecting pathways
 proprioceptive sensory pathways
 vestibular system
Cerebellar Dysfunction: Anatomy
Cerebellar parts Functions Signs
Posterior
(Flocculo-nodular lobe)
Archicerebellum
Body eq...
Cardinal features - Cerebellar pathology
– Stance and gait
– Poor regulation and coordination of skilled
movements (Dysmet...
Core Symptoms
• Difficulty with balance of gait
• Clumsiness of hands
• Dysarthria
• Gaze problems
Manifestations- Stance and gait
– Wide based stance & Gait
– Gait- staggering, irregular steps, lateral veering.
– Cerebel...
Limb coordination
• Asynergia- movements are broken into isolated subsequent steps , lack
easiness/ smoothness
• Dysdiadoc...
Tremor
• kinetic (intention) tremor
• static (postural) tremor may also occur.
• Related to hypotonia.
• In some cases of ...
Muscle tone
• Hypotonia is a typical cerebellar sign.
• Wider excursion of hands on shaking the arms.
• Obliteration of th...
Speech- Dysarthria
• Altered articulation of words
• Abnormal fluency of speech.
• Scanning Dysarthria
• Slurring
Ocular Motor Functions
• Smooth pursuit movements
• Saccades
• Certain clinical cerebellar syndromes might have characteri...
Classification
Congenital
Hereditary
Autosomal Dominant
Autosomal Recessive
Congenital
DNA repair defects
Metabolic disord...
Etiology
• Degenerative – MSA, Progressive myoclonic epilepsy
• Stroke
– cerebellar, thalamic, brainstem, pontomedullary j...
Etiology
• Paraneoplastic
• Autoimmune
– Anti- GAD antibodies
• Infectious/post-infectious-
– rubella
– H.influenza
– Vari...
Paraneoplastic-
cerebellardegenerations (PCD)
• associated with specific tumor
type antineuronal (anti purkinje
cell antib...
Antigliadin antibodies
• Celiac disease or sprue is interesting cause of
ataxia
• Celiac disease is gluten sensitive enter...
Genetic Ataxias
• Mendelian AR and AD ataxias have a higher frequency than other genetic ataxias.
• Prevalence – 1/50,000 ...
Hereditary Ataxias: Dominant

Spinocerebellar Ataxias

Adult-onset leukodystrophy

Branchial myoclonus &
Spastic parapa...
Hereditary Ataxia: Recessive
 Ataxia Telangectasia:
ATM; 11q22
 Ataxia telangectasia-like:
MRE11; 11q21
 Baltic Myoclon...
Hereditary Ataxia: Metabolic,Congenital &X-linked
METABOLIC
Abetalipoproteinemia
Biotinidase Deficiency
Cerebrotendinous
X...
Spinocerebellar Ataxia (SCA)
Dominant SCA syndromes have many overlapping
signs: Difficult to distinguish on clinical gro...
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...
Relationship between ADCAs and SCAs
ADCA type SCA type
I -Cerebellar plus
(Pyramidal, Extra-pyramidal,
Ophthalmoplegia, & ...
SCA: Clinical Syndromes
•SCA 1: Hypermetric saccades; ++Tendon reflexes; Evoked motor
potentials Long conduction times
•SC...
Polyneuropathy in SCA
Axonal; Sensory or Sensory-Motor
SCA1: 42%; More with ↑ CAG repeats
SCA2: 80%
SCA3: 54%; More wit...
SPINOCEREBELLAR ATAXIA 1 ;SCA 1
SPINOCEREBELLAR ATORHY I
OLIVOPONTOCREBELLAR ATORPHY I; OPCA 1
OPCA I
MENZEL TYPE OPCA
 C...
SPINOCEREBELLAR ATAXIA 2; SCA 2
SPINOCEREBELLAR ATROPHY II
OLIVOPONTOCEREBELLAR ATROPHY, HOLGUIN TYPE
OLIVOPONTOCEREBELLAR...
SPINOCEREBELLAR ATAXIA 3 ; SCA 3
MACHODO-JOSEPH DIEASE,MJD
AZOREAN NEUROLOGIC DISEASE
NIGROSPINODENTATAL DEGENERATION, SPI...
SPINOCEREBELLAR ATAXIA 4; SCA 4
SPINOCEREBELLAR ATAXIA WITH SENSORY AXONAL NEUROPATHY
 CLINICAL SYNOPSIS
 Neurological
...
SPINOCEREBELLAR ATAXIA 5; SCA5
 CLINICAL SYNOPSIS
 Neurological
 Miscellaneous
 Gene Map locus ; 11p12-q12
 spinocere...
SPINOCEREBELLAR ATAXIA 6; SCA6
 CLINICAL SYNOPSIS
 Neurological
 Miscellaneous
 Labs
 Gene Map Locus: 19p13.1-p13.2 C...
SPINOCEREBELLAR ATAXIA 7: SCA7
OLIVOPONTOCEREBELLAR ATROPHY -III,OPCA 3
OPCA WITH RETINAL DEGENERATION
OPCA WITH MACULAR D...
SPINOCEREBELLAR ATAXIA 8: SCA 8
 CLINICAL SYNOPSIS
 Neurological
 Miscellaneous
 Labs
 Gene map locus- 13q21 CTG 100-...
SPINOCEREBELLAR ATAXIA 9: SCA 9
SPINOCEREBELLAR ATAXIA 10: SCA 10
 CLINICAL SYNOPSIS
 Neurological
 Miscellaneous
 Gene Map locus- 12q13
 predominant...
SPINOCEREBELLAR ATAXIA 11: SCA 11
 CLINICAL SYNOPSIS
 Neurological
 Miscellaneous
 Labs
 Gene map locus - 15q14-21.3
...
SPINOCEREBELLAR ATAXIA 12: SCA 12
 CLINICAL SYNOPSIS
 Neurological
 Miscellaneous
 Labs
 Gene map locus 5q31-q33 CAG ...
SPINOCEREBELLAR ATAXIA 13: SCA 13
 CLINICAL SYNOPSIS
 Neurological
 Miscellaneous
 Labs
 Gene map locus 19q13.3-
q13....
SPINOCEREBELLAR ATAXIA 14: SCA 14
 CLINICAL SYNOPSIS
 Neurological
 Miscellaneous
 Labs
 Gene map locus-19q13.4-qter
...
DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY; DRPLA
MYOCLONIC EPILEPSY WITH CHOREOATHETOSIS
NAITO-OYANAGI DISEASE; NOD
ATROPHIN 1,...
EPISODIC ATAXIA, TYPE 1; EA1
PAROXYSMAL ATAXIA WITH NEUROMYOTONIA, HEREDITARY
EPISODIC ATAXIA WITH MYOKYMIA; EAM
ATAXIA, E...
EPISODIC ATAXIA, TYPE 2; EA2
PERIODIC VESTIBULOCEREBELLAR CEREBELLOPATHY,
HEREDITARY PAROXYSMAL ATAXIA,
FAMILIAL PAROXYSMA...
CHOREOATHETOSIS/SPASTICITY, EPISODIC; CSE
CHOREOATHETOSIS, PAROXYSMAL, WITH EPISODIC ATAXIA
CHOREOATHETOSIS, KINESIGENIC, ...
Episodic Ataxias
Name Chromos
ome
Mutation Protein Clinical
EA type 1 12p Missense K-channel,
KCNA1
Interictal myokimia ey...
FRIEDREICH’S ATAXIA
 CLINICAL SYNOPSIS Gene Map Locus: 9q13 GAA 66->1700 ( N< 42)
 Neurological: Cerebellar ataxia
Dysar...
Evaluation
• History & Physical Examination
• Careful family history
• Standard laboratory including lipids and thyroid
• ...
Clinical History
• Accurate family history
• Look for anticipation- earlier onset , heavier clinical
expression in subsequ...
Ataxia Rating Scales
• International Co-operative Ataxia Rating scale
(ICARS)
– Evaluation of efficacy of ataxia treatment...
DIAGNOSIS
 Recognize progressive ataxia syndrome and associated features
 Oculomotor : slow saccades
 Bulbar : facial, ...
DIAGNOSIS Continued
 Recognize typical family history
 Exclude non inherited causes of ataxia
 Establish specific bioch...
Clues to SCAs
Age at onset: childhood onsetSCA 7, 13, DRPLA Young adult: SCAl, 2, 3, 21older
adult: SCA 6
Prominent antici...
INVESTIGATIONS: Reasonable Approach
 CBC, electrolytes,
glucose, BUN, creatinine
 ANA
 Thyroid function tests
 Fasting...
Laboratory
• Few recessive forms with biochemical
abnormalities
• ↓ Vitamin A – AVED
• ↓ Vit. E, A, Lipoprotein in ABL ( a...
Imaging
 CT
 MRI
 PET
 Cerebellum, brainstem atrophy, enlarged IV
ventricle
 Above +  T2 signal putamen, substantia ...
Neuro-radiology
• FRDA- cervical spinal cord atrophy, mild cerebellar atrophy
• Predominant vermian atrophy – AR ataxia- A...
MANAGEMENT
 Genetic counseling -- inheritance pattern, risk to
relatives, predictive value, prenatal test , implication
f...
PHARMACOLOGICAL THERAPY
 Serotinin System
 Cholinergic System
 GABA
 Dopamine
 Neuropeptide
 Glutamine
 L 5HT Troui...
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):7...
Resources
National Ataxia Foundation
2600 Fernbrook Lane, Suite 119
Minneapolis, MN 55447
Phone: 763-553-0020
Fax: 763-553...
Table 1. Autosomal Dominant Cerebellar Ataxias: Molecular
Genetics
Disease
Name
Locus Gene Protein
Normal
CAG#
Abnormal 1
...
Table 2. Autosomal Dominant Cerebellar Ataxias: Clinical
Features
Diseas
e
Name
Freque
ncy in
ADCA
Average Onset
(Range in...
Table 3. Examples of Autosomal Recessive Hereditary
Ataxias: Molecular Genetics
Disease Name
Chromosome
Locus
Gen
e
Protei...
Table 4. Examples of Autosomal Recessive Hereditary Ataxias: Clinical Features
Disease Name
Population
Frequency
Onset (Ra...
PATHOGENESIS
 Accumulation of glutamate @ cleft leads to degeneration of
post synaptic neurons
  Glutamate catabolism i...
PATHOGENESIS
 Accumulation of glutamate @ cleft leads to degeneration of
post synaptic neurons
  Glutamate catabolism i...
RECENT THEORIES
 Botez’98
 Drug cocktail L 5-HT(1000mg) , Amantidine (200mg) ,
Thiamine (50mg)
 ? Role - Remacemide ( N...
Pharmacotherapy
The Cerebellum 2004:3 107-111
Diagnostic Approach-
Progressive imbalance
Subramony & Nance : Diagnosis and Management of the inherited ataxias. The Neur...
Autosomal recessive ataxias
Mariotti etal. J Neurology (2005) 252: 511 - 518
Autosomal Dominant
Mariotti etal. J Neurology (2005) 252: 511 - 518
Autosomal Dominant Ataxias
F:ataxiaSpinocerebellar Ataxias.xls
A-TAX-IA
Cerebellar Dysfunction: Anatomy
Cerebellar lesion Signs
Posterior
(Flocculo-nodular
lobe Archicerebellum)
Eye movement dis...
Clinical Manifestations of
Cerebellar Dysfunctions
• Cerebellum- modulates motor functions
• Archicerebellum- ( flocculono...
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03 01-06 approach to ataxia

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03 01-06 approach to ataxia

  1. 1. Approach to Ataxia ALOK SAHAY, MD Assistant Professor – Neurology University of Cincinnati 3/1/06
  2. 2. Definition literal meaning -without order clumsiness loss of co-ordination
  3. 3. Genesis  cerebellum and its connecting pathways  proprioceptive sensory pathways  vestibular system
  4. 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. 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. 6. Core Symptoms • Difficulty with balance of gait • Clumsiness of hands • Dysarthria • Gaze problems
  7. 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. 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. 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. 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. 11. Speech- Dysarthria • Altered articulation of words • Abnormal fluency of speech. • Scanning Dysarthria • Slurring
  12. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 35. SPINOCEREBELLAR ATAXIA 9: SCA 9
  36. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 68. Pharmacotherapy The Cerebellum 2004:3 107-111
  69. 69. Diagnostic Approach- Progressive imbalance Subramony & Nance : Diagnosis and Management of the inherited ataxias. The Neurologist 1998; 4(6) :327- 338
  70. 70. Autosomal recessive ataxias Mariotti etal. J Neurology (2005) 252: 511 - 518
  71. 71. Autosomal Dominant Mariotti etal. J Neurology (2005) 252: 511 - 518
  72. 72. Autosomal Dominant Ataxias F:ataxiaSpinocerebellar Ataxias.xls
  73. 73. A-TAX-IA
  74. 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. 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

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