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Approach to Ataxia
Presenter: Dr Divya
Preceptor: Prof Achal K Srivastava
Search strategy
• Bradley’s Neurology in clinical Practice, sixth edition
• Handbook of Clinical Neurology, Vol. 103 (3rd ...
Ataxia
 Ataxia = from Greek- a- [lack of]+ taxia [order]
"lack of order
 Of rate, rhythm and force of contraction of vol...
Neural-Localization
Cerebellum (most common)
Sensory pathways (Sensory Ataxia)
 posterior columns, dorsal root ganglia,...
Sensory Ataxia
 Loss of distal joint, position sense
 Absence of cerebellar signs such as dysarthria or nystagmus
 Loss...
Causes of sensory ataxia
Polyneuropathy Paraneoplastic sensory neuronopathy
Sjogren’s syndome
Miller Fisher Syndrome
Dyspr...
Cortical Ataxias
 FRONTAL LOBE ATAXIA refers to disturbed coordination due to
dysfunction of the contralateral frontal lo...
Vestibular dysfunction
 Vertigo is prominent
 Consistent fall to one side
 Nystagmus
 Limb ataxia is absent
 Speech i...
Thalamic Ataxias
 transient ataxia affecting contralateral limbs after lesion of
anterior thalamus
 may see associated m...
Paleocerebellum
Archicerebellum
Vermis  Fastigial nucleus
Balance and
ocular movement
Intermediate Interposed nuclei
Exe...
Clinical features of cerebellar disease
 Ataxia (appendicular or axial)
 Dysmetria
 Dyssynergia
 Dysdiadochokinesia
 ...
Cerebellar Sensory Ataxia Frontal Ataxia
Base of support Wide-based Narrow base, looks down Wide-based
Velocity Variable S...
Differentiation of imbalance due to frontal gait
disorder and extra pyramidal disorders from
cerebellar ataxia
Features Fr...
Cerebellar Ataxia: Classifications
 Congenital or acquired
 Acute or subacute or chronic
 Familial or non familial
 AD...
Hereditary Group
Autosomal dominant cerebellar Ataxias
Spinocerebellar ataxia type 1-31, SCA36, Episodic ataxias
Autosomal...
Cerebellar Ataxias classification (Contd..)
Non hereditary Group (Sporadic)
Degenerative progressive
MSA-C, Idiopathic lat...
Developmental malformation/congenital
Dandy-Walker Malformation
Chiari Malformation
Vermial Agenesis etc.
Cerebellar Ataxi...
Diagnostic Approach
Meticulous evaluation of History
 Age at Onset
 Course of disease
 Drug intake
 Family History
 P...
History
• Age at onset
 Childhood (congenital, metabolic, infectious, posterior fossa
tumors, hereditary ataxias - more c...
• Drug intake
– Phenytoin, barbiturates, lithium, immunosuppressants
(methotrexate, cyclosporine), chemotherapy (fluoroura...
• Distribution of ataxia
– Symmetric - Acquired, Hereditary, degenerative ataxias
– Asymmetric- Vascular, Tumors, congenit...
In Children
History:
 refusal to walk or with a wide-based, "drunken" gait.
 Vertigo, dizziness and vomiting
 Personali...
symmetrical signs Focal and Ipsilateral Cerebellar Signs
Acute (Hours to
Days)
Subacute (Days to
Weeks)
Chronic (Months
to...
Examination
• Neurological examination
• Other system evaluation
 Breast Lump, mass per-abdomen etc.
• Rating scales
 In...
Ancillary tests
Neuro imaging
 MRI of brain and spine
Electro diagnostic tests
 EMG/NCV, EEG, evoked potentials, ERG
Tes...
• Genetic tests (available in India)
 AD: SCA 1, 2, 3, 6, 7, 8, 10, 11,12, 14, 17,23 and 28; DRPLA
 AR: FRDA, AOA1 and 2...
• Laboratory studies
 Mitochondrial
• Serum lactate and pyruvate
 Other
• Heavy metals, peripheral blood smear for acant...
Hereditary Group
Autosomal dominant cerebellar Ataxias
Spinocerebellar ataxia type 1-31, SCA36, Episodic ataxias
Autosomal...
INTRODUCTION:
Autosomal Dominant Cerebellar Ataxias
 Clinically and genetically heterogeneous group of
neurodegenerative ...
Signs of cerebellar ataxia
Pigmentory retinal
degeneration
Ophthalmoplegia
pure cerebellar syndrome
Signs of cerebellar at...
Spinocerebellar ataxias: Clinico genetics
SCA1- (CAG)n
SCA2- (CAG)n
SCA3- (CAG)n
SCA6- (CAG)n
SCA7- (CAG)n
SCA8- (CTG)n
SC...
Clinical behavior of Common SCA subtypes
Late onset 3rd to 4th decade
Diffuse Neuro degeneration
predominantly OPCA
Variab...
SCA Subtypes and distinguishing features
Signs that Distinguishes SCA subtypes
Benign course SCA 6
UMN signs SCA 1,7,8 and 3
Akinetic rigid syndrome SCA 3,2,17 & 1...
Guide to efficient genetic testing
THE LANCET Neurology Vol 3 May 2004
Hereditary Group
Autosomal dominant cerebellar Ataxias
Spinocerebellar ataxia type 1-31, SCA36, Episodic ataxias
Autosomal...
Autosomal recessive cerebellar ataxias
Introduction:
Autosomal recessive cerebellar ataxia (ARCAs) are group of
neurodege...
Friedreich ataxia
 One of the most common hereditary ataxias
 Prevalence: 2 – 4/100,000
 1 in 40,000 in Caucasians popu...
Diagnostic criteria
Journal of Child Neurology 27(9
Mitochondrial Gene Chromosome Pathogenic mechanism
Friedreich's Ataxia FXN 9q13 Mitochondrial Fe overload
Infantile onset ...
Disease Additional features over
Cerebellar Ataxia
Distinguishable features Laboratory
findings
Cerebellar ataxia with sen...
Disease Additional features over Cerebellar Ataxia Distinguishable features Laboratory findings
Cerebellar ataxia with sen...
Disease Additional features over Cerebellar Ataxia Distinguishable features Laboratory findings
Cerebellar ataxia with sen...
Genetic Testing Protocol of ataxias(AIIMS)
Spinocerebellar Ataxia
Aut.Dominant Aut.RecessiveSporadic
LOCA (>25) EOCA (<25)...
Hereditary Group
Autosomal dominant cerebellar Ataxias
Spinocerebellar ataxia type 1-31, SCA36, Episodic ataxias
Autosomal...
X-linked ataxia
Fragile X associated Tremor-Ataxia syndrome
(FXTAS)
Major Diagnostic criteria:
 Onset >50 years, M>F
 Ne...
FXTAS Genetic features
 Expanded CGG repeat
 FMR gene
 Chromosome Xq27.3
 Premutation repeat length
 55-200
 Elevate...
Sporadic ataxias
• Multiple system atrophy (MSA)
• Toxins/metabolic
• Paraneoplastic cerebellar degeneration
• Immune-medi...
 Clinical features:
– Parkinsonism
• Asymmetric, postural/action
tremor, early gait problems, +
dopa responsive
– Cerebel...
MSA diagnosis Gilman S Neurology2008
Central ataxia, Lower limb tremor, Psychosis,
Dementia
Damage to GABA-A receptor, Impaired Glucose
metabolism,VitB1 defici...
Anticonvulsant-
Phenytoin,
carbamazepine
Mild-Moderate dose dependent
ataxia,nystagmus,peripheral
neuropathy and brisk DTR...
Etiology- IgA/IgG Anti-Gliadin Ab,
Anti-endomysial Ab and
Ab against Tissue Trans-glutaminase
Rx-Gluten free diet, I.V.-IG...
 224 patients with various causes of ataxia from North Trent
and 44 patients with sporadic idiopathic ataxia from The
Ins...
The prevalence of antigliadin antibodies in the familial group
was
8 out of 59 (14%)
54 out of 132 (41%) in the sporadi...
Hadjivassiliou et al. Brain(2003),126,685-691
Immune mediated – GAD ataxia
• Clinical phenotype
 Onset 20-75 years
 F > M
 Neurologic: Ataxia, nystagmus, dysarthria
...
Arch Neurol. 2001;58:225-230
Arch Neurol. 2001;58:225-
SREAT
 Sub acute onset, formerly known as Hashimoto’s encephalopathy
 Ataxia progressing over weeks, with cognitive dist...
Hashimoto’ Encephalopathy: Systematic Review
of the Literature
(The Journal of Neuropsychiatry and Clinical
Neurosciences ...
Paraneoplastic cerebellar degeneration
 Clinical features:
 Onset precedes neoplasm
 Pancerebellar syndrome: Gait and l...
Antibody Condition Freq.
Anti-Yo (Purkinje cell antobody type1) Breast and ovarian Ca 0.38
Anti-Hu (Anti neuronal nuclear ...
When to suspect?
• Age :Late (60 -70 yrs)
• Onset: Sub acute
• Progression: weeks to months then stabilize
• Compatible cl...
• In a 12-year period, >5000 samples for the presence of
antineuronal antibodies
• A total of 137 patients were identified...
Management
• Symptomatic treatment
• Early detection & treatment of cancer
• Immunosuppersion: Corticosteroids / IVIg
VitB1 Acute or subacute
onset, Psychosis,
dementia, confusion,
seizures, peripheral
neuropathy
Hemorrhagic
lesion around 3...
INFECTIONS
 VZV in children
 EBV in children
 Bickerstaff’s encephalitis (brainstem ophthalmoplegia,
ataxia, lower cra...
Creutzfeldt–Jakob Disease
• Rapidly progressive disorder with cerebellar ataxia.
• Sooner or later, patients develop a ple...
Diagnostic approach to sporadic adult-onset
ataxia
www.thelancet.com/neurology Vol 9 January
2010
www.thelancet.com/neurology Vol 9 January
Diagnostic approach to sporadic adult-onset
ataxia
Idiopathic late-onset cerebellar ataxia
 Diagnosis of exclusion
 One can debate where early-onset cerebellar ataxia ends...
Ataxia with seizures
• Anti GAD ataxia
• Anti gliadin ataxia
• Mitochondrial ataxia
• Episodic ataxia
• DRPLA
• SCA 10, SC...
Ataxia with Neuropathy
• Friedreich ataxia
• AOA2
• Fragile X syndrome
• Vit E deficiency ataxia
• Anti gliadin ataxia
• S...
Neuro-ophthalmologic evaluation in ataxia
Handbook of Clinical Neurology, Vol. 103 (3rd series)
Non-cerebellar neurological signs in ataxias
Handbook of Clinical Neurology, Vol. 103 (3rd series)
Conclusions:
An approach to ataxia is based on knowledge of its symptoms and
causes
Knowledge of differentiating clinica...
Genotype-Phenotype correlations in SCA1
Higher repeats are associated with earlier onset and severe disease
Homozygous e...
Genotype-Phenotype correlations in SCA2
Higher repeats are associated with earlier onset
Homozygous expansion- no increa...
Genotype-Phenotype correlations in SCA3
Earlier onset with Higher repeats and inverse correlation
Homozygous expansion- ...
Genotype-Phenotype correlations in SCA7
Earlier onset with higher repeats and anticipation
Greater expandability during ...
Genotype-Phenotype correlations in SCA 17
Weaker anticipation in SCA17
Transmission of alleles are relatively stable due...
UncharacterizedCharacterized
Where to next??
Phenotypic dilemma and challenges for novel gene identifications in
Uncharact...
DIAGNOSIS OF ATAXIA PATIENTS IN ATAXIA CLINIC,
AIIMS (Unpublished)
7%
12%
3%
1%
12%
4%
61%
SCA1
SCA2
SCA3
SCA7
SCA12
FRDA
...
Clinical Scenario
• 62/M, no prior co morbidities
• 3-year history of gradually worsening unsteadiness and shaking of
his ...
Case follow-up
 Besides ataxia, our patient reported urinary urgency and had
pyramidal features due to spinal cord involv...
Could this be genetic?
• A negative family history, even done properly
does not exclude a genetic cause.
• Patients with s...
Case follow-up
 In our patient, mutation analysis of the CACNA1A
gene was positive, with 22 CAG repeats on the
expanded a...
Localization of cerebellar lesions
Signs and symptoms Regions most probably involved
Gait ataxia Anterior vermis
Limb atax...
Gilman S Neurology2008
Approach to ataxia
Approach to ataxia
Approach to ataxia
Approach to ataxia
Approach to ataxia
Approach to ataxia
Approach to ataxia
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Approach to ataxia

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DM Seminar
Dr Divya
SR Neuro, AIIMS

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Approach to ataxia

  1. 1. Approach to Ataxia Presenter: Dr Divya Preceptor: Prof Achal K Srivastava
  2. 2. Search strategy • Bradley’s Neurology in clinical Practice, sixth edition • Handbook of Clinical Neurology, Vol. 103 (3rd series), Ataxic Disorders • http://www.ataxia.org -National Ataxia Foundation web site • http://www.ncbi.nlm.nih.gov/books/NBK1138/ Detailed information about ataxias • http://www.clinicaltrials.gov – clinical trials information • Pubmed-with the search terms “spinocerebellar ataxia”,“Friedreich’s ataxia”, “sporadic ataxia”, “sensory ataxia”, “approach to ataxia”, “ataxia diagnosis” • The Cochrane Library
  3. 3. Ataxia  Ataxia = from Greek- a- [lack of]+ taxia [order] "lack of order  Of rate, rhythm and force of contraction of voluntary movements  Disorganized, poorly coordinated, or clumsy movements  Traditionally used specifically for lesions involving – Cerebellum or it’s pathways – Proprioceptive sensory pathways
  4. 4. Neural-Localization Cerebellum (most common) Sensory pathways (Sensory Ataxia)  posterior columns, dorsal root ganglia, peripheral N. Frontal lobe lesions-fronto-cerebellar fibers
  5. 5. Sensory Ataxia  Loss of distal joint, position sense  Absence of cerebellar signs such as dysarthria or nystagmus  Loss of tendon reflexes  Corrective effects of vision on sensory ataxia  Romberg sign • Sensory neuropathy and posterior column disease of the spinal cord (sensory ataxia)
  6. 6. Causes of sensory ataxia Polyneuropathy Paraneoplastic sensory neuronopathy Sjogren’s syndome Miller Fisher Syndrome Dysproteinemia Cisplatin Pyridoxine excess Acute sensory neuronopathy Chronic ataxic neuropathy Myelopathy Multiple sclerosis Tumour or cord compression Vascular malformation Vacuolar myelopathy Myeloneuropathy Freidriech’s Ataxia Vitamin B12 deficiency Vitamin E deficiency Tabes dorsalis Nitrous oxide
  7. 7. Cortical Ataxias  FRONTAL LOBE ATAXIA refers to disturbed coordination due to dysfunction of the contralateral frontal lobe  Results from disease involving the frontopontocerebellar fibers en route to synapse in the pontine nuclei.  Hyper reflexia, increased tone and Release reflexes  A lesion of the “SUPERIOR PARIETAL LOBULE” (areas 5 and 7 of Brodmann) may rarely result in ataxia of the contralateral limbs
  8. 8. Vestibular dysfunction  Vertigo is prominent  Consistent fall to one side  Nystagmus  Limb ataxia is absent  Speech is normal  Joint position sense is normal Patient complains of vertigo rather than imbalance
  9. 9. Thalamic Ataxias  transient ataxia affecting contralateral limbs after lesion of anterior thalamus  may see associated motor (pyramidal tract) signs from involvement of internal capsule  also can result in asterixis in contralateral limbs (hemiasterixis)
  10. 10. Paleocerebellum Archicerebellum Vermis  Fastigial nucleus Balance and ocular movement Intermediate Interposed nuclei Execution of movements and gait Lateral Cortex Dentate nucleus Motor planning, limb coordination FloculusVestibulo-occular reflex Neocerebellum Cerebellum
  11. 11. Clinical features of cerebellar disease  Ataxia (appendicular or axial)  Dysmetria  Dyssynergia  Dysdiadochokinesia  Rebound Phenomenon  Dysarthria  Tremor  Titubation and increased postural sway  Hypotonia  Asthenia  Nystagmus
  12. 12. Cerebellar Sensory Ataxia Frontal Ataxia Base of support Wide-based Narrow base, looks down Wide-based Velocity Variable Slow Very slow Stride Irregular, lurching Regular with path deviation Short, shuffling Romberg +/– Unsteady, falls +/– Heel-shin Abnormal +/– Normal Initiation Normal Normal Hesitant Turns Unsteady +/– Hesitant, multistep Postural instability + +++ ++++ Falls Late event Frequent Frequent
  13. 13. Differentiation of imbalance due to frontal gait disorder and extra pyramidal disorders from cerebellar ataxia Features Frontal gait disorder Extrapyramidal Cerebellar ataxia Posture Upright Stooped, flexed trunk Stooped, leans forward Stance Wide based Narrow Wide based Initiation of gait Start hesitation Start hesitation Normal Stepping Shuffles Shuffles Staggers, lurches Stride length Short Short Variable Speed Very slow Slow Normal, slow Festination Rare Common Absent Arm swing Exaggerated Reduced, absent Normal, exaggerated Heel – toe Unable Normal Unable Turning corners Freezes, shuffles Freezes Veers away Heel –shin test Normal Normal Abnormal Postural reflexes Impaired Preserved till late +/- Falls Common Late uncommon
  14. 14. Cerebellar Ataxia: Classifications  Congenital or acquired  Acute or subacute or chronic  Familial or non familial  AD or AR or SPORADIC  Ipsilateral signs or bilateral signs  Symmetrical or asymmetrical  Progressive or slowly progressive, static or improving, recurrent/episodic  A/W HF,CN, Pyramidal, Extrapyramidal, Peripheral Neuropathy Features 9/13/2016 15
  15. 15. Hereditary Group Autosomal dominant cerebellar Ataxias Spinocerebellar ataxia type 1-31, SCA36, Episodic ataxias Autosomal Recessive cerebellar Ataxias Friedreich’s ataxia, Ataxia Telengiectasia, spastic ataxia X-linked cerebellar ataxias Fragile X tremor ataxia syndrome Mitochondrial Myoclonus Epilepsy with Ragged Red Fibers(MERRF), Kearns Syre Syndrome (KSS) Contd… Classification
  16. 16. Cerebellar Ataxias classification (Contd..) Non hereditary Group (Sporadic) Degenerative progressive MSA-C, Idiopathic late onset cerebellar ataxia (IOCA) Non-progressive developmental disorders Cayman ataxia, Joubert syndrome Toxins induced cerebellar degeneration Alcohol, Anticonvulsants, Anticancer drugs etc Autoimmunity associated Multiple sclerosis, Gluten ataxia, Ataxia with anti-GAD Ab Paraneoplastic cerebellar degeneration Infection mediated Post viral infection cerebellitis, Enteric fever, Adeno/retroviral, malaria, Prions
  17. 17. Developmental malformation/congenital Dandy-Walker Malformation Chiari Malformation Vermial Agenesis etc. Cerebellar Ataxias classification (Contd..)
  18. 18. Diagnostic Approach Meticulous evaluation of History  Age at Onset  Course of disease  Drug intake  Family History  Personal Social & Occupational information  Distribution of ataxia  History of other system illness Neurological evaluation Ancillary tests
  19. 19. History • Age at onset  Childhood (congenital, metabolic, infectious, posterior fossa tumors, hereditary ataxias - more common)  Adult (sporadic ataxias, hereditary ataxias) • Course of illness/progression  Acute (metabolic/toxic, infectious, inflammatory, traumatic)  Subacute (metabolic/toxic, infectious, inflammatory, paraneoplastic, tumor)  Chronic (more likely genetic, degenerative, tumor, paraneoplastic)
  20. 20. • Drug intake – Phenytoin, barbiturates, lithium, immunosuppressants (methotrexate, cyclosporine), chemotherapy (fluorouracil, cytarabine) • Family history – Study at least 3 generations – Consanguinity – Ethnicity • Social/Occupational History – Alcohol and drug use, toxins (heavy metals, solvents, thallium), smoking (Vascular) History
  21. 21. • Distribution of ataxia – Symmetric - Acquired, Hereditary, degenerative ataxias – Asymmetric- Vascular, Tumors, congenital causes • Other system illness – Gastrointestinal symptoms- gluten ataxia – Mass lesion- paraneoplastic ataxias History
  22. 22. In Children History:  refusal to walk or with a wide-based, "drunken" gait.  Vertigo, dizziness and vomiting  Personality and behavioral changes.  Abnormal mental status  A history of head trauma ,neck trauma  Patients with a recent infection or vaccination  Previous similar episodes of acute ataxia.  Children with family members with ataxia
  23. 23. symmetrical signs Focal and Ipsilateral Cerebellar Signs Acute (Hours to Days) Subacute (Days to Weeks) Chronic (Months to Years) Acute (Hours to Days) Subacute (Days to Weeks) Chronic (Months to Years) Intoxication: alcohol, lithium, diphenylhydantoin, barbiturates (positive history and toxicology screen) Acute viral cerebellitis (CSF supportive of acute viral infection) Postinfection syndrome Intoxication: mercury, solvents, gasoline, glue; cytotoxic chemotherapeutic drugs Alcoholic- nutritional (vitamin B1 and B12 deficiency) Lyme disease Paraneoplastic syndrome Anti-gliadin antibody syndrome Hypothyroidism Inherited diseases Tabes dorsalis (tertiary syphilis) Phenytoin toxicity Hereditary ataxia AD/AR Vascular: cerebellar infarction, hemorrhage, or subdural hematoma Infectious: cerebellar abscess (positive mass lesion on MRI/CT, positive history in support of lesion) Neoplastic: cerebellar glioma or metastatic tumor (positive for neoplasm on MRI/CT) Demyelinating: multiple sclerosis (history, CSF, and MRI are consistent) AIDS-related multifocal leukoencephalopat hy (positive HIV test and CD4+ cell count for AIDS) Stable gliosis secondary to vascular lesion or demyelinating plaque (stable lesion on MRI/CT older than several months) Congenital lesion: Chiari or Dandy- Walker malformations (malformation noted on MRI/CT) Abbreviations: CSF, cerebrospinal fluid; CT, computed tomography; MRI, magnetic resonance imaging.
  24. 24. Examination • Neurological examination • Other system evaluation  Breast Lump, mass per-abdomen etc. • Rating scales  International Cooperative Ataxia Rating Scale (ICARS)  Scale for the assessment and rating of ataxia(SARA)  Tremor scales  Unified MSA Rating Score (UMSARS)
  25. 25. Ancillary tests Neuro imaging  MRI of brain and spine Electro diagnostic tests  EMG/NCV, EEG, evoked potentials, ERG Tests of autonomic dysfunction  Tilt-table tests, sympathetic skin responses and other tests Ophthalmologic examination  Pigmentary retinopathy, macular degeneration,  cataracts, Kayser-Fleischer rings
  26. 26. • Genetic tests (available in India)  AD: SCA 1, 2, 3, 6, 7, 8, 10, 11,12, 14, 17,23 and 28; DRPLA  AR: FRDA, AOA1 and 2, AT, ARSACS  X-linked: FXTAS  Mitochondrial –entire genome sequencing • Laboratory studies  Metabolic Thyroid function, vitamins B12, E, and B1, serum cholesterol & plasma lipoprotein profile, serum cholestanol & urine bile alcohol, phytanic acid, toxicology screen  Immune function Immunoglobulin levels, Antigliadin antibodies, GAD antibodies, paraneoplastic antibodies Ancillary tests
  27. 27. • Laboratory studies  Mitochondrial • Serum lactate and pyruvate  Other • Heavy metals, peripheral blood smear for acanthocytes, very long chain fatty acids, hexosaminidase A/B, alpha fetoprotein & immunoglobulins, serum ceruloplasmin & 24 hour urinary copper • Tissue studies  Muscle, skin and nerve biopsies • CSF studies  Cell count, glucose and protein, oligoclonal bands, 14-3-3 protein, GAD antibodies, paraneoplastic antibodies, Ancillary tests
  28. 28. Hereditary Group Autosomal dominant cerebellar Ataxias Spinocerebellar ataxia type 1-31, SCA36, Episodic ataxias Autosomal Recessive cerebellar Ataxias Friedreich’s ataxia, Ataxia Telengiectasia, spastic ataxia X-linked cerebellar ataxias Fragile X tremor ataxia syndrome Mitochondrial Myoclonus Epilepsy with Ragged Red Fibers(MERRF), Kearns Syre Syndrome (KSS) etc.
  29. 29. INTRODUCTION: Autosomal Dominant Cerebellar Ataxias  Clinically and genetically heterogeneous group of neurodegenerative disorders.  Characterised by progressive cerebellar and spinal cord dysfunction.  Clinical Features: Gait Ataxia, Limb Incoordination, Dysarthria Pyramidal and Extrapyramidal involvement Occulomotor incordination Peripheral Neuropathy Retinal degeneration
  30. 30. Signs of cerebellar ataxia Pigmentory retinal degeneration Ophthalmoplegia pure cerebellar syndrome Signs of cerebellar ataxia Pyramidal features Extrapyramidal signs amyotrophy ADCA -I ADCA-II ADCA-III SCA -1, 2, 3, 4, 8, 12, 13, 17, 18*, 19/22*, 20*, 21*, 23*, 24*, 25*, 27, 28*, 29*, DRPLA SCA 7 SCA -4, 5, 6, 11, 14, 15, 22*, 26* * Mapped loci (disease gene unknown) Harding classification- Clinico genetic Harding AE. Classification of the hereditary ataxias and paraplegias.Lancet. 1983;1:1151–115
  31. 31. Spinocerebellar ataxias: Clinico genetics SCA1- (CAG)n SCA2- (CAG)n SCA3- (CAG)n SCA6- (CAG)n SCA7- (CAG)n SCA8- (CTG)n SCA10- (ATTCT)n SCA12- (CAG)n SCA17- (CAG)n SCA31- (TGGAA)n SCA36- (GGCCTG)n DRPLA-(CAG)n FRDA- (GAA)n SCA 4- PLEKHG4 SCA 5- β III spectrin SCA11- TTBK-2 SCA13- KCNC3 SCA 14- PRKCG SCA 16/15-ITPR1 SCA23- PDYN2 SCA 27- FGF14 SCA28- AFG3L2 SCA 9 undescribed SCA 18 7q22-q32 SCA 20 11p13-q11 SCA 21 7p21.3-p15.1 SCA19/ 22 1p21-q21 SCA 24 1p36 SCA 25 2p21-p13 SCA 26 19p13.3 SCA 29 3p26 SCA30 4q34.3-q35.1 Repeat expansion Linkage mappedMutation (point/Ins/del) SCA -1, 2, 3, 8, 12, 13, 17, 18*, 19/22*, 20*, 21*, 23*, 24*, 25*, 27, 28*, 29*, DRPLA SCA -7 SCA -4, 5, 6, 11, 14, 15, 22*, 26* SCA -10, 17 Cerebellar ataxia Pigmentory retinal degeneration Cerebellar ataxia Pyramidal Extrapyramidal amyotrophyADCA-I ADCA-II ADCA-III ADCA-IV pure cerebellar syndrome Cerebellar ataxia and Seizures
  32. 32. Clinical behavior of Common SCA subtypes Late onset 3rd to 4th decade Diffuse Neuro degeneration predominantly OPCA Variable rates of progression Rapid progression: ADCA-I, ADCA-II and ADCA-IV Repeat expansion SCA progresses rapidly (except SCA6) Higher repeats leads to increase severity of the disease Slow progression: ADCA-III (Pure cerebellar forms) Variable age at onset Anticipation
  33. 33. SCA Subtypes and distinguishing features
  34. 34. Signs that Distinguishes SCA subtypes Benign course SCA 6 UMN signs SCA 1,7,8 and 3 Akinetic rigid syndrome SCA 3,2,17 & 12,21 Chorea SCA 2,1,3 Action tremor SCA 12,16 Slow saccades SCA 2 & 7 may be in 1,3 Downbeat nystagmus SCA 6 Hyporeflexia/Areflexia SCA 2,4,3 & 19,21 Vision loss SCA 7 Seizure SCA 10 Myoclonus SCA14 or SCA19 Cognitive impairment SCA2,14,19,21,23
  35. 35. Guide to efficient genetic testing THE LANCET Neurology Vol 3 May 2004
  36. 36. Hereditary Group Autosomal dominant cerebellar Ataxias Spinocerebellar ataxia type 1-31, SCA36, Episodic ataxias Autosomal Recessive cerebellar Ataxias Friedreich’s ataxia, Ataxia Telengiectasia, spastic ataxia X-linked cerebellar ataxias Fragile X tremor ataxia syndrome Mitochondrial Myoclonus Epilepsy with Ragged Red Fibers(MERRF), Kearns Syre Syndrome (KSS) etc.
  37. 37. Autosomal recessive cerebellar ataxias Introduction: Autosomal recessive cerebellar ataxia (ARCAs) are group of neurodegenerative disorders More than 20 genes are known to cause ARCAs Infantile-adult onset (generally <25 yrs) Cerebellar ataxias with predominant peripheral neuropathy Other features: Cardiac involvement, Muscular involvement, immunodeficiency, metabolic derangements etc. FRDA accounts for the major prevalent ARCA
  38. 38. Friedreich ataxia  One of the most common hereditary ataxias  Prevalence: 2 – 4/100,000  1 in 40,000 in Caucasians populations  Carrier frequency: 1/60 – 1/100 • Slowly progressive ataxia • Initial presentation b/n 5-15yrs • Most are wheelchair bound by late teens -early 20s • Scoliosis and pes cavus in 10% • Heart abnormalities cause premature death in 60% to 80%  Intronic GAA repeat expansions in the FXN gene  About 25% of FXN mutation carriers have an atypical phenotype, such as late onset, for example up to 64 years  FA with retained tendon reflex The Cochrane Library 2012, Issue 4
  39. 39. Diagnostic criteria Journal of Child Neurology 27(9
  40. 40. Mitochondrial Gene Chromosome Pathogenic mechanism Friedreich's Ataxia FXN 9q13 Mitochondrial Fe overload Infantile onset cerebellar Ataxia (IOCA) C10orf2 10q24 Mitochondrial DNA replication CoQ10 deficiency (Adult) UK UK Reduced ATP synthesis in Mitochondria Metabolic Ataxia with Vitamin E deficiency (AVED) TTPA 8q13.1-13.3 (Met.)Impaired a-tocopherol mediated Vit E and VLDL interaction Abetalipoproteinemia (ABL) MTP 4q22-24 (Met.)Impaired Lipoprotein metabolism Cerebello tendinous Xanthomatosis (CTX) CYP27 2q33-ter Imapired Bile acid Biosynthesis Late Onset Tay sac's disease (LOTS) HEXA 15q23-24 Glicosphingolipid accumulation DNA repair defect Ataxia Telengiectasia (AT) ATM 11q22-23 DNA damage Ataxia Telengiectasia like disorder (ATLD) MRE11 11q21 DNA damage Ataxia with Occulomotor Apraxia 1 (AOA1) APTX 9p13 Imapired DNA repair Ataxia with Occulomotor Apraxia 2 (AOA2) SETX 9q34 Imapired DNA repair Spinocerebellar ataxia with axonal neuropathy (SCAN1) TDP1 14q31-32 DNA repair Mitochondrial recessive ataxia syndrome(MIRAS) POLG 15q22-26 Impaired Mitochondrial DNA replication and damage repair Protein folding defect Autosomal recessive ataxia of Charlevoix-Saguenay (ARSACS) SACS 13q11 Deficient Chaperon mediated protein folding Marinesco-Sjögren’s syndrome (MSS) SIL1 5q31 Impaired HSP70- mediated protein folding Refsum Disease PHYH, PEX7 10pter-11.2, 6q21-22.2 Autosomal recessive cerebellar ataxia: The Implicated genes and pathology
  41. 41. Disease Additional features over Cerebellar Ataxia Distinguishable features Laboratory findings Cerebellar ataxia with sensory Axonal neuropathy MRI-spinal atrophy FRDA Pes cavus, Amyotrpohy, Extensor Plantar, Nystagmus Cardiomyopathy, DM GAA expansion in FXN MRI-Spinal +Cerebellar Atrophy IOSCA Pes cavus, Amyotorphy, Ophthalmoplegia,Cognitive Impairment, Chorea Seizures,Hearing loss, Hypogonadism - MRI-Normal AVED Pes Cavus, Extensor Plantar, Head Tremor Retinitis Pigmentosa, Cardiomyopathy Low VitE ABL Pes cavus, Amyotrophy Retinitis Pigmentosa, Lipid Malabsorption, Cardiomyopathy Low VitE, low lipoprotein, acanthocytes Clinical approach to ARCAs- using MRI findings and Nerve conduction studies
  42. 42. Disease Additional features over Cerebellar Ataxia Distinguishable features Laboratory findings Cerebellar ataxia with sensorymotor Axonal neuropathy MRI-Cerebellar Atrophy LOTS Amyotrophy, tremor, Myoclonus Saccadic Intrusion, Prominent Extrapyramidal, Seizures,Psychiatric Impairment - SCAN1 Pes Cavus, Amyotrophy Low albumin AT Occulomotor Apraxia, Amyotrophy,Tremor Myoclonus, Extrapyramidal, Babinski Sign Telengiectasia,Lymphoid cancer, Radiosensitivity,Immunodeficiency, DM High alpha-fetoprotein and low immunoglobin ATL Occulomotor Apraxia, Extrapyramidal Radiosensitivity,Immunodeficiency low immunoglobin AOA1 Occulomotor apraxia,Pes cavus, Amyotrophy, tremor, Extrapyramidal, cognitive impairment Scoliosis Low albumin, High Cholesterol AOA2 Occulomotor Apraxia, Pes Cavus, amyotrophyTremors, Extrapyramidal, cognition Impairment Saccadic Intrusion,Scoliosis High alpha-fetoprotein, High cholesterol MRI-Spinal +Cerebellar Atrophy ARSACS Pes Cavus, Amyotrophy, Spasticity, extensor Plantar, cogitive Impairment Saccadic Intrusion, Hypermyelinated Retinal fibers - MRI-Cerebellar Atrophy + WMH CTX Pes Caus Amyotrophy, Spasticity, myoclonus, Parkinsonism Psychiatric Impairment,Tendon Xanthomas,Seizures,Cataract,Liver failure High cholesterol, High bile alcohols MIRAS Pes cavus, Amyotrophy, tremors, Myoclonus, Choreoathetosis Saccadic Intrusion, Psychiatric Impairment,Seizures,Migraine,Heari Liver failure
  43. 43. Disease Additional features over Cerebellar Ataxia Distinguishable features Laboratory findings Cerebellar ataxia with sensorymotor Demyelinating neuropathy MRI-Cerebellar Atrophy MSS Amyotrophy, tremor, Hypotonia Psychomotor and cognitive, Impairment, Scoliosis,Cataract, Hypertropic Hypogonadism, Rhabdomyolysis - MRI-Normal Refsum Disease Pes cavus, Amyotrophy Retinitis Pigmentosa,Cardiomyopathy,Hearin g,Renal Failure Renal failure, high phytanic acid,High CSF proteins Others Cerebellar ataxia and Hypogonadotropic Hypogonadism BNS Cerebellar ataxia, hypotrophic Hypogonadism hypotrophic Hypogonadism - CoQ10 deficiency (Adult onset) CoQ10 deficiency (Adult onset) - Congenital cerebellar Ataxia CA (Cayman ataxia) Hypotonia, Tremor, Cognitive Impairment MRI-Cerebellar hypoplasia - JS (Vermial Agenesis) (JST1-JST10) Infantile Onset, Vertical gaze paresis,Nystagmus, ptosis, Retinopathy,Mental retardation Molar Tooth Sign,Episodic Hypernea or apnea of new Born -
  44. 44. Genetic Testing Protocol of ataxias(AIIMS) Spinocerebellar Ataxia Aut.Dominant Aut.RecessiveSporadic LOCA (>25) EOCA (<25)SCA 1 SCA 2 SAC 3 SCA 7 SCA 12 FRDA NO YES YES NO SCA 6 SCA 8 SCA 17 DRPLA YES NO Rare types of SCAs (ADCA) screening Trying to establish investigation guidelines for ARCA genes Level 20 Level 10 Level 30 features suggestive of SCA LOCA-Late onset cerebellar ataxi EOCA-Early onset cerebellar atax SCA27 SCA28 Age at Onset (Yrs) 10-30 >30 Variable SCA11 SCA14 SCA23 SCA5 SCA13 SCA14 SCA15 SCA28
  45. 45. Hereditary Group Autosomal dominant cerebellar Ataxias Spinocerebellar ataxia type 1-31, SCA36, Episodic ataxias Autosomal Recessive cerebellar Ataxias Friedreich’s ataxia, Ataxia Telengiectasia, spastic ataxia X-linked cerebellar ataxias Fragile X tremor ataxia syndrome Mitochondrial Myoclonus Epilepsy with Ragged Red Fibers(MERRF), Kearns Syre Syndrome (KSS) etc.
  46. 46. X-linked ataxia Fragile X associated Tremor-Ataxia syndrome (FXTAS) Major Diagnostic criteria:  Onset >50 years, M>F  Neurologic: Gait ataxia, tremor, parkinsonism, cognitive decline, polyneuropathy, autonomic dysfunction  Systemic: Premature ovarian failure  Brain MRI: cerebral/cerebellar atrophy, T2 signal in middle cerebellar peduncles  Neuropathology: intranuclear inclusions in brain and spinal cord Brunberg et al, 2002
  47. 47. FXTAS Genetic features  Expanded CGG repeat  FMR gene  Chromosome Xq27.3  Premutation repeat length  55-200  Elevated levels FMR1 mRNA  Toxic gain of function?  Decreased FMR1 mRNA translational efficiency Hagerman and Hagerman, 2004
  48. 48. Sporadic ataxias • Multiple system atrophy (MSA) • Toxins/metabolic • Paraneoplastic cerebellar degeneration • Immune-mediated ataxias (gluten, anti-GAD) • Infectious etiology
  49. 49.  Clinical features: – Parkinsonism • Asymmetric, postural/action tremor, early gait problems, + dopa responsive – Cerebellar • Gait and limb ataxia, nystagmus, dysarthria – Autonomic • Orthostatic hypotension, bladder dysfunction, impotence – Other • Hyperreflexia, antecollis, inspiratory stridor, RBD, dystonia • Pathology: – Neuronal cell loss and gliosis – Glial cytoplasmic inclusions – No Lewy bodies Beware of MSA C
  50. 50. MSA diagnosis Gilman S Neurology2008
  51. 51. Central ataxia, Lower limb tremor, Psychosis, Dementia Damage to GABA-A receptor, Impaired Glucose metabolism,VitB1 deficiency MRI-Superior cerebellar and cerebral atrophy Alcohol abstinence,VitB1 replacement Pathophysiology MRI Treatment Toxins- Alcoholic cerebellar degeneration(ACD)
  52. 52. Anticonvulsant- Phenytoin, carbamazepine Mild-Moderate dose dependent ataxia,nystagmus,peripheral neuropathy and brisk DTR Loss of PC and granule cells Serum level of drug, MRI-variable atrophy of cerebellum Stop the drug, Hemodialysis and Intensive management Anticancer Drugs- 5-fluorouracil,Cytosin arabinoside Generalized cerebellar synndrome, encephalopathy - MRI-pancerebellar atrophy Stop the drug, Hemodialysis and Intensive management Lithium cerebellar syndrome, Tremors, Hyper-reflexias - Serum Li level, history of concomittent treatment-CPZ Hemodialysis and Intensive care management Amiadarone Cerebellar ataxia, Peripheral neuropathy,Myoclonus, encephalopathy and rest tremor - MRI-cerebellar atrophy Drug withdrawl and treatment of drug related hypothyroidism Agent Clinical features Pathology Inv Rx Drug induced ataxias Toxins- • Metals Bismuth, Mercury (parasthesiass, restricted visual defects), Lead • Solvents  Paint thinners , toluene (Cognitive defects PLUS pyramidal tract signs)
  53. 53. Etiology- IgA/IgG Anti-Gliadin Ab, Anti-endomysial Ab and Ab against Tissue Trans-glutaminase Rx-Gluten free diet, I.V.-IG Invg-Serum-IgA,IgG-antigliadin, anti endomyseium, TTG, MRI- Cerebllar atrophy and WMH, Intestinal Biopsy Patho-Ab targets PC due to share antigenicity of gluten Clinical features-50-60 Yrs onset, Gait Ataxia, Peripheral neuropathy and gluten sensitivity Immune mediated – Gluten ataxia
  54. 54.  224 patients with various causes of ataxia from North Trent and 44 patients with sporadic idiopathic ataxia from The Institute of Neurology, London, were screened for the presence of antigliadin antibodies  A total of 1200 volunteers were screened as normal controls
  55. 55. The prevalence of antigliadin antibodies in the familial group was 8 out of 59 (14%) 54 out of 132 (41%) in the sporadic idiopathic group 5 out of 33 (15%) in the MSA-C group  149 out of 1200 (12%) in the normal controls The prevalence in the sporadic idiopathic group from London was 14 out of 44 (32%) The difference in prevalence between the idiopathic sporadic groups and the other groups was highly significant (P < 0.0001 and P < 0.003, respectively) Hadjivassiliou et al. Brain(2003),126,685-691
  56. 56. Hadjivassiliou et al. Brain(2003),126,685-691
  57. 57. Immune mediated – GAD ataxia • Clinical phenotype  Onset 20-75 years  F > M  Neurologic: Ataxia, nystagmus, dysarthria  Systemic: Autoimmune disease  Studies: Anti-GAD Antibodies in serum, CSF  Brain MRI: cerebellar atrophy in some • Treatment  Steroids, IVIG?
  58. 58. Arch Neurol. 2001;58:225-230
  59. 59. Arch Neurol. 2001;58:225-
  60. 60. SREAT  Sub acute onset, formerly known as Hashimoto’s encephalopathy  Ataxia progressing over weeks, with cognitive disturbance, myoclonus, seizures  Patients have high serum thyro peroxidase antibody levels, although thyroid function is normal in half of the cases  The mean age at onset is 45–55 years,  Five times more common in women than  Patients often have other autoimmune disorders  Readily treatable and improves dramatically with corticosteroids  The sooner treatment is started, the better the outcome
  61. 61. Hashimoto’ Encephalopathy: Systematic Review of the Literature (The Journal of Neuropsychiatry and Clinical Neurosciences 2011; 23:384 –390)
  62. 62. Paraneoplastic cerebellar degeneration  Clinical features:  Onset precedes neoplasm  Pancerebellar syndrome: Gait and limb ataxia, dysarthria, nystagmus, oculomotor dysfunction  Evolution: Rapid over weeks to months, then stabilize  Loss of Purkinje cells in the cerebellar cortex, deep cerebellar nuclei & inferior olivary nuclei  ? T cell mediated  PCD can be associated with any cancer, but most common: – Lung cancer (small-cell) – Ovarian/Breast carcinoma – Hodgkins lymphoma Brain (2003), 126, 1409-1418
  63. 63. Antibody Condition Freq. Anti-Yo (Purkinje cell antobody type1) Breast and ovarian Ca 0.38 Anti-Hu (Anti neuronal nuclear antibody type1) Small cell lung Ca (SCLC) 0.32 Anti-Tr Hodgkin Lymphoma 0.14 Anti-mGluR1 (metabotrpin glutamate receptor) Hodgkin Lymphoma 0.04 AntiRi (Anti neuronal nuclear antibody type1) SCLC, Breast, Ovarian ca 0.12 Anti-VGCC (Voltage gated calcium channel) SCLC Anti-CRMP5 (Collapsin receptor mediated protein)/Anti-CV2 SCLC Anti-ZIC4 (zinc finger protein) SCLC Paraneoplastic ataxia associated antibodies
  64. 64. When to suspect? • Age :Late (60 -70 yrs) • Onset: Sub acute • Progression: weeks to months then stabilize • Compatible clinical history • CSF : Pleocytosis, oligoclonal bands • MRI: Normal in initial stage, cerebellar atrophy develops in subsequent months • FDG-PET Scan: Hypermetabolism • If initial screening is negative , repeat screening is advisable Brain (2003):126; 1409-1418
  65. 65. • In a 12-year period, >5000 samples for the presence of antineuronal antibodies • A total of 137 patients were identified with a paraneoplastic neurological syndrome and high titer (>400) antineuronal antibodies • Fifty (36%) of these patients had antibody associated PCD, including 19 anti-Yo, 16 anti-Hu, seven anti-Tr, six anti-Ri and two anti-mGluR1 • While 100% of patients with anti-Yo, anti-Tr and anti-mGluR1 antibodies suffered PCD, 86% of anti-Ri and only 18% of anti- Hu patients had PCD • All patients presented with subacute cerebellar ataxia progressive over weeks to months and stabilized within 6 months • The majority had both truncal and appendicular ataxia Brain (2003), 126, 1409±1418
  66. 66. Management • Symptomatic treatment • Early detection & treatment of cancer • Immunosuppersion: Corticosteroids / IVIg
  67. 67. VitB1 Acute or subacute onset, Psychosis, dementia, confusion, seizures, peripheral neuropathy Hemorrhagic lesion around 3rd ventricle, mamillary body and thalamic nuclei Serum VitB1 level and MRI VitB1 replaceme nt VitB12 sensory ataxia, megalblastic anemia Peripheral nerve damage serum Vit B12 level and peripheral smear VitB12 replaceme nt VitE cerebellar syndrome,sensory neuropathy and arreflexia Cerebellar atrophy VitE level VitE replaceme nt Agent Clinical features Pathology Investigati ons Rx Vitamin deficiency induced Ataxias
  68. 68. INFECTIONS  VZV in children  EBV in children  Bickerstaff’s encephalitis (brainstem ophthalmoplegia, ataxia, lower cranial nerve palsies)  HIV ( Lymphomas, PML, Infections, Toxoplasmosis)  CJD (17% classic CJD, Ataxic variant of CJD)  Syphilis (Tabes Dorsalis)  Whipple’s disease
  69. 69. Creutzfeldt–Jakob Disease • Rapidly progressive disorder with cerebellar ataxia. • Sooner or later, patients develop a plethora of other neurological signs: dementia, myoclonus and Parkinsonism • Gerstmann Sträussler-Scheinker disease is characterized by onset at age 20–40 years with progressive cerebellar ataxia and, In many patients, spastic paraparesis • The pathological changes are unique with amyloid plaques throughout the brain • MRI features: Pulvinar sign and cortical ribboning on DWI • CSF: 14-3-3 protein and increased tau levels • EEG: periodic synchronous biphasic or triphasic sharp wave complexes • Patients usually die within a year • Familial CJD has earlier age of onset and longer clinical course than sporadic CJD http://neurology.thelancet.com Vol 4 October 2005
  70. 70. Diagnostic approach to sporadic adult-onset ataxia www.thelancet.com/neurology Vol 9 January 2010
  71. 71. www.thelancet.com/neurology Vol 9 January Diagnostic approach to sporadic adult-onset ataxia
  72. 72. Idiopathic late-onset cerebellar ataxia  Diagnosis of exclusion  One can debate where early-onset cerebellar ataxia ends and idiopathic late onset cerebellar ataxia begins  Some prefer the term ‘sporadic adult-onset ataxia’  This is clearly an aetiologically heterogeneous group  Long term follow-up is needed to identify ‘conversion’ to MSA that may occur later Postgrad Med J 2012;88:407e417. doi:10.1136/postgradmedj-2011-000108rep
  73. 73. Ataxia with seizures • Anti GAD ataxia • Anti gliadin ataxia • Mitochondrial ataxia • Episodic ataxia • DRPLA • SCA 10, SCA 7 • CJD • SREAT • SeSAME syndrome • Co Q deficiency • SCN2A mutations • OPCA Ataxia with Dementia • Anti gliadin ataxia • FXTAS syndrme • SREAT • SCA 17, 19, 21, 2, 1, 6 • HIV/AIDS • Mitochondrial disease • Amyloid ataxia
  74. 74. Ataxia with Neuropathy • Friedreich ataxia • AOA2 • Fragile X syndrome • Vit E deficiency ataxia • Anti gliadin ataxia • SCA 12, 18,25,27,8,3,4 • ARSACS • Refsum disease • Ataxic sensory neuronopathy of Sjogren syndrome
  75. 75. Neuro-ophthalmologic evaluation in ataxia Handbook of Clinical Neurology, Vol. 103 (3rd series)
  76. 76. Non-cerebellar neurological signs in ataxias Handbook of Clinical Neurology, Vol. 103 (3rd series)
  77. 77. Conclusions: An approach to ataxia is based on knowledge of its symptoms and causes Knowledge of differentiating clinical and investigative features takes clinicians closer to the etiological diagnosis Treatable causes must be identified and ruled out Autosomal Dominant cerebellar ataxias in India are more prevalent than recessive ataxias Genetic testing is prudent for providing better insight into the management.
  78. 78. Genotype-Phenotype correlations in SCA1 Higher repeats are associated with earlier onset and severe disease Homozygous expansion- no increase in severity Small disease alleles (39-44) interrupted: Mild Phenotype, Ataxic/non ataxic features Medium Size alleles (39-50) Pure CAG: Ataxia and Pyramidal syndrome Large Size Alleles (>50) Pure CAG: Ataxia and Pyramidal syndrome & Amytrophic Lateral sclerosis Higher Size Alleles (>91): Juvenile disease
  79. 79. Genotype-Phenotype correlations in SCA2 Higher repeats are associated with earlier onset Homozygous expansion- no increase in severity Allelic variations of RAI 1 and CACNA1A influences age at onset Disease duration X CAG length affects occurrence of slow saccades, Fasciculation, Amyotrophy, Areflexia and Vibration senses Small disease alleles (32-37): Postural Tremors and Parkinsonism, late onset disease Medium Size alleles (38-44) : Ataxia, areflexia and slowing of saccades Large Size Alleles (>45) : Onset <20 years, Chorea and dementia Higher Size Alleles (>91) : Ataxia, Dystonia, Myoclonus, Cardiac failure, optic atrophy
  80. 80. Genotype-Phenotype correlations in SCA3 Earlier onset with Higher repeats and inverse correlation Homozygous expansion- confers increasing severity Small disease alleles (52-73): Axonal Neuropathy and Parkinsonism (Type-III MJD) Medium Size alleles (73-80) : Ataxia and Diplopia (Type-II MJD) Large Size Alleles (80-86) : Ataxia, Dystonia and spasticity (Type-I MJD) Higher Size Alleles (>86) : Rare cases predominant Dystonia (Type-IV)
  81. 81. Genotype-Phenotype correlations in SCA7 Earlier onset with higher repeats and anticipation Greater expandability during transmission of alleles Recurrent denovo expansions Small disease alleles (36-41): Cerebellar ataxia without Retinal involvement Medium Size alleles (42-49) : Ataxia preceedes Vision diminution Large Size Alleles (49-60) : Vision loss preceedes Ataxia Higher Size Alleles (>80) : Juvenile Onset Extreme High Length Alleles : Infantile Onset, Developmental failure, Multisystem involvement (>200)
  82. 82. Genotype-Phenotype correlations in SCA 17 Weaker anticipation in SCA17 Transmission of alleles are relatively stable due to interruptions Homozygous individual shows increasing severity Small disease alleles (43-50): Involuntary movements and Impaired cognition Huntington disease like phenotype Medium Size alleles (50-60) : Ataxia,Brisk reflexes and Dystonia Large Size Alleles (>60) : Ataxia, spasticity, Psychiatric impairment and dementia
  83. 83. UncharacterizedCharacterized Where to next?? Phenotypic dilemma and challenges for novel gene identifications in Uncharacterized SCAs SCA1 SCA2 SCA3 AD AR EOCA LOCA Cerebellar Gait ataxia 100 100 100 71.4 79.3 91.6 87.8 UL-ataxia 100 96 89.4 71.4 96.5 84.7 80.4 Dysarthria 92.8 90 94.7 66.6 68.9 83.3 78 Occulomotor Nystagmus 35.7 6 57.8 23.8 31 37.5 21.9 Slowing of Saccades 35.7 78 57.8 33.3 31 41.6 39 Broken pursuit 26 3 57.8 42.8 31 54 48.7 Motor system Muscle cramps 9.5 11 0 0 0 4.1 2.4 Fasciculations 11.9 37 15.7 9.5 6.8 13.8 9.7 Amyotrophy 0 2 84.9 0 0 0 0 Extrapyramidal Extrapyramidal 9.5 18 13.9 14.2 6.8 9.7 21.9 Pyramidal Hyperreflexia 33.3 16 68.4 23.8 24.1 36.1 21.9 Arreflexia 7.1 23 0 9.8 6.8 12.5 4.8 Extensor plantar 23.8 18 26.3 23.8 27.8 26.3 7.3 EPS NCV 60 73 38.4 35.2 37.5 47.9 44.8 AFT 75 65 53.8 61.1 75 55 64 other Dementia 4.7 4 15.7 0 17.2 11.1 0 Myoclonus 0 2 0 0 6.8 0 0 Seizures 0 1 0 0 6.8 5.5 0 VERTIGO 0 0 15.7 0 0 0 0 PES CAVUS/SCOLIOSIS 0 0 0 0 6.8 0 0 Polyphagia 0 1 0 0 0 0 0 Parkinson Phenotype 0 3 0 0 0 0 0 Visual 0 0 5.2 4.7 6.8 5.5 4.8 Dysphagia 9.5 6 0 14.3 0 6.9 2.4 1001 Absent Frequency % AD: Autosomal dominant AR:Autosomal recessive EOCA: early onset sporadic cerebellar ataxia LOCA: Late onset sporadic cerebellar ataxia
  84. 84. DIAGNOSIS OF ATAXIA PATIENTS IN ATAXIA CLINIC, AIIMS (Unpublished) 7% 12% 3% 1% 12% 4% 61% SCA1 SCA2 SCA3 SCA7 SCA12 FRDA Uncharacterized-SCA Total Families= 1500 Characterized= 585 Uncharacterized= 915
  85. 85. Clinical Scenario • 62/M, no prior co morbidities • 3-year history of gradually worsening unsteadiness and shaking of his hands on action • His speech and swallowing were normal, but with some urinary urgency • He drank 3–4 glasses of wine a day • No family history • O/E : titubation, a bilateral terminal tremor on finger–nose testing, dysmetria during finger-chasing, abnormal heel-to-shin testing, mild gait ataxia and clearly disturbed tandem gait, and brisk tendon re- fl exes with bilateral extensor plantar responses • Normal serum vitamin levels and thyroid function • MR scan of the brain showed cerebellar atrophy, mainly of the vermis
  86. 86. Case follow-up  Besides ataxia, our patient reported urinary urgency and had pyramidal features due to spinal cord involvement  The cerebellar atrophy and slow progression suggested a degenerative process  Routine blood tests were normal, including the gluten sensitivity screen  Alcohol excess seemed an unlikely cause
  87. 87. Could this be genetic? • A negative family history, even done properly does not exclude a genetic cause. • Patients with sporadic ataxia may particularly have recessive disorders, but also occasionally dominant, X linked and mitochondrial diseases
  88. 88. Case follow-up  In our patient, mutation analysis of the CACNA1A gene was positive, with 22 CAG repeats on the expanded allele  The final diagnosis was therefore SCA-6
  89. 89. Localization of cerebellar lesions Signs and symptoms Regions most probably involved Gait ataxia Anterior vermis Limb ataxia Lateral hemispheres Dysarthria Posterior left hemisphere & vermis Titubation Any zone, esp. ant. Vermis & associated deep nuclei Action tremor Dentate & interposed nuclei, or cerebellar outflow to ventral thalamus Palatal tremor Dentate nucleus, Guillain Mollaret triangle Saccadic dysmetria Dorsal vermis Square wave jerks Cerebellar outflow Gaze evoked nystagmus Flocculus & paraflocculus Higher cognitive changes Lateral hemispheres
  90. 90. Gilman S Neurology2008

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