03 01-06 approach to ataxia

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ATAXIA

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  • Incoordination of voluntary movements Clumsiness produced by dysfunction of the cerebellum or cerebellar pathways
  • impairment of joint position sense resulting from interruption of afferent nerve fibers in the peripheral nerves, posterior roots, or posterior columns of the spinal cord. The effect of these lesions is to deprive the patients of the knowledge of the position of their limbs
  • Movements are inaccurate and poorly controlled. The term ataxia includes several abnormalities of voluntary movements:
  • static (postural) tremor may also occur may cause arm instability and defective postural fixation at shoulder and elbow.
  • Hypotonia is a decrease in the normal resistance offered by muscles to passive manipulation When an affected limb is shaken flapping movements of the hands appear of wider excursion than normal.
  • Disorder may be a simple slowing of speech or may manifest as a slurring and scanning Dysarthria called because the words are broken into syllables. As the disease progresses, both slurring and slowness may occur and words might become difficult to understand
  • Oculomotor apraxia is a disorder of saccade initiation, and it has been described as an impaired ability to generate saccades on command, although induced saccades during spontaneous visual search and optokinetic stimulation are normal The term oculomotor apraxia has also been used to describe the inability to coordinate eyes-head movements when the head turns toward a lateral target and the head reaches the target before the eyes
  • Complex and includes all types of neurological pathological processes. Most patients presenting with ataxia will have sporadic disorder, there is increasing attention to genetic ataxias because of recent rapid advances.
  • spinocerebellar ataxia with axonal neuropathy SCAN
  • Incidence of dominant spinocerebellar and Fredreich triplet repeats among 361 ataxia families
  • 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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