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Atassia

L'atassia (dal greco ataxi, disordine) un disturbo consistente nella progressiva perdita della coordinazione muscolare che quindi rende difficoltoso eseguire i movimenti volontari. Il centro della coordinazione dei movimenti muscolari il cervelletto che elabora gli impulsi portati ai muscoli dal midollo spinale e dai nervi periferici. L'atassia pu quindi essere provocata da problemi sia a livello del midollo spinale che a livello dei nervi periferici. Le conseguenze si manifestano con la mancanza di coordinazione fra tronco e braccia, tronco e capo, ecc. Vi sono inoltre dei disturbi associati, quali incoordinazione dei movimenti dell'occhio, incontinenza, difficolt di deglutizione e movimenti involontari di arti, capo e tronco.

SEGNI CARDINALI DELLE LESIONI CEREBELLARI


1. Ipotonia 2. Tremore 3. Atassia N.B.: la lesione del cervelletto non causa deficit di forza muscolare

LATASSIA PUO INTERESSARE QUALSIASI SEGMENTO CORPOREO Arti superiori Arti inferiori Tronco Atassia del gesto Atassia della marcia Atassia posturale

DISTURBI DEL MOVIMENTO OCULARE


Dismetria oculare Saccadi ipo- o ipermetriche Incursioni di saccadi nei movimenti di inseguimento lento Nistagmo da paralisi di sguardo i pz non sono in grado di mantenere una posizione di sguardo eccentrica

CORRELAZIONE ANATOMOCLINICA
Sindrome Emisferica Atassia degli arti Tremore Ipotonia Disartria N.B.: i segni sono ipsilaterali alla lesione Eziologia, ex.: Ictus cerebri (SCA) Neoplasie

Atassie Cerebellari Acquisite


EZIOLOGIA ESAMI DA CONSIDERARE

Atassie Cerebellari Acquisite


EZIOLOGIA ESAMI DA CONSIDERARE

Associated cancer
syndromes Anti-Yo (PCA-1)
(ANNA-1)
SCLC

Other paraneoplastic
Gynaecological, breast..Anti-Hu
PEM, PSN, Anti-Tr, Hodgkin's lymphoma..

Anti-Ri (ANNA-2) SCLC, gynaecological, breast, Opsoclonus myoclonus syndr Anti-mGluR1 Anti-CV2 (CRMP5) Anti-ZIC4 Anti-VGC Hodgkin's lymphoma. SCLC, thymoma, PEM SCLC.. SCLC LEMS

ANNA-1/2=anti-neuronal nuclear antibody type 1/2. CRMP5=collapsin response mediator protein 5. LEMS=LambertEaton myasthenic syndrome. mGluR1=metabotropic glutamate receptor type 1. PCA1=Purkinje cell antibody type 1. PEM=paraneoplastic encephalomyelitis. PSN=paraneoplastic sensory neuropathy. SCLC=small-cell lung cancer. VGCC=voltage-gated calcium channel. ZIC4=zinc finger protein 4.

Atassie Cerebellari Acquisite


EZIOLOGIA ESAMI DA CONSIDERARE

G. Holmes G. Seitelberger

N. Friedreich

Anita Harding

Cerebellar ataxias
Gene changes regulating storage or levels of brain metabolites becaming toxic to cerebellar cells (Metabolic ataxias with different age of onset) Abnormalities in homeobox genes regulating cerebellar development (Congenital ataxias) Activation of genes leading to neurodegeneration and apoptosis (Degenerative ataxias)

Classificazione Genotipica delle Atassie Spinocerebellari NOME


LOCUS CROMOSOMICO FENOTIPO

Classificazione Genotipica delle Atassie Spinocerebellari


NOME LOCUS CROMOSOMICO FENOTIPO

Classificazione Genotipica delle Atassie Spinocerebellari


NOME LOCUS CROMOSOMICO FENOTIPO

Classificazione Genotipica delle Atassie Spinocerebellari


NOME LOCUS CROMOSOMICO FENOTIPO

Atrofia cerebellare

Dominant ataxia

Molecular mechanisms of neurodegeneration in spinocerebellar ataxias.

Dueas A M et al. Brain 2006;129:1357-1370


The Author (2006). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Atassie dominanti da poliglutammina

Classificazione Genotipica delle Atassie Spinocerebellari


NOME LOCUS CROMOSOMICO FENOTIPO

Atassia di Friedreich e fratassina


Mutazioni del gene FRDA (locus 9q13; 7 esoni, di cui il 6 non codificante; due splicing alternativi), che codificano la proteina FRATASSINA La fratassina sembra svolgere un ruolo sia nella formazione dei gruppi Fe-S, sia nellattivazione dei meccanismi di difesa dagli stress ossidativi Il deficit di fratassina determina gravi alterazioni negli enzimi mitocondriali e nelle loro funzioni, sia a causa dei problemi nella loro sintesi, sia a causa dei danni ossidativi. Le alterazioni enzimatiche causano anche laccumulo di ferro mitocondriale, che contribuisce ad ulteriori danni ossidativi.

BIOSINTESI DEI GRUPPI FE-S

? FRATASSINA
?
OMEOSTASI DEL FERRO

?
STRESS OSSIDATIVO

Atassia di Friedreich

Electrophysiological and nerve biopsy: comparative study in FA and in FA with vitamin E deficiency Zouari et al. Neuromusc. Disord. 8: 416-425, 1998

Sono stati studiati 15 pazienti per ogni gruppo

Nella FA vi una grave e precoce neuronopatia periferica assonale, caratterizzata da una importante riduzione di ampiezza dei potenziali di azione sensitivi ed una importante perdita delle fibre mieliniche con completa scomparsa delle grosse fibre mieliniche senza alcun processo rigenerativo Nel deficit di vitamina E vi una neuropatia sensitiva assonale pi lieve, con modesta perdita delle fibre mieliniche e presenza di rigenerazione Grave alterazione dei somatosensoriali in ambedue potenziali evocati

Terapia del deficit di vitamina E Follow-up


Click to edit Master text styles Second level Third level Fourth level Fifth level

Classificazione Genotipica delle Atassie Spinocerebellari


NOME LOCUS CROMOSOMICO FENOTIPO

Classificazione Genotipica delle Atassie Spinocerebellari NOME


LOCUS CROMOSOMICO FENOTIPO

Classificazione Genotipica delle Atassie Spinocerebellari NOME


LOCUS CROMOSOMICO FENOTIPO

Acanthocytes

A-beta-lipopoproteinemia Atassia Neuropatia periferica Retinopatia Acantocitosi Malassorbimento dei grassi Abetalipoproteinemia Deficit di vitamina E Mutazione nel gene della proteina transfer microsomale dei trigliceridi o mutazioni nel gene dell apolipoproteina B

Ataxia-teleangiectasia
Autosomal recessive inheritance Conjunctival Teleangiectasias, gaze nystagmus, Bronchitis, bronchiectasias Hypogonadism, impaired spermatogenesis Cutaneous teleangiectasia, caf-au-lait-spots, progeric skin changes, sclerodermatous skin changes

Ataxia teleangiectasia
Ataxia Telangiectasia Choreoathetosis Ocular apraxia

High alfa fetoprotein Low IgA levels CD4+/CD8+ ratio reversed

Peripheral neuropathy Mutation in AT gene, encoding a protein Frequent bronchitis with a putative Lymphoproliferative phosphatidylinositoldisorders 3-kinase domain

Ataxia-Oculomotor apraxia syndrome


Cerebral ataxia, oculomotor apraxia, choreoatethosis Immunoglobulin normal, normal chromosome. AFP normal. Tand B-lymphocyte markers and chromosome 7 and 14 normal No tendency to frequent infections Onset later that AT Linkage to 9p.13.3, aprataxin gene defect (involved in DNA repair mechanisms). Recently a second form has been identified, with mutation in senataxin (DNA repair mechanisms)

Refsum disease Cerebellar signs with ataxia Chronic polyneuritis Anosmia Cardiac changes (ECG alterations, congestive hearth failure) Neurosensorial deafness Ichthyosis Pigmentary rethynopathy Phytanic acid accumulation Phytanic acid oxidase deficiency Good response with a diet

Carbohydrate deficiency syndrome


Psychomotor retardation Generalized hypotonia, hyporeflexia Trunkal ataxia and cerebellar hypoplasia Peripheral demyelination Serum glycoprotein decrease Decrease of N-acetylglucosaminyltransferase Deficiency of sialic acid, galactose and Nacetylglucosamine in total glycoproteins (transferrin isoforms)

Co Q deficiency
Autosomal recessive disorder with a encompasses several main phenotypes:

clinical

spectrum

that

a myopathic form, with myoglobinuria, epilepsy and ataxia a severe infantile syndrome with encephalopathy and renal disease an ataxic form presenting with cerebellar atrophy a neonatal presentation with fatal evolution Leigh syndrome in adulthood liver failure plus Leigh syndrome Variable degree of CoQ deficiency in muscle and/or fibroblasts causing decreased activities of NADH:cit c oxidoreductase and succinate:cit c oxidoreductase of the MRC. Treatment response has been remarkable in most cases, highlighting the importance of an early diagnosis of these disorders.

CoQ10 Deficiency and ataxia


Cranial MRI from the index case at 12 years of age (A) and her father at 35 years of age (B). Cerebellar atrophy was observed.

Electron microscopy examination of muscle biopsy, which showed the presence of an important subsarcolemmic mitochondrial accumulation.

CoQ10 Deficiency and ataxia

Effect of CoQ supplementation and evaluation of ICARS scale and plasma CoQ concentration over 16 months of follow-up in case 1. Above columns, plasma CoQ concentrations (mol/L) and doses applied (mg/day in brackets) are stated. A write test was also performed, showing a clear improvement after CoQ supplementation.

Joubert syndrome
Joubert syndrome (JS) and related disorders (JSRD) are a group of developmental delay/multiple congenital anomalies syndromes in which the obligatory hallmark is the molar tooth sign (MTS), a complex midbrainhindbrain malformation visible on brain imaging, first recognized in JS. Estimates of the incidence of JSRD range between 1/80,000 and 1/100,000 live births, although these figures may represent an underestimate. The neurological features of JSRD include hypotonia, ataxia, developmental delay, intellectual disability, abnormal eye movements, and neonatal breathing dysregulation. These may be associated with multiorgan involvement, mainly retinal dystrophy, nephronophthisis, hepatic fibrosis and polydactyly, with both inter- and intra-familial variability. JSRD are classified in six phenotypic subgroups: Pure JS; JS with ocular defect; JS with renal defect; JS with oculorenal defects; JS with hepatic defect; JS with orofaciodigital defects. With the exception of rare Xlinked recessive cases, JSRD follow autosomal recessive inheritance and are genetically heterogeneous. Ten causative genes have been identified to date, all encoding for proteins of the primary cilium or the centrosome, making JSRD part of an expanding group of diseases called "ciliopathies".

Mutations in the cilia gene ARL13B lead to the classical form of Joubert syndrome. Cantagrel V, et al Am J Hum Genet. 2008 Aug;83(2):170-9.

Atassie disendocrine IPOTIROIDISMO


Gli ormoni tiroidei modulano i fenomeni della maturazione, della migrazione cellulare, della differenziazione e della sinaptogenesi Sono riportati numerosi dati sulleffetto dellipo ed ipertirodismo sulla maturazione soprattutto del cervelletto Latassia regredisce nel corso della terapia con estratti tiroidei

Atassie nutrizionali
Deficit di tiamina Encefaloneuro-miopatia alcoolica Beri-beri Pellagra

Atassie secondarie ad avitaminosi

Beri-Beri o Avitaminosi B1
Polineuropatia, atassia Insufficienza cardiaca Aumento della piruvicemia

Pellagra o deficit di Vitamina PP


Manifestazioni cutanee (eritema solare) Manifestazioni neurologiche (atassia, sindrome cordonale posteriore, polineuropatia, sordit. Epilessia) Manifestazioni digestive (anoressia, gastrite) Manifestazioni psichiche (Ansia, depressione, stati di confusione) Abnorme escrezione urinaria di coproporfirine

Episodic ataxia and channelopathies


The gene for type 1 is located to Chr 12p (K+channels) The gene for type 2 is located on Chr 19p (Ca+channels, CAG repeat) Treatment with acetazolamide is most effective in type 2

Episodic ataxia, type 1


Autosomal dominant inheritance Hand posture resembling carpopedal spasm Calf muscle enlargement Episodic ataxia, dysarthria, Myokymia, Jerking movement of face and limbs Continuous spontaneous activity on EMG at rest

Episodic ataxia, type I


Muscle biopsy with enlargement of type I muscle fibers, consistent with deberbation Symptoms precipitated by sudden movement, stresss, exertion, fatigue Inset in childhood Variable response to acetazolamide Mutations in the KCNA1 (potassium voltagegated channel) gene

Episodic ataxia type 2


The calcium channel mRNA/protein containing the CAG repeat/polyglutamine tract is most intensely expressed in Purkinje cells (PC). In pathological brains, numerous oval or rodshaped aggregates were seen exclusively in PC and were not ubiquinated. The mechanism of neurodegeneration is associated with cytoplasmic aggregations of the alfa-1A calcium channel protein caused by a small CAG repeat polyglutamine expansion in CACNA1A
Ishikawa K et al, Hum Molec Genet 8: 1185-1193, 1999

Episodic Ataxia, type 2


Autosomal dominant inheritance Headache, nystagmus Tinnitus, Gaze evoked

Episodic ataxia, Vertigo, myotonia, weakness, paresthesias, EEG with paroxysmal activity, atrophy of cerebellar vermis

Episodic ataxia, type 2


Symptoms precipitated by sudden movement, stress, exertion, fatigue Response to acetazolamide Caused by mutations in the calcium ion channel gene CACNA1A

Episodic Ataxia, type 2


Autosomal dominant inheritance Headache, nystagmus Tinnitus, Gaze evoked

Episodic ataxia, Vertigo, myotonia, weakness, paresthesias, EEG with paroxysmal activity, atrophy of cerebellar vermis

Episodic ataxia and channelopathies


Type 1, with myochymia and attacks which usually last a few minutes and may occur several times a day. Type 2, with interictal nystagmus, and attacks which last for several hours to a day or more, paroxysmal choreoathetosis with episodic ataxia with attacks lasting for about 20 min and occurring at varying intervals, and familial hemiplegic migraine, with transient hemiplegia presenting during aura of a migraine headache. Dominant inheritance

Sindrome di Marinesco-Sjogren

Autosomica recessiva Ritardo mentale Cataratta Atassia cervelletto e tronco Atrofia

tti MT et al. MRI findings in Marinesco-Sjogren syndrome. Neuro-Ophthalmol 1994 tti MT et al. Optic atrophy in Marinesco-Sjogren syndrome: an additional ocular feature. phthal Paediatr Genet 1993

S. Marinesco-Siogren
Atassia Cerebellare Ritardo mentale Spasticit Cataratta Congenita, nistagmo, strabismo Ritardo nella crescita e statura bassa Ipogonadismo ipergonadotropo Ipotonia muscolare e miopatia Ereditariet autosomica recessiva

Forme trattabili di atassia metabolica


Malattia con le urine a sciroppo ramificati Altre aminoaciduri Deficit di ornitina transcarbamilasi Restrizione proteica, sodio ed altri disordini del ciclo dellurea benzoato Deficit di Biotinidasi Aggiunta di Biotina ricchi in acido fitanico Restrizione dietetica degli dacero aminoacidi

Malattia di Refsum Restrizione dietetica di cibi Deficit di Vitamina E

Assunzione di vitamina E

Malattia di Wilson Agenti chelanti il rame Xantomatosi cerebrotendinea Acido chenodeossicolico

Interaction of drugs on genotype


15 years old, female, health. Obesity since childhood. Severe dietary restriction, and use of anorexiziting drugs as phentermine, fenfluoramine, diethylpropion for 1 year. Ataxia with cerebellar atrophy at MR Normal biochemistry, muscle biopsy mitDNA analysis showed intergenomic 9bp deletion, usually not considered pathogenetic Interaction of drugs with mitDNA (??)