Maladiile neurologice ereditare: Miastenia. Distrofiile musculare progresive. Miotonia. Neuropatia ereditar Charcot-Marie-Tooth.Morbul Wilson. Ataxiile ereditare. Paraplegia spastic familialStrumpell.

V. Lisnic

Obiective Miastenia: manifestrile clinice, diagnosticul, tratamentulDistrofiile musculare progresive (miopatii ereditare): Miopatia Duchenne, Becker, Erb-Rot.Miotonia. Amiotrofia neural Charcot-Marie-Tooth.Distrofia hepato-lenticular (morbul Wilson). Manifestrile clinice, tratamentul.Ataxiile degenerative ereditare: morbul Friedreich, ataxia ereditar Pier-Marry.Paraplegia spastic familial Strumpell.

Criteriile maladiilor ereditare Transmiterea pe vertical din generaie n generaieManifestrile clinice apar la o anumit vrstNu toi membrii familiei sunt afactai (legile de transimtere genetic a informaiei ereditare (Mendel etc)

Mariajul unui brbat cu 2 femeiMariaj de rudenieMariaj nelegitimSibiMortBrbat sntosFemeie sntoasBrbat afectatFemeie afectatsauProbandSex nedeterminatMort prematurAvort medicalMariajGemini univitileniGemini bivitileniHeterozigoiMariaj lipsit de copiiSimbolurile geneologice

Transmitere autosomal dominant

Transmitere autosomal recesiv

Transmitere dominant X-linkat

AlisaVictoriaAlexandraNicolai IIAlexei

Afectarea transmisiunii neuromusculareMyasthenia gravisSindromul Lambert - Iton

iasteniaIncidena 2-5/1 mln./anPrevalena 1/10.000F/M=3:2Vrf de mbolnvire F decada 2-3 B decada 5-6.

iasteniaFatigabilitate patologic n grupe de muchi cu mai puine uniti motorii (extraoculari, bulbare) Variabilitatea intensitii manifestrilor, accentuare dup efort i n jumtatea a doua a zileiRecuperarea forei dup o pauz scurt, administrare inhibitori ai colinesterazeiImplicarea muchilor inervai de diferii nerviLipsa tulburrilor de sensibilitate, durerii, extrem de rar fasciculaii i atrofii

The neuromuscular junction and the proteins involved in neuromuscular transmission.Jacob S et al. Pract Neurol 2009;9:364-3712009 by BMJ Publishing Group Ltd

Manifestrile clinice de debut ale miasteniei

Simptomul%Diplopie41Ptoz25Dizartrie16Slbiciunea membrelor inferioare13Slbiciune generalizat11Disfagie10Slbiciunea membrelor superioare7Slbiciunea muchilor mastictori7Hermann C.Jr. Myasthenia gravis. Current concepts. West J med 1985; 142:797-809

Ptoz bilateral la privire susinut n sus (proba Simpson)*

Testul cu gheaMai popular la oftalmologi dect la neurologiPlasarea pungii cu ghea (2 min) amelioreaz ptoza

Metode complimentare de diagnosticProba antiholinesterazicEdrophonium (Tenzilon)Neostigmin (Proserin)Teste neurofiziologiceStimulare repetativ a nervilorEMG pe o singur fibrAnticorpi la receptori AcH, MuSKCT/IRM a mediastinumuluiBiopsia timusului

Testul cu EdrophoniumTehnica0,6 mg AtropinPeste 3 min2 mg EdrophoniumPeste 30 s (n cazul lipsei efectelor adverse) + 8 mgComplicaii (rare)Aritmii cardiaceInsuficien respiratorieConvulsii

Testul cu Edrophoniumpn la test dup test

Anticorpi la receptorii de acetilcolinStandard de aur rezultate fals pozitive practic nu existPozitiv la 50% miastenie ocular i 85% MGNu sunt alte investigaii necesare pentru confirmarea diagnosticului

Corelaii dintre form i titru AC

Clasa MG (Osserman)Titrul AC/RAcHRezultate pozitive, %R. (remisiune)0,7924I. (Ocular)2,1750II.A Uor generalizat49,880II.B De gravitate medie (muchii respiratori nu-s implicai)57,9100III. M. acut, rapid progresiv 78,5100IV. Miastenie cr. grav205,389(dup Tindall RS)

Examinri neurofiziologiceA1/A5 > 1,1 (10%)Sensibilitatea mai maerela pacienii cu MG, dar i la ei circa 70%EMG pe o singur fibr jitter majorat

Sensibilitatea, specificitatea i limitrile testelor utilizate n miastenia gravis

Sensibilitatea (%)Specificitatea (%)DezavantajeleTestul cu Edrophonium (Tensilon)80-9080-90Monitoring cardiac obligatoriuEMG pe o singur fibr10085Necesit personal antrenat i echipamentAnticorpi AchR55100Deseori fals negative n miastenia ocularTestul de repaos50100Frecvent fals negativTest cu ghea pe ochi90-95100n cazul unei ptoze profunde poate fi mai puin exprimat

Investigaii suplimentareIRM cerebral SeronegativTest Tensilon negativEMG negativCreatinfosfokinaza seruluiBiopsie muscularFuncia glandei tiroide

Timom la TC

Left median compound muscle action potential (CMAP) to thenar muscles of unexpectedly small amplitude (upper trace).Petty R Pract Neurol 2007;7:265-2672007 by BMJ Publishing Group LtdSindromul Lambert-Iton

MR scans showing periaqueductal lesion (presumed glioma) causing obstructive hydrocephalus in a patient who had been treated for one year, without success, for seronegative ocular myasthenia (unilateral ptosis and diploplia).Hilton-Jones D Pract Neurol 2007;7:405-4112007 by BMJ Publishing Group Ltd

Management miasteniei gravis, forma ocular.Hilton-Jones D Pract Neurol 2007;7:405-4112007 by BMJ Publishing Group Ltd

Managementul miasteniei gravis generalizate.Hilton-Jones D Pract Neurol 2007;7:405-4112007 by BMJ Publishing Group Ltd

MiopatiileDistrofiile musculare progresiveUn grup de maladii ereditare, caracterizate prin slbiciune muscular i atrofia muchilor

Distrofia muscular Duchenneea mai frecvent form de Distrofie muscularTipul de motenire recesiv X- lincat (preponderent sufer brbaii)Debut pn la vrsta de 5 anin adolescen dificene motorii majoren deceniul 3 al vieii exitus

Distrofia muscular DuchenneSimptome precoce:Mers pe vrful degetelorMers de raImposibilitatea alergriiIniial se afecteaz muchii centurilor pelviene, apoi humero-scapulare, ulterior muchii membrelor i muchii respiratoriPseudohipertrofia muchilor gambelorSemnul Govers

Pseudohipertrofia muchilor gambei

*Scara Govers

Distrofia muscular Duchennen stadiile tardive implicarea muchilor cardiaci i retard mintal

Administrarea Prednisolon 0,75 mg/cg/zi puin amelioreaz progresia maladiei

Distrofia muscular DuchenneDiagnosticulEMGCreatinfosfokinaza majorare exprimatExaminare genetic-molecular gena codific distrofina

Distrofia muscular Becker

Se aseamn cu distrofia DuchenneNivelul distrofinei n muchi nu este modificat, dar este calitativ diferit Debut mai tardiv 10-11 aniExitus mai trziu 42 aniAfectarea cardiomiocitelor i retardul mintal nu sunt caracteristice

TratamentTratament specific mu existKinetoterapie, edine fizioterapeuticeMsuri ortopedice (profilaxia deformitilor i contracturilor)Evitarea regimului ndelungat de pat

*

*

iotoniaSe caracterizeaz prin relaxare ntrziat a muchilor dup contractarea lor datorat modificrilor patologice ale membranei fibrelor musculare

Distrofia miotonicTip de motenire autosom-dominantSe manifest n deceniile 3-4 ale vieiiMajorarea numrului repetrilor trinucleotidelor (CTG) n gena pe cromosoma 19 (19q13.2 - 19q13.3), Codific miotonin-proteinkinaza

Distrofia miotonicSlbiciunea i atrofia muchilor feei, m. sternocleidomastoideus, m. poriunilor distale ale membrelorCataractPle frontalDiabet zaharatTulburri de conducere cardiacModificri de intelect

Distrofia miotonicEMG descrcri de frecven nalt, amplitudinea crora undulat crete i se micoreaz sunet pentru avion czndPentru diminuarea miotoniei sulfat de hinin (300 400 mg 3 ori/zi), procainamid (0,5-1 g 4 ori/zi) sau fenitoin (100 mg 3 ori/zi)

Miotonia congenital (boala Thomsen)Se transmite pe cale autosomal-dominantutaie pe cromozomul al 7-aMiotonie generalizat fr de slbiciune muscularSe manifest ndat dup natere

Neuropatiile erditareCharcot-Marie-Tooth:Tip demielinizant (CMT 1)Tip neuronal (CMT 2)

Preponderent se transmite pe cale autosomal-dominantSlbiciunea i atrofia poriunii distale ale membrelorPicior scobitAbolirea ROTngroarea trunchiurilor nervoase la palpaieu sau fr de tulburri de sensibilitate

The typical lower limb appearances of CMT1A with distal wasting, pes cavus and clawed toes.Reilly M M Pract Neurol 2007;7:93-1052007 by BMJ Publishing Group Ltd

Two onion bulb formations in a sural nerve biopsy from an infant with severe CMT1.Reilly M M Pract Neurol 2007;7:93-1052007 by BMJ Publishing Group Ltd

Current known causative genes for CMT.Reilly M M Pract Neurol 2007;7:93-1052007 by BMJ Publishing Group Ltd

Algorithm for molecular diagnosis of autosomal dominant and X linked CMT1.Reilly M M Pract Neurol 2007;7:93-1052007 by BMJ Publishing Group Ltd

Boala Wilson

(degenerescen hepatolenticular)

Maladie autosomal-recesivGena pe cromozomul al 13-a (13q14-21)Dereglarea asocierii cuprului cu proteina de transport ceruloplasminaCu se depune n creier, ficat, rinichi, cornee.

Manifestrile clinice ale bolii WilsonDebut n perioada de copilri sau adultul tnrManifestri somaticeInelul Kaizer - Fleisher inele cafenii pe cornee (depuneri de Cu)Ciroza ficatului

Kayser-Fleischer ring in III:1 before treatment (fig 1A) and after treatment with antichelation therapy for 15 months (Fig 1B and 1 C).Nicholl D J et al. J Neurol Neurosurg Psychiatry 2001;70:514-5162001 by BMJ Publishing Group Ltd

Manifestri neurologiceAsociate de afectarea nucleului caudat, putamen, scoarei cerebrale i cerebelare:(debut pn 20 de ani) Distonie sau parkinsonism cu semne piramidale(debut la o vrst mai mare) Tremor n repaus sau posturalMicri coreice n membre, balismGrimase, poze patologiceAtaxieAccese epilepticeTulburri psihice (demen, lentoarea activitii psihice, dereglri de memorie i atenie, dereglri de comportament i personalitate, psihoze cu halucinaii)

DiagnosticulDiminuarea concentraiei Cu i ceruloplasminei n serul sanguinMajorarea excreiei Cu prin urin timp de 24 de oreBiopsia ficatului majorare exprimat a concentraiei Cu i ciroz

IRMAtrofie cortical, modificarea ganglionilor bazalibotul pandei uriaebotul pandei mici A and B, T1-weighted axial MR images show bilateral increased signal intensity in the globus pallidus (arrows) and midbrain (arrowhead).

TratamentPenicillamin 1,5 2 g/sut per osSulfat de Zn (200 mg/sut per os) pentru micorarea absorbiei Cu n intestinTransplant de ficat

Ataxia FriedreichSe transmite pe cale autosomal - recesivMajorarea numrului repetrii trinucleotidelor GAAGena Frataxin 9q13-q21.1

Ataxia FriedreichAtaxia mersuluiDisfuncie cerebeloas, mini nendemnaticeAtaxie senzitiv cu pierderea ROTImplicarea tractului piramidal slbiciune n membrele inferioare i semne patologice

Ataxie cerebeloas ereditar Pier-Marry

Ataxie cerebeloas progresiv.Se transmite pe cale autosomal-dominantGena patologic grad mare de expresie. Nu se observ omiterea generaiilor.

Ataxie cerebeloas ereditar Pier-Mari

Hipoplazia cerebelului, uneori atrofia olivelor, puntei VaroliDegenerescen combinat a sistemelor spinale, asemntoare cu ataxia spino-cerebelar FriedreichVrsta medie de debut - 34 de ani

Paraplegia spastic familial(boala Strumpell)

Transmitere autosomal-dominant (debuteaz n primul deceniu de via)Transmitere autosomal-recesiv(debuteaz mai trziu, dar evolueaz mai grav)X-lincat

Paraplegia spastic familial(boala Strumpell)Paraparez spastic inferioar profund (pn la paraplegie)Limitate micrile n membrele inferioare, preponderent din cauza spasticitii i nu slbiciuniiTulburri de sensibilitate li sfincteriene nu se depisteaz, reflexele abdominale sunt pstrate

Paraplegia spastic familial(boala Strumpell)Pacientul merge cu greu, dar poate sta n picioare timp ndelungatProgreseaz lent, pacienii mult timp pot fi api de lucruBaclofen, midocalm, tropatin, scopalamin pentru micorarea tonusului muscular.Tratament ortopedic

The neuromuscular junction and the proteins involved in neuromuscular transmission. Several of the proteins at the neuromuscular junction are targets for autoimmune disorders (AChR and MuSK in myasthenia gravis, VGCC in LambertEaton myasthenic syndrome and VGKC in neuromyotonia). Genetic mutations can affect several of these proteins (AChR, Rapysn, MuSK, Dok-7, etc) causing congenital myasthenic syndromes. ACh, acetylcholine; AChE, acetylcholinesterase; AChR, acetylcholine receptor; MuSK, muscle specific tyrosine kinase; VGCC, voltage gated calcium channel; VGKC, voltage gated potassium channel; VGSC voltage gated sodium channel.Left median compound muscle action potential (CMAP) to thenar muscles of unexpectedly small amplitude (upper trace). Muscles exercised for 20 seconds and CMAP amplitude increments by 300% (lower trace).MR scans showing periaqueductal lesion (presumed glioma) causing obstructive hydrocephalus in a patient who had been treated for one year, without success, for seronegative ocular myasthenia (unilateral ptosis and diploplia). The diploplia resolved following shunting but the ptosis, which showed mild fatigability, was unchanged. (Courtesy of Dr P Anslow; reproduced from Pract Neurol 2002;2:1737.)Management of ocular myasthenia gravis. (Reproduced from Pract Neurol 2005;5:1827.)Management of generalised myasthenia gravis. AChR, anti-acetylcholine receptor antibody. (Reproduced from Pract Neurol 2005;5:1827.)The typical lower limb appearances of CMT1A with distal wasting, pes cavus and clawed toes.Two onion bulb formations in a sural nerve biopsy from an infant with severe CMT1. Layers of redundant Schwann cell processes (arrows) separated by collagen surround thinly myelinated (A) and demyelinated (B) axons. Magnification 9000.Current known causative genes for CMT. AD, autosomal dominant; AR, autosomal recessive; PMP-22, peripheral myelin protein 22; MPZ, myelin protein zero; LITAF, lipopolysaccharide-induced tumour necrosis factor; EGR2, early growth response 2; GJB1, gap junction protein, beta 1; DI, dominant intermediate; GDAP1, ganglioside-induced differentiation-associated protein 1; MTMR2, myotubularin-related protein 2; MTMR13, myotubularin-related protein 13; KIAA1985, K1AA1985 protein; NDRG1, N-myc downstream-regulated gene 1; PRX, periaxin; CTDP1, CTD phosphatase, subunit 1; KIF1B, Kinesin family member 1B-; MFN2, mitofusin 2; RAB7, RAS-associated protein RAB7; GARS, glycyl-tRNA synthetase; NEFL, neurofilament, light polypeptide 68 kDa; HSP 27, heat shock 27 kDa protein 1; HSP 22, heat shock 22 kDa protein 8; LMNA, lamin A/C; MED25, mediator of RNA polymerase II, subunit 25; DMN2, dynamin 2; YARS, tyrosyl-tRNA synthetase.Algorithm for molecular diagnosis of autosomal dominant and X linked CMT1. PMP-22, peripheral myelin protein 22; MPZ, myelin protein zero; LITAF, lipopolysaccharide-induced tumour necrosis factor; EGR2, early growth response 2; GJB1, gap junction protein, beta 1; NEFL, neurofilament, light polypeptide 68 kDa.Kayser-Fleischer ring in III:1 before treatment (fig 1A) and after treatment with antichelation therapy for 15 months (Fig 1B and 1 C). Note the partial clearance of the Kayser-Fleischer rings on the inferior aspect and persistence on the superior aspect of the cornea (fig 1 C and fig 1 B respectively).