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Sartori, Stefano (2010) VALUTAZIONE DEL RUOLO DEI GENI ARX E CDKL5 NELLE ENCEFALOPATIE EPILETTICHE AD EZIOLOGIA SCONOSCIUTA CON INSORGENZA NEL PRIMO ANNO DI VITA. [Tesi di dottorato]

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Abstract (inglese)

SUMMARY
Introduction:
Epileptic encephalopathies starting within the first year of life are a group of etiologically and clinically heterogeneous disorders in which cognitive, sensory, and/or motor functions deteriorate mainly as a consequence of epileptic activity. Many etiological factors including hereditary and non-hereditary conditions have been reported. However, in up to a third of all cases determining the underlying cause is not possible. Recently the CDKL5 and ARX genes have been found to be involved in the pathogenesis of refractory early onset epilepsy, in neurologically delayed patients.
Objective:
To investigate the pathogenic role of CDKL5 and ARX in epileptic encephalopathy of unknown aetiology starting within the first year of life and to characterize the electroclinical picture associated with mutations of these genes.
Patients and Methods:
Eighty patients (40 females and 40 males, including two related boys, born to asymptomatic monozygotic twin sisters) with epileptic encephalopathy of unknown aetiology, with onset in the first year of life, were recruited and screened for mutations in the CDKL5 and ARX genes by DHPLC and direct sequence analysis. Retrospective clinical, neurological and epileptological data, and EEG recordings were collected and comprehensively evaluated.
Results:
Six novel de novo CDKL5 pathogenic mutations (3 missense; 2 nonsense; 1 frameshift mutations) were found in five females and in one 47,XXY male, for an overall mutation rate of 8% which, in female patients alone, account for a prevalence of 12,5%. Three male subjects, including a sporadic case and the two related boys, were found to carry two different, previously unreported, missense mutations of the ARX gene, accounting for a mutation rate of 7,5 % among the male patients of our cohort and demonstrating that mutations of the ARX gene, other than expansions of the polyalanine tracts, are involved in the pathogenesis of the epileptic encephalopathies.
Assessment of the electroclinical profile in our patients with CDKL5 mutations (mean age: 5,8 years, ranging from 15 months to 11 years) showed the following features:
a) early onset epilepsy (1-16 weeks of life) (6/6) in neurologically delayed girls with axial hypotonia and poor eye contact (6/6); frequent ab initio mixture of two or more types of seizures sometimes associated in the same event, such as spasms (4/6), myoclonias (4/6), focal seizures (3/6), and apparently generalized tonic or tonic-clonic seizures (2/6);
b) normal background activity on EEG at the onset of epilepsy (6/6), with presence of focal or multifocal interictal epileptiform and slow abnormalities (4/6);
c) unremarkable brain imaging (6/6);
d) subsequent progressively deterioration of the EEG background activity (6/6) and appearance - usually within the first two years of life - of an unusual electrical pattern characterized by high/very high amplitude more or less diffuse theta (4/6) or delta (1/6) activity with superimposed, often subcontinuous, multifocal high amplitude abnormalities (5/6) with tendency to become synchronous (4/6);
e) at the same time, increased frequency and persistence of multiple types of seizures, mainly tonic (3/6) and spasms (5/6), that, along with the increased EEG paroxysmal activity, contributed to the neurodevelopmental stagnation or regression (6/6), configuring an epileptic encephalopathy.
All these aspects collectively represent the earliest key clinical features that we have identified as a clear indication for CDKL5 molecular analysis.
The possible appearance of Rett-like clinical features, such as stereotypies (5/6) or autonomic dysfunctions (1/6), and the possible evolution to a myoclonic epileptic encephalopathy with pseudoperiodic bursts of abnormalities (3/6), represent further, but fairly late aspects that orient the diagnosis.
The three patients with ARX mutations (mean age: 7 years, ranging from 2 to 16 years) displayed at onset early infantile epileptic encephalopathy with suppression burst (EIEE), known as Ohtahara Syndrome. In the neonatal period (3/3), they presented a typical EEG pattern characterized by bursts of paroxysmal activity separated by episodes of flat or low amplitude tracing (3/3). Spasms or tonic spasms (2/3) were the main types of seizures at onset, in association with focal hemiclonic seizures (1/3), tonic seizures (1/3) and massive (1/3) or erratic myoclonias (1/3). A transition from EIEE into atypical West Syndrome (3/3), was followed, in the oldest patient of our series, by evolution into a Lennox-Gastaut-like syndrome. A severely compromised neurodevelopment (3/3) with profound mental retardation (3/3), absence of social skill (3/3) and tetra paresis (3/3) were evident at follow up, whereas longitudinal imaging showed brain atrophy (3/3).
Conclusions:
Our data confirm the pivotal role of CDKL5 and ARX mutations in the pathogenesis of epileptic encephalopathies in infancy and identify early key clinical and EEG phenotypical features. With the aid of these tools, in the clinical setting, molecular analysis of these two genes, CDKL5 for females and ARX for males, should be considered in neurologically compromised neonates and infants, with early onset severe, otherwise unexplained, epilepsy.

Abstract (italiano)

SOMMARIO
Introduzione:
Le encefalopatie epilettiche ad esordio nel primo anno di vita sono un gruppo clinicamente ed eziologicamente eterogeneo di disordini in cui le funzioni cognitive, sensoriali, e/o motorie si deteriorano principalmente a causa dell’attività epilettica. Numerosi sono i fattori eziologici che sono stati riportati, incluse condizioni ereditarie e non ereditarie. Comunque, in quasi un terzo dei casi non è possibile identificare una causa sottostante. Recentemente è stato segnalato il coinvolgimento dei geni CDKL5 ed ARX nella patogenesi dell’epilessia refrattaria ad esordio precoce, in bambini neurologicamente compromessi.
Obiettivi:
Investigare il ruolo patogenetico di CDKL5 ed ARX nelle encefalopatie epilettiche ad eziologia sconosciuta con esordio nel primo anno di vita e caratterizzare i quadri elettroclinici associati con mutazioni di tali geni.
Pazienti e metodi
Sono stati reclutati ed analizzati per mutazioni di CDKL5 ed ARX, mediante DHPLC e sequenziamento diretto, ottanta pazienti (40 femmine e 40 maschi, inclusi 2 cugini, nati da madri asintomatiche gemelle monozigoti) con encefalopatia epilettica ad eziologia sconosciuta con esordio durante il primo anno di vita. I dati clinici, neurologici, epilettologici e le registrazioni EEG sono stati retrospettivamente raccolti e globalmente valutati.
Risultati:
Sono state identificate 6 nuove mutazioni patogenetiche de novo di CDKL5 (3 missense; 2 nonsense; 1 frameshift) in 5 femmine e in un maschio 47,XXY, per un tasso complessivo di mutazione pari all’8%, ovvero una prevalenza del 12,5 % se si considerano solamente le femmine. In tre soggetti maschi, tra cui un caso sporadico ed i due cugini, sono state identificate due nuove diverse mutazioni missense del gene ARX (per un tasso di mutazione pari a 7,5% considerando esclusivamente i soggetti maschi della nostra coorte), dimostrando che mutazioni di ARX, diverse dalle espansioni dei tratti polialaninici, possono essere coinvolte nella patogenesi delle encefalopatie epilettiche.
La valutazione del profilo elettroclinico dei nostri pazienti con mutazioni del gene CDKL5 (età media: 5,8 anni, range 15 mesi - 11 anni) ha evidenziato le seguenti caratteristiche:
a) esordio precoce di epilessia (1-16 settimane di vita) (6/6) in bambini neurologicamente compromessi con ipotonia assiale e scarso contatto visivo (6/6); frequente commistione ab initio di più tipi di crisi, talora associate nel medesimo evento, quali spasmi (4/6), mioclonie (4/6), crisi focali (3/6), e crisi tonico o tonico cloniche apparentemente generalizzate (2/6);
b) normale attività di fondo all’EEG all’esordio (6/6) con presenza di anomalie intercritiche epilettiformi o lente, focali o multifocali (4/6);
c) neuroimaging non significativo (6/6);
d) successivo progressivo deterioramento dell’attività EEG di fondo (6/6) e comparsa - generalmente entro il secondo anno di vita - di un pattern elettrico inusuale caratterizzato da un’attività theta (4/6) o delta (1/6) di ampio/amplissimo voltaggio, più o meno diffusa, con sovrascritte, spesso subcontinue, anomalie multifocali ampie (5/6) con tendenza a divenire sincrone (4/6);
e) contemporaneo incremento in frequenza e persistenza di più tipi di crisi, principalmente crisi toniche (3/6) e spasmi (5/6), che, assieme all’aumento dell’attività EEG parossistica, contribuivano alla stagnazione o regressione dello sviluppo neurologico (6/6), configurando un’encefalopatia epilettica.
Tutti assieme questi aspetti costituiscono le più precoci caratteristiche cliniche che abbiamo identificato come una chiara indicazione all’analisi molecolare di CDKL5.
La possibile comparsa di caratteristiche cliniche Rett-like, quali stereotipie (5/6) o disfunzioni autonomiche (1/6), e la possibile evoluzione verso un’encefalopatia mioclonica con burst pseudoperiodici di anomalie (3/6), rappresentano ulteriori, ma un po’ tardivi, aspetti che orientano la diagnosi.
I tre pazienti identificati con mutazioni del gene ARX (età media: 7 anni, range 2 - 16 anni) presentavano all’esordio una early infantile epileptic encephalopathy with suppression burst (EIEE), nota come Sindrome di Ohtahara. Nel periodo neonatale (3/3), era presente un pattern caratterizzato da burst di attività parossistica separata da episodi di appiattimento o attenuazione in voltaggio del tracciato (3/3). Spasmi o crisi toniche (2/3) costituivano il principale tipo di crisi all’esordio, in associazione con crisi emicloniche (1/3), toniche (1/3) e mioclonie massive (1/3) o erratiche (1/3). Una transizione da EIEE a Sindrome di West atipica (3/3), era seguita, nel paziente più vecchio della nostra serie, da un’evoluzione verso una sindrome di Lennox-Gastaut-like. Uno sviluppo neurologico severamente compromesso (3/3) con ritardo mentale profondo (3/3), assenza di abilità sociali (3/3) e tetraparesi (3/3) erano evidenti al follow up, mentre i controlli neuroradiologici mostravano atrofia cerebrale (3/3).
Conclusioni:
I nostri dati confermano il ruolo cruciale di mutazioni dei geni CDKL5 e ARX nella patogenesi delle encefalopatie epilettiche dell’infanzia ed identificano delle caratteristiche fenotipiche chiave, sia cliniche che EEG. Con l’aiuto di questi strumenti, l’analisi molecolare di questi due geni (CDKL5 per le femmine ed ARX per i maschi) dovrebbe essere presa in considerazione, nella pratica clinica, in neonati e lattanti neurologicamente compromessi, con epilessia severa ad esordio precoce, altrimenti non spiegata.

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Tipo di EPrint:Tesi di dottorato
Relatore:Laverda , Anna Maria
Dottorato (corsi e scuole):Ciclo 22 > Scuole per il 22simo ciclo > MEDICINA DELLO SVILUPPO E SCIENZE DELLA PROGRAMMAZIONE > MALATTIE RARE
Data di deposito della tesi:NON SPECIFICATO
Anno di Pubblicazione:25 Gennaio 2010
Parole chiave (italiano / inglese):ARX, CDKL5, encefalopatie epilettiche, epilessia, sindrome di Ohtahara
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/38 Pediatria generale e specialistica
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Pediatria
Codice ID:2458
Depositato il:28 Set 2010 12:56
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