<\/p>\n
ABSTRACT:<\/strong><\/p>\n Tuberous sclerosis (TS) is an autosomal dominant multi system genetic disorder characterized by the presence of multiple tumoroushamartomatous lesions in different organs. The cerebral lesions are represented by cerebral and cerebellar cortical tubers,subependymal nodules, cerebral white matter radial signs. The psychiatric features associated to tuberous sclerosis are mentaldelay, behaviour abnormalities including autistic spectrum disorders and diff erent cognitive impairment, sleep disorders. The risk factors for cognitive behaviour abnormalities in tuberous sclerosis are the number and localization of cortical tubers, history ofinfantile spasms (mainly with early onset), persistent seizures and abnormal genetic program.<\/p>\n This article reviews the literature data on the psychiatric manifestations in tuberous sclerosis and the possible risk factors implied as well as their influence in the occurrence and outcome of these features.<\/p>\n <\/p>\n <\/p>\n The tuberous sclerosis (TS) is an autosomal dominant geneticalaly transmitted disease, characterized by skin abnormalities and the emergence of hamartoma tumour lesions in di\ufb00erent \u00a0organs, especially the brain, heart, liver, kidney and eye. The aetiology of psychiatric manifestations associated with TS is in constant debate. The number and location of cortical tubers, and the presence of early infantile spasms or of temporal epileptiform electroencephalographic abnormalities are potential risk factors for developing mental retardation, autism and autism spectrum disorders.<\/p>\n <\/p>\n The association of\u00a0mental retardation\u00a0<\/em>with tuberous sclerosis (TS) has been identi\ufb01ed since the \ufb01rst\u00a0cases described by Bourneville in 1880. For a long time, mental retardation was considered one of the characteristic signs of this disease and a diagnostic criterion of Voght\u2019s classical diagnostic triad developed in 1908. Subsequent studies on population have concluded that mental retardation is not present in all patients with TS, some of them having even normal intellect; retardation is not a consequence of the disease but an associated aspect in TS (1.2, 3). The prevalence of mental retardation in TS\u00a0 is between 30 and 80%. The degree of the disorder is variable, although some authors (4) claim that patients with TS that combines\u00a0with mental retardation are severely a\ufb00ected. Mental\u00a0delay is a common \u00a0aspect in the TS, \u00a0about 50% of patients \u00a0have a serious \u00a0disease (3). Joinson and colleagues\u2019 study \u00a0published in 2003, which analyses the incidence of mental retardation in a group of 109 patients with TS, highlights its presence in about 44% of patients, 30.5% having severe impairment with IQ under 21, while 14% had IQ between 21 and 70, and\u00a055.5% had normal IQ (5).<\/p>\n Studies in recent years have attempted to \u00a0clarify the \u00a0factors \u00a0involved \u00a0in the \u00a0intellectual \u00a0impairment of patients with TS, why some patients \u00a0are severely a\ufb00ected while others have normal intellect. Etiopathogenesis of mental retardation in TS is controversial. It seems to be dependent on the presence of early infantile spasms, on the number and location of cortical tubers in the brain revealed by brain MRI neuroimaging (1.5).<\/p>\n The role of infantile spasms in determining mental retardation is supported \u00a0by cases of TS with normal development until \u00a0the occurrence of spasms. It is rare the situation \u00a0where an individual \u00a0with TS without \u00a0infantile \u00a0spasms has a severely a\ufb00ected level of \u00a0intellectual\u00a0 \u00a0development. \u00a0On \u00a0the\u00a0 \u00a0other hand, acknowledging the involvement of infantile \u00a0spasms in determining intellectual \u00a0impairment \u00a0would mean that their intellectual impairment should improve or even normalize \u00a0with treatment. The action of infantile spasms is likely to overlap with the causal mechanisms of brain pathology in TS (1). In the study by Joinson and \u00a0colleagues, \u00a0all patients \u00a0with TS \u00a0and mental\u00a0retardation \u00a0had \u00a0also \u00a0a \u00a0history of early-onset \u00a0crises under \u00a0the \u00a0age of 12 months \u00a0and often \u00a0the seizures were part of infantile \u00a0spasms (5). On the other hand, acknowledging the involvement of infantile spasms in determining intellectual impairment would mean that their \u00a0intellectual impairment \u00a0with \u00a0treatment should improve or even normalize. Infantile \u00a0spasms action is likely to overlap with the causal mechanisms of brain pathology \u00a0in TS \u00a0(1). In \u00a0the \u00a0study \u00a0by \u00a0Joinson \u00a0and colleagues all patients with TS\u00a0 who had had mental retardation \u00a0and \u00a0history \u00a0of early-onset \u00a0crises \u00a0under the age of 12 months and often seizures were part of infantile \u00a0spasms (5). Prolonged duration of infantile spasms, prolonged duration since the initiation \u00a0of the treatment until \u00a0achieving remission \u00a0of these spasms, as well as the poor control of the crises that arose after the infantile \u00a0spasms are elements strongly correlated with the occurrence of mental retardation in patients with TS (6).<\/p>\n As for the cortical tubers, there is a signi\ufb01cant \u00a0as- sociation between their number and the level of intel- ligence quotient (IQ) (1.7). The relationship between the large number of cortical \u00a0tubers and the degree of cognitive impairment \u00a0in TS was demonstrated using modern neuroimaging techniques. The higher the number of cortical tubers is, the higher the degree of intellectual impairment. The average number of corti- cal tuber is higher in patients who also have a history of infantile spasms, compared with those without in- fantile spasms. Patients with over 10 cortical tubers are severely a\ufb00ected while those with less than \ufb01ve tubers may have varied cognitive impairment \u00a0(8). Goodman and colleagues, too, say that there is a positive \u00a0linear relationship between the total number of tubers and the degree of intellectual impairment, the presence of more than 7 cortical tubers representing a high risk of intellectual impairment (9). O\u2019Callaghan in his study also found \u00a0an \u00a0average of 10 tubers in patients with severe intellectual impairment. On the other hand, there is a report \u00a0of a patient with 27 cortical tubers whose IQ was 130, so we must be cautious about formulating a prognosis on the level \u00a0of intellectual development based on the number of cortical \u00a0tubers revealed by means of neuroimaging (1). Although the number of cortical tuber is correlated with intellectual impairment, normal cognitive function is compatible with extensive brain damage and present epileptic seizures (10).<\/p>\n The \u00a0degree of mental \u00a0retardation in TS is in\ufb02uenced not only by the number of cortical\u00a0 tubers, but\u00a0also by their location in certain speci\ufb01c brain areas (4). The separate analysis of the number of cortical tubers according to their location and the IQ shows a close correlation \u00a0between the number in each speci\ufb01c brain lobe and \u00a0the degree of intellectual \u00a0impairment.The frontal lobe seems to play a central role in determin- ing the neural bases of intelligence (11). Based on this \ufb01nding,it is assumed that the frontal cortical locations of the tubers are more frequently associated with severe retardation; \u00a0so that we can say that the degree of intel- lectual impairment in TS is in close correlation with the extent of cortical tubers at frontal level (12). \u00a0More recent studies claim \u00a0that the number of tubers in the occipital lobe and then in the frontal lobe represent a signi\ufb01cant predicting element of the IQ score (1).<\/p>\n At the same time, however, cortical and sub-corti- cal abnormalities \u00a0are also responsible for the occur- rence \u00a0of epileptic \u00a0seizures \u00a0and of epilepsy, which in turn may have adverse e\ufb00ects on intellectual \u00a0develop- ment resulting in severe brain dysfunction, \u00a0especially in cases with \u00a0f requent \u00a0and \u00a0severe seizures \u00a0(4).Thus, children with TS who develop epilepsy before the age of \ufb01ve years and especially those with early infantile spasms, will have \u00a0a \u00a0more \u00a0severe degree of impaired intellectual development (13).<\/p>\n Separate analysis of the in\ufb02uence of infantile spasms and of cortical tubers shows a strong correlation with \u00a0the degree of disorder of the intelligence level. Analysis of the two associated variables (number of cortical \u00a0tubers and epilepsy) is strongly correlated with the degree of intelligence of individuals \u00a0with TS (1).The presence of bilateral cortical tubers and early onset seizures are signi\ufb01cantly correlated with cognitive impairment in TS \u00a0(14). Recent \u00a0data argue that cognitive development in TS is in\ufb02uenced more by the young age at the onset of seizures than by the number of cortical tubers (15).<\/p>\n The nature of genetic mutations causing TS also affects the degree of intellectual \u00a0impairment in patients with TS (16, 17). Patients with TS presenting TSC \u00a02 gene mutation \u00a0have a more severe disease compared with those with impaired TSC 1 gene, possibly by the existence of an associated second somatic mutation in the TSC2 gene with or by the dominantly negative e\ufb00ect of TSC \u00a02 mutation. The damage of TSC2 gene results in a larger brain damage which in turn will cause a more severe intellectual impairment. There are also patients with TSC1 \u00a0gene mutation with severe intellectual impairment, thus the question arises whether other factors might cause this.<\/p>\n In most cases mental retardation in tuberous scle- rosis occurs early and progressively.<\/p>\n Patients with TS and normal intelligence quotient (IQ) may have speci\ufb01c cognitive de\ufb01cits such as delay in language acquisition, \u00a0visual \u00a0and spatial disorders, dyscalculia, dyspraxia and memory di\ufb03culties \u00a0(4, 10,\u00a018). Patients with TS, normal IQ \u00a0and language disorders have a particular \u00a0impairment of the receptive language (5).<\/p>\n In conclusion, the factors incriminated in the oc-currence of mental retardation in patients with TS are represented by: a history \u00a0of early-onset \u00a0crises, especially the aspect of infantile \u00a0spasms, number and location of the cortical tubers detected at neuroimaging tests, and the types of genetic mutation (1, 5, 9, 17).<\/p>\n <\/p>\n Behavioural disorders are common in the TS and are represented by autistic \u00a0spectrum disorders, hyper-kinetic \u00a0syndrome or only attention de\ufb01cit, aggression and sleep disorders (19.20). Patients with TS and severe mental retardation may associate repetitive abnormal head movements, rocking and even self-harm.<\/p>\n The emergence of behavioural disturbances in ST is mainly related to the presence of epilepsy. Some authors argue that the presence of seizures and, respectively, of epilepsy is the \u00a0main \u00a0determinant \u00a0element of these disorders \u00a0(18.19) while \u00a0other authors have shown that there is no signi\ufb01cant correlation between epilepsy and behavioural disorders in patients with TS so that epilepsy would not constitute the only isolated factor incriminated in their appearance (21).<\/p>\n The most common behavioural disorder in patients with TS is the\u00a0attention \u00a0<\/strong>de\ufb01cit hyper-kinetic syndrome.\u00a0<\/strong>It is now \u00a0present \u00a0in around 20% \u00a0of patients (21, 22, and 23) and may be worsened by epileptic seizures.<\/p>\n A<\/strong>utism or autistic spectrum disorders\u00a0<\/strong>are \u00a0the second important psychiatric manifestation found in patients with TS (24).<\/p>\n The prevalence of autism\u00a0and\u00a0pervasive developmental disorders in the general population is 2 per\u00a01,000 inhabitants, while the TS prevalence rate is 1:\u00a06000 (25). There is a male \u00a0predominance in autism disorder (4:1), yet unexplained (12).TS seems to be the etiological \u00a0cause in about 1% of autism cases in general (26). But the actual percentage may be higher since not all patients with autism were carefully\u00a0evaluated for signs characteristic of tuberous sclerosis. More recent epidemiological studies have shown that TS may be responsible for 3-4% of autism cases in general (12, 25). The frequency of autism in TS varies between 17 and 61% in di\ufb00erent epidemiological studies. Curatolo and colleagues identify autism in 26% \u00a0of all patients with TS, \u00a0all of them having mental retardation accompanied by an IQ below 40 (19). Hunt \u00a0and Shepherd found in their study of 1993 an incidence of 24% while Smalley reported an incidence of 54% (26, 23). More recent studies report an incidence of autism in TS of 16% – 25% (25, 27). Variations in the incidence of autism in TS in various studies may be explained by the smaller number of patients and the use of more stringent or more lenient criteria for diagnosis. Using DSM III R and ICD 10 criteria, Calderon found an incidence of autism in TS of 26%, while Gilberg reported an incidence of 50%, and Bolton an incidence of 61% (28, 20, 29). Autism seems to a\ufb00ect both sexes equally, di\ufb00erently from what is generally observed in autism which is mainly a\ufb00ecting mainly males (12). Autistic behaviour in patients with TS was \ufb01rst described in 1932 by Critchley and Earl, 11 years before Kanner\u2019s classic reporting on early infantile autism (30). Only in the 1980s it became evident that patients with TS frequently show autistic aspects (31, 26, and 12).<\/p>\n Despite \u00a0progress made in recent years, the neurobiological bases of associating autism with TS \u00a0are still insu\ufb03ciently known. Factors incriminated in the occurrence of this abnormal behaviour in TS are: the number and location of cortical and sub-cortical tubers, generalized damage in brain development, mental retardation, the e\ufb00ect of crises and\/or of electroencephalographic abnormalities and an abnormal genetic programme (25, 32).<\/p>\n Neuroimaging studies in patients with autism in general showed no signi\ufb01cant brain alterations except for increased brain volume in some cases, corresponding to a large head perimeter but with no signs of macrocephaly. Starting from this \ufb01nding, it has been assumed that \u00a0the \u00a0location of the cortical \u00a0tubers in speci\ufb01c areas of brain in TS could have a causative role in autism. In general the number of cortical tubers in TS is higher in the frontal lobe, and then in the parietal, the temporal ones, in the cerebellum and the occipital lobe. Autism associated with TS could represent an early dysfunction at the level of associative areas due to the location of the cortical tubers, with the temporal and the frontal lobes as areas involved in autism and in other pervasive developmental disorders (29, 33, 32, 19). Curatolo and colleagues have observed that patients with TS who developed a precocious form \u00a0of autism, under the age of 2, had cortical tubers localized predominantly at the pari- etotemporal level, while patients with autism who developed TS later, between the age of 3 and 5 years old had \u00a0lesions mainly on the frontal\u00a0 and occipital lobes (19). The PET Research (Positron Emission Tomography) showed decreased glucose metabolism in bilateral temporal gyri in patients with autism and TS (34). Bolton and Gri\ufb03ths, too, revealed a close association between the location of the cortical tubers in the temporal lobes and autism in TS (29). Analysing 18 patients with TS they detected autism in 9 cases, with 8 of the 9 patients having temporal tubers while the other nine patients had neither autism nor any tubers in the temporal lobes. But Bolton\u2019s study is limited to the use of only the cerebral CT scan in the imaging \u00a0investigation of certain patients which makes it possible to underestimate the cortical tubers in patients who have not been investigated by cerebral MRI (29). Seri examined the presence of autism in 14 patients with TS who had been investigated only by brain NMR examination; he found cortical tubers in the temporal lobe in only 7 patients with autism, and only in these cases he also found impaired auditory evoked potentials (35).<\/p>\n<\/div>\n The presence of cortical tubers at the temporal level is a necessary but insu\ufb03cient condition for the development of autistic spectrum disorders in TS. There are patients with TS and temporal tubers without autism, so that one cannot appreciate what individuals \u00a0with TS and temporal cortical tubers may develop autism (36). Cortical tubers from the cerebellar level seem to have a role in autism in TS, too (37). But not all studies take this aspect into consideration. Discrepancies in studies on the relationship\u00a0 between the location of brain and cerebellum tubers and autism are probably due to the use of only brain CT examination in initial studies which may result in letting the cortical tubers unobserved both the cerebral and especially the cerebellar ones, since CT examination is limited in determining the posterior fossa lesions.<\/p>\n Some authors claim that there is a more signi\ufb01cant correlation between the number of cortical tubers and autism compared to their location (19). When analysing only the in\ufb02uence of the number of cerebral cortical tubers one ignores the fact that between the cerebellum and the cortical and sub-cortical structures there are extensive reciprocal connections, and the damage to the cerebellum in TS may also have a role in triggering autism (37).<\/p>\n Epilepsy a\ufb00ect \u00a0up to 92% of patients with TS (38). Several epidemiological \u00a0studies \u00a0suggest an increased incidence \u00a0of autism in patients with\u00a0TS and epilepsy,\u00a0<\/strong>epilepsy being considered \u00a0a risk factor for autism in children with TS (33, 38, 39). About 6.5% of patients with autism in general have epilepsy before the diagnosis of autism (40), and 15-20% of autistic children without a history of clinical seizures have epileptiform electroencephalographic (EEG) anoma- lies (41). Prolonged \u00a0EEG video \u00a0studies in children with autism and cognitive decline revealed epileptiform electroencephalographic abnormalities\u00a0 in 46% of cases while magnetoencephalography (MEG) has identi\ufb01ed epileptic\u00a0 abnormalities in 82% of autistic patients with regression (41, 42). EEG studies show that the risk for the development of autistic spectrum disorders in children with TS increases when there is obviously \u00a0a temporal epileptogenic \u00a0focus (31). PET studies (Positron Emission Tomography) \u00a0performed on children with infantile \u00a0spasms reveal the fact that hypometabolism of the \u00a0bilateral \u00a0temporal \u00a0lobe is a predictive factor for an evolution to autism (43).<\/p>\n Patients with TS have more cortical tubers which may act as epileptic foci causing multiple seizures, often multi-focal and di\ufb03cult to control ones. The greater the number of cortical tubers, the earlier the onset of epilepsy appears to be. Usually, epilepsy starts in infancy with crises having an aspect of infantile spasms, the presence of infantile \u00a0spasms being frequently associated with the occurrence of a disorder in the autistic spectrum. Most patients with TS and autism have a history of infantile spasms and mental retardation so that \u00a0the question arises of whether \u00a0seizures \u00a0are \u00a0the cause of the manifestation of autism or they are different ways of expression for the same brain dysfunc- tion, through genetic determinism; thus the common underlying pathology is a mutual cause responsible for the occurrence both of epilepsy and of autism and mental retardation (44). There is a high rate of infantile spasms in patients with TS and autism (20, 26). There is also an increased incidence of autism in patients with TS \u00a0and epilepsy, and especially with \u00a0infantile spasms (33). About 58% of patients with infantile spasms and TS from the series of Hunt \u00a0and Denis have associated autism (21). But there are a large number of patients with TS and autism without infantile \u00a0spasms, as well as patients with TS and spasms without autism and\u00a0patients with TS and spasms without autism, so that nobody can claim with certainty the existence of a direct causal link between autism and infantile \u00a0spasms in TS (39). Although infantile spasms are a risk factor, there must be other aspects of TS than spasms alone to predispose to the development of autism (31, 45). The mechanisms determining \u00a0infantile \u00a0spasms to contribute to the development of these behaviour disorders are not su\ufb03ciently known yet (25). Infantile \u00a0spasms are considered to be a particular form of expression characteristic of the infant. They are caused by the su\ufb00ering of a still immature brain\u00a0 that is in its full process of development. Although \u00a0they are not a su\ufb03cient \u00a0cause for the occurrence of autism spectrum disorders, their presence in these patients suggests that the mechanisms which determine their emergence are largely the same as for the emergence of autistic disorders. It is unclear whether epileptiform electroencephalographic abnormalities and seizures have an e\ufb00ect on the cognitive function and on the occurrence of autistic behaviour or are the result of the same underlying pathology causing the emergence of autism (39, 44, 45). The presence of temporal epileptic foci in children with TS and autism brings into question the possibility that the increased risk for this dysfunction should originate in the precocious and non-speci\ufb01c disruption of the functional development of neural systems that support the representation of social behaviour in the temporal lobes (36). If epileptic seizures or epileptiform discharges contribute or are the cause of autism, it is assumed that the treatment with antiepileptic drugs or surgery in these situations could improve the development. The high rate of response of the infantile spasms to treatment with Vigabatrin (80-100%) (46), could provide an opportunity to determine whether the control of infantile spasms may in\ufb02uence the cognitive function and the evolution of behaviour and prevent the occurrence of autistic behaviour in ST (12). Some authors argue that early control of infantile \u00a0spasms can cause cognitive behavioural improvement in ST (13).There are few data to support the use of antiepileptic medications in patients without clinical seizures in order to improve behaviour. But there are no clinical trials that should address this issue and no justi\ufb01cation \u00a0for surgery in patients with autism or autistic regression with EEG abnormalities in the absence of untreatable epilepsy (44).<\/p>\n<\/div>\n Regarding\u00a0th<\/strong>e assumption of genetic determinism,\u00a0<\/strong>it seems that TSC2 gene leads to a higher expression of tuberin at the level of the brain regions involved in autistic disorders, the candidate gene for autism being potentially located on the 16p13 chromosome (48). The large deletions in the 16p13.3 region detected in patients with TS \u00a0who associated also both polycystic kidney disease and autism might potentially a\ufb00ect an- other gene responsible for the development of autism (12). Patients with TS and TSC2 gene damage would thus be more prone to the development of autistic spectrum disorders, since autism re\ufb02ects a direct e\ufb00ect of the abnormal genetic program (32). Sequencing the terminal two megabases on the short arm of chromosome 16 containing \u00a0the TSC2 locus revealed the existence of the linkage for the bipolar a\ufb00ective disorder and epilepsy as well as for autism in the same \u00a0area. An\u00a0autis<\/em>m susceptibility locus\u00a0<\/em>has been identi\ufb01ed in\u00a0the 16p13.3 region (49). However, further studies are\u00a0needed to determine if there is any association between one of the two loci, TSC and autism (12).<\/p>\n Recent data suggest that any of these factors could not correlate alone with the development of autism in children with TS (32). Disruption of brain functions includes the combination of multiple factors such as location of cortical tubers, seizures and early infantile spasms in particular, acting on a developing brain, brain development disorders in the areas involved in the occurrence of autistic spectrum disorders and the possible linkage between TS \u00a0genes and the gene responsible for the occurrence of autism (27).<\/p>\n S<\/strong>leep disorders\u00a0<\/strong>are another common manifestation in children with TS, but their prevalence is\u00a0poorly known. The aspect of these disorders is different, which may be \u00a0either nocturnal ambulatory automatisms, or early awakenings or daytime sleepiness (49). Studies on large samples of patients with TS are needed where polysomnographic recordings should record the total sleep duration, the number of awakenings and transitional stages, the duration of the REM sleep and of the deep sleep. In the study conducted in 1995 by Bruni and colleagues (50) on a small sample of only 10 patients with TS, they found a reduction of the total sleep time and of the deep sleep period, with increased number \u00a0of awakenings and transitional stages, increased number of awakenings after falling asleep and decreased duration of REM sleep. TS may be associated with f requent awakenings but they may be related to hypnic epileptic seizures in patients with inadequately controlled epilepsy (Hunt\u00a01994). In these cases, in order to establish the cause video-EEG is required for longer periods, sometimes even at home. Nocturnal \u00a0seizures are usually frontal and may join complex motor movements which must\u00a0be distinguished from true sleep disorders in order to receive appropriate medicine treatment. The most frequent sleep disorder found in children with ST is the increase the period of falling asleep.<\/p>\n <\/p>\n The concept of intellectual \u00a0and cognitive impairment in TS was substantially revised in recent years. The idea according to which all patients with TS inevitably present mental retardation has proved to be misleading. Mental retardation occurs less f requently than initially \u00a0thought a\ufb00ecting approximately 40% of patients (2, 5). Intellectual impairment seems to be correlated with the type of genetic mutation, the extension of brain abnormalities, age of the onset of seizures and their types (1, 5, 16, 17). In order to appreciate the participation of each factor, independently, to the degree of intellectual impairment it is necessary to perform prospective longitudinal studies on large samples of representative patients (36).<\/p>\n Patients with TS are at risk of developing an autiTSic spectrum disorder especially when there are cortical tubers in the temporal lobe, in association with temporal epileptiform discharges, with early onset seizures, under the age of three years in particular with aspect of infantile spasms and persistent seizures under medicine treatment (36). All these factors constitute together useful clinic indicators for assessing prognosis. Each factor taken in isolation does not represent a su\ufb03cient cause, even if a necessary one, which might determine an autistic behaviour. Some patients with TS \u00a0develop autistic behaviour following a speci\ufb01c location of the cortical tubers; others may experience speci\ufb01c epileptic phenomena, while still others may probably su\ufb00er from a deletion in an adjacent but independent gene which is critical for the genesis of autism (12). Clearly the underlying pathology of TS is prone to multiple intertwined morbidities, including mental retardation, epilepsy, behavioural dis- orders, with higher incidence of autism or of autistic spectrum disorders. Early diagnosis of autism associated with TS could allow early treatment and bet- ter development potential. Improving \u00a0the treatment of epilepsy in patients with TS, including the good answer of spasms to Vigabatrin as well as the success of epilepsy surgery may allow an independent analysis of the e\ufb00ects of localization of lesions, of mental retardation or of genotype on behaviour (12) and the elimination or reduction \u00a0of epilepsy as a variable \u00a0in distinguishing \u00a0possible factors which determine the occurrence of autism in TS.<\/p>\n <\/p>\n Correspondence to<\/strong>: <\/p>","protected":false},"excerpt":{"rendered":" ABSTRACT: Tuberous sclerosis (TS) is an autosomal dominant multi system genetic disorder characterized by the presence of multiple tumoroushamartomatous lesions in different organs. The cerebral lesions are represented by cerebral and cerebellar cortical tubers,subependymal nodules, cerebral white matter radial signs. The psychiatric features associated to tuberous sclerosis are mentaldelay, behaviour abnormalities including autistic spectrum disorders […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_exactmetrics_skip_tracking":false,"footnotes":""},"categories":[276,275],"tags":[283],"class_list":["post-2212","post","type-post","status-publish","format-standard","hentry","category-numar-1-vol-2011","category-vol-2011","tag-carmen-burloiu"],"_links":{"self":[{"href":"https:\/\/snpcar.ro\/en\/wp-json\/wp\/v2\/posts\/2212","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/snpcar.ro\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/snpcar.ro\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/snpcar.ro\/en\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/snpcar.ro\/en\/wp-json\/wp\/v2\/comments?post=2212"}],"version-history":[{"count":3,"href":"https:\/\/snpcar.ro\/en\/wp-json\/wp\/v2\/posts\/2212\/revisions"}],"predecessor-version":[{"id":2215,"href":"https:\/\/snpcar.ro\/en\/wp-json\/wp\/v2\/posts\/2212\/revisions\/2215"}],"wp:attachment":[{"href":"https:\/\/snpcar.ro\/en\/wp-json\/wp\/v2\/media?parent=2212"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/snpcar.ro\/en\/wp-json\/wp\/v2\/categories?post=2212"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/snpcar.ro\/en\/wp-json\/wp\/v2\/tags?post=2212"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}
\nINTRODUCTION<\/h2>\n
MENTAL RETARDATION AND TUBEROUS SCLEROSIS<\/h2>\n
BEHAVIOURAL DISORDERS AND TUBEROUS SCLEROSIS<\/h2>\n
CONCLUSIONS<\/h2>\n
BIBLIOGRAPHY:<\/h2>\n
\n
\nCarmen Burloiu “Al. Obregia” Hospital, Pediatric Neurology Clinic, Bucharest<\/p>\n<\/div>\n