Showing papers by "Guy A. Rouleau published in 2008"

TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis

Abstract: Recently, TDP-43 was identified as a key component of ubiquitinated aggregates in amyotrophic lateral sclerosis (ALS), an adult-onset neurological disorder that leads to the degeneration of motor neurons. Here we report eight missense mutations in nine individuals--six from individuals with sporadic ALS (SALS) and three from those with familial ALS (FALS)--and a concurring increase of a smaller TDP-43 product. These findings further corroborate that TDP-43 is involved in ALS pathogenesis.

PTPRD (protein tyrosine phosphatase receptor type delta) is associated with restless legs syndrome.

Abstract: We identified association of restless legs syndrome (RLS) with PTPRD at 9p23-24 in 2,458 affected individuals and 4,749 controls from Germany, Austria, Czechia and Canada. Two independent SNPs in the 5' UTR of splice variants expressed predominantly in the central nervous system showed highly significant P values (rs4626664, P(nominal/lambda corrected) = 5.91 x 10(-10), odds ratio (OR) = 1.44; rs1975197, P(nominal/lambda corrected) = 5.81 x 10(-9), OR = 1.31). This work identifies PTPRD as the fourth genome-wide significant locus for RLS.

Contribution of TARDBP mutations to sporadic amyotrophic lateral sclerosis

Abstract: Aims and background: Mutations in the TARDBP gene, which encodes the TAR DNA binding protein (TDP-43), have been described in individuals with familial and sporadic amyotrophic lateral sclerosis (ALS). We screened the TARDBP gene in 285 French sporadic ALS patients to assess the frequency of TARDBP mutations in ALS. Results: Six individuals had potentially deleterious mutations of which three were novel including a Y374X truncating mutation and P363A and A382P missense mutations. This suggests that TARDBP mutations may predispose to ALS in approximately 2% of the individuals followed in this study. Conclusion: Our findings, combined with those from other collections, brings the total number of mutations in unrelated ALS patients to 17, further suggesting that mutations in the TARDBP gene have an important role in the pathogenesis of ALS.

Genetics of familial amyotrophic lateral sclerosis

Abstract: The completion of the Human Genome Project, together with a better understanding of some of the emerging genetic patterns of human disease, has enabled a thorough examination of the most appropriate genetic models for amyotrophic lateral sclerosis (ALS). The pathology and epidemiology of ALS have been intensively studied since Adar, Charcot, and Duchenne first described the disease in the 1860 s. Results of genetic studies that have emerged over the past two decades have led to the identification of SOD1 as a well-established causative gene for ALS. However, the identification of SOD1 has not been followed up by the identification of other genes responsible for classic ALS. This leads to the speculation that more complex genetic mechanisms are involved than initially assumed. While mutations in single genes are still likely to constitute a small proportion of ALS cases, the genes responsible for ALS in families with clusters of two or three affected individuals, and more particularly in sporadic cases, are far from being determined. Multigenic, somatic mutation, and gene-environment models may all contribute to the genetic etiology of ALS. The challenge now lies in determining which models are the most appropriate to dissect out the genetic components involved. This research will ultimately aid in identifying the cumulative risk of developing ALS.

Mutations in the calcium-related gene IL1RAPL1 are associated with autism

Abstract: In a systematic sequencing screen of synaptic genes on the X chromosome, we have identified an autistic female without mental retardation (MR) who carries a de novo frameshift Ile367SerfsX6 mutation in Interleukin-1 Receptor Accessory Protein-Like 1 (IL1RAPL1), a gene implicated in calcium-regulated vesicle release and dendrite differentiation. We showed that the function of the resulting truncated IL1RAPL1 protein is severely altered in hippocampal neurons, by measuring its effect on neurite outgrowth activity. We also sequenced the coding region of the close related member IL1RAPL2 and of NCS-1/FREQ, which physically interacts with IL1RAPL1, in a cohort of subjects with autism. The screening failed to identify non-synonymous variant in IL1RAPL2, whereas a rare missense (R102Q) in NCS-1/FREQ was identified in one autistic patient. Furthermore, we identified by comparative genomic hybridization a large intragenic deletion of exons 3-7 of IL1RAPL1 in three brothers with autism and/or MR. This deletion causes a frameshift and the introduction of a premature stop codon, Ala28GlufsX15, at the very beginning of the protein. All together, our results indicate that mutations in IL1RAPL1 cause a spectrum of neurological impairments ranging from MR to high functioning autism.

Mutations in the nervous system–specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II

Abstract: HereditarysensoryandautonomicneuropathytypeII�(HSANII)�isanearly-onsetautosomalrecessivedisorder� characterizedbylossofperceptiontopain,�touch,�andheatduetoalossofperipheralsensorynerves.�Muta- tionsinhereditarysensoryneuropathytypeII�(HSN2),�asingle-exonORForiginallyidentifiedinaffected� familiesinQuebecandNewfoundland,�Canada,�werefoundtocauseHSANII.�WereportherethatHSN2 is� anervoussystem-specificexonofthewith-no-lysine(K)-1�(WNK1)�gene.�WNK1 mutationshavepreviously� beenreportedtocausepseudohypoaldosteronismtypeIIbuthavenotbeenstudiedinthenervoussystem.� GiventhehighdegreeofconservationofWNK1�betweenmiceandhumans,�wecharacterizedthestructureand� expressionpatternsofthisisoforminmice.�ImmunodetectionsindicatedthatthisWnk1/Hsn2 isoformwas� expressedinsensorycomponentsoftheperipheralnervoussystemandCNSassociatedwithrelayingsensory� andnociceptivesignals,�includingsatellitecells,�Schwanncells,�andsensoryneurons.�Wealsodemonstrate� thatthenovelproteinproductofWnk1/Hsn2�wasmoreabundantinsensoryneuronsthanmotorneurons.� ThecharacteristicsofWNK1/HSN2�pointtoapossibleroleforthisgeneintheperipheralsensoryperception� deficitscharacterizingHSANII.

Lithium response and genetic variation in the CREB family of genes.

Abstract: Bipolar disorder (BD) is a severe psychiatric disorder that affects 1% of the population. Recently, there have been many attempts to identify specific genes that are involved in BD; however, the task of finding susceptibility genes is not easy due to the complexity of the disorder. Since lithium (Li) has been used for over 40 years now as an effective prophylactic agent and response to Li treatment seems to be, at least in part, genetically determined, classification according to Li response is a manner through which more homogeneous populations can be obtained for investigation. It has previously been suggested that Li exerts an effect on signal transduction pathways, such as the cyclic adenosine monophosphate (cAMP) pathway. We carried out an association study of BD with CREB1, CREB2 and CREB3 genes, located at ch 2q32.3-q34, 22q13.1 and 9pter-p22.1, respectively. A total of three promoter single nucleotide polymorphisms (SNP), 14 SNPs in the UTR, 6 exonic and 15 intronic SNPs were investigated for their frequency and haplotype distribution in a BD sample of 180 lithium responders and 69 nonresponders and 127 controls using a SNaPshot multiplex reaction from Applied Biosystems, a modified fluorescent single base pair extension procedure. Following correction for multiple testing, our results suggest that the CREB1-1H SNP (G/A change, P < 0.002) and the CREB1-7H SNP (T/C change, P < 0.002) may be associated with BD and/or lithium response.

Sirtuin inhibition protects from the polyalanine muscular dystrophy protein PABPN1

Abstract: Oculopharyngeal muscular dystrophy (OPMD) is caused by polyalanine expansion in nuclear protein PABPN1 [poly(A) binding protein nuclear 1] and characterized by muscle degeneration. Druggable modifiers of proteotoxicity in degenerative diseases, notably the longevity modulators sirtuins, may constitute useful therapeutic targets. However, the modifiers of mutant PABPN1 are unknown. Here, we report that longevity and cell metabolism modifiers modulate mutant PABPN1 toxicity in the muscle cell. Using PABPN1 nematodes that show muscle cell degeneration and abnormal motility, we found that increased dosage of the sirtuin and deacetylase sir-2.1/SIRT1 exacerbated muscle pathology, an effect dependent on the transcription factor daf-16/FoxO and fuel sensor aak-2/AMPK (AMP-activated protein kinase), while null mutants of sir-2.1, daf-16 and aak-2 were protective. Consistently, the Sir2 inhibitor sirtinol was protective, whereas the Sir2 and AMPK activator resveratrol was detrimental. Furthermore, rescue by sirtinol was dependent on daf-16 and not aak-2, whereas aggravation by resveratrol was dependent on aak-2 and not daf-16. Finally, the survival of mammalian cells expressing mutant PABPN1 was promoted by sirtinol and decreased by resveratrol. Altogether, our data identify Sir2 and AMPK inhibition as therapeutic strategies for muscle protection in OPMD, extending the value of druggable proteins in cell maintenance networks to polyalanine diseases.

Als2 mRNA splicing variants detected in KO mice rescue severe motor dysfunction phenotype in Als2 knock-down zebrafish

Abstract: Recessive ALS2 mutations are linked to three related but slightly different neurodegenerative disorders: amyotrophic lateral sclerosis, hereditary spastic paraplegia and primary lateral sclerosis. To investigate the function of the ALS2 encoded protein, we generated Als2 knock-out (KO) mice and zAls2 knock-down zebrafish. The Als2(-/-) mice lacking exon 2 and part of exon 3 developed mild signs of neurodegeneration compatible with axonal transport deficiency. In contrast, zAls2 knock-down zebrafish had severe developmental abnormalities, swimming deficits and motor neuron perturbation. We identified, by RT-PCR, northern and western blotting novel Als2 transcripts in mouse central nervous system. These Als2 transcripts were present in Als2 null mice as well as in wild-type littermates and some rescued the zebrafish phenotype. Thus, we speculate that the newly identified Als2 mRNA species prevent the Als2 KO mice from developing severe neurodegenerative disease and might also regulate the severity of the motor neurons phenotype observed in ALS2 patients.

BDNF protein levels are decreased in transformed lymphoblasts from lithium-responsive patients with bipolar disorder.

Abstract: Objectif : Le facteur neurotrophique derive du cerveau (FNDC) joue un role cle dans la neuroplasticite et est mis en cause dans des troubles de l'affectivite. Des etudes ont demontre des concentrations elevees de FNDC chez les patients qui prenaient du lithium et d'autres thymoregulateurs. Nous voulions analyser la concentration de FNDC chez les patients atteints d'un trouble bipolaire (TB) repondant au lithium afin de comprendre davantage le role du FNDC dans la pathophysiologie du TB. Methodes : Nous avons mesure par dosage immunoenzymatique les lymphocytes B transformes pour determiner les proteines dans le FNDC. Resultats : Les concentrations de FNDC etaient plus faibles de 36 % dans les lymphoblastes provenant de patients atteints d'un TB (n = 12) que dans ceux des participants temoins jumeles (n = 13), et 55 % moins eleves que chez les membres de leur parente non atteints (n = 14). Le lithium a reduit considerablement les concentrations de FNDC chez les patients atteints de TB et les participants temoins en bonne sante, meme si elles sont demeurees plus faibles (33 %) chez les patients atteints de TB apres le traitement. Conclusion : La diminution des concentrations de FNDC peut constituer un element du processus pathophysiologique du TB chez un sous-groupe d'individus atteints de la maladie qui repondent au lithium. On pense qu'un mecanisme compensatoire protege contre l'expression phenotypique du TB les patients apparentes non touches qui sont genetiquement predisposes.

A novel duplication confirms the involvement of 5q23.2 in autosomal dominant leukodystrophy.

Abstract: Objective: To identify the underlying locus and disease-causing mutation for adult-onset autosomal dominant leukodystrophy (ADLD). Design Previously, an adult-onset ADLD locus on chromosome 5q23 was mapped between markers D5S1495 and CTT/CCT15. This region contains 13 known and putative candidate genes. A 2-point linkage analysis confirmed linkage of a large multigenerational French Canadian family to chromosome 5q23. In addition, screening of the 13 genes within the candidate interval as well as 5 neighboring genes was completed, followed by comparative genomic hybridization. Subjects A multigenerational French Canadian family with ADLD mimicking progressive multiple sclerosis was identified and studied. Eight affected family members were available for the study and presented with autonomic dysfunction as well as upper motorneuron signs affecting gait. Results The thorough candidate gene approach did not identify any mutation. Consequently, a whole-chromosome comparative genomic hybridization for chromosome 5 identified a 280-kilobase duplication within the chromosomal band 5q23.2 in 2 affected individuals. This duplication contains 3 genes: LMNB1, FLJ36242 , and MARCH3 . Conclusion We have identified a novel duplication on chromosomal band 5q23.2 in a French Canadian family with ADLD that supports the implication of duplicated LMNB1 as the disease-causing mutation. However, additional functional studies of lamin B1 overexpression are necessary to elucidate the involvement of lamin B1 in myelination and in degenerative disorders such as ADLD and multiple sclerosis.

HMSN/ACC truncation mutations disrupt brain-type creatine kinase-dependant activation of K+/Cl- co-transporter 3.

Abstract: The potassium-chloride co-transporter 3 (KCC3) is mutated in hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC); however, the molecular mechanisms of HMSN/ACC pathogenesis and the exact role of KCC3 in the development of the nervous system remain poorly understood. The functional regulation of this transporter by protein partners is also largely unknown. Using a yeast two-hybrid approach, we discovered that the C-terminal domain (CTD) of KCC3, which is lost in most HMSN/ACC-causing mutations, directly interacts with brain-specific creatine kinase (CK-B), an ATP-generating enzyme that is also a partner of KCC2. The interaction of KCC3 with CK-B was further confirmed by in vitro glutathione S-transferase pull-down assay, followed by sequencing of the pulled-down complexes. In transfected cultured cells, immunofluorescence labeling showed that CK-B co-localizes with wild-type KCC3, whereas the kinase fails to interact with the inactive truncated KCC3. Finally, CK-B's inhibition by DNFB results in reduction of activity of KCC3 in functional assays using Xenopus laevis oocytes. This physical and functional association between the co-transporter and CK-B is, therefore, the first protein-protein interaction identified to be potentially involved in the pathophysiology of HMSN/ACC.

Administration of testosterone results in reversible deterioration in Kennedy’s disease

Abstract: Kennedy’s disease, or spinal and bulbar muscular atrophy (SBMA), is an X-linked neurodegenerative disease characterised by slowly progressive muscle weakness and atrophy of bulbar, facial and limb muscles accompanied by partial androgen insensitivity. The disease is caused by the expansion of a trinucleotide CAG repeat in the gene encoding the androgen receptor (AR).1 There is no known treatment, although animal studies suggest that androgen deprivation may be of benefit.2 3 In this report, we describe a patient with SBMA who experienced significant worsening of his symptoms during treatment with testosterone, followed by complete reversal to pretreatment functioning on cessation of therapy. A now 67-year-old male first presented in 1995 with a 10 year history of difficulty walking. Examination revealed bilateral gynaecomastia and testicular atrophy. Cognitive examination was within normal limits. Examination of cranial nerves revealed fasciculation of the mentalis muscle and fasciculation and mild atrophy of the tongue. In the upper limbs, there was slight wasting of the abductor policis brevis, and absent brachioradialis and triceps reflexes bilaterally, while examination of the lower limbs revealed weakness of the illiopsoas and gastrocnemius muscles bilaterally (grade 4+ out of 5, and 4 out of 5, respectively), absent reflexes throughout and mild sensory loss in a stocking distribution. Nerve conduction studies were consistent with a predominantly motor axonal neuropathy, and electromyography showed widespread denervation. The clinical …

50bp deletion in the promoter for superoxide dismutase 1 (SOD1) reduces SOD1 expression in vitro and may correlate with increased age of onset of sporadic amyotrophic lateral sclerosis.

Abstract: The objective was to test the hypothesis that a described association between homozygosity for a 50bp deletion in the SOD1 promoter 1684bp upstream of the SOD1 ATG and an increased age of onset in SALS can be replicated in additional SALS and control sample sets from other populations. Our second objective was to examine whether this deletion attenuates expression of the SOD1 gene. Genomic DNA from more than 1200 SALS cases from Ireland, Scotland, Quebec and the USA was genotyped for the 50bp SOD1 promoter deletion. Reporter gene expression analysis, electrophoretic mobility shift assays and chromatin immunoprecipitation studies were utilized to examine the functional effects of the deletion. The genetic association for homozygosity for the promoter deletion with an increased age of symptom onset was confirmed overall in this further study (p=0.032), although it was only statistically significant in the Irish subset, and remained highly significant in the combined set of all cohorts (p=0.001). Functional ...

ALS predisposition modifiers: knock NOX, who's there? SOD1 mice still are.

Abstract: The discovery that Zn/Cu superoxide dismutase (SOD1) gene mutations are responsible for 15–20% of familial forms of amyotrophic lateral sclerosis (ALS)1 led to extensive studies of the susceptibility of the motor neuron to oxidative stress. The role of the normal SOD1 function—the conversion of toxic superoxide into less damaging hydrogen peroxide—in ALS pathogenesis remains unclear. It is, however, known that the restricted expression of mutant SOD1 in either motor neurons, microglia or astrocytes has repeatedly been demonstrated to be insufficient for an effective triggering of ALS symptoms.2 Microglia, in particular, have the capacity to recognize a stressed neuron and either attempt to restore the function (immune response) or release toxic factors to prune the compromised neurons. In the case of ALS, this is particularly damaging because the neurons already have difficulty coping with superoxide radicals, which wildtype SOD1 would typically reduce and remove. It was observed that one of the redox-related genes, which is specifically upregulated in activated microglia in spinal cords responding in ALS, is NOX2.3 The NADPH oxidase (NOX) enzymes operate by generating reactive oxygen species in a coordinated manner, often in response to inflammatory signals or microorganisms (Figure 1). Thus, by knocking out NOX2 or other redox-related genes, it could be predicted that motor neurons would have less damaging and fewer insults from activated microglia. In an article by Marden et al4, a hemizygous mouse that harbors a G93A SOD1 mutation was crossed with a mouse null for the NOX1 or the NOX2 genes. This result had a dramatic effect on the lifespan, in particular of NOX2-null mutant SOD1 mice, which survived on average 229 days compared with 132 days for the mice only with a G93A point mutation. This increase of almost 100 days is one of the largest effects observed for SOD1 mutant mice; most manipulations influence lifespan by at most 10–20 days. The exact nature of this benefit is not fully understood and should be the source of compelling future research.

A locus for primary lateral sclerosis on chromosome 4ptel-4p16.1.

Abstract: Background Primary lateral sclerosis (PLS) is an adult-onset upper motor neuron disease resulting in spinal and bulbar spasticity. A family with 8 individuals diagnosed with PLS was previously reported. Objective To identify a locus for a large family with PLS. Methods A 550-marker whole-genome scan was performed on this family followed by fine mapping with sequence-tagged site markers to identify a candidate region. Results A locus was identified for this family between the telomere of chromosome 4 and marker D4S2928 (4ptel-4p16.1). A maximum lod score of 3.01 was obtained for marker D4S2936. The region spans 23.17 cM (10.2 megabase pairs) and encompasses 130 genes. Conclusions PLS1 does not map near any other identified loci for upper or lower motor neuron diseases and thus represents a novel locus for PLS.

A novel mutation in a large French-Canadian family with LGMD1B.

Abstract: Contexte : La dystrophie musculaire des ceintures type 1 B est une maladie autosomique dominante caracterisee par un debut tardif, une atteinte des muscles proximaux associee a des complications cardiaques comme des blocs de conduction auriculo-ventriculaires, une cardiomyopathie congestive et une mort subite. Objectif: Le but de cette etude etait de definir l'expression phenotypiques d'une nouvelle mutation du gene LMNA qui cause la dystrophie musculaire des ceintures de type 1B. Methodes : Nous avons identifie une grande famille canadienne-francaise presentant le phenotype LGMD 1B accompagne d'un trouble de conduction cardiaque, qui etait porteuse d'une nouvelle mutation du gene LMNA. Nous definissons le spectre de ses variations phenotypiques dans cette famille au moyen d'une evaluation neurologique et cardiaque complete, d'une biopsie musculaire et d'etudes de l'ARN et de l'ADN. Resultats : Le cas index et 12 apparentes a risque ont ete evalues. En tout, nous avons identifie sept porteurs d'une nouvelle mutation du gene LMNA (IVS9-3C>G). Les trois patients qui presentaient des symptomes avaient tous une atteinte cardiaque, mais seulement deux presentaient une faiblesse proximale. La seule biopsie musculaire disponible a montre une expression normale de la lamine A/C localisee a l'enveloppe nucleaire. L'etude de l'ARN a montre une perte de transcription de l'exon 10 causee par une mutation d'epissage IVS9-3C a G. Conclusions: Ce diagnostic a des implications importantes pour les patients atteints et leur fratrie parce qu'ils peuvent eventuellement avoir besoin d'un stimulateur cardiaque.

Autosomal Dominant Sensory Ataxia: A Neuroaxonal Dystrophy

Abstract: Autosomal dominant sensory ataxia (ADSA), a rare hereditary ataxia, is characterized by progressive dysfunction of central sensory pathways. Its pathological features have not been previously documented. We report a case of a 61-year-old man with ADSA who died of congestive heart failure. Autopsy specimens of brain, thoracolumbar spinal cord, peripheral nerve and skeletal muscle were examined. There was no abnormality on gross examination. Microscopically, there were occasional swollen axons within the cerebral cortex and deep nuclei, particularly the subthalamic nucleus, with no neuronal loss, gliosis or microglial activation. There were many axonal spheroids within the medulla, particularly in the dorsal column nuclei. Axonal spheroids were also seen in the dorsal columns and ventral horns in the thoracolumbar spinal cord, but there was no Wallerian degeneration or demyelination. Amyloid precursor protein (APP) immunostaining of some of the spheroids suggested continuing dysfunction of axoplasmic flow in some regions. There was mild inflammation of peripheral nerve roots but no spheroid, and patchy chronic inflammation of skeletal muscle. In summary, the major pathological process in ADSA is a neuroaxonal dystrophy most prominent in the dorsal columns and dorsal column nuclei, consistent with the clinical pattern of central sensory pathway degeneration.

A novel locus for idiopathic generalized epilepsy in French-Canadian families maps to 10p11.

Abstract: Idiopathic generalized epilepsy (IGE) has evidence of a strong genetic etiology. We conducted genomewide linkage analysis for genes responsible for familial IGE in French-Canadian pedigrees. Twenty families segregating autosomal dominant epilepsy were collected. Four larger IGE families sufficiently powerful for independent linkage analysis were genome-scanned and follow-up fine mapping was performed over regions with LOD scores >3.0. The genotyping of 16 smaller families was carried out at significantly linked loci for supportive linkage analysis and haplotype comparisons. One of the four families provided a significant linkage result at marker D10S1426 on chromosome 10 (two-point LOD score = 3.05, theta = 0, multipoint LOD score = 3.18). Fine mapping revealed a segregating haplotype and key recombination breakpoints, suggesting a candidate gene interval of 6.5 Mb. Multipoint linkage analyses using the additional 16 families yielded a maximum LOD score under heterogeneity of 4.23 (alpha = 0.34) at this locus. Evaluation of recombination breakpoints in these families narrowed the candidate region to 1.7 Mb. Sequencing of the two known genes in this region, NRP1 and PARD3, was negative for mutation. Replication of linkage to this locus in other cohorts of IGE families is essential to characterize the underlying genetic mechanism for the disease. © 2008 Wiley-Liss, Inc.

Refinement of the SPG9 locus on chromosome 10q23.3‐24.2 and exclusion of candidate genes

Abstract: Background and purpose: The hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders, characterized by a progressive spasticity of the lower limbs. So far, 33 different loci (SPGs) have been mapped and the 15 genes responsible have been identified. We mapped a locus responsible for a form of spastic paraplegia, complicated by bilateral cataracts, gastroesophageal reflux with persisting vomiting and amyotrophy to chromosome 10q23.3–q24.2, in an Italian family. The critical region was in a 12 cm chromosomal interval between markers D10S564 and D10S603 (SPG9, MIM601162). In the same region, two other forms of HSP have been recently mapped: SPG27 and SPG33. In the latter case, the gene responsible has been identified. Materials and methods: To better characterize this region, we genotyped individuals from SPG9-linked families using additional markers and reduced the candidate region to a 4.8 Mb, excluding several genes by positional cloning. Results: The refined SPG9 locus is positioned completely within SPG27 and does not include the SPG33 gene. Discussion: Fifty-two transcripts are present in the refined critical region and 25 strong candidates have been excluded as disease causing genes by direct sequencing. Six of them were also excluded as responsible for SPG27.

A closer look at the history and genetics of Tourette syndrome

Abstract: th century. Nevertheless, some evidence indicates the disorder may have been recognised at least two thousand years ago. Tic like behaviours were recorded by Aretaeus of Cappadocia and several centuries later by Sprenger and Kraemer, followed by other descriptions. The English writer Samuel Johnson, author of the first English Language Dictionary, showed repetitive body twitches, facial grimaces, barks and grunts, among other tics. He was observed in situations such as going in or out at a door using a certain number of steps, from a certain point, which indicated he had also obsessivecompulsive behaviour. There was some evidence of features of TS as well as co-morbid conditions such as hyperactivity, obsessivecompulsive behaviour or rage attacks in other famous artists and world leaders. Some authors have even proposed that the creative, determined, competitive, and persistent nature of certain people may be related to the presence of TS. Clinicians have observed that some patients are particularly sensitive to the feelings and experiences of others, and more prone to outside stimuli. In this way, empathy could be a common quality in these patients. In 1825, Jean Marc Gaspard Itard made the first known medical description of TS based on two cases, one of which was later followed by Jean-Martin Charcot. In 1885 Gilles de la Tourette put together information from previous fragmented reports and wrote a complete and formal description, thus establishing a novel clinical entity. Behavioural abnormalities such as obsessions, compulsions, inattentiveness and hyperactivity, commonly observed in TS patients, were considered mental tics at the time. Current diagnostic criteria are very similar to Gilles de la Tourette’s description. TS is characterized by the presence of multiple motor and one or more vocal tics. In this disorder, tics are not caused by the direct physiologic effects of a substance or a general medical condition. Tic symptomatology is persistent for over a year, and in this period, tics are not absent for more than three consecutive months. There is no exact consensus between the DSM-IV and the Tourette Syndrome Classification Study Group of whether the age of onset should be prior to 18 or 21 years of age, how cases of onset after 21 years should be diagnosed, and if marked distress or significant impairment caused by tics is necessary to define the condition as definite TS. However, the text revision of the DSM-IV (TR) no longer specifies that TS symptoms have to cause distress or impair the functioning of the patients. With respect to the age of onset, the ICD10 Classification of Mental and Behavioural Disorders describes the onset almost always in childhood or adolescence, and in this way it would no longer exclude cases with later onset. Numerous studies confirmed in the 20 th century that genetics plays an important role in the etiology of TS. Family studies proved that the disease runs in families. First-degree relatives of TS patients are indeed in greater risk for TS than the general population. Twin and adoption studies demonstrated that genes have an important role in the etiology of TS, and as much as 90% of the vulnerability to this syndrome could be affected by genes. In addition, environmental, epigenetic and even stochastic factors may affect the susceptibility to TS. At the molecular level, linkage in families and association in unrelated TS subjects have been the main methods used to search for vulnerability genes. Sequencing of almost the entire human genome made it possible to assess the gene expression of thousands of genes on a single chip; recent studies reported a preliminary specific profile in the blood of TS patients. If confirmed, this finding could be useful in the identification of genetic factors related with TS. Given the multi-factorial nature of TS, a thorough clinical description in large samples should be considered; besides association, linkage and sequencing studies, possible gene-gene and geneenvironment interactions would also need to be analysed, as well as epigenetic factors, and gene expression patterns.