Pubmed du 23/12/08

lundi 5 janvier 2009

1. Delgado-Escueta AV, Bourgeois BF. Debate : Does genetic information in humans help us treat patients ? PRO—genetic information in humans helps us treat patients. CON—genetic information does not help at all. Epilepsia ;2008 (Dec) ;49 Suppl 9:13-24.

PRO : In the past decade, genotyping has started to help the neurologic practitioner treat patients with three types of epilepsy causing mutations, namely (1) SCN1A, a sodium channel gene mutated in Dravet’s sporadic severe myoclonic epilepsy of infancy (SMEI and SMEB) ; (2) laforin (dual specificity protein phosphatase) and malin (ubiquitin E3 ligase) in Lafora progressive myoclonic epilepsy (PME) ; and (3) cystatin B in Unverricht-Lundborg type of PME. Laforin, malin, and cystatin B are non-ion channel gene mutations that cause PME. Genotyping ensures accurate diagnosis, helps treatment and genetic counseling, psychological and social help for patients and families, and directs families to organizations devoted to finding cures for specific epilepsy diseases. In SCN1A and cystatin B mutations, treatment with sodium channel blockers (phenytoin, carbamazepine, oxcarbazepine, lamotrigine) should be avoided. Because of early and correct diagnosis by genotyping of SCN1A mutations, the avoidance of sodium channel blockers, and aggressive treatment of prolonged convulsive status, there is hope that Dravet’s syndrome may not be as severe as observed in all past reports. Genotyping also identifies nonsense mutations in Lafora PME. Nonsense mutations can be corrected by premature stop codon readthrough drugs such as gentamicin. The community practitioner together with epilepsy specialists in PME can work together and acquire gentamicin (Barton-Davis et al., 1999) for "compassionate use" in Lafora PME, a generalized lysosome multiorgan storage disorder that is invariably fatal. In Unverricht-Lundborg PME, new cohorts with genotyped cystatin B mutations have led to the chronic use of antioxidant N-acetylcysteine and combination valproate clobazam or clonazepam plus antimyoclonic drugs topiramate, zonisamide, piracetam, levetiracetam, or brivaracetam. These cohorts have minimal ataxia and no dementia, questioning whether the syndrome is truly progressive. In conclusion, not only is genotyping a prerequisite in the diagnosis of Dravet’s syndrome and the progressive myoclonus epilepsies, but it also helps us choose the correct antiepileptic drugs to treat seizures in Dravet’s syndrome and Unverricht-Lundborg PME. Genotyping also portends a brighter future, helping us to reassess the true course, severity, and progressive nature of Dravet’s syndrome and Unverricht-Lundborg PME and helping us craft a future curative treatment for Dravet’s syndrome and Lafora disease. Without the genotyping diagnosis of epilepsy causing mutations we are stuck with imprecise diagnosis and symptomatic treatment of seizures. CON : Genotyping of epilepsy may help to better understand the genetics of epilepsy, to establish an etiology in a patient with epilepsy, to provide genetic counseling, and to confirm a clinical diagnosis. However, critical analysis reveals that genotyping does not contribute to an improved treatment for the patients. In order to improve treatment, genotyping would have to (1) improve our ability to select the drug of choice for a given epilepsy or epileptic syndrome ; (2) improve our ability to predict the individual risk of adverse reactions to certain drugs ; (3) improve our ability to avoid unnecessary treatments or treatments that could aggravate seizures. Many example illustrate the lack of impact of genetic information on the treatment outcome : we do not treat Dravet syndrome more successfully since SCN1A testing became available ; we do not treat Lafora disease more successfully since testing for laforin and malin became available ; we do not need to know the genetic nature of Unverricht-Lundborg disease or test for the cystatin B mutation in order to select or avoid certain drugs ; we do not treat Rett syndrome more successfully since MECP2 testing became available ; we do not treat JME more successfully since we know its genetic origin ; we do not treat autosomal dominant nocturnal frontal lobe epilepsy more successfully since we know its genetic origin and can test for its mutation. The clinical characteristics as well as the response to treatment of these epilepsy syndromes have been well established before genotyping became available. It can not be argued that genotyping is necessary for establishing a diagnosis or ensure accurate diagnosis. Since not all individuals with given syndromes have been shown to have the corresponding mutation, the clinical diagnosis must have been based on well-established clinical criteria. In addition, the presence or absence of the mutation in a given patient has never been shown to specifically predict the response to any form of treatment, positive or negative. Finally, the appropriate psychological and social help in a given patient will not depend on the identification of a mutation. This does not leave any role for genotyping in epilepsy for the sole reason of improving treatment of the patient. Claiming that the result of genotyping predicts optimal treatment in certain epilepsies is equivalent to stating that genotyping for diabetes has become available and that, based on this breakthrough, insulin can now be selected as the treatment of choice in those who test positive.

2. Lu HM, Bao XH, Cao GN. [Electroencephalogram characteristics of Rett syndrome]. Zhonghua Er Ke Za Zhi ;2008 (Aug) ;46(8):630-632.

3. Mandell DS, Wiggins LS, Carpenter LA, Daniels J, Diguiseppi C, Durkin MS, Giarelli E, Morrier MJ, Nicholas JS, Pinto-Martin JA, Shattuck PT, Thomas KC, Yeargin-Allsopp M, Kirby RS. Racial/Ethnic Disparities in the Identification of Children With Autism Spectrum Disorders. Am J Public Health ;2008 (Dec 23)

Objectives. We sought to examine racial and ethnic disparities in the recognition of autism spectrum disorders (ASDs). Methods. Within a multisite network, 2568 children aged 8 years were identified as meeting surveillance criteria for ASD through abstraction of evaluation records from multiple sources. Through logistic regression with random effects for site, we estimated the association between race/ethnicity and documented ASD, adjusting for gender, IQ, birthweight, and maternal education. Results. Fifty-eight percent of children had a documented autism spectrum disorder. In adjusted analyses, children who were Black (odds ratio [OR]=0.79 ; 95% confidence interval [CI]=0.64, 0.96), Hispanic (OR=0.76 ; CI=0.56, 0.99), or of other race/ethnicity (OR=0.65 ; CI=0.43, 0.97) were less likely than were White children to have a documented ASD. This disparity persisted for Black children, regardless of IQ, and was concentrated for children of other ethnicities when IQ was lower than 70. Conclusions. For some children with ASD, the presence of intellectual disability may affect professionals’ further assessment of developmental delay. Our findings suggest the need for continued professional education related to the heterogeneity of the presentation of ASD.

4. Moscavitch SD, Szyper-Kravitz M, Shoenfeld Y. Autoimmune pathology accounts for common manifestations in a wide range of neuro-psychiatric disorders : The olfactory and immune system interrelationship. Clin Immunol ;2008 (Dec 17)

Smell has traditionally been considered a less important sense when compared to sight or hearing, but recent research has unraveled important features inherent to the sense of smell. Once considered just a chemical sensor for sampling the environment, data from animal models and human studies currently imply numerous and complex effects of smell on behavior, mood, and on the immune response. In this review we discuss a possible inter-relationship between olfactory impairment, autoimmunity and neurological/psychiatric symptoms in several diseases affecting the central nervous system (CNS) such as Parkinson, Alzheimer’s disease, autism, schizophrenia, multiple sclerosis and neuropsychiatric lupus erythematosus. We suggest that common manifestations are not mere coincidences. Current data from animal models show that neuropsychiatric manifestations are intimately associated with smell impairment, and autoimmune dysregulation, via autoantibodies (anti-NMDAR, anti-ribosomal P) or other mechanisms. From clues of pathological manifestations, we propose a novel approach to the understanding of the interactions between the CNS, the smell and the immune system.

5. Shiow LR, Paris K, Akana MC, Cyster JG, Sorensen RU, Puck JM. Severe combined immunodeficiency (SCID) and attention deficit hyperactivity disorder (ADHD) associated with a coronin-1A mutation and a chromosome 16p11.2 deletion. Clin Immunol ;2008 (Dec 19)

Defects causing severe combined immunodeficiency (SCID) have been reported in pathways mediating antigen receptor rearrangement, antigen receptor and cytokine signaling, and purine metabolism. Recognizing that the actin regulator Coronin-1A is essential for development of a normal peripheral T cell compartment in mouse models, we identified absence of Coronin-1A in a girl with T-B+NK+ SCID who suffered recurrent infections including severe post-vaccination varicella at age 13 months. Murine Coronin-1A is essential for the release of T cells from the thymus, consistent with the paradoxically detectable thymus in our patient. Molecular analysis revealed a 2 bp deletion in the paternal CORO1A coding sequence paired with a 600 kb de novo deletion encompassing CORO1A on the maternal allele. This genomic region at 16p11.2 is subject to recurrent copy number variations associated with autism spectrum disorders, including attention deficit and hyperactivity, present in our patient. This case highlights the first link between actin cytoskeleton regulation and SCID.

6. Yoo HJ, Lee SK, Park M, Cho IH, Hyun SH, Lee JC, Yang SY, Kim SA. Family- and population-based association studies of monoamine oxidase A and autism spectrum disorders in Korean. Neurosci Res ;2008 (Nov 30)

Monoamine oxidase A gene (MAOA) has been thought to be a candidate gene implicated in autism spectrum disorder (ASD). This study evaluates the relationship between ASDs and MAOA markers (i.e., uVNTR and four single nucleotide polymorphisms (SNPs)) in 151 Korean family trios with children diagnosed with ASDs, and 193 unrelated Korean controls. The result of case-control global haplotype analysis also showed a statistically significant difference in haplotype frequencies between ASD patients and controls (male d.f.=5, p<0.001 ; female d.f.=7, p<0.001). With the specific haplotype analyses, the frequencies of the most frequent haplotype (AGG) with three SNPs (rs5906883+rs1137070+rs3027407) in ASD showed significant statistical differences between ASD patients and controls in both the male and female groups (d.f.=1, male p=0.001, female p<0.001). In a family-based association test (FBAT) analysis, it was observed that, in the dominant model, a three-repeat allele of a MAOA-uVNTR marker was preferentially transmitted in ASDs (Z=2.213, p=0.027). Moreover, in the global haplotype analysis, the statistically significant evidence of associations with ASD were demonstrated in additive and dominant models (additive chi(2)=11.349, d.f.=2, p=0.003 ; dominant chi(2)=6.198, d.f.=2, p=0.045).


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