La délimitation moléculaire et clinique du syndrome de microdeletion 2p15p16.1

Aperçu: G.M.

La micro-délétion interstitielle 2p15p16.1 est un syndrome chromosomique rare signalé précédemment chez 33 patients. Il se caractérise par une déficience intellectuelle, un retard de développement, des "troubles du spectre de l'autisme", une microcéphalie, une faible taille, des caractéristiques dysmorphiques et de multiples défauts d'organes congénitaux. Il est défini comme un syndrome du gène contigu et deux régions critiques ont été proposées , les loci 2p15 et 2p16.1. Néanmoins, les patients avec délétion des deux régions critiques ont partagé des caractéristiques similaires du phénotype et la corarélation génotype-phénotype n'est toujours pas clair.  

Les chercheurs examinent tous les cas publiés et décrivent trois patients supplémentaires, afin de définir plus précisément la corrélation phénotype-génotype. Ils discutent ensuite de la contribution des gènes inclus dans la suppression du phénotype anormal. les trois nouveaux patients comparativement à des cas précédents ont mis en évidence que malgré deux régions critiques, la suppression distale à 2p16.1 et la suppression proximale à 2p15 sont associées à des phénotypes très proches les uns des autres.

Am J Med Genet A. 2017 Jun 1. doi: 10.1002/ajmg.a.38302.

Molecular and clinical delineation of 2p15p16.1 microdeletion syndrome

Lévy J^1,2, Coussement A³, Dupont C¹, Guimiot F^2,4, Baumann C¹, Viot G³, Passemard S^1,2, Capri Y¹, Drunat S¹, Verloes A¹, Pipiras E^1,2,5, Benzacken B^1,2,5, Dupont JM³, Tabet AC^1,6.

Author information

1

Genetics Department, AP-HP, Robert-Debré University Hospital, Paris, France.

2

INSERM UMR1141, Paris Diderot University, AP-HP, Robert-Debré Hospital, Paris, France.

3

Cytogenetics Laboratory, APHP, Cochin Hospital, Paris Descartes University, Paris, France.

4

Department of Developmental Biology, APHP Robert-Debré hospital, Paris Diderot University, Sorbonne Paris Cité, Paris, France.

5

University Hospital Jean-Verdier, Department of Cytogenetic, Embryology and Histology, Bondy, France.

6

Neuroscience Department, Génétique Humaine et Fonction Cognitive Unit, Pasteur Institute, Paris, France.

Abstract

Interstitial 2p15p16.1 microdeletion is a rare chromosomal syndrome previously reported in 33 patients. It is characterized by intellectual disability, developmental delay, autism spectrum disorders, microcephaly, short stature, dysmorphic features, and multiple congenital organ defects. It is defined as a contiguous gene syndrome and two critical regions have been proposed at 2p15 and 2p16.1 loci. Nevertheless, patients with deletion of both critical regions shared similar features of the phenotype and the correlation genotype-phenotype is still unclear. We review all published cases and describe three additional patients, to define the phenotype-genotype correlation more precisely. We reported on two patients including the first prenatal case described so far, carrying a 2p15 deletion affecting two genes: XPO1 and part of USP34. Both patients shared similar features including facial dysmorphism and cerebral abnormalities. We considered the genes involved in the deleted segment to further understand the abnormal phenotype. The third case we described here was a 4-year-old boy with a heterozygous de novo 427 kb deletion encompassing BCL11A and PAPOLG at 2p16.1. He displayed speech delay, autistic traits, and motor stereotypies associated with brain structure abnormalities. We discuss the contribution of the genes included in the deletion to the abnormal phenotype. Our three new patients compared to previous cases, highlighted that despite two critical regions, both distal deletion at 2p16.1 and proximal deletion at 2p15 are associated with phenotypes that are very close to each other. Finally, we also discuss the genetic counseling of this microdeletion syndrome particularly in the course of prenatal diagnosis.

© 2017 Wiley Periodicals, Inc.

PMID: 28573701

DOI: 10.1002/ajmg.a.38302

Corps calleux épais chez les enfants

Aperçu: G.M.

Un corpus callosum épais (TCC) peut être associé à un résultat très grave chez les fœtus, mais sa présentation clinique chez les enfants plus âgés semble nettement différente.

Sur 2.552 images d'IRM cérébrales, celles de 37 enfants ont d'abord été considérées comme montrant une TCC. L'imagerie initiale a été examinée par un neuroradiologue expérimenté, qui a confirmé le diagnostic chez 34 enfants (1,3%): 13 avaient une neurofibromatose-1 (NF-1), 9 avaient une épilepsie, 3 avaient un syndrome de malformation capillaire macrocéphalique (MCM), 3 avaient un trouble du spectre de l'autisme,  1 avait une malformation Chiari-1 et 1 avait une circonférence croisée accrue. Aucun trouble neurologique spécifique ne peut être défini chez sept enfants.  Un TCC est une malformation rare du cerveau qui peut être trouvée dans les neuropathologies avec des mécanismes pathognomoniques apparemment divers, tels que NF-1 et MCM. Ce n'est pas nécessairement associé à des conditions de vie en danger, mais plutôt une découverte relativement bénigne, de nature différente de celle rapportée chez les fœtus.

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J Clin Neurol. 2017 Apr;13(2):170-174. doi: 10.3988/jcn.2017.13.2.170.

Thick Corpus Callosum in Children

Schupper A^1,2, Konen O^2,3, Halevy A^1,2, Cohen R^1,2, Aharoni S^1,2, Shuper A^1,4.

Author information

1

Department of Pediatric Neurology and Epilepsy Center, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.

2

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

3

Department of Radiology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.

4

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. savinoam@013.net.

Abstract

BACKGROUND AND PURPOSE:

A thick corpus callosum (TCC) can be associated with a very grave outcome in fetuses, but its clinical presentation in older children seems to be markedly different.

METHODS:

The corpus callosum (CC) was defined as thick based on observations and impressions. We reviewed cases of children who were diagnosed as TCC based on brain magnetic resonance imaging (MRI) studies. The pertinent clinical data of these children were collected, and their CCs were measured.

RESULTS:

Out of 2,552 brain MRI images, those of 37 children were initially considered as showing a TCC. Those initial imaging were reviewed by an experienced neuroradiologist, who confirmed the diagnosis in 34 children (1.3%): 13 had neurofibromatosis-1 (NF-1), 9 had epilepsy, 3 had macrocephaly capillary malformation (MCM) syndrome, 3 had autistic spectrum disorder, 1 had a Chiari-1 malformation, and 1 had increased head circumference. No specific neurologic disorder could be defined in seven children. The measured thickness of the CC in these children was comparable to those published in the literature for adults.

CONCLUSIONS:

A TCC is a rare brain malformation that can be found in neuropathologies with apparently diverse pathognomonic mechanisms, such as NF-1 and MCM. It is not necessarily associated with life-threatening conditions, instead being a relatively benign finding, different in nature from that reported in fetuses.

PMID: 28406584

DOI: 10.3988/jcn.2017.13.2.170

Altération de l'intégrité de la matière blanche chez les adultes avec un diagnostic de trouble du spectre de l'autisme et un QI > 100: une étude d'imagerie par tenseur de diffusion

Aperçu: G.M.

Des altérations de la matière blanche (WM) ont été rapportées chez les enfants et les adultes avec un diagnostic de trouble du spectre de l'autisme (TSA). En particulier, la connectivité déficiente des structures limbiques peut être liée aux déficits sociaux. Les résultats hétérogènes pourraient être expliqués en fonction des différences dans les caractéristiques et la méthodologie de l'échantillon. Dans ce contexte, les formes non syndromiques peuvent différer considérablement de structure WM par rapport aux formes secondaires du TSA.

l'intégrité de WM a été évaluée grâce aux marqueurs d'imagerie : l'anisotropie fractionnée (FA) et la diffusivité moyenne (MD).

L'étude a mis en évidence une réduction significative de la FA dans le groupe TSA dans le genou et le corps du corps calleux (CC). Une augmentation du MD a été détectée dans le cortex cingulaire antérieur sugénual (sACC). Les modifications apportées au sACC pourraient être associées à des déficits de «théorie de l'esprit».

 

Acta Psychiatr Scand. 2017 Apr 13. doi: 10.1111/acps.12731.

Altered white matter integrity in adults with autism spectrum disorder and an IQ >100: a diffusion tensor imaging study

Nickel K¹, Tebartz van Elst L¹, Perlov E^1,2, Endres D¹, Müller GT¹, Riedel A¹, Fangmeier T¹, Maier S¹.

Author information

1

Section for Experimental Neuropsychiatry, Department for Psychiatry & Psychotherapy, Medical Center - University of Freiburg, Freiburg, Germany.

2

Luzerner Psychiatrie, Hospital St. Urban, St. Urban, Switzerland.

Abstract

OBJECTIVE:

White matter (WM) alterations have been reported in children and adults with autism spectrum disorder (ASD). In particular, impaired connectivity of limbic structures may be related to social deficits. Heterogeneous findings could be explained in terms of differences in sample characteristics and methodology. In this context, non-syndromic forms might differ substantially in WM structure from secondary ASD forms.

METHOD:

In an attempt to recruit a homogeneous study sample, we included adults with high-functioning ASD and an IQ > 100 to decrease the influence of syndromic forms being often associated with cognitive deficits. Diffusion tensor imaging (DTI) was performed in 30 participants with ASD and 30 pairwise-matched controls. Fractional anisotropy (FA) and mean diffusivity (MD) as surrogate imaging markers for WM integrity were calculated.

RESULTS:

We found a significant FA decrease in the ASD group in the genu and body of the corpus callosum (CC). Increased MD was detected in the subgenual anterior cingulate cortex (sACC).

CONCLUSION:

The finding of decreased WM integrity in the genu of the CC is in line with earlier studies reporting a decreased number of interhemispheric fibers in the frontal lobe of ASD. Alterations in the sACC might be associated with 'Theory of mind' deficits.

© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

PMID: 28407202

DOI: 10.1111/acps.12731

Agénese partielle et hypoplasie du Corps Calleux dans l'autisme idiopathique

Aperçu: G.M.

Pour tester l'hypothèse selon laquelle les anomalies du développement du corps calleux (CC) contribuent à la pathogenèse de l'autisme, l'étude a caractérisé le type, la topographie et la gravité de la pathologie CC correspondant aux zones CC réduites qui sont détectées par imagerie par résonance magnétique dans les cerveaux de 11 personnes avec un diagnostic d'autisme et 11 témoins.  

Le CC sensiblement plus mince, la zone CC réduite et le déficit axonal uniforme chez tous les sujets autistes ont été classés comme hypoplasie CC. Ainsi, le sous-produit de l'agénésie et de l'hypoplasie CC partielle est la réduction des connexions axonales entre les zones corticales connues pour être impliquées dans les altérations comportementales observées chez les personnes avec un diagnostic d'autisme. 

J Neuropathol Exp Neurol. 2017 Mar 1;76(3):225-237. doi: 10.1093/jnen/nlx003.

Partial Agenesis and Hypoplasia of the Corpus Callosum in Idiopathic Autism

Wegiel J¹, Flory M¹, Kaczmarski W¹, Brown WT¹, Chadman K¹, Wisniewski T¹, Nowicki K¹, Kuchna I¹, Ma SY¹, Wegiel J¹.

Author information

1

From the Departments of Developmental Neurobiology (JW, WK, KN, IK, SYM, JW), Research Design and Analysis Services (MF), Human Genetics (WTB), and Behavioral Pharmacology (KC), New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York; and Departments of Neurology, Pathology and Psychiatry, NYU Langone Medical Center, New York, New York (TW).

Abstract

To test the hypothesis that developmental anomalies of the corpus callosum (CC), contribute to the pathogenesis of autism, we characterized the type, topography, and severity of CC pathology corresponding to reduced CC areas that are detected by magnetic resonance imaging in the brains of 11 individuals with autism and 11 controls. In the brains of 3 autistic subjects, partial CC agenesis resulted in complete or partial lack of interhemispheric axonal connections in CC segments III-V. In these cases, a combination of focal agenesis and uniform axonal deficit caused reduction of CC areas by 37%, of axon numbers by 62%, and of the numerical density of axons by 39%. In the CC of 8 autistic subjects without agenesis, there was an 18% deficit of the midsagittal CC area, 48.4% deficit of axon numbers, and 37% reduction of the numerical density of axons. The significantly thinner CC, reduced CC area, and uniform axonal deficit in all autistic subjects were classified as CC hypoplasia. Thus, the byproduct of partial CC agenesis and hypoplasia is reduction of axonal connections between cortical areas known to be involved in behavioral alterations observed in people with autism.

2017 American Association of Neuropathologists, Inc. This work is written by US Government employees and is in the public domain in the US.

PMID: 28395085

DOI: 10.1093/jnen/nlx003

Corpus Callosum Area in Children and Adults with Autism

Traduction: A. F.-R.

La zone du corps calleux chez les enfants et les adultes atteints d'autisme .

Prigge MB , Lange N , Bigler ED , Merkley TL , Neeley ES , Abildskov TJ , Froehlich AL , Nielsen JA , JR Cooperrider , Cariello UN , Ravichandran C , Alexander AL , Lainhart JE .

Source

Programme interdépartemental en neurosciences de l'Université de l'Utah, Salt Lake City, UT, USA, Département de psychiatrie, Faculté de médecine, Université de l'Utah, Salt Lake City, UT, USA.

Résumé

Malgré les conclusions répétées sur la structure du corps calleux qui est anormale dans l'autisme, les trajectoires de développement de la croissance du corps calleux dans ce désordre (neuronal) n'ont pas encore été signalés. 

Dans cette étude, nous avons examiné la taille du corps calleux dans une perspective de développement à travers une tranche d'âge de 30 ans dans un grand échantillon transversal de personnes atteintes d'autisme par rapport à un échantillon au développement typique. La zone médian du corps calleux (Sagittal) et les 7 sous-régions Witelson ont été examinés chez 68 hommes avec autisme (âge moyen de 14,1 années; âgés de 3 à 36 ans) et 47 hommes avec un développement typique (âge moyen 15,3 années; âgés de 4 à 29 ans). Contrôle du volume total du cerveau, une plus grande variabilité dans la zone du corps calleux totale a été trouvée dans l'autisme . Dans l'autisme , l'augmentation des zones sagittal ont été associés à une gravité réduite de comportements autistiques, une intelligence supérieure, et une plus grande vitesse de traitement (p = 0,003, p = 0,011, p = 0,013, respectivement). Une tendance à la différence entre les groupes en matière de développement isthme a été retrouvée (p = 0,029, non corrigé). 

Ces résultats suggèrent que la zone du corps calleux des personnes atteintes d'autisme bénéfice d’une fonctionnalité accrue. Notre examen transversal montre également des anomalies de maturation potentielles dans l'autisme , un résultat qui devrait être examiné plus avant avec des données longitudinales.

Callosal fiber length and interhemispheric connectivity in adults with autism: Brain overgrowth and underconnectivity

Traduction: G.M. 

La longueur des fibres du corps calleux et la connectivité interhémisphérique chez les adultes atteints d'autisme: prolifération cérébrale et sous connectivité

Lewis JD, Theilmann RJ, Fonov V, P Bellec, Lincoln A, Evans AC, Townsend J. 

Source
Institut neurologique de Montréal, l'Université McGill, Montréal, Québec, Canada. jlewis@bic.mni.mcgill.ca. a

Résumé

Les adultes typiques montrent une relation inverse entre la longueur des fibres du corps calleux et le degré de connectivité inter-hémisphérique. L'hypothèse a été émise que cela pourrait être une conséquence de l'influence des retards de conduction et des coûts cellulaires au cours du développement sur ​​la taille des axones, qui tous deux augmentent avec la longueur des fibres.
Le trouble du spectre autistique (TSA) fournit un test de cette hypothèse: les enfants atteints de TSA sont connus pour avoir des cerveaux plus denses; donc, les adultes atteints de TSA devrait montrer des réductions en matière de connectivité interhémisphérique proportionnelles à leur degré de prolifération cérébrale pendant le développement.
Cette prédiction a été testée en évaluant la relation entre la taille et la structure du corps calleux et la longueur des fibres du corps calleux, en ajustant le volume intracrânien, dont on pense qu'il  refléte la taille maximale du cerveau atteint au cours du développement.
En utilisant la tractographie pour estimer la longueur des fibres calleuses émanant de toutes les aires du cortex, ainsi que les régions du corps calleux à travers lesquelles elles passent , nous montrons que les adultes atteints de TSA montrent une relation inverse entre la longueur des fibres du corps calleux, ajusté pour le volume intracrânien, et la taille du corps calleux , et une relation positive entre la longueur des fibres du corps calleux et la diffusion radiale.
Les résultats fournissent un support pour l'impact hypothétique de la longueur des fibres au cours du développement.

Researchers gain insight into why brain areas fail to work together in autism

Researchers have found in two studies that autism may involve a lack of connections and coordination in separate areas of the brain.

In people with autism, the brain areas that perform complex analysis appear less likely to work together during problem solving tasks than in people who do not have the disorder, report researchers working in a network funded by the National Institutes of Health. The researchers found that communications between these higher-order centers in the brains of people with autism appear to be directly related to the thickness of the anatomical connections between them.

In a separate report, the same research team found that, in people with autism, brain areas normally associated with visual tasks also appear to be active during language-related tasks, providing evidence to explain a bias towards visual thinking common in autism.

"These findings provide support to a new theory that views autism as a failure of brain regions to communicate with each other," said Duane Alexander, M.D., Director of NIH's National Institute of Child Health and Human Development. "The findings may one day provide the basis for improved treatments for autism that stimulate communication between brain areas."

The studies and the theory are the work of Marcel Just, Ph.D., D.O. Hebb Professor of Psychology at Carnegie Mellon University in Pittsburgh, Pennsylvania, and Nancy Minshew, M.D., Professor of Psychiatry and Neurology at the University of Pittsburgh School of Medicine and their colleagues. The research was conducted by the Collaborative Program of Excellence in Autism, a research network funded by the NICHD and the National Institute on Deafness and Other Communication Disorders.

People with autism often have difficulty communicating and interacting socially with other people. The saying "unable to see the forest for the trees" describes how people with autism frequently excel at details, yet struggle to comprehend the larger picture. For example, some children with autism may become spelling bee champions, but have difficulty understanding the meaning of a sentence or a story.

An earlier finding by these researchers described how a group of people with autism tended to use parts of the brain typically associated with processing shapes to remember letters of the alphabet. A news release detailing that finding appears at http://www.nichd.nih.gov/new/releases/final_autism.cfm.

Participants with autism in both current studies had normal I.Q. There were no significant differences between the participants with and without autism in age or I.Q.

The first of the two new studies recently was published online in the journal Cerebral Cortex. In that study, the researchers used a brain imaging technique known as functional magnetic resonance imaging, or fMRI, to view the brains of people with autism as well as a comparison group of people who do not have autism. All of the study participants were asked to complete the Tower of London test. The task involves moving three balls into a specified arrangement in an array of three receptacles. The Tower of London is used to gauge the functioning of the prefrontal cortex.

This brain area, located in the front, upper part of the brain, deals with strategic planning and problem-solving. The prefrontal cortex is the executive area of the brain, in which decision making, judgment, and impulse control reside.

A little further back is the parietal cortex, which controls high-level visual thinking and visual imagery, supporting the visual aspects of the problem-solving. Both the prefrontal and parietal cortex play a critical part in performing the Tower of London test.

In the normal participants, the prefrontal cortex and the parietal cortex tended to function in synchrony (increasing and decreasing their activity at the same time) while solving the Tower of London task. This suggests that the two brain areas were working together to solve the problem.

In the participants with autism, however, the two brain areas, prefrontal and parietal, were less likely to function in synchrony while working on the task.

The researchers made another discovery, for the first time finding a relationship between this lower level of synchrony and the properties of some of the neurological "cables" or white matter fiber tracts that connect brain areas.

White matter consists of fibers that, like cabling, connect brain areas. The largest of the white matter tracts is known as the corpus callosum, which allows communication between the two hemispheres (halves) of the brain.

"The size of the corpus callosum was smaller in the group with autism, suggesting that inter-regional brain cabling is disrupted in autism," Dr. Just said.

In essence, the extent to which the two key brain areas (prefrontal and parietal) of the autistic participants worked in synchrony was correlated with the size of the corpus callosum. The smaller the corpus callosum, the less likely the two areas were to function in synchrony. In the normal participants, however, the size of the corpus callosum did not appear to be correlated with the ability of the two areas to work in synchrony.

"This finding provides strong evidence that autism is a disorder involving the biological connections and the coordination of processing between brain areas," Dr. Just said.

He added, however, that the thickness, or extent, of connections between brain areas may not be the basis for the disorder. Although the neurological connections between the prefrontal cortex appear to be reduced in autism, the brains of people with autism have thicker connections between certain brain regions within each hemisphere.

"At this point, we can say that autism appears to be a disorder of abnormal neurological and informational connections of the brain, but we can't yet explain the nature of that abnormality," Dr. Just said.

In the second study, published online in the journal Brain, the researchers examined the extent to which brain areas involved in language interact with brain regions that process images. Dr. Just explained that earlier studies, as well as anecdotal accounts, suggest that people with autism rely more heavily on visual and spatial areas of the brain than do other people.

In this study, the researchers used fMRI to examine brain functioning in participants with autism and in normal participants during a true-false test involving reading sentences with low imagery content and high imagery content. A typical low imagery sentence consisted of constructions like "Addition, subtraction, and multiplication are all math skills." A high imagery sentence, "The number eight when rotated 90 degrees looks like a pair of eyeglasses," would first activate left prefrontal brain areas involved with language, and then would involve parietal areas dealing with vision and imagery as the study participant mentally manipulated the number eight.

As the researchers expected, the visual brain areas of the normal participants were active only when evaluating sentences with imagery content. In contrast, the visual centers in the brains of participants with autism were active when evaluating both high imagery and low imagery sentences.

"The heavy reliance on visualization in people with autism may be an adaptation to compensate for a diminished ability to call on prefrontal regions of the brain," Dr. Just said.

The second study also confirmed the observations in the first study--that the prefrontal and parietal brain regions of the cortex in people with autism were less likely to work in synchrony than were the brains of normal volunteers. The second study also confirmed that the extent to which the two parts of the cortex could work together was correlated with the size of the corpus callosum that connected them. Dr. Just and his colleagues are conducting additional studies to ascertain the nature of the abnormality of the connections in the brains of people with autism.