Le syndrome de la délétion 22q13 tient son nom des deux chercheuses Kathy Phelan et Heather M.Dermid.
Il n'est détecté que depuis très peu d'années grâce aux progrès des techniques de recherche.
Début 2007, nous avons participé à une recherche effectuée par le Dr Phelan aux Etats-Unis. Celle-ci vise à étudier la corrélation entre la taille de la délétion et les difficultés de tous ordres (cognitives, comportementales, de communication...) rencontrées par les enfants touchés par la délétion 22q13.
Camille et chacun de nous avons donc envoyé quelques cc3 de sang par delà l'Atlantique.
L'étude ne fait que commencer et ses résultats risquent d'être très longs avant d'être communiqués.
Explication de Kathy Phelan :
« En juillet 2007, le Centre de génétique de Greenwood en Caroline du Sud a commencé une recherche pour étudier la taille de la délétion chez les personnes porteuses du syndrome Phelan McDermid.
Utilisant les techniques de génétique moléculaire, les chercheurs examinent l’ADN pour déterminer quels marqueurs spécifiques sont absents le long du chromosome 22.
Selon la littérature, il y a une grande variation dans la taille de la délétion sans conséquence significative sur les caractéristiques physiques ou comportementales.
Les études précédentes ont examiné moins de 60 individus.
Il est à espérer qu’en étudiant une population d’individus plus large, les caractéristiques physiques et développementales pourront être reliées à la taille de la délétion et à des régions spécifiques du chromosome 22.
Pour participer à l’étude, un échantillon de sang de la personne concernée est nécessaire, ainsi qu’un échantillon d’un des deux parents (les deux parents si c’est possible).
Le Centre de Génétique de Greenwood peut fournir si necessaire les formulaires d’autorisation, les tubes de prélèvement et les enveloppes d’expédition.
En fonction de la taille de l’enfant, trois tubes de sang sont optimaux,avec les conservateurs suivants :
(1) Sodium héparine
Si l’enfant est trop petit pour pouvoir obtenir tout ce sang, l’héparine de sodium avec 7-8 cc est la plus importante. Si un second tube peut être obtenu, il faudra ajouter le tube d’EDTA. Les trois mêmes tubes seront demandés aux parents.
Comme il s’agit d’une étude, les résultats ne seront pas disponibles rapidement. Cependant, il sera donné à chaque parent l’information concernant son enfant pour qu’il puisse ainsi comparer la taille de la délétion de celui-ci avec l’ensemble de la taille de la délétion du groupe d’étude ».
Many of you have participated in research studies conducted by Greenwood Genetic Center (GGC) (the studies for which you gave blood, answered questions, and had your child examined by GGC staff). The findings were published here, http://www.ncbi.nlm.nih.gov/pubmed/21984749, on October 7th, 2011.
Since the actual text of the article cannot be posted here without violating copyright laws, the following summarizes the findings.
- Participants ranged from 5 months to 40 years, average age of participants was 7.6 year.
- Deletion sizes ranged from 0.22 Mb to 9.22 Mb, average deletion size was 5.08 Mb
- No common breakpoints were observed
Larger Deletion Sizes
Larger deletion sizes were associated with:
- Neonatal hypotonia
- Neonatal hyporeflexia
- Neonatal feeding problems
- Speech/language delay
- Delayed age at crawling
- Delayed age at walking
- Severity of developmental delay
- Male genital anomalies
- Dysplastic toenails
- Large or fleshy hands
- Tall stature
- Facial asymmetry
- Full brow
- Atypical reflexes
Smaller Deletion Sizes
Smaller sizes were associated with:
- Autism Spectrum Disorder
- Aggressive behavior
Physical Examination by GGC Staff
In patients who underwent a physical examination by GGC staff, the most common features were:
- Developemental delay
- Expressive speech/language delay
- Long eyelashes
- Increased pain tolerance
- Dysplastic toenails
Autism spectrum disorder was reported in 26% of patients over age 3. The authors note that the analysis of autism was subject to several limitations: Primarily that they relied on parent report of autism diagnosis, rather than diagnosis through a standardized instrument.
Severity of developmental delay, as reported by parents, was significantly associated with deletion size.
Speech was delayed or absent in all participants
- No individuals with deletions greater than 5.3 Mb were reported to speak in sentences
- 39% of patients with deletions smaller than 5.3 Mb speak in sentences
- Deletion size was negatively correlated with number of words spoken
Growth was non-linearly associated with deletion size.
- Those with normal stature had the smallest median deletion (4.8 Mb)
- Those with tall stature (>95th percentile) had a median deletion of 6.18 Mb
- Those with short stature (<5th percentile) had the largest median deletion size at 8.06 Mb
- The authors hypothesize that there may be other clinically important genes located near Shank3, since deletion size is associated with a more severe phenotype.
- The study was in part supported by the Phelan-McDermid Syndome Foundaton (through a student training grant for Sara Sarasua).
Une étude sur la délétion 22q13 est actuellement en cours en Italie, financée par le Téléthon.
Ce projet porte sur le rôle du gêne Shank 3/Prosap 2 dans les symptômes neurologiques des patients affectés par le syndrôme de la délétion 22q13.
Les buts principaux de l'étude sont :
- d'effectuer une relation précise entre le phénotype et le génotype
- savoir si d'autres gênes contribuent au phénotype des patients
- étude approfondie du gêne Shank 3, notamment son rôle dans la formation et le fonctionnement des synapses.
La chercheuse biologiste Clara Bonaglia, (ainsi que Carlo Sala, responsable de l'étude), après avoir étudié 25 patients italiens, recherche d'autres familles concernées par des délétions 22q13 simples, des anneaux 22, des délétions 22q13 déséquilibrées.
L'ADN de ces patients sera analysé avec la méthode a-CGH, technique permettant une sensibilité accrue pour la détection d'aberrations chromosomiques bien au-delà des techniques classiques par bande (FISH).
Il est possible ainsi de déterminer en une seule expérience la taille de la zone délétée et d'identifier d'autres microscopiques déséquilibres chromosomiques qui peuvent contribuer au phénotype.
Les résultats permettront d'établir une relation plus précise entre le déséquilibre chormosomique et le syndrome de la délétion 22q13 et d'identifier dans de futures études le mécanisme molléculaire qui aboutit à la délétion 22q13.
Les familles intéressées par cette étude devront faire parvenir des prélèvements sanguins (parents + enfant) via leur généticien. Les modalités plus précises restent encore à définir.
Source : Clara Bonaglia
IGF-1 tests in New-York
Growth factor improves autism symptoms in mice
By Deborah Rudacille
19 October 2011
Growth spurt: Insulin-like growth factor 1, a protein that regulates nerve cell growth and development, shows promise as an autism treatment.
Mice lacking a copy of SHANK3, a gene associated with autism and intellectual disability, show marked improvements in brain signaling after being treated with insulin-like growth factor-1 (IGF-1), according to unpublished findings presented Saturday at the International Congress of Human Genetics in Montreal, Canada.
Impaired expression of SHANK3 prevents synapses, the junctions between neurons, from forming properly. This leads to a defect in signaling between neurons. IGF-1 appears to correct these deficits, allowing nerve cells to communicate normally, says Joseph Buxbaum, who presented the findings at the meeting.
“The synapse is immature in these mice,” he says. “IGF-1 appears to drive the process forward and they become fully mature synapses.”
Based on these findings, the researchers are poised to begin a clinical trial of the drug in children with autism early next year, he says. Because IGF-1 is already approved in the United States for use in children with short stature, the U.S. Food and Drug Administration is allowing the researchers to proceed directly to clinical trials for its use as an autism treatment.
IGF-1 also reverses symptoms of Rett syndrome, a disorder that includes features of autism, in mice1. “We showed that IGF-1 regulates many different signals that can affect synaptic function,” says Mriganka Sur, professor of neuroscience at the Massachusetts Institute of Technology, whose mouse work led to trials of IGF-1 for Rett.
When administered systemically, IGF-1 crosses the blood-brain barrier, which is unusual for such a large molecule, Sur says. Once in the brain, the molecule appears to influence the growth of synapses.
In a safety and efficacy trial of the drug in 12 girls with the disorder, aged 2 to 12 years, a team led by Omar Khwaja at Children’s Hospital Boston has found that the drug does not seem to have any serious adverse effects.
What’s more, after two weeks of treatment, the drug appears to improve breathing and heart rate, which are abnormal in children with Rett, according to Khwaja, director of the Rett syndrome program at Children’s Hospital Boston.
“The findings are definitely promising,” says Khwaja. “We believe IGF-1 affects a fundamental deficit in autism — abnormal maturation of synapses.”
The researchers are recruiting another 30 participants for a study, set to begin in January 2012, that will fully explore treatment effects.
SHANK3 is located in the chromosomal region 22q13. Deletions in this region lead to Phelan-McDermid syndrome, characterized by extreme intellectual disability, delayed or absent speech, and gait and motor problems. About 80 percent of those with the syndrome also show features of autism.
Buxbaum’s team debuted the first SHANK3 mouse model in December 20102. Since then, two other groups have also introduced SHANK3 mouse models, although each model shows a different set of deficits in social behavior3,4.
SHANK3 is part of the post-synaptic density, a protein complex that helps organize synapses. Two other proteins in the same family, SHANK1 and SHANK2, are also involved in forming synapses.
Evidence suggests that SHANK2 and SHANK3 lay the groundwork for synaptic development, Buxbaum says. “Once they pass a certain threshold, SHANK1 comes in and locks down the synapse,” he says.
In mice that don’t make enough SHANK3, neuronal signaling is disrupted. Specifically, it affects proteins called AMPA receptors, which use the chemical messenger glutamate to create excitatory signals in the brain. “When you knock out one copy [of SHANK3], AMPA receptors do not cluster in the postsynaptic density,” says Buxbaum. Without AMPA, the synapse cannot create the kinds of robust connections between neurons that underlie learning and memory.
Electrophysiological studies of brain slices in the SHANK3 mutants show that IGF-1 turns this around. “If you give IGF-1 to the mice for two weeks, at the clinical dose, you get complete recovery and reversal of these deficits,” says Buxbaum.
The researchers are planning to evaluate IGF-1’s effects in 30 children with Phelan-McDermid syndrome, looking for improvement in core symptoms of autism.
Buxbaum’s group also plans to use quantitative measures to assess IGF-1’s effect on two of the core features of Phelan-McDermid syndrome — motor and severe language deficits. For example, LENA, a digital language processor, detects distinctive speech patterns and can measure improvements in speech.
Children with the disorder also have a distinctive gait, says Alexander Kolevzon, clinical director of the Seaver Autism Center in New York City and an investigator on the study.
“All of these kids have some gait disturbances, delays in achieving motor milestones, low muscle tone. It’s not a typical gait that you would see in someone with other disorders, and it has real functional relevance,” he says.
The researchers plan to use a three-dimensional motion capture system that uses sensors attached to joints to assess improvements in gait.
Sur points out that though hundreds of genes are involved in autism, most affect synaptic function in some way. Testing a drug that is already approved for use in children and has been shown to affect synaptic function in mouse models is, he says, “a rational way of approaching autism therapeutics in a short time frame.”
1: Tropea D. et al. Proc. Natl. Acad. Sci. USA 106, 2029-2034 (2009) PubMed
2: Bozdagi O. et al. Mol. Autism 1, 15 (2010) PubMed
3: Bangash M.A. et al. Cell 145, 758-772 (2011) PubMed
4: Peça J. et al. Nature 472, 437-442 (2011) PubMed
Mis en ligne le 31 janvier 2012
Another article about IGF-1 :
Two Family Meetings on Autism Subtypes Set the Tone for IMFAR
May 20, 2010
This is a guest post by Autism Speaks’ staff members Leanne Chukoskie, Ph.D., Jane Pickett, Ph.D., and Andy Shih, Ph.D.
One of the challenges in pursuing the causes of autism spectrum disorders is the heterogeneity of symptoms and life history of the individuals affected. On Wednesday, one day before the start of the International Meeting for Autism Research (IMFAR), meetings of two family foundations centered on specific genetic syndromes for autism moved past these challenges to offer hope for recovery.
The Phelan-McDermid Syndrome Foundation (PMSF) was one of the family foundations that hosted a meeting of international scientists, clinicians and parents to better understand PMSF. Katy Phelan, Ph.D. (Molecular Pathology Laboratory Network, TN) presented a characterization of the individuals affected, as many scientists working with animal models of this disorder have met very few, if any, persons with PMS. Dr. Phelan reviewed the cluster of symptoms present typically early in life, including a “floppy” infant, general developmental delays and poor or absent speech. She also reviewed evidence that led to the recognition that individuals with PMS had some form of mutation in the SHANK 3 gene on chromosome 22.
The meeting soon shifted to animal models and presentations from several researchers who presented greater detail about the role of the protein SHANK 3 at synapses, or junctions of neurons, which are crucial for learning and memory functions. It was shown that SHANK 3 is responsible for tying together two receptors for the common excitatory transmitter glutamate at the synapse. Through a series of careful experiments examining the structure and function of synapses when more or less SHANK 3 protein was present, Joseph Buxbaum, Ph.D. (Mount Sinai School of Medicine, NY) and colleagues learned that SHANK 3 controlled the physical connections that underlie plasticity of the synapses (the mechanism that underlies learning and memory). After achieving this detailed understanding of how the system develops and stabilizes in the animal, the next step was to attempt to rescue normal function in these animals that lack SHANK 3. A related set of receptors present on the cells (AMPA receptors) was targeted with the drug called IGF1. Injections of IGF1 into the mouse travelled across the protective barrier that encases the brain and had the desired effects on the cells, rescuing the structure and function of the synapses that had the atypical SHANK 3 proteins.
Lastly before a dinner gathering where parents scientists and clinicians can share ideas with each other more informally, Sarah Curran, Ph.D. (Kings College, London) presented on new technology that may allow the creation of stem cell lines for deeper analysis of the effect of a single individual’s mutations (the SHANK 3 gene can have mutations at several places, potentially leading to different effects on the functioning of the SHANK 3 protein) by analyzing a single complete hair from an affected person.
Creation date : 27/03/2007 · 10:15
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