22q13 deletion syndrome
Encyclopedia
22q13 Deletion Syndrome (spoken as twenty two q one three), also known as Phelan-McDermid Syndrome, is a genetic disorder caused by a microdeletion on chromosome 22. The deletion occurs at the terminal end of the chromosome
at the location designated q13.3. This microdeletion is rarely uncovered by typical genetic screening, therefore a fluorescence in situ hybridization, or FISH, test is recommended to confirm the diagnosis. Recent work indicates Phelan-McDermid Syndrome may also be caused by errors in a single gene (SHANK3/PROSAP2) in the q13.3 region. Errors on the same gene have been associated with Autism Spectrum Disorder (ASD).
This genetic disorder is characterized by general hypotonia, absent to delayed speech, and global developmental delays. There are approximately 600 reported cases of Phelan-Mcdermid Syndrome worldwide
Physical
Behavioral
of Shank3 is thought to be the responsible for the neurological deficits of the syndrome.
The proteins encoded by the Shank genes assemble glutamate receptor
s with their intracellular signaling apparatus and cytoskeleton at the postsynaptic density
. They are important for the formation and stabilisation of synapse
s:
In 2006, a group led by Thomas Bourgeron
from the Pasteur Institute
in France, found anomalies of the 22q13 locus in five children with diagnosis of autism and Asperger syndrome
. While the absence of the Shank3 gene was found in children with the typical characteristics of the Phelan-McDermid syndrome, its duplication was found in one child diagnosed with Asperger syndrome, a type of high-functioning autism
.
Van Bokhoven et al. (1997) have also assigned the WNT7B gene to 22q13. Wnt7b acts through Dvl1 to the regulation of dendritic development. found that its overexpression resulted in increased dendritic branching in cultured mouse hippocampal neurons. Knockout mice for Dvl1 are viable, fertile and structurally normal, but show reduced social interaction and abnormal sleeping patterns. Heterozygous knockout mice for Shank3 are viable. Bangash et al. created a gain-of-function transgenic mouse bearing a deletion at the C terminus of Shank3 that mimics clinical mutations and define a biochemical pathway linking mutant Shank3 to the proteasomal degradation of Shank3 and NMDA
type glutamate receptors subunit NR1. PMID 21565394 The heterozygous mutant mice display autism-like behavioral deficits and also exhibit schizophrenia-like phenotypes, consistent with altered glutamate receptor function. Consistent with this, the mice have deficits in NMDA LTP
, LTD
and enhanced mGluR LTD similar to Fragile-X. These results suggest that NMDA receptor degradation could be a shared feature of both Autism and Schizophrenia. Homozygous PDZ domain knockout mice from another lab also display autistic-like behaviours and striatal dysfunction.
(FISH), has only been available since 1998, and currently requires specialized laboratory facilities. Current thinking is that 22q13 deletion syndrome remains largely under-diagnosed, and may be one of the principal causes of idiopathic mental retardation.
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
at the location designated q13.3. This microdeletion is rarely uncovered by typical genetic screening, therefore a fluorescence in situ hybridization, or FISH, test is recommended to confirm the diagnosis. Recent work indicates Phelan-McDermid Syndrome may also be caused by errors in a single gene (SHANK3/PROSAP2) in the q13.3 region. Errors on the same gene have been associated with Autism Spectrum Disorder (ASD).
This genetic disorder is characterized by general hypotonia, absent to delayed speech, and global developmental delays. There are approximately 600 reported cases of Phelan-Mcdermid Syndrome worldwide
Characteristics
Individuals with a 22q13 deletion can suffer from a range of symptoms, with mild to very serious physical and behavioral characteristics. Possible symptoms are:Physical
- Absent to severely delayed speech: 99%
- HypotoniaHypotoniaHypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
(poor muscle tone): 97% - Normal to accelerated growth: 95%
- Increased tolerance to pain: 86%
- Thin, flaky toenails: 78%
- Large, fleshy hands: 68%
- Prominent, poorly formed ears: 65%
- Pointed chin: 62%
- DolichocephalyDolichocephalyDolichocephaly is another word for scaphocephaly, a condition where the head is longer than would be expected, relative to the width of the head.It can present in cases of Sensenbrenner syndrome, Sotos syndrome, as well as Marfan syndrome.-External links:...
(elongated head): 57% - Ptosis (eyelid)Ptosis (eyelid)Ptosis is a drooping of the upper or lower eyelid. The drooping may be worse after being awake longer, when the individual's muscles are tired. This condition is sometimes called "lazy eye", but that term normally refers to amblyopia...
(droopy eyelids): 57% - Poor thermoregulationThermoregulationThermoregulation is the ability of an organism to keep its body temperature within certain boundaries, even when the surrounding temperature is very different...
: 51%
Behavioral
- Chewing on non food items (clothing, bedding, toys):70%
- Teeth grinding: (percent undetermined)
- Autistic behaviors: (percent undetermined)
- Tongue thrusting: (percent undetermined)
- Hair pulling: (percent undetermined)
- Aversion to clothes: (percent undetermined)
Etiology
The deletion affects the terminal region of the long arm of chromosome 22 (the paternal chromosome in 75% of cases), from 22q13.3 to 22qter. Although the deletion is most typically a result of a de novo mutation, there is an inherited form resulting from familial chromosomal translocations involving the 22 chromosome. In the de novo form, the size of the deletion is variable and can go from 130kbp (130,000 base pairs) to 9Mbp (9,000,000 base pairs). While some clinical signs correlate with the size of the deletion, the main traits of the syndrome appear to be independent of the deletion size, and only related to the presence of the Shank3 gene. The haploinsufficiencyHaploinsufficiency
Haploinsufficiency occurs when a diploid organism only has a single functional copy of a gene and the single functional copy of the gene does not produce enough of a gene product to bring about a wild-type condition, leading to an abnormal or diseased state...
of Shank3 is thought to be the responsible for the neurological deficits of the syndrome.
The proteins encoded by the Shank genes assemble glutamate receptor
Glutamate receptor
Glutamate receptors are synaptic receptors located primarily on the membranes of neuronal cells. Glutamate is one of the 20 amino acids used to assemble proteins and as a result is abundant in many areas of the body, but it also functions as a neurotransmitter and is particularly abundant in the...
s with their intracellular signaling apparatus and cytoskeleton at the postsynaptic density
Postsynaptic density
The postsynaptic density is a protein dense specialization attached to the postsynaptic membrane. PSDs were originally identified by electron microscopy as an electron-dense region at the membrane of a postsynaptic neuron...
. They are important for the formation and stabilisation of synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
s:
- Experimentally induced expression of Shank3 has been shown to be sufficient to induce functional dendritic spines in aspinyDendritic spineA dendritic spine is a small membranous protrusion from a neuron's dendrite that typically receives input from a single synapse of an axon. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body...
cerebellar neurons. - Neural network activity up- or down regulates large groups of postsynaptic proteins through ubiquitinUbiquitinUbiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
-mediated protein degradation. Shank proteins were identified as one of the few postsynaptic densityPostsynaptic densityThe postsynaptic density is a protein dense specialization attached to the postsynaptic membrane. PSDs were originally identified by electron microscopy as an electron-dense region at the membrane of a postsynaptic neuron...
proteins that can be degraded by ubiquitinUbiquitinUbiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
ation
In 2006, a group led by Thomas Bourgeron
Thomas Bourgeron
Thomas Bourgeron is a French scientist working at the Institut Pasteur. The group he leads has discovered the first monogenic mutations involved in autism.-References:...
from the Pasteur Institute
Pasteur Institute
The Pasteur Institute is a French non-profit private foundation dedicated to the study of biology, micro-organisms, diseases, and vaccines. It is named after Louis Pasteur, who made some of the greatest breakthroughs in modern medicine at the time, including pasteurization and vaccines for anthrax...
in France, found anomalies of the 22q13 locus in five children with diagnosis of autism and Asperger syndrome
Asperger syndrome
Asperger's syndrome that is characterized by significant difficulties in social interaction, alongside restricted and repetitive patterns of behavior and interests. It differs from other autism spectrum disorders by its relative preservation of linguistic and cognitive development...
. While the absence of the Shank3 gene was found in children with the typical characteristics of the Phelan-McDermid syndrome, its duplication was found in one child diagnosed with Asperger syndrome, a type of high-functioning autism
High-functioning autism
High-functioning autism is an informal term applied to autistic people who are deemed to be "higher functioning" than other autistic people, by one or more metrics. There is no consensus as to the definition. HFA is not yet a recognised diagnosis in the DSM-IV-TR or the ICD-10.The amount of...
.
Van Bokhoven et al. (1997) have also assigned the WNT7B gene to 22q13. Wnt7b acts through Dvl1 to the regulation of dendritic development. found that its overexpression resulted in increased dendritic branching in cultured mouse hippocampal neurons. Knockout mice for Dvl1 are viable, fertile and structurally normal, but show reduced social interaction and abnormal sleeping patterns. Heterozygous knockout mice for Shank3 are viable. Bangash et al. created a gain-of-function transgenic mouse bearing a deletion at the C terminus of Shank3 that mimics clinical mutations and define a biochemical pathway linking mutant Shank3 to the proteasomal degradation of Shank3 and NMDA
NMDA
N-Methyl-D-aspartic acid or N-Methyl-D-aspartate is an amino acid derivative which acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor...
type glutamate receptors subunit NR1. PMID 21565394 The heterozygous mutant mice display autism-like behavioral deficits and also exhibit schizophrenia-like phenotypes, consistent with altered glutamate receptor function. Consistent with this, the mice have deficits in NMDA LTP
LTP
- Science and technology :* Lunar Transient Phenomena, a short-lived change in appearance of Earth's moon* Long-tailed pair, a differential pair amplifier* Lightweight Telephony Protocol, a signaling protocol...
, LTD
LTD
- Business and finance :*Ltd. or Ltd, denotes a business incorporated under the laws of England, Wales, Scotland, Canada, other Commonwealth countries, the Republic of Ireland, Cyprus, Israel and some Anglophone countries in Africa, like Ghana or Nigeria....
and enhanced mGluR LTD similar to Fragile-X. These results suggest that NMDA receptor degradation could be a shared feature of both Autism and Schizophrenia. Homozygous PDZ domain knockout mice from another lab also display autistic-like behaviours and striatal dysfunction.
Incidence
The incidence of the 22q13 deletion syndrome is uncertain. The advanced genetic technique essential for diagnosis, fluorescent in situ hybridizationFluorescent in situ hybridization
FISH is a cytogenetic technique developed by biomedical researchers in the early 1980s that is used to detect and localize the presence or absence of specific DNA sequences on chromosomes. FISH uses fluorescent probes that bind to only those parts of the chromosome with which they show a high...
(FISH), has only been available since 1998, and currently requires specialized laboratory facilities. Current thinking is that 22q13 deletion syndrome remains largely under-diagnosed, and may be one of the principal causes of idiopathic mental retardation.
External links
- GeneReviews: 22q13.3 deletion syndrome
- 22q13.org, Support group for families of children affected by the 22q13 deletion syndrome.
- Alliance22 (in French)