| MECP2 duplication syndrome | |
|---|---|
| Other names | X-linked intellectual disability-hypotonia-recurrent Infections syndrome |
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| This condition is due to MECP2 overexpression | |
| Specialty | Medical genetics |
MECP2 duplication syndrome (M2DS) is a rare disease that is characterized by severe intellectual disability and impaired motor function. It is an X-linked genetic disorder caused by the overexpression of MeCP2 protein.
Symptoms of M2DS include infantile hypotonia and failure to thrive, delayed psychomotor development, impaired speech, abnormal or absent gait, epilepsy, spasticity, gastrointestinal motility problems, recurrent infections, and genitourinary abnormalities. [1] [2] [3] Many of those affected by M2DS also fit diagnostic criteria for autism. [4] M2DS can be associated with syndromic facies, namely an abnormally flat back of the head, underdevelopment of the midface, ear anomalies, deep-set eyes, prominent chin, pointed nose, and a flat nasal bridge. [4]
M2DS is one of the several types of X-linked intellectual disability. The cause of M2DS is a duplication of the MECP2 or Methyl CpG binding protein 2 gene located on the X chromosome (Xq28). [5] The MeCP2 protein plays a pivotal role in regulating brain function. Increased levels of MECP2 protein results in abnormal neural function and impaired immune system. [4] Mutations in the MECP2 gene are also commonly associated with Rett syndrome in females. Advances in genetic testing and more widespread use of Array Comparative Genomic Hybridization has led to increased diagnosis of MECP2 duplication syndrome. [6] It is thought to represent ~1% of X-linked male mental disability cases. [7] Females affected by this condition often do not show symptoms. [4]
Diagnosis is made based on genetic testing. [4]
Treatment is supportive and based on symptoms. [4]
The syndrome primarily affects young males. [7] Preliminary studies suggest that prevalence may be 1.8 per 10,000 live male births. 50% of those affected do not live beyond 25 years of age, with deaths attributed to the impaired immune function. [8]
M2DS was first described in 1999. [4]
In a Nature article published on November 25, 2015, it was revealed that researchers at the Baylor College of Medicine, led by Dr. Huda Y. Zoghbi, have reversed MECP2 Duplication Syndrome in adult symptomatic mice using antisense therapy. [9] Mice treated with an experimental ASO administered through the central nervous system had a reduction of MECP2 protein to normal levels and symptoms of hypoactivity, anxiety, and abnormal social behavior were resolved. Additionally, the seizure activity of the mice and abnormal EEG discharges were abolished. Initial studies demonstrated that reducing the MECP2 protein levels to the correct amount also normalized the expression of the other genes controlled by the MECP2 protein.[ citation needed ]
Rett syndrome (RTT) is a genetic disorder that typically becomes apparent after 6–18 months of age and almost exclusively in females. Symptoms include impairments in language and coordination, and repetitive movements. Those affected often have slower growth, difficulty walking, and a smaller head size. Complications of Rett syndrome can include seizures, scoliosis, and sleeping problems. The severity of the condition is variable.
Rubinstein–Taybi syndrome (RTS) is a rare genetic condition characterized by short stature, moderate to severe learning difficulties, distinctive facial features, and broad thumbs and first toes. Other features of the disorder vary among affected individuals. These characteristics are caused by a mutation or deletion in the CREBBP gene, located on chromosome 16, and/or the EP300 gene, located on chromosome 22.
Ubiquitin-protein ligase E3A (UBE3A) also known as E6AP ubiquitin-protein ligase (E6AP) is an enzyme that in humans is encoded by the UBE3A gene. This enzyme is involved in targeting proteins for degradation within cells.
MECP2 is a gene that encodes the protein MECP2. MECP2 appears to be essential for the normal function of nerve cells. The protein seems to be particularly important for mature nerve cells, where it is present in high levels. The MECP2 protein is likely to be involved in turning off several other genes. This prevents the genes from making proteins when they are not needed. Recent work has shown that MECP2 can also activate other genes. The MECP2 gene is located on the long (q) arm of the X chromosome in band 28 ("Xq28"), from base pair 152,808,110 to base pair 152,878,611.
A trinucleotide repeat expansion, also known as a triplet repeat expansion, is the DNA mutation responsible for causing any type of disorder categorized as a trinucleotide repeat disorder. These are labelled in dynamical genetics as dynamic mutations. Triplet expansion is caused by slippage during DNA replication, also known as "copy choice" DNA replication. Due to the repetitive nature of the DNA sequence in these regions, 'loop out' structures may form during DNA replication while maintaining complementary base pairing between the parent strand and daughter strand being synthesized. If the loop out structure is formed from the sequence on the daughter strand this will result in an increase in the number of repeats. However, if the loop out structure is formed on the parent strand, a decrease in the number of repeats occurs. It appears that expansion of these repeats is more common than reduction. Generally, the larger the expansion the more likely they are to cause disease or increase the severity of disease. Other proposed mechanisms for expansion and reduction involve the interaction of RNA and DNA molecules.
In genetics and cell biology, repression is a mechanism often used to decrease or inhibit the expression of a gene. Removal of repression is called derepression. This mechanism may occur at different stages in the expression of a gene, with the result of increasing the overall RNA or protein products. Dysregulation of derepression mechanisms can result in altered gene expression patterns, which may lead to negative phenotypic consequences such as disease.
CDKL5 is a gene that provides instructions for making a protein called cyclin-dependent kinase-like 5 also known as serine/threonine kinase 9 (STK9) that is essential for normal brain development. Mutations in the gene can cause deficiencies in the protein. The gene regulates neuronal morphology through cytoplasmic signaling and controlling gene expression. The CDKL5 protein acts as a kinase, which is an enzyme that changes the activity of other proteins by adding a cluster of oxygen and phosphorus atoms at specific positions. Researchers are currently working to determine which proteins are targeted by the CDKL5 protein.
X-linked intellectual disability refers to medical disorders associated with X-linked recessive inheritance that result in intellectual disability.
Potocki–Lupski syndrome (PTLS), also known as dup(17)p11.2p11.2 syndrome, trisomy 17p11.2 or duplication 17p11.2 syndrome, is a contiguous gene syndrome involving the microduplication of band 11.2 on the short arm of human chromosome 17 (17p11.2). The duplication was first described as a case study in 1996. In 2000, the first study of the disease was released, and in 2007, enough patients had been gathered to complete a comprehensive study and give it a detailed clinical description. PTLS is named for two researchers involved in the latter phases, Drs. Lorraine Potocki and James R. Lupski of Baylor College of Medicine.
Pitt–Hopkins syndrome (PTHS) is a rare genetic disorder characterized by developmental delay, epilepsy, distinctive facial features, and possible intermittent hyperventilation followed by apnea. Pitt–Hopkins syndrome can be marked by intellectual disabilities as well as problems with socializing. It is part of the clinical spectrum of Rett-like syndromes.
Huda Yahya Zoghbi, born Huda El-Hibri, is a Lebanese-born American geneticist, and a professor at the Departments of Molecular and Human Genetics, Neuroscience and Neurology at the Baylor College of Medicine. She is the director of the Jan and Dan Duncan Neurological Research Institute. She became the editor of the Annual Review of Neuroscience as of 2018.
Epilepsy-intellectual disability in females also known as PCDH19 gene-related epilepsy or epileptic encephalopathy, early infantile, 9 (EIEE9), is a rare type of epilepsy that affects predominately females and is characterized by clusters of brief seizures, which start in infancy or early childhood, and is occasionally accompanied by varying degrees of cognitive impairment. The striking pattern of onset seizures at a young age, genetic testing and laboratory results, potential developmental delays or developmental regression and associated disorders, eases diagnosis.
Autism spectrum disorder (ASD) refers to a variety of conditions typically identified by challenges with social skills, communication, speech, and repetitive sensory-motor behaviors. The 11th International Classification of Diseases (ICD-11), released in January 2021, characterizes ASD by the associated deficits in the ability to initiate and sustain two-way social communication and restricted or repetitive behavior unusual for the individual's age or situation. Although linked with early childhood, the symptoms can appear later as well. Symptoms can be detected before the age of two and experienced practitioners can give a reliable diagnosis by that age. However, official diagnosis may not occur until much older, even well into adulthood. There is a large degree of variation in how much support a person with ASD needs in day-to-day life. This can be classified by a further diagnosis of ASD level 1, level 2, or level 3. Of these, ASD level 3 describes people requiring very substantial support and who experience more severe symptoms. ASD-related deficits in nonverbal and verbal social skills can result in impediments in personal, family, social, educational, and occupational situations. This disorder tends to have a strong correlation with genetics along with other factors. More research is identifying ways in which epigenetics is linked to autism. Epigenetics generally refers to the ways in which chromatin structure is altered to affect gene expression. Mechanisms such as cytosine regulation and post-translational modifications of histones. Of the 215 genes contributing, to some extent in ASD, 42 have been found to be involved in epigenetic modification of gene expression. Some examples of ASD signs are specific or repeated behaviors, enhanced sensitivity to materials, being upset by changes in routine, appearing to show reduced interest in others, avoiding eye contact and limitations in social situations, as well as verbal communication. When social interaction becomes more important, some whose condition might have been overlooked suffer social and other exclusion and are more likely to have coexisting mental and physical conditions. Long-term problems include difficulties in daily living such as managing schedules, hypersensitivities, initiating and sustaining relationships, and maintaining jobs.
Epigenetics of human development is the study of how epigenetics effects human development.
Mouse models have frequently been used to study Down syndrome due to the close similarity in the genomes of mice and humans, and the prevalence of mice usage in laboratory research.
Xp11.2 duplication is a genomic variation marked by the duplication of an X chromosome region on the short arm p at position 11.2, defined by standard karyotyping (G-banding). This gene-rich, rearrangement prone region can be further divided into three loci - Xp11.21, Xp11.22 and Xp11.23. The duplication could involve any combination of these three loci. While the length of the duplication can vary from 0.5Mb to 55 Mb, most duplications measure about 4.5Mb and typically occur in the region of 11.22-11.23. Most affected females show preferential activation of the duplicated X chromosome. Features of affected individuals vary significantly, even among members of the same family. The Xp11.2 duplication can be 'silent' - presenting no obvious symptoms in carriers - which is known from the asymptomatic parents of affected children carrying the duplication. The common symptoms include intellectual disabilities, speech delay and learning difficulties, while in rare cases, children have seizures and a recognizable brain wave pattern when assessed by EEG (electroencephalography).
Bosch–Boonstra–Schaaf optic atrophy syndrome is a rare autosomally inherited condition characterised by developmental delay, intellectual disability and decreased visual acuity.
Ocular albinism late onset sensorineural deafness (OASD) is a rare, X-linked recessive disease characterized by intense visual impairments, reduced retinal pigments, translucent pale-blue irises and moderately severe hearing loss from adolescence to middle-age. It is a subtype of Ocular Albinism (OA) that is linked to Ocular albinism type I (OA1). OA1 is the most common form of ocular albinism, affecting at least 1/60,000 males.
X chromosome reactivation (XCR) is the process by which the inactive X chromosome (the Xi) is re-activated in the cells of eutherian female mammals. Therian female mammalian cells have two X chromosomes, while males have only one, requiring X-chromosome inactivation (XCI) for sex-chromosome dosage compensation. In eutherians, XCI is the random inactivation of one of the X chromosomes, silencing its expression. Much of the scientific knowledge currently known about XCR comes from research limited to mouse models or stem cells.
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