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Caroline Covini, Vice-president
“MECP2 duplication syndrome is a severe disease which changes the life of the whole family. We hope to bring comfort and support to the families dealing with such a tough diagnosis.”
Caroline Covini, Vice-president
MECP2 duplication syndrome is a rare genetic disorder affecting mainly boys. The syndrome is caused by a duplication of genetic material located on the terminal region (Xq28) of the X chromosome, involving the MECP2 gene as well as other related genes (IRAK1, GDI1, FLNA, L1CAM, IDH3G…). The size of the duplication and the severity of the symptoms vary greatly from one patient to another without, however, establishing strong links between these two variables.
The protein encoded by the MECP2 gene, called MeCP2 (methyl CpG binding protein 2), plays a central role in the regulation of other proteins responsible for brain development and function.
Duplication of the gene leads to overproduction of the MeCP2 protein, thus preventing the regulation of other proteins. This results, clinically, in moderate to severe intellectual disability (ID), delayed psychomotor development, and very poor or absent language.
When mutations lead to the production of a non-functional MeCP2 protein, symptoms similar to MECP2 duplication syndrome appear. This is called Rett syndrome.
Consequently, the amount of MeCP2 protein present in the tissues must be precisely regulated: neither too low, nor too high, to ensure the proper functioning of the neuronal network.
Duplication of the MECP2 gene is caused by a mutation located on the terminal region of the X chromosome. In more than 90% of cases, the duplication is inherited from an asymptomatic carrier mother. The term carrier is used when the person is a carrier of the genetic defect, but this defect is not manifested clinically.
During a pregnancy, there is a 50% chance of giving birth to an affected boy and a 50% chance of giving birth to a girl with the mutation. Very rarely do girls develop a symptomatic form of the disease.
Males (XY) have only one X chromosome. The duplication of the MECP2 gene causes severe symptoms in any case.
In contrast to men, women (XX) have two X chromosomes. A duplication of the MECP2 gene very rarely affects a woman, because the X chromosome with duplicated material is inactivated and the MeCP2 protein level remains normal.
In rare cases, the mutation is expressed in women because of unfavorable inactivation of the mutated X chromosome, or because the mutation is transposed to another chromosome. In both cases, symptoms range from psychiatric problems (depression and anxiety) to severe symptoms identical to those found in affected men.
Duplication of the MECP2 gene can also occur during fertilization. This is called a de novo mutation because neither parent carries the genetic mutation.
The main symptoms found in patients with MECP2 duplication syndrome are:
However, documented cases of MECP2 duplication syndrome are limited. A child with the syndrome may not have all the symptoms listed. In addition, the symptoms and their intensity may change with age.
It is difficult to establish because the clinical forms are diverse and health professionals, apart from specialists, are not familiar with recognizing them.
The diagnosis can be evoked on the clinical presentation, in a male child presenting a combination of the following signs:
The diagnosis must be considered in front of a multiple disability situation with severe ID and very poor or absent language associated with a combination of signs such as:
Because MECP2 duplication syndrome is so widely underdiagnosed due to the variability of symptoms, the exact prevalence of the syndrome is currently unknown. It is currently estimated at 1/150,000 male births.
Currently, the number of cases worldwide is unknown. However, it is possible that MECP2 gene duplication syndrome may account for 1-2% of unexplained intellectual disabilities and/or autism.
Therefore, it is important to record all diagnosed cases through existing registries.
Families affected by the MECP2 duplication syndrome present the syndrome on video. Find the videos here.
There are a large number of genetic diseases caused by gene duplications.
These diseases are expressed by different symptoms, but the principle of treatment of a duplication could be applied to another syndrome resulting from the duplication of a gene.
Scientific advances in one duplication can therefore lead to progress in others.
A complete article about other genetic duplications is in preparation. For more details, come back later…
In contrast to MECP2 duplication syndrome, mutations in the MECP2 gene can occur during fertilization and can lead to the production of a non-functional or less active MeCP2 protein.
Mutations that inactivate the MECP2 gene or decrease the activity of the MECP2 protein are responsible for Rett syndrome, whose symptoms are similar to MECP2 duplication syndrome.
The Rett syndrome was first described in 1966 by Andreas Rett. It is predominantly expressed in girls with an incidence of 1 in 10,000 to 15,000 births. However, a few rare cases of Rett syndrome have been diagnosed in boys.
The syndrome is relatively well studied and a marketing authorization application for a drug (Trofinetide, Acadia) is currently under review in the United States.
