Rett-like or atypical Rett...
Before the CDKL5 disorder was established as a distinct entity, children with CDKL5 were often diagnosed as having an atypical form of Rett syndrome - atypical Rett or a Rett-like condition. Rett syndrome is caused by mutations in the MeCP2 gene, also located on the X-chromosome. However, apart from mutations in the CDKL5 gene, there are a number of other genetic mutations that are also associated with Rett-like features and these are outlined below. The names atypical Rett and Rett-like are both applied to these conditions. I have found no clear view from the literature on which is more appropriate. I have assumed that “Rett-like” tends to relate to the clinical features observed while “atypical Rett” is used as a diagnosis. However, the terms appear to be interchangeable.
Chromosome 1 - Netrin G1
The Netrins are a family of proteins involved in axon guidance or migration during the development of the nervous system. Netrin G1 belongs to this group and is coded for by a gene on chromosome 1. A report in the European Journal of Human Genetics reported a mutation disrupting the Netrin G1 gene in a girl with features of Rett syndrome.
Chromosome 2 - MAP2
A report in Clinical Genetics describes a 14 year old girl with autism and some Rett-like features. She had a deletion in chromosome 2 which included the MAP2 gene. This gene codes for a protein that belongs to the microtubule -associated protein family and is involved in the assembly of microtubules essential for the development of neurons.
Chromosome 5 - MEF2C
MEF2C, or myocyte enhancer factor 2C, is a gene that codes for a protein that belongs to a family of proteins involved in the formation of muscles. A report in Clinical Genetics describes a mutation in the MEF2C gene as a rare cause of atypical Rett
A duplication of part of the long arm of chromosome 11 (11q) has been reported in the American Journal of Medical Genetics, in a girl with atypical Rett syndrome.
Chromosome 14 - FOXG1
FOXG1 or forkhead box G1, to give it its full name, is a gene located on chromosome 14. The gene codes for a protein that regulates other genes and is therefore known as a transcriptional factor. Mutations in the FOXG1 gene have been found to produce a congenital version of Rett syndrome - that is there is no period of normal development. There are a number of reports ( report 1, report 2, report 3)
There is a condition known as Chromosome 18q syndrome, which is due to a deletion of part of the long arm of chromosome 18. Affected children display a spectrum of features including short stature, intellectual disability and poor muscle tone. Other features can include abnormalities of the hands feet, skull and face. A report in the American Journal of Medical Genetics describes a child with a deletion in this area of chromosome 18 who had some features of Rett syndrome. The authors suggest that this is a form of atypical Rett and that it might indicate a role for the genes in the distal region of chromosome 18q in the aetiology of Rett syndrome.
X-Chromosome - Fragile X
Fragile X syndrome is caused by mutations in the FMR1 gene on the X-chromosome. The associated protein, which is present in many tissues, appears to play a role in the development of the synapses between nerve cells. A report in Genetic Counselling describes a girl with classical features of Rett syndrome who had a mutation in the FMR1 gene.
So...what's in a name.....?
As you can see, the mutations responsible for all these conditions occur in several different chromosomes. While their similarity with Rett may just be co-incidental, this may also indicate that they are all in some way involved in the same molecular biological process which requires the co-ordinated action of many different proteins coded for by genes across the human genome of which CDKL5 is just one!
At the moment, these conditions, when they occur, are generally still labelled as "Rett-like" or "Atypical Rett" - for understandable reasons. Rett syndrome as a condition has been recognised the longest and perhaps provides the best basis for appreciating the clinical features of the other conditions. However, the recognition and understanding of genetic diseases, their phenotypes and the relationship between genes through the interaction of the complicated molecular processes they code for is still obviously being researched and established. Ultimately, it may be that they are all inter-related equally and should therefore, perhaps, come under the umbrella of a new name - such as below. This is just a thought that I have had and not an established or accepted view.