Hopeful news but not peer-reviewed
A new report describes success in a very small trial with a new drug that targets behavioral signs of Fragile X syndrome. This syndrome, which affects about one in every five thousand children, mostly boys, usually involves some form of intellectual disability along with a suite of typical physical characteristics, including large jaws and ears and elongated faces. It is the most common known heritable cause of intellectual disability and has also been associated with autism.
Novartis has been working on an experimental drug targeting some of the behavioral manifestations of Fragile X and has just reported, via interview, positive results from a small trial. Because the results are not public and have not been peer reviewed, the nature of the improvements is unknown, as is the nature of the drug itself. All that is known is that a parameter in the treatment group improved in some, but not all, participants with Fragile X. Also, the drug targets reduction of the synaptic noise that people with Fragile X experience. This reduction in neural background noise, it is thought, may pave the way for more typical neurological development.
Why is the X fragile?
The X chromosome consists of many many genes. Some of these sequences may contain repeats of the same three nucleotides, or letters of the DNA alphabet. For example, a gene section might have 50 repeats of the sequence C-A-G. These trinucleotide repeats, as they are known, are associated with a few well-known disease states when they occur in larger numbers. At a certain low number of repeats, they may have no effect, but when the number of repeats increases, a phenomenon known as trinucleotide expansion, the result can be disease. Huntington’s disease is one well-known disorder associated with trinucleotide expansion, and the general rule is that the more repeats there are, the more severe and/or the earlier the onset of the disorder.
On the X chromosome, where these repeats achieve sufficient numbers to result in Fragile X syndrome, the X chromosome itself looks like it’s literally at a breaking point. This visual fragility is what gave the disorder its name when this chromosome characteristic was discovered in 1969. A parent who carries an X chromosome with relatively few repeats does not have Fragile X, but the gene is in a state known as a premutation. Thanks to various rearrangements and events during cell division, this premutation can expand even in a single generation to sufficient numbers of repeats to cause the disorder in an offspring.
Because the relevant gene is on the X chromosome, Fragile X is an X-linked disorder. It’s more prevalent among males than among females because males receive only one X chromosome. Without the second X chromosome backup that females have, males are stuck with whatever genes–and mutations–are present on the single X chromosome they receive.
What is the autism link?
Fragile X underlies a small percentage of diagnosed cases of autism, between 2 and 6%. Because of the usual genetic complexity underlying autism, Fragile X is also the most common known single-gene cause of autism.
These prematurely reported results have also yielded some speculation that a drug that is effective in reducing background noise and improving behaviors for people with Fragile X might do the same for autistic people, even if their autism isn’t related to Fragile X. With nothing in the way of peer-reviewed findings to consider and results available only via interview, such hopes remain in the purely speculative realm.
For your consideration
Males are born with a single X chromosome. Females have two. The X chromosome has hundreds of genes on it. How is it that women can walk around with a double dose of these genes, or conversely, men can be healthy with a half dose?
Trinucleotide expansion occurs when a trinucleotide repeat sequence expands in numbers of repeats, potentially evolving from a premutation to a full-blown disruption of a gene. What are some possible mechanisms by which this expansion might occur?
In the article related to this report, there is reference to “synaptic noise” and to the idea that a drug might reduce this noise and allow more space for typical development. What do you think “synaptic noise” is, physiologically, and how might a drug target this noise?