Point mutation, illustration
Computer graphic illustration depicting a point mutation. A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a sequence of DNA or RNA. Point mutations have a variety of effects on the downstream protein product consequences that are moderately predictable based upon the specifics of the mutation. These consequences can range from benign (e.g. synonymous mutations) to catastrophic (e.g. frameshift mutations), with regard to protein production, composition, and function.

Patients with a rare type of genetic disease caused by mutations in the PIK3CA gene could benefit from treatment with a therapy developed to treat breast cancer, according to research from the University of Paris.

PIK3CA-related overgrowth spectrum (PROS) describes a group of rare diseases that cause non-cancerous tissue overgrowth in different organs around the body depending on the specific disease. For example, fibroadipose hyperplasia can cause overgrowth of limbs and megalencephaly-capillary malformation syndrome can cause brain overgrowth and there are several other similar conditions affecting organs around the body.

PROS conditions are almost always caused by spontaneous mutations in the PIK3CA gene that are not inherited. This gene is also the most commonly mutated gene in breast cancer, and, as a result a PIK3CA inhibitor drug, alpelisib, has recently been developed by Novartis and approved for the treatment of advanced breast cancer with mutations in this gene.

No approved treatments currently exist for patients with PROS syndromes so Guillaume Canaud, a professor at the University of Paris and Necker Hospital for Sick Children, and colleagues investigated whether alpelisib could be a good option for these patients. While PROS is not cancer, it can be life threatening and causes significant disability to those affected.

As reported in the Journal of Experimental Medicine, two infants with PROS were treated with alpelisib to test the viability of the treatment. One patient was an 8-month-old girl with voluminous vascular malformation and the other was a 9-month-old boy who had asymmetric growth of different body parts, an enlarged right side of the brain and West syndrome.

After 12 months of daily treatment with 25 mg/day of alpelisib, both children showed big improvements in symptoms with no adverse effects reported from the drug. “Given the well-established safety profile of alpelisib at the approved 300-mg dose in adults, these low exposures support the continuous treatment of 25 mg alpelisib in these young patients with PROS,” said Canaud in a press statement.

Many symptoms were improved. More specifically, the girls right leg reduced significantly in size and she was able to stand and walk with help, something she had not been able to do previously. The boy had experienced epileptic spasms before treatment and these reduced significantly after taking alpelisib.

If possible is particularly important to address these types of symptoms at an early age so that growth and development can follow as normal a path as possible. It is now hoped that these children will have a much-improved developmental pathway due to the treatment.

“The results of alpelisib treatment in these two infants are encouraging, but they should be interpreted with caution and will have to be confirmed by future studies,” cautions Canaud.

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