 Our bodies are made up of trillions of cells. All of these cells are further subdivided into specialized compartments. One such compartment is the nucleus, which houses our genes. Genes are responsible for providing all of the instructions for making our cells function. Thus, they are the building blocks of who we are and essentially give us our ability to see, walk, talk, digest food, etc. Our genes miraculously give our cells the correct instructions most of the time. But they can sometimes give the wrong instructions when there is a mistake or mutation in the genetic sequence. This can lead to significant health problems. One type of genetic mutation results in a metabolic disorder known as congenital disorders of glycosylation, or CDGs, so named because they impact glycosylation, the process of adding sugar modifications to proteins. Proteins are the molecules responsible for carrying out the instructions that genes provide, and adding sugar molecules to certain proteins is critical to allow the proteins to do their jobs properly. While all CDGs are relatively uncommon, GPI anchor CDGs are among the rarest. GPI anchor CDGs impact genes in the GPI anchor pathway, which is a specific type of sugar modification that allows proteins to sit on the cell surface. There are about 30 genes involved in the GPI anchor pathway, and almost all of them have been associated with a CDG. Pig A is one of those genes, and the one that we will take a closer look at here. Pig A mutations are rare with only about 30 people ever having been identified as having the mutation. This subset is further restricted because the Pig A mutation is X-linked, meaning that the disease is primarily observed in males. The most common symptoms associated with Pig A CDG are seizures, significant developmental delays in motor and verbal skill, respiratory complications, visual impairment, muscle tone abnormalities, and gastrointestinal problems. Pig A mutations also cause a lower life expectancy, with many affected babies passing away early in life due to respiratory complications. In addition to severely debilitating physical symptoms associated with Pig A CDG, there are also no widely available treatments. Available treatments are primarily limited to those used to manage symptoms. There are, however, a couple of treatment approaches worth exploring, but to understand them, we have to first understand what the Pig A gene does. Pig A is part of a group of proteins involved in the very first step in the GPI anchor pathway. These proteins add a fat to the sugar N-acetylglycosamine to produce N-acetylglycosamine phosphatidylenosatol. Let's call it Gliknak PI. Gliknak PI itself is ultimately transformed into a compound called GPI that plays a critical role in normal organ development throughout the body and in the development and maturation of the nervous system. One potential treatment option is to bypass the need for a functional Pig A enzyme and directly give the patient Gliknak PI. Other potential treatments include enzyme replacement therapy to replace the Pig A enzyme and gene therapy to replace the Pig A gene. There are several important considerations with this type of treatment to ensure that the therapy is targeted to the correct locations. One, it has to pass through the blood-brain barrier to be able to get to affected cells in the brain. And two, it has to be able to go through the cell membrane to enter the cell and perform its function. While Pig A mutations are currently rare and not well understood, the increased usage of DNA sequencing technologies increases the likelihood that we will see more and more people diagnosed every year. Therefore, new therapeutic options will become increasingly important. Much more research needs to be done to understand the Pig A mutation and how it leads to the complex medical issues we see. Awareness and increased funding are critical for progressing towards a Pig A CDG cure. For more information, visit www.piga-cdg.com