This article and other news can be found in the latest issue of our newsletter which can be downloaded/viewed here: June 2018.
No one can say exactly how many people in the world have a NBIA disorder, but we can guess based on how many people have been diagnosed so far. Today, PKAN is the most common type of NBIA disorder, closely followed by PLAN and BPAN. However, overall numbers are not the entire story and there are three main factors that are contributing to a recent rise in BPAN diagnoses.
Discovery of the WDR45 Mutation
PANK2 gene mutations were discovered to be the cause of PKAN in 2003. Three years later the PLAN gene, PLA2G6, was discovered and ten years later mutations in the WDR45 gene were determined to be the cause of BPAN. Sequencing an individual’s DNA and finding a mutation in a specific gene is the most accurate way to give someone a diagnosis of NBIA. Doctors have only been able to make genetic diagnoses of BPAN for five years, instead of twelve to fifteen for PLAN and PKAN. However, most diseases are never diagnosed with genetic testing and only rely on clinical features. In other words, doctors can examine a patient and give them a diagnosis. However, this can be especially difficult in BPAN.
Clinical Features of BPAN
Individuals with BPAN are usually brought to see a doctor when they are young due to characteristics such as broad developmental delay, repetitive or even autistic behavior, and seizures. Unlike the symptoms of PKAN, these clinical features are common among a number of diseases, making it very difficult for doctors to diagnose. Additionally, the presence of brain iron accumulation on MRI may not show up until early adulthood for many individuals with BPAN. In comparison, people with PKAN have very distinct, “eye of the tiger” MRI patterns from a young age, making PKAN an easier disease to diagnose clinically. Once clinical features of a suspected genetic disease, such as PKAN or BPAN, are identified, a gene panel can be ordered. This is a genetic test of a few genes that are likely to have mutations based on the patients symptoms. The recent addition of the WDR45 gene to seizure panels has lead to an increase in early BPAN diagnoses. Also, as more research is done on BPAN, MRI characteristics for BPAN patients are emerging, creating a more defined clinical picture of the disease.
Whole Exome Sequencing
The last piece of this story is Whole Exome Sequencing(WES). WES is a type of genetic testing that is increasingly being used to diagnose patients with non-specific clinical features (like in BPAN). Unlike gene panels, WES does not focus on a few genes, but looks at all the coding genes in an individual’s DNA and catches most mutations that are present. In the past 18 months, our team has seen almost as many BPAN diagnoses as all the other NBIA disorders combined. This recent increase may be a result of targeted genetic testing with seizure panels, broad genetic testing using WES, and simply “catching up” with all the people who went undiagnosed before the discovery of the WDR45 gene. If the amount of people with BPAN continues to grow at the same rate, then BPAN may very well overtake PKAN and PLAN as the most common NBIA disorder. Time will tell whether this is true.
These numbers were gathered through our database at OHSU, and represent people who have reached out to us, come for clinic visits, or participated in research.