Update on FSHD2 and SCA28
In early 2013, two reports were published in the scientific literature about genes on chromosome 18p that potentially had relevance for people with 18p-. We immediately held a webinar for the families of individuals with 18p deletions who are enrolled in the research program to explain the findings and what we planned to do next. Since that time, we have learned more about the role those genes might play in the development of the conditions they cause, and want to share updates here.
SMCHD1. People with Facioscapulohumeral Dystrophy Type 2 (FSHD2) were identified with mutations in the SMCHD1 gene that resulted in the loss of function of one of their two copies of that gene. This state is analogous to having a deletion of one copy of the gene as is the case with people with 18p-. This made us very concerned that people with 18p deletions might develop FDSH2. FSHD2 is a late onset type of muscular dystrophy usually beginning in adolescence or young adulthood. It primarily affects the muscles of the face, shoulders and upper arms. Additionally, affected individuals often have high frequency hearing loss. However, the individuals reported in the literature with FSHD2 also had a certain DNA configuration around their DUX4 gene on chromosome 4. We contacted the leaders in FSHD2 research in The Netherlands and they analyzed the DNA of our study participants with 18p- to determine if any of them also had that same configuration on chromosome 4. A few individuals did have that configuration, a few did not, but most had a configuration that was borderline for risk. We also began assessing people with 18p- deletions for first signs of the condition; with a questionnaire, in-person exams at the Registry conference and continuing with video recordings. We have yet to identify anyone with 18p- and FSHD2, but we remain vigilant. Because this is a late onset condition and our study population is relatively young, we continue to assess participants for first signs by asking participants to do a video interview every few years.
The second gene, AFG3L2, was identified as a cause of Spinocerebellar Ataxia Type 28 (SCA28). This is a very rare condition only identified in a couple of families, which means little is known about it. Just as in the case of FSHD2, the individuals diagnosed with SCA28 had mutations in one copy of the causative gene (AFG3L2 in this case) that made it nonfunctional. This again would be analogous to having one copy of the gene deleted, as in 18p-. The average age of onset of symptoms is 24 years. The most common symptoms include progressively uncoordinated walking, dysarthria speech articulation issues, abnormal eye movements and droopy eyelids. The process of evaluation mentioned above also included questions and evaluations aimed at diagnosing SCA28. To date, we have not identified anyone with an 18p deletion with this condition. However, because individuals with 18p- often have speech issues we focused on that aspect in our continuing follow-up evaluations.
Our continuing evaluation, for both FSHD2 and SCA28, is done simultaneously and involves using an iPad to record the face of the participant while they make certain facial movements such as raising their eyebrows, puckering their lips and then smiling. In addition, participants are asked to repeat several sentences. The evaluations can take place in-person at the Chromosome 18 Registry conference or can also be mailed to families to do at home. We are asking participants to redo the evaluation every few years so any changes can be observed.
So far, no one with an 18p deletion has been identified with either of these conditions. But we remain concerned because most individuals are young and just now entering the typical age of onset. Stay tuned for more updates from the Research Center, as we will continue to assess our 18p- research participants for signs of these conditions.
