ALS4: Amyotrophic Lateral Sclerosis type 4

 

ALS is a form of motor neuron disease. It belongs to a group of neurodegenerative disorders characterized by progressive weakness and atrophy of skeletal muscle due to the selective degeneration of motor neurons. ALS is characterized by clinical and pathological features of upper and lower motor neuron degeneration, originating in the brain stem and spinal cord. Approximately 90% of ALS cases are sporadic and 10% are familial. There are currently sixteen identified types of ALS. While the majority of ALS types are eventually fatal, ALS type 4 is not. 

 

ALS4 can now be determined by blood test at birth. Mild symptoms usually begin to appear sometime during childhood or the teens. People with ALS4 show different levels of motor difficulties throughout their lifetime but, by their 20s or 30s, most experience challenges walking, navigating stairs or other uneven surfaces, as well as limitations in the finer movements of their hands and feet. Most ALS4-affected people require canes, walkers and wheelchairs by their 50s or 60s, with males being somewhat more impacted than females. Depending on their other health issues, some who have ALS4 have spent the last decade of their life as quadriplegics. 

Scientific description of ALS4:  ALS4 is "an autosomal-dominant form of juvenile ALS due to a mutation (L389S) in the Senataxin (SETX) gene that encodes a DNA/RNA helicase (Chen et al., 2004). The senataxin protein, SETX, interacts with RNA Pol II (Chen et al., 2006, Ursic et al., 2004, Yüce and West, 2013) and plays a role in resolving R loops, particularly in transcription pause sites (Mischo et al., 2011, Skourti-Stathaki et al., 2011, Suraweera et al., 2009, Yüce and West, 2013). The mutation at position 389 corresponds to the N terminus of SETX, which interacts with other nuclear proteins, including RNA Pol II (Yüce and West, 2013). (Grunseich, Lis, Cheung et al., 2014)" Interestingly, a different mutation in the SETX gene causes a debilitating balance disorder known as Ataxia with Oculomotor Apraxia type 2 (AOA2). Researchers around the world are beginning to study the two disease processes comparatively in order to understand the different DNA behavior that results at the cellular level from the two mutations in the SETX gene. 

Our story: We are members of a family of refugees from the religious wars in England who arrived in Maryland in 1664. By the 1700s many of our ancestors began exhibiting a characteristic limp and other generalized weaknesses. Most residents of Southern Maryland knew of this family peculiarity, but there was no medical understanding of our family's condition until 1994 when researchers led by Drs. John Griffin and David Cornblath of Johns Hopkins met with over one hundred family members for a long weekend "reunion" in Solomon's Island. After examining family members and assembling a 10' long genealogical chart that showed common "affected" ancestors dating back to the 1700s, the doctors returned to Hopkins and set up a research team who analyzed their extensive findings from the reunion. In 1998 two family members (who had pre-arranged autopsies upon their deaths) enabled the Hopkins team to identify the disease as a form of ALS and to name it ALS type 4, juvenile amyotrophic lateral sclerosis. It took until 2004 before researchers, led by Phillip Chance, located the 'cause' of ALS4 as a mutation in the SETX (senataxin) gene located on chromosome 9q34. 

 

Our mission:  Our mission in establishing this website is three-fold: (1) to connect ALS4 family members (affected and non-affected) with each other; (2) to facilitate dialog between ALS4 families and researchers; and (3) to open more avenues of advocacy for ourselves so we can increase the speed in which treatments are achieved and ease our journeys with ALS4 in the meantime.

 

Where we are today: The research journey of the past 21 years has been a complicated investigation that is going to the very heart of genetic coding and messaging within the body's cells. The ALS4 answer remains elusive but hope increases every year as foundational research has spread world-wide. Since the 1994 identification of 49 ALS4-affected family members in Maryland, researchers have discovered additional ALS4-affected individuals in at least 5 other countries (http://alsod.iop.kcl.ac.uk/Overview/gene.aspx?gene_id=SETX).  My immediate family has been seen by research doctors at Johns Hopkins, NIH, University of California San Diego (UCSD), and University of California Los Angeles (UCLA). Although I don't know their names, I understand that about 50 other ALS4 family members have been seen at Hopkins and NIH. We are also very privileged to have received the attention and support of Dr. Vivian Cheung, Senior Researcher with the Howard Hughes Medical Institute. Dr. Cheung knowns many researchers nationwide and is now advocating for ALS4 in medical and funding circles. She will share her compassionate, professional insights with us on the Forum pages of this website. We look forwarding to building an ALS4 virtual community together with you.