Abstract
This paper describes the founding of the SLC6A1 Connect organization, which offers resources to patients and families with SLC6A1 diagnoses while keeping current with a scientific overview of the disorder. Following the birth of her two lovely twins, Amber Freed noticed how her son, Maxwell, missed motor development milestones and would often stare. Eventually, these signs led to a diagnosis of an SLC6A1 variant. The SLC6A1 gene is located on the short arm of chromosome 3 and the gene encodes for the gamma-aminobutyric acid (GABA) transporter 1 (GAT-1) protein. This transporter is responsible for the reuptake of the inhibitory neurotransmitter, GABA. The transporter usually removes GABA from the synapse space between two neurons, limiting over-excitability in the brain, which can lead to seizures and motor deficits as Amber noticed in her son, Maxwell. Amber realized that there were nearly no treatment options for her son’s condition so she began forming connections with scientists and doctors. Initially, she flew to see Dr. Steven Gray, with whom she developed a research plan for a gene replacement therapy to treat the variant along with a design for a clinical trial. Not only this but they needed to raise four million dollars to fund these endeavors. Freed founded the SLC6A1 Connect organization to raise money and awareness and put together a network of dedicated researchers and families. Since then, the organization has raised over two million dollars and grown to offer families a base of support. The organization even hosts a yearly symposium with families, scientists, and biotech or pharmaceutical companies worldwide. In addition, we detail how the organization now offers informational resources to families to help them understand the science behind the variant and ways to help their children such as registry links and genetic testing options. These endeavors have led the organization to collaborate with scientists based on institutions such as Vanderbilt University Medical Center, UT Southwestern Medical Center, the Cleveland Clinic, and many industrial pharmaceutical partners.
Plain language summary
SLC6A1 Connect offers many resources that patients and families afflicted by the SLC6A1 mutation benefit from. This mutation prevents a transporter from being encoded which typically allows for the proper levels of GABA in the brain to be maintained. Without this protein, there is a lack of GABA regulation and the brain is too excitable leading to seizures and motor delays. On our website, families are able to access scientific summaries of relevant publications in the field and can find plain-language summaries of the science behind the mutation. Additionally, symposiums are held once a year to allow families to hear from experts in the field and directly engage with them by asking questions. We aim to make scientific findings more understandable and accessible. The organization also allows them to become directly involved in the research, development, and medical treatment processes. Parents are able to help raise money through fundraising initiatives and receive regular information about genetic testing & registry programs. Overall, these organizational offerings have greatly benefited pediatric SLC6A1 patients, as seen through the patient family testimonies of Ms. Freed and the Fry family. Overall, throughout this paper we detail the resources made available to researchers, physicians, and families in the SLC6A1 Community.
Keywords
Organization founding and background
When Colorado mother, Amber Freed, brought home her two lovely twins in March of 2017—Maxwell and Riley—all was well. However, in the coming months, Freed would start to notice that Maxwell was not quite matching his twin sister, Riley, in terms of development. A devoted mother, Amber noticed these signs early—Maxwell would stare off for long periods of time and unfortunately was not gaining the same level of motor development as his sister. Freed first noticed this when Maxwell would not roll over to reach his toys. Ultimately, she knew something was not quite right.
Freed took Maxwell to a plethora of doctors, and although she was initially told not to worry, she persisted. Eventually, in 2018, Freed was able to learn that her son, Maxwell, had a pathogenic SLC6A1 variant—one so rare it is only named for its genetic origin. Freed searched as much as she could, but was unable to find any information online regarding the variant. Even her doctors told her that little could be done to help Maxwell, as reported by DeSantis 2 in 2020.
SLC6A1’s significance in neurological function
SLC6A1 is a gene located on the short (p) arm of chromosome 3 in the 3p25.3 region, pivotal in the human genome for its role in encoding gamma-aminobutyric acid (GABA) transporter 1 (GAT-1). 4 This particular protein is integral to neurological development and function, specifically the neurotransmitter transport system. GAT-1 is the primary mechanism for the recycling of GABA in the brain. GABA is the primary inhibitory neurotransmitter in the central nervous system and plays an important role in regulating excitability throughout the central nervous system (CNS), which is essential for typical brain functioning and overall neurological health, according to the Children’s Hospital of Philadelphia. 7
Imagine your brain as a bustling city, buzzing with messages zipping between neurons like cars on busy streets (Figure 1). Think of GABA like the brakes on your car. When things get too fast or hyperactive, GABA hits the brakes, slowing down the signals between neurons and preventing over-excitability. This delicate balance between “stop” and “go” is important for everything from learning and mood to sleep and movement. This is where SLC6A1 comes into play. This gene encodes a protein called GAT-1, which acts like a dedicated traffic cop for GABA action. GAT-1 scoops up used GABA from the “street” (the synapse between neurons) and ushers it back into the “garage” (the neuron) or glial cells, where it can be recycled and reused. This keeps GABA levels in balance, ensuring your brain stays calm and regulated.
Analogies for understanding common neurological conditions associated with SLC6A1 variations.
Link between SLC6A1 and rare genetic diseases
Those with SLC6A1-related disorders typically have a pathogenic variant in the gene. Unfortunately, for those with a pathogenic SLC6A1 variant, the lack of a fully functional GABA transporter will disrupt the neurotransmission regulation system of the brain. Just like a faulty stop light can lead to disorder on the road, variants affecting the SLC6A1 gene can disrupt GABA’s flow. This can lead to an imbalance of too much GABA on the street and not enough in the garage. This “traffic jam” can cause various problems, such as seizures and developmental deficits in areas such as motor skills, according to a recent report by Beghi. 1 Key clinical presentations include developmental delays, particularly in cognitive and language skills, behavioral issues, and a predisposition to epilepsy. Specifically, the phenotypes associated with pathogenic variants in SLC6A1 include hypotonia, intellectual disability (ID) or developmental delays, language disorders or speech delays, autism spectrum disorders (ASD), sleep issues, and seizures. These are some of the same symptoms that Freed noticed in Maxwell and also reported by other parents with kids with SLC6A1 variants. However, it is important to note that the clinical presentation of disorders stemming from SLC6A1 variants can vary greatly. Some individuals experience mild symptoms, while others may have severe neurological impairments. The nature and location of the variance within the SLC6A1 gene often determine the severity and type of neurological disorder that develops. Disruptions in the GABAergic signaling pathway can lead to significant neurological impairments, making the study of SLC6A1 and its variants especially relevant in the context of rare neurological disorders. Understanding the function of SLC6A1 and its role in GABAergic signaling can provide insights into the mechanisms underlying various neurological conditions. Furthermore, a significant number of patients with SLC6A1 variants often present with comorbid conditions that can significantly impact their overall health and developmental outcomes. The prevalence and significance of these comorbidities vary, but they include conditions such as developmental delay, epilepsy, ASD, attention-deficit/hyperactivity disorder, hypotonia, movement disorders or ataxia, and ID. 8 The presence of these comorbid conditions can significantly affect the outcomes for patients with SLC6A1-related disorders.
Taking initiative
Left with no answers about this seemingly “ghost mutation,” Freed decided it was time to take the initiative herself. Up until this point, she was working actively as a successful investment analyst at Janus Henderson Investors. Using her tenacious attitude and her “immunity to rejection,” curated throughout her time in finance, Freed 3 set out to build a team of geneticists ready to tackle SLC6A1 variants. She began researching day and night to find the best scientists and bring them to Maxwell’s side. Freed even sent UberEats cookies and offered to fly and meet with them in person regardless of where they were based.
Freed found Dr. Steven Gray and booked flights to a conference she knew he would be presenting at. Following the conference, Freed met Dr. Gray for 4 h while they devised a plan for Maxwell. From that day on, the goal was clear: to develop a gene replacement therapy for SLC6A1-related disorders, the two of them would design a clinical trial for themselves. There was just one issue—this endeavor would cost at least four million dollars. Not only would Freed have to form a team of scientists, but she would also have to find the funding as well to support research on understanding how the variant in SLC6A1 affects brain function. On September 23, 2019, Freed flew to Nashville and met Dr. Katty (Jing-Qiong) Kang at Vanderbilt University Medical Center and supported Dr. Kang’s lab for a large research project on SLC6A1 mutations.
Freed noted that hearing your child has a rare disease with no name or treatment was the darkest moment of her life. In that darkness, she found empowerment knowing that the opportunity of driving research and treatments for individuals with SLC6A1 variant diagnoses began with her.
When starting, Freed founded SLC6A1 Connect, an organization offering a base of operations for collecting funds and putting together a team. With a background in finance and a commendable attitude of perseverance, Freed and the SLC6A1 Connect organization were able to raise over two million dollars by 2019. Since then, the organization has passed four million dollars in funding. Not only has this superhuman financial feat garnered SLC6A1 Connect press attention, but it has also allowed for the development of a scientific team and the start of improvements for those afflicted with an SLC6A1 variant.
Parental struggles and information access
While information related to ongoing research is extremely helpful to families wanting to learn more about SLC6A1 variants and to raise awareness alike, easy access was not always available. In addition to a lack of treatment options, one of the biggest challenges faced by families in the rare disease community has historically been a lack of information available to them. In the wake of a diagnosis, families need a way to learn more about not only the science behind the disease but how to find support and best help their child.
Freed said, “I utilized social media in the earliest days of SLC6A1 Connect to amplify my message which met meant hashtagging #SLC6A1 thousands of times across numerous platforms. I leveraged my personal story to garner the interest of major media publications like People and the Huff Post to help tell my story.”
The Fry family received an SLC6A1-related diagnosis for their son, Charlie in 2019. Fry said, “Our doctors did not know anything about SLC6A1 and we were left to search on Google. The first article that appeared was from the HuffPost which led us directly to Amber. SLC6A1 Connect became the center of our universe in trying to help our son.”
To help those wanting to learn more, SLC6A1 Connect has become a “one stop shop,” as Amber proudly advertises. We expanded our website to include a “Resources” tab which offers a multitude of resources for the entire SLC6A1 community, including patients and parents, scientists, and clinicians (Table 1). Some of the resources available on this tab include a scientific overview, an SLC6A1 Resources and Informational Summaries component, a Parent Bootcamp, Patient Resources, Scientific Resources, and Community Resources alike (Figure 2). Here, with a single visit to the website, parents can learn about the science behind the mutation while also finding helpful resources. Under the “Patient Resources” tab, parents can find recommended doctors and access to genetic testing and registries as well. In addition to making information available to parents, SLC6A1 Connect has also partnered with genetic organizations such as Simons Searchlight to increase data access for researchers and members of the community. By helping families register their children, we can make data more available to researchers and allow parents to aid in their child’s journey through receiving and living with the diagnosis of an SLC6A1 variant-related disorder. In fact, Dr. Dennis Lal of the Cleveland Clinic is even working to develop a parent portal where families can access patient registries and relevant information. These registries are projected to accelerate the research & treatment development process while also allowing parents to become more interconnected with organizations able to help their children.
Information and resources available on SLC6A1 Connect’s website.
This table outlines many of the scientific, clinical, and personal resources available through SLC6A1 Connect.
Dispersal chart of resources offered by SLC6A1 connect.
This inclusion of a Parent Bootcamp and Scientific Overview information has been a pivotal step in breaking down informational barriers for parents. In addition, resources like these serve as a bridge between the patient and family community and the medical professionals working toward a cure. Following this logic, SLC6A1 Connect offers a yearly Symposium hosted in various cities where parents and medical professionals alike can hear about ongoing research efforts and developments in clinical trials or other patient treatment efforts. This allows researchers to critique and draw from each other’s work in pursuit of a cure. In addition to listening, parents can present themselves and voice their experiences with SLC6A1 variant diagnoses to shed light on how the organization can better serve our community. Parents are also able to directly engage with researchers and physicians during Q&A sessions, which allows parents to take direct action for their children and feel connected to treatment efforts.
Freed states, “SLC6A1 Connect is now the handbook for children with SLC6A1 variants and empowers families to advocate for their children. The Symposium boasted over 40 families all striving for the same mission - to help their children.”
Whitney Feldman is the mother of an affected little boy and attended the Symposium. Whitney said, “Rare disease families receive a shocking diagnosis and the isolation is devastating. The Symposium was a moment of community, understanding and compassion. We are small but we are mighty.”
SLC6A1 Connect also offers information and resources to scientific researchers under the “Scientist Resources” tab. Here, researchers can see the available models as listed:
There are also more specialized lines available upon request or direct contact:
iPSC with Crispr Control Line: email Amber Freed directly.
GABA neurons: email Amber Freed directly.
Fibroblasts & LCLs can be ordered via the Coriell Institute.
In addition, members of the SLC6A1 community can keep up with active projects to stay up-to-date with current research.
Ultimately, SLC6A1 Connect has been able to provide information to parents which allows them to learn more about their children’s conditions than would be possible without such resources. The organization has also done an excellent job of providing ways for parents to become active contributors to the treatment process themselves, by allowing parents to help raise money for the organization through and by directly engaging with researchers. With these resources and opportunities, the SLC6A1 community can thrive.
Prevalence and genetic relations
SLC6A1 variant-related disorders are autosomal dominant neurodevelopmental disorders that are caused by a de novo variant, meaning that they typically arise from a pathogenic variant for the first time in a family, rather than having appeared previously. 6 The most commonly demonstrated occurrence is a single incidence of a SLC6A1 variant in a family. However, each child of someone with a pathogenic variant of SLC6A1 would have a 50% chance of inheriting the variant. 6 Once the variant is identified, prenatal and preimplantation testing are available to confirm its presence. While many testing options are available, multigene panels and exome sequencing are the two methods best able to detect the single nucleotide variants that cannot be as easily detected with the more broad chromosomal microarray analysis. 6 Think of the multigene panels and exome sequencing as allowing for more specific detection of the variant affecting the SLC6A1 gene.
SLC6A1-related neurodevelopmental disorder is very rare, as less than 500 individuals have confirmed cases around the globe, with an incidence of 2.65 in 100,000 live births. 7 It is important to note that variants in SLC6A1 are not related to the pathogenic variants of other conditions. However, the other genes are used in differential diagnosis of the disorder. 6 This means that these diseases must also be considered when diagnosing a patient who is presenting with pathogenic SLC6A1 variant-related symptoms or similar symptoms. These genes include:
Scientific developments
For the patient and family community of SLC6A1, research and medical developments provide hope for their children moving forward. Freed and SLC6A1 Connect have formed a comprehensive network of medical experts including researchers and physicians alike. In addition to genetic research, Dr. Kimberly Goodspeed 4 has taken the lead on a clinical trial aimed at ameliorating negative symptoms stemming from pathogenic SLC6A1 variants through the administration of the glycerol-phenylbutyrate drug, Ravicti, 4 a drug based on the research findings from Dr. Katty Kang’s lab at Vanderbilt University Medical Center. Recently, Dr. Demarest of the Colorado Aurora Children’s Hospital has become a lead caretaker for many children in the SLC6A1 community. Dr. Katty Kang at Vanderbilt University is actively researching the functional deficits stemming from variations within the GABAergic signaling pathway, specifically those affecting the SLC6A1 gene. Her lab hypothesizes that the altered function caused by the defective GABA transporter can be corrected by either causing the functional allele of the gene to be overexpressed to compensate for the loss of function or using innovative drugs that restore the expression and functionality of the gene altogether. 5 These drugs are often small molecules that restore the protein function of the altered SLC6A1 gene. Such treatments are being researched and developed by SLC6A1 Connect in collaboration with academic institutes such as Vanderbilt University Medical Center and Pharmaceutical company partners.
Genetic therapy treatments for pathogenic SLC6A1 variants are also being researched to advance them from the in vitro, or laboratory/cell culture stage, to the in vitro, or mouse model stage, all the way to clinical trials in humans that would allow for FDA approval. Dr. Steven Gray heads a lab at the UT Southwestern Medical Center, which aims to replace the missing SLC6A1 gene in the brain cells by packaging a functional copy of the gene into a safe, Adeno-Associated Virus, or AAV9 vector. A crucial component of this research process is the capability to test therapies in mouse models, which are engineered to have the same variant or genetic code, as occurred in Maxwell. The creation of these mouse models and further genetic therapy research occurs under the direction of Dr. Katherin Meyer at the Nationwide Children’s Hospital. As of now, gene replacement trials are being conducted in mice to test their efficacy. Eventually, the children with the variant will hopefully receive a spinal tap where non-infectious viral vectors containing a functional copy of the SLC6A1 gene will be introduced through a spinal tap procedure. Currently, this genetic therapy is still under development at locations throughout the world. In the United States, Dr. Gray’s UT Southwestern Hospital lab, Vanderbilt University Medical Center, and the Cleveland Clinic are all actively working to develop a genetic therapy treatment that will garner FDA approval, as stated by Freed. 3
Several treatment methods are being developed and the future certainly looks bright for those in the SLC6A1 Connect community. Despite these strides, clinical trials can take years and even if FDA approval was garnered, another two million dollars would be needed for Freed to continue ahead with development, making fundraising a critical component of the SLC6A1 Connect’s efforts. Overall, Amber Freed has made unimaginable strides for her son, Maxwell, in pioneering a medical research community for the SLC6A1 community.
Conclusion
We affirm that patients and families afflicted by all types of SLC6A1 variants benefit from the resources offered by the SLC6A1 Connect organization. These include streamlined information in the form of summaries and symposiums which make scientific findings both more understandable and accessible. The organization not only presents information to families but allows them to become directly involved in the research, development, and medical treatment processes. Through fundraising initiatives and increased access to genetic testing & registry programs, parents can take an active role in aiding their children. Overall, these organizational offerings have greatly benefited patients diagnosed with SLC6A1 variants, particularly those with pathogenic variants, as seen through the patient family testimonies of Ms. Freed and the Fry family.
