Strides in STXBP1 Research March
So, what was new in March of 2025?
There were several research papers published in March that mentioned STXBP1. Three of the papers involved diagnosing cohorts of patients with epilepsies; the studies were performed in three different countries. Researchers in Turkey performed genetic testing on 128 children with neonatal- and infantile-onset genetic epilepsies. They found pathogenic variants in several genes including STXBP1, which accounted for approximately 6% of children who had neonatal or early infantile onset of epilepsy and approximately 4% of children who had late infantile onset of epilepsy. Identification of the pathogenic variants allowed for targeted antiseizure therapy in 79/128 children and these children had lower rates of drug-resistance. In a single-center study conducted in India, 147 children with a mean age of seizure onset of 5.5 yrs were given whole genome sequencing. Pathogenic variants were identified in 91 of the 147 children. STXBP1 was the fourth most common causative gene, seen in 4 of the 91 children. Similar to the Turkish study, the identification of specific genetic causes for epilepsy in these children led to therapeutic decision making. Researchers in Greece performed a retrospective analysis of movement disorders in a cohort of 82 patients with developmental and epileptic encephalopathy (DEE). Approximately 60% of the patients had DEE due to either a confirmed or suspected genetic variant, including STXBP1. They found that movement abnormalities highly associated with STXBP1 included ataxia and tremor, while hyperkinetic movement abnormalities were associated with several other genes.
As we age, our motor function declines, that is, our movement precision, coordination, and strength become worse. Underlying this decline is an imbalance in the excitatory/inhibitory (E/I) tone in our nervous system. E/I balance refers to the interaction between excitatory synapses, predominantly mediated by glutamatergic signaling, and inhibitory synapses, primarily facilitated by GABAergic neurotransmission in the nervous system. In a review paper, a group of Chinese scientists discussed some key genes that play a role in maintaining E/I balance and how dysfunction of these genes may lead to E/I imbalance and motor function pathology. One of the genes discussed was STXBP1. They noted that while STXBP1 haploinsufficiency results in an overall decrease in synaptic function, there is a more profound reduction in GABAergic signaling resulting in E/I imbalance and the motor difficulties observed in STXBP1-RD. The authors suggest that reduced STXBP1 function (among several other gene candidates) could be a potential cause for normal age-related motor decline and that increasing STXBP1 expression might be therapeutic in treating normal motor aging as well as other pathological motor conditions such as Amyotrophic Lateral Sclerosis (ALS). Currently there is no solid evidence that STXBP1 expression decreases in normal aging, but perhaps this paper provides some rationale to study this question more thoroughly.
Our STXBP1 colleagues in the Netherlands published the results of semi-structured interviews with parents of children with STXBP1-RD. The aim of the study* was to better understand the day-to-day experiences of caregivers to help inform future research and therapeutic development. Twenty-one parents were interviewed and asked questions concerning topics involving the diagnosis process, how their child is impacted by their symptoms, how does caring for their child affect the family, and what are their family needs (among other questions). Parents shared that they often felt continuously engaged in caring for their child, describing a constant state of being ‘switched on.’ Their experiences were captured through five key actions: (1) providing care for their child, (2) understanding and responding to their child’s needs while also seeking acknowledgment of those needs, (3) looking for solutions and appropriate care options, (4) juggling caregiving responsibilities alongside other aspects of their lives, and (5) managing the emotional challenges associated with their roles. The authors conclude that to support STXBP1 patient families, a broad approach is needed that includes medical treatment, other therapies, such as speech or physiotherapy, and providing social support for the entire family.
The gut microbiota refers to the thousands of bacteria, yeast, parasites, and viruses that inhabit the digestive tract (gastrointestinal tract). Over the past several years there is growing evidence that there is some form of ‘communication’ between this microbiota and the brain, or a ‘microbiota-gut-brain axis (MGBA)’. A group of Italian researchers led by Pasquale Striano, who is partially funded by the Foundation and the Million Dollar Bike Ride, published their findings examining gut microbiota in children with epilepsy (including confirmed or suspected genetic epilepsies). They compared these children to healthy control children but also compared antiseizure medication (ASM)-resistant children with epilepsy with ASM-sensitive children. The researchers found that children with ASM-resistant epilepsy had a unique gut microbiota composition compared to those with ASM-sensitive epilepsy and healthy individuals. This discovery suggests that the MGBA could play a role in epilepsy, that resistance to ASMs may in part be due to gut microbiota, and that targeting the gut microbiota might be a new treatment approach for ASM resistance.
*Sietske A. L. van Till, Sybren Sybesma, Hilgo Bruining, Matthijs Verhage and Eline M. Bunnik1
