CTNNB1 syndrome is a rare neurodevelopmental disorder that affects many parts of the body and is caused by autosomal dominant de novo variations in the CTNNB1 gene.
Introduction
CTNNB1 syndrome is an extremely rare disorder that affects just over 430 known individuals worldwide. It is a neurodevelopmental disorder caused by variations in the CTNNB1 gene, which encodes the β-catenin protein. Patients affected typically have a wide range of symptoms, some of which include disruptions to the development of the brain, eyes, muscles, hair, stature, and more. At this time, there is no cure for CTNNB1 syndrome. However, several different drug modalities to target the CTNNB1 gene are being explored, which could prevent the progression of symptoms in CTNNB1 syndrome patients. In this piece, we explore the history, genetic basis, clinical symptoms, patient resources, and future of the therapeutic landscape relating to CTNNB1 syndrome.
Tell Me About This Rare Disease
Genetic basis: CTNNB1 syndrome is caused by deletions, partial deletions, or other genetic variations that cause a loss-of-function in the CTNNB1 gene product, located on chromosome 3 (locus 3p22.1) [1]. This typically happens due to de novo pathogenic variations, but in rare cases may be inherited in an autosomal dominant pattern [2]. The CTNNB1 gene is known to have a high expression during embryonic development and early childhood, suggesting that it has an important function in brain development [3]. The CTNNB1 gene has also been identified as a proto-oncogene in certain cancers when mutated, but within the central nervous system, mutations in this gene can result in different neurodevelopmental disorders including CTNNB1 syndrome [3].
The CTNNB1 gene encodes a protein called β-catenin, a multifunctional protein that plays a crucial role in cell-cell adhesion and is a key component of the Wnt signaling pathway (Figure 1) [1] [4]. β-Catenin is expressed in a wide range of cell and tissue types, leading its alteration to negatively affect the development of many different systems within the body [1]. As the downstream effector of the highly conserved Wnt signaling pathway, β-catenin translocates to the nucleus to initiate transcription of genes regulating cell proliferation, survival, differentiation, and migration [5]. β-Catenin is also an integral component in maintaining and forming adherens junctions, which provide cell-cell contact and tissue stability [5]. It is speculated that β-catenin also plays a major role in learning and memory [6]. Due to the multifunctional nature of β-catenin, loss-of-function variants of this protein cause the varied symptoms we see in patients with CTNNB1 syndrome.
Clinical Presentation: CTNNB1 syndrome does not have a published set of clinical diagnostic criteria, however, common symptoms patients may experience have been identified. A mutation in the CTNNB1 gene can affect the development of many different parts of the body, including the brain, eyes, muscles, hair, stature, among others. Symptoms often include mild to severe intellectual or developmental delay, vision impairment, ophthalmologic issues, sleep issues, myopia, hypermetropia, coordination/balance problems (ataxia), truncal hypotonia, dystonia, speech/communication delays, behavioral issues, and microcephaly [1] [2]. Behavioral and social difficulties may include autism spectrum disorder (ASD), inattention, hyperactivity or passiveness, aggression, self-mutilation, tantrums, uncontrolled laughter, anxiety, disruptions to sleep, restlessness, sensory issues, and depression [1] [2].
Less common symptoms can also include intrauterine growth restriction, short stature, oral-motor feeding problems, impaired perception of pain (nociception), scoliosis, and particular facial features [1] [2] [8]. Seizures have also been documented in some CTNNB1 patients, and patient families believe these may be more common [9]. Some individuals affected also experience a regression in neurodevelopmental, motor, and speech symptoms, however, this is not widespread across the entire CTNNB1 syndrome population [2]. CTNNB1 syndrome has not been found to affect or shorten life expectancy and some adults are able to care for themselves and raise a family with the support of others [2].
Incidence: The incidence of CTNNB1 syndrome is still unknown, however, there are approximately 430 known diagnoses worldwide. As of October 2021, the incidence was estimated at 2.6 – 3.2 per 100,000 live-born infants [1] [10].
Brief history:
2012: CTNNB1 de novo mutations were found to be linked to autism spectrum disorder (ASD) patients [3] [11].
2012: CTNNB1 mutations were found in intellectual disability (ID) patients by the Institute for Genetic and Metabolic Disease at the Radboud University Medical Center in Nijmegen [3] [12].
2016: Community Facebook group formed [13].
2017: CTNNB1 Syndrome Awareness Worldwide (CSAW) was established as the first patient advocacy group for CTNNB1 syndrome [14].
2019: Advancing CTNNB1 Cures and Treatments (ACCT) was formed as a nonprofit to fund research for CTNNB1 syndrome [15].
2020: First CTNNB1 International Research Conference is held online hosted by ACCT in collaboration with CSAW [16].
2021: CTNNB1 Foundation, The Gene Therapy Research Institute, is founded in February.
2022: ACCT merged with CSAW to create CTNNB1 Connect and Cure [15].
2024: The CTNNB1 Foundation will begin its first natural history study called the Dragonfly Study [17].
The State of the Disease Today: Today, people with CTNNB1 syndrome manage their unique neurological and physiological symptoms through supportive care. Currently, several different therapeutic strategies are being examined including gene replacement therapy, small molecule-based therapeutics, and RNA-based therapies. However, at this time, there is no therapeutic available that can cure or reverse the symptoms of this disorder.
What is it like to be a patient with this disease?
Who are the patients? CTNNB1 syndrome has not been shown to shorten life expectancy so patients can be any age. Patients with CTNNB1 syndrome are often diagnosed in early childhood due to the impact of symptoms. Since 2012, when the disorder was identified, there have been reports of patients ranging in age from several months to about 50 years old [2].
What do current treatment options look like? There is no targeted treatment or cure for CTNNB1 syndrome, however supportive care is available. This supportive care varies depending on the severity and symptoms of the disorder but may include a team of neurologists, speech-language pathologists, physiatrists, occupational therapists, physical therapists, a feeding team, ophthalmologists, audiologists, equine therapists, and developmental pediatricians [2] [18]. Mobility aids such as canes, walkers, or wheelchairs may also be used to assist in walking and movement.
Are there advocacy groups? Yes! CTNNB1 Connect and Cure and CTNNB1 Foundation are major advocacy groups that help connect families, create awareness, and provide resources to families affected by CTNNB1 syndrome [15] [19]. The Once Upon A Gene Podcast hosted by Effie Parks is also a great resource for CTNNB1 families as she shares her experiences parenting a child with CTNNB1 syndrome and talks with other parents raising children with rare genetic disorders and disabilities [9]. In addition, there is a Facebook group that parents of children with CTNNB1 syndrome can join to be connected to other patient parents [13]. Around the globe, there are also organizations in France (CTNNB1 France) [20], Spain (Asociación CTNNB1 España) [21], and Italy (CTNNB1 Italia) [22].
Are there genetic tests? Yes! CTNNB1 syndrome can be diagnosed by whole exome sequencing (WES) [10], chromosomal microarray analysis (CMA), or multigene panels [2]. Individuals can check their eligibility for free genetic testing through Probably Genetic, a genetic testing organization that is partnered with CTNNB1 Connect and Cure and helps provide free genetic testing to individuals or families with rare genetic diseases [10].
How do scientists and clinicians study this disease?
Are there good/any model systems scientists can use to develop drugs? Scientists have developed various mouse models to study CTNNB1 syndrome and the importance of β-catenin in neurodevelopment [3]. There are mouse models with Ctnnb1 deficiency, mutations in Ctnnb1, and over-expression models. For example, a mouse model with a missense mutation in β-catenin displays characteristics of intellectual disability, including deficits in spatial learning and memory and disruption in motor function (Figure 3) [3].
Have natural history studies been done? The CTNNB1 Foundation will launch its first natural history study this June; the Dragonfly Study will enroll at least 30 patients [17]. In addition, CTNNB1 Connect and Cure are partnered with Ciitizen and Simons Searchlight to enroll patients in natural history studies to improve care and better treatments for CTNNB1 syndrome [24]. CTNNB1 Connect and Cure funded a natural history study that outlined clinical features of patients with CTNNB1 syndrome [25] [26]. Additionally, the ongoing University of Washington’s Autism Center’s TIGER Study gathers information on individuals with known genetic mutations that are associated with autism spectrum disorder, intellectual disability, and/or developmental delay [27].
Certain physicians or centers that are experts? Many researchers are involved in studying this genetic disorder to move closer to finding a targeted treatment, only some are highlighted here due to space constraints. Dr. Jennifer Bain is a physician-scientist from Columbia University who studies developmental disorders such as CTNNB1 and serves on the board of CTNNB1 Connect and Cure’s scientific advisory board [28]. Dr. Wendy Chung from Boston Children’s Hospital recently published a study that further characterized features of individuals with CTNNB1 syndrome [26]. Dr. Leszek Lisowski and Dr. Andrea Perez from the Children’s Medical Research Institute in Australia and Dr. Roman Jerala from the National Institute of Chemistry in Slovenia are leading teams working on gene therapy approaches for treating CTNNB1 syndrome. Dr. Damjan Osredkar and Dr. Nina Žakelj, are leading the Natural History Study efforts in the Children's Hospital at the University Medical Centre Ljubljana [29] [30].
What are the major challenges in studying and curing this disease? De novo mutations in CTNNB1 linked to intellectual disability are a relatively new discovery and CTNNB1 syndrome is very rare. Scientists and clinicians are still researching connections between the genetic mutations and clinical presentation of patients with diagnosed cases of CTNNB1 syndrome. So far, there has been a vast amount of genotypic and phenotypic variability from patient to patient [23].
The Cure Corner: What is needed for a cure?
What are current therapies and treatments lacking? Due to the rarity and novelty of CTNNB1 syndrome, there are currently no targeted treatments or standardized treatments available for patients [31]. However, there are many potential drug strategies in the early stages of development, which we will discuss below.
Are there companies already developing drugs? Currently, companies and institutions are investigating multiple modes of possible therapeutics for CTNNB1 syndrome. One approach that is currently being evaluated for safety and efficacy is a gene replacement therapy approach which intrathecally delivers a healthy copy of the human CTNNB1 gene through an adeno-associated virus (AAV) vector (Figure 4) [32]. Michele Jacob and Jonathan Alexander from Tufts University and Florence Wagner from MIT have filed a patent for a small molecule as a possible therapeutic to upregulate levels of wild-type β-catenin protein by inhibiting proteins involved in degrading it such as glycogen synthase kinase 3β (GSK3β) [23] [33] [34]. RNA-based therapies are discussed below.
Could an RNA therapeutic fit the need? As a central molecule in the Wnt/β-catenin pathway, β-catenin is degraded when the signaling pathway is turned off (Figure 5). CTNNB1 syndrome results from not enough β-catenin protein. At present, RNA therapeutics for CTNNB1 syndrome act by inhibiting the degradation of β-catenin to allow its accumulation to normal levels in the cell [35]. Current strategies include skipping exon 3 to promote stabilization of β-catenin [36]. Other RNA therapeutic strategies include editing phosphorylation sites that help regulate the degradation of the β-catenin mRNA or downregulating proteins involved in degrading β-catenin [37].
Conclusion
CTNNB1 syndrome is a relatively newly discovered disorder and there is much more to be learned about it. With a growing population of people with CTNNB1 diagnoses, the need for a therapeutic is only increasing. At this time, it is not clear which modality will correct the genetic mutations causing CTNNB1 syndrome most effectively, however, scientists, clinicians, and patient families continue to push the research forward in hopes of discovering a cure that will work for all CTNNB1 patients.
A special thanks to Melissa Keenan and Effie Parks for their insight and review of this article prior to publication.
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