10 most relevant advances and findings in TEA that 2024 left behind
We tell you about the most important advances in diagnosis, genetics and neuroimmunology that are transforming the approach to ASD.
As we move into 2025 and beyond, the future of autism research has become a bright light at the end of the tunnel, growing ever stronger and larger. Researchers continue to explore year after year how genetics, immunology, metabolism, environment, brain development, and gut health all play a role in fundamental autism, and since the origin is multifactorial, its approach must be as well.
New diagnostic tools have been developed to detect autism earlier than ever before, and the neurodiversity movement is helping to change the way we think about autism from a condition to a set of treatable diseases, thereby breaking down boundaries with respect and support for the family unit.
Whether through improved treatments, earlier diagnoses, or simply creating a more inclusive society, the goal of autism research is to improve the lives of people with ASD and help them reach their full potential.
There is still much to learn, but each discovery brings us closer to understanding and supporting autism in all its complexity.
That's why today we bring you 10 findings that were relevant in 2024 in terms of Autism, which could shape 2025:
1. Poor neuronal junction generates CPEB4 and idiopathic ASD.
Studies have shown that people with idiopathic ASD and people with schizophrenia have a decreased inclusion of a 24-nucleotide microexon in the CPEB4 gene, an RNA-binding protein that recognizes, mediates and regulates translation through the assembly of translation-regulating ribonucleoprotein complexes.
CPEBs are involved in the transport and localization of messenger RNA (mRNA) and have an important role in cell division, neuronal development, learning and memory.
The aim of this study was to study the molecular basis of nCPEB4 activation and how the absence of me4 in the NTD affects the properties of nCPEB4 translation-repression condensates. We thus demonstrated how me4 ensures proper regulation of nCPEB4, and suggested why a reduction in its inclusion degree in TEA results in a dominant-negative decrease in CPEB4 activity.
The study made a novel proposal that low me4 inclusion leads to the onset of ASD because it promotes CPEB4 aggregation, which in turn leads to low CPEB4 activity after neuronal depolarization and, as a consequence, low expression of ASD genes.
In particular, this mechanism provides a justification for the negative dominant effect, since a degree of me4 inclusion below the minimum can lead to cooperative and irreversible aggregation.
Garcia-Cabau C, Bartomeu A, Tesei G, Cheung KC, Pose-Utrilla J, Picó S, Balaceanu A, Duran-Arqué B, Fernández-Alfara M, Martín J, De Pace C, Ruiz-Pérez L, García J, Battaglia G, Lucas JJ, Hervás R, Lindorff-Larsen K, Méndez R, Salvatella X. Mis-splicing of a neuronal microexon promotes CPEB4 aggregation in ASD. Nature. 2024 Dec 4. doi: 10.1038/s41586-024-08289-w. Epub ahead of print. PMID: 39633052.
2. A new genetic mutation associated with Rett Syndrome
Research into the MECP2 (Methyl CpG Binding Protein 2) gene has revealed its crucial role in causing Rett syndrome, a neurodevelopmental disorder that primarily affects girls. MECP2 is located on the X chromosome and is essential for regulating neuronal development; mutations in this gene disrupt its normal function, leading to loss of motor and language skills, as well as behavioral and cognitive problems.
Recent research has shown that these mutations can lead to dysfunction in synapses and communication between neurons, contributing to the symptoms of the syndrome. In addition, potential therapies are being explored, including genetic interventions and drugs that can restore MECP2 function.
In contrast, copy number gains encompassing MECP2 lead to MRXSL, an X-linked genomic disorder primarily affecting males, with an estimated prevalence of one in 100,000 live male births. The clinical presentation among individuals with MRXSL is variable but is defined by core features including infantile hypotonia, severe developmental delay/intellectual disability (DD/ID), poor or absent speech, progressive spasticity, gastrointestinal problems, frequent respiratory infections, and epilepsy.
Pehlivan D, Bengtsson JD, Bajikar SS, Grochowski CM, Lun MY, Gandhi M, Jolly A, Trostle AJ, Harris HK, Suter B, Aras S, Ramocki MB, Du H, Mehaffey MG, Park K, Wilkey E, Karakas C , Eisfeldt JJ, Pettersson M, Liu L, Shinawi MS, Kimonis VE, Wiszniewski W, Mckenzie K, Roser T, Vianna-Morgante AM, Cornier AS, Abdelmoity A, Hwang JP, Jhangiani SN, Muzny DM, Mitani T, Muramatsu K, Nabatame S, Glaze DG, Fatih JM, Gibbs RA, Liu Z, Lindstrand A, Sedlazeck FJ, Lupski JR, Zoghbi HY, Carvalho CMB. Structural variant allelic heterogeneity in MECP2 duplication syndrome provides insight into clinical severity and variability of disease expression. Genome Med. 2024 Dec 18;16(1):146. doi:10.1186/s13073-024-01411-7. PMID: 39696717; PMCID: PMC11658439.
3. TEA in the face of NRXN1 variations
Research on the NRXN1 (neurexin 1) gene has gained relevance in the study of various neuropsychiatric disorders, such as autism, schizophrenia, depression and attention deficit hyperactivity disorder (ADHD). NRXN1 encodes proteins that are key components in the formation and function of neuronal synapses, playing a vital role in the connection between neurons.
Genetic studies have associated variations and deletions in the NRXN1 gene with an increased risk of developing these disorders. In particular, mutations in NRXN1 have been shown to negatively impact synaptic communication, which may lead to an increased risk of neurocognitive and behavioural dysfunctions. Evidence suggests that these alterations may contribute to the heterogeneity of symptoms observed in autism and schizophrenia.
Furthermore, recent research has indicated that individuals carrying variants in NRXN1 may present with ADHD traits and depressive symptoms, further highlighting the importance of this gene in predisposing to various conditions. These findings underscore the need to continue investigating the role of NRXN1 to better understand its function in the neurobiology of these disorders and potentially develop targeted treatments.
4. The SHANK3 gene and its relationship with neurological disorders
Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder caused by haploinsufficiency of the SHANK3 gene, located on chromosome 22, due to a deletion or sequence variant. Approximately 25% of individuals with PMS have epilepsy.
Treatment of epilepsy in PMS may require multiple anticonvulsants and, in a minority of cases, seizures remain poorly controlled. Converging lines of evidence in different experimental models indicate that the Ras-ERK pathway is involved in the pathophysiology of seizure generation and neurobehavioral symptoms in PMS.
5. The electroencephalogram in early diagnosis of ASD
Electroencephalography (EEG) is a technique used to record brain activity through electrodes placed on the scalp. Scalp EEG has shown promise in diagnosing a variety of neurological disorders, including epilepsy, Alzheimer's disease, and Parkinson's disease, among others.
Recent studies have explored the potential of EEG to identify biomarkers for autism spectrum disorder (ASD). Researchers have collected EEG data from individuals with ASD and applied machine learning (ML) and deep learning (DL) algorithms to classify them as either ASD or typically developing (TD).
The proposed system is an ear-worn device that integrates EEG acquisition and electrode-skin impedance (ESI) monitoring to ensure comfort and signal quality. This compact and discreet device allows for continuous 24/7 monitoring of brain activity, enabling the identification of potential biomarkers for early detection of ASD. Early diagnosis is crucial for timely intervention and optimal treatment outcomes, as it has been shown to significantly improve the prognosis of individuals with ASD.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and social interaction and restricted and repetitive patterns of behavior, interests, or activities. Given the lack of a specific pharmacological treatment for ASD and the clinical heterogeneity of the disorder, current biomarker research efforts are primarily focused on identifying markers to determine risk for ASD or to assist with early diagnosis.
A wide range of potential biomarkers for ASD are currently being investigated. Proteomic analyses indicate that plasma/serum levels of many proteins are altered in ASD, suggesting that a panel of proteins may provide a blood biomarker for ASD. In this study, serum samples from 76 children with ASD and 78 typically developing (TD) children, aged 2–10 years, were analyzed to identify potential early biomarkers of ASD. A total of 1,125 proteins were analyzed. There were 86 downregulated proteins and 52 upregulated proteins in ASD (FDR < 0.05).
By combining three different algorithms, we found a panel of 12 proteins that identified ASD, these 12 proteins were significantly different in ASD compared to TD children, and 4 were significantly correlated with ASD severity as measured by ADOS total scores. A panel of serum proteins was identified that may be useful as a blood biomarker for ASD in children.
7. EHMT1 and KMT2C genes are related to ASD and KLEFS.
Kleefstra syndrome spectrum disorder (KLEFS) is an autosomal dominant disorder that can cause intellectual disability and autism spectrum disorders. KLEFS encompasses Kleefstra syndrome-1 (KLEFS1) and Kleefstra syndrome-2 (KLEFS2), with KLEFS1 accounting for over 75%.
However, little information is available about KLEFS2. KLEFS1 is caused by a subtelomeric chromosomal abnormality resulting in a deletion at the end of the long arm of chromosome 9, which contains the EHMT1 gene, or by variants in the EHMT1 gene and the KMT2C gene that cause KLEFS2. Variants in MBD5, SMARCB1, NR1I3, and other genes, known as the KLEFS gene, can also lead to KLEFS.
Most children with KLEFS2 display a variety of conditions, including ID, ASD, hypotonia, and distinctive features. However, the clinical presentation and diagnostic criteria for KLEFS2 are currently lacking, and its long-term prognosis is poorly understood, with 11 of 17 patients with KLEFS2 presenting with D.
Congenital heart defects, including tetralogy of Fallot, incomplete development of aortic arch hypoplasia, aortic stenosis, mitral valve stenosis, pulmonary artery stenosis, pulmonary hypertension, and atrial or ventricular septal defects, have been reported in patients with KLEFS1. In addition, cases of ventricular systolic dysfunction and dilated cardiomyopathy have been documented.
8. CACNAC1C gene, Classic Timothy syndrome and ASD
The spectrum of syndromic and non-syndromic phenotypes of CACNA1C-related disorders can be correlated depending on the pathogenic variant affecting calcium current.
It can significantly affect the cardiovascular sphere, generating non-syndromic long QT syndrome, non-syndromic short QT syndrome, which carry a risk of sudden death; also Brugada Syndrome (which has ST segment elevation in right precordial leads) with a short QT interval; another syndrome that can be observed is classic Timothy Syndrome (prolonged QT interval, autism and congenital heart disease) with or without unilateral or bilateral cutaneous syndactyly.
Regarding the phenotypes of CACNA1C-related neurodevelopmental disorder, in which features tend to favor one or more of the following: developmental delay/intellectual disability, hypotonia, epilepsy, and/or ataxia.
Napolitano C, Priori SG. CACNA1C-Related Disorders. 2006 Feb 15 [updated 2024 Dec 19]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024. PMID: 20301577.
9. The intestinal microbiome and neuroimmunological pathways
The intestinal microbiome is defined as the set of symbiotic bacteria that colonize the human digestive tract, which experiences dynamic changes throughout life, which can be affected by diet, age and even indiscriminate use.
The research carried out seeks to clarify the bilateral neuroimmunological pathways that determine the role of intestinal microbiome dysbiosis, not only as a cause but also as a byproduct of many neurodegenerative diseases of the CNS, such as:
Alzheimer's disease (AD)
Parkinson's disease (PD)
But also in the context of various behavioral and psychiatric pathological conditions such as:
Depressive disorders
Anxiety disorders
Schizophrenia
Autism spectrum disorder (ASD)
One of the key components for regulation is the vagus nerve, an element of the parasympathetic nervous system, which regulates immune responses. It can detect the metabolites of the intestinal microbiome and transfer this intestinal information to the CNS, through its afferents, as in a process of pseudoneurotransmission.
Scientific interest towards microbiome-based therapies is increasing as psychobiotics (which are strains of probiotics/prebiotics with specific properties to influence the gut-brain axis) appear to be able to exert a beneficial effect in many CNS disorders. Lifestyle modifications, such as dietary interventions through the intake of psychobiotics that could improve the capacity of the intestinal microbiome to produce beneficial metabolites that exert therapeutic effects on intestinal permeability, cognitive function and immunity.
10. Variants of the CHD8 gene as a risk factor for ASD
The CHD8 gene encodes chromodomain helicase DNA-binding protein 8 (CHD8), this is a transcription regulator expressed in almost all cell types and is involved in many cellular processes including the cell cycle, cell adhesion, neuron development, myelination and synaptogenesis. Some mutations of the gene CHD8 lead to neurodevelopmental syndromes with core symptoms of autism.
It is also a high risk factor for ASD and a genetic cause of a distinct neurodevelopmental syndrome with core symptoms of autism, macrocephaly and facial dysmorphism, acts as a chromatin regulator that binds to the promoters of actively transcribed genes through genome-targeting mechanisms. Therefore, any dysfunction of the protein CHD8 may affect the expression of genes involved in neurodevelopmental pathways and the pathogenesis of ASD. However, the specific pathophysiological mechanism linking these processes is not yet fully understood, and research is ongoing to better understand this genetic variant.
Bonus: Vitamin C as a cellular reprogrammer in fragile X syndrome
Fragile X syndrome (FX) is the most common form of genetically inherited cognitive impairment and mental retardation, with a prevalence of 1 in 3,600 in the population (varying by geographic region), and is one of the major forms of Autism Spectrum Disorders (ASD). Patients with FX display a set of symptoms and phenotypes, including severe intellectual disability, attention deficits, problems with speech and social interaction, aggression, hyperactivity, and high susceptibility to seizures. FX has a massive impact on the lives of both patients and their families.
Since FX is caused by epigenetic silencing of FMR1 and not by a mutation in the coding region, one therapeutic strategy might be to reverse hypermethylation of the gene locus and thereby reactivate the silenced gene. Murine models of FX have partial or complete deletions of the Fmr1 gene to prevent expression of functional FMRP, but human embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) carrying >200 CGG repeat expansions are powerful models to study FX.
In previous studies, ascorbic acid (AsA) has been shown to affect chromatin conformation/reprogramming or DNA methylation, in this study, we treated FX iPSCs and brain organoids with AsA and evaluated its effects on FMR1 methylation status, mRNA expression, and organoid morphology. We found that AsA reduces FMR1 methylation and increases FMR1 expression in FX iPSCs, which has a similar effect in FX brain organoids. Furthermore, AsA treatment upregulated genes previously identified as downregulated in FX and partially rescued the morphological development of FX brain organoids.
In our blog we also have more interesting articles from different areas such as neurology, genetics, immunology and the gut-brain axis related to neurodevelopmental pathologies that could be of interest to you or your loved ones. Here is the direct link to the blog:
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