The different clinical facets of SYN1-related neurodevelopmental disorders

Abstract

Synapsin-I (SYN1) is a presynaptic phosphoprotein crucial for synaptogenesis and synaptic plasticity. Pathogenic SYN1 variants are associated with variable X-linked neurodevelopmental disorders mainly affecting males. In this study, we expand on the clinical and molecular spectrum of the SYN1-related neurodevelopmental disorders by describing 31 novel individuals harboring 22 different SYN1 variants. We analyzed newly identified as well as previously reported individuals in order to define the frequency of key features associated with these disorders. Specifically, behavioral disturbances such as autism spectrum disorder or attention deficit hyperactivity disorder are observed in 91% of the individuals, epilepsy in 82%, intellectual disability in 77%, and developmental delay in 70%. Seizure types mainly include tonic-clonic or focal seizures with impaired awareness. The presence of reflex seizures is one of the most representative clinical manifestations related to SYN1. In more than half of the cases, seizures are triggered by contact with water, but other triggers are also frequently reported, including rubbing with a towel, fever, toothbrushing, fingernail clipping, falling asleep, and watching others showering or bathing. We additionally describe hyperpnea, emotion, lighting, using a stroboscope, digestive troubles, and defecation as possible triggers in individuals with SYN1 variants. The molecular spectrum of SYN1 variants is broad and encompasses truncating variants (frameshift, nonsense, splicing and start-loss variants) as well as non-truncating variants (missense substitutions and in-frame duplications). Genotype-phenotype correlation revealed that epileptic phenotypes are enriched in individuals with truncating variants. Furthermore, we could show for the first time that individuals with early seizures onset tend to present with severe-to-profound intellectual disability, hence highlighting the existence of an association between early seizure onset and more severe impairment of cognitive functions. Altogether, we present a detailed clinical description of the largest series of individuals with SYN1 variants reported so far and provide the first genotype-phenotype correlations for this gene. A timely molecular diagnosis and genetic counseling are cardinal for appropriate patient management and treatment.

Inhibiting the expression of PGK1 can improve the damage of nerve cells caused by acrylamide

“…It is primarily expressed in the central and peripheral nervous systems and is associated with early neuronal development, synaptic growth and development, and regulation of neurotransmitter release. Changes in Syn1 lead to alterations in synaptic homeostasis, which have been shown to cause neuronal developmental disorders, and the regulation of Syn1 expression has been shown to promote neuronal dendrite growth (Yan, et al 2022;Hedegaard, et al 2013;Parenti, et al 2022). The results of this study showed that as the exposure concentration increased, the protein expression levels of BDNF and Syn1 in the hippocampal tissue of SD rats were significantly reduced.…”

Identification of molecular signatures defines the differential proteostasis response in induced spinal and cranial motor neurons

“… 49 Synapsins (Syn1, Syn2) are a family of presynaptic phosphoproteins with roles in neuronal development through the regulation of the number of synaptic vesicles available for neurotransmitter release. 50 The Arp2/3 complex regulates the actin-myosin network and is subsequently involved in dendrite development and function. 51 , 52 …”

SYN1 is associated with immune infiltrates and might be a prognostic biomarker for glioma

“…Due to their involvement in synaptogenesis and neurotransmitter release control, synapsins may play a crucial role in various neuropsychiatric disorders. (5) Previous studies have reported low expression of SYN1 in several medulloblastoma cell lines. (6)…”