Application of extracorporeal membrane oxygenation in respiratory and circulatory support of preterm infants: a multicenter retrospective study in China.

Repeat expansion disorders are a heterogeneous group of diseases caused by a shared genetic alteration: the repetition beyond a pathogenic threshold (repeat expansion) of short tandem repeats (STRs, also known as microsatellites) within specific genes []. STRs are polymorphic repeats of short nucleotide sequences (up to six base pairs in tandem) widely distributed across both coding and non-coding regions of the human genome, accounting for approximately 3% of its content. In physiological conditions, STRs can act as regulatory elements, modulating DNA methylation, transcription, and alternative splicing []. However, due to their intrinsic instability STRs are prone to aberrant repetition that, once expanded beyond their physiological length, induce structural alterations in DNA and trigger a range of molecular mechanisms of RNA or protein gain/loss-of-function, ultimately creating a toxic cellular environment that drives disease onset. Despite sharing distinctive molecular features, including genetic instability, strong correlation between repeat length and disease severity, and anticipation (earlier onset in successive generations), repeat expansion disorders exhibit diverse pathogenic mechanisms depending on the genomic location of the repeat and its specific pathological threshold, resulting in highly heterogeneous clinical manifestation []. Expansions within coding regions typically lead to the production of toxic proteins, such as polyglutamine (polyQ) tracts, whereas non-coding expansions are associated to transcriptional silencing, RNA toxicity, formation of nuclear RNA foci, and repeat-associated non-AUG (RAN) translation []. Collectively, these disorders predominantly affect the nervous system and are characterized by progressive neurodegeneration, high clinical variability, and a significant disease burden, with an estimated prevalence of approximately 1 in 3000 individuals worldwide []. Among repeat expansion disorders, spinocerebellar ataxias (SCAs) represent a clinically and genetically heterogeneous group of autosomal dominant neurodegenerative diseases characterized by progressive cerebellar ataxia, impaired coordination, dysarthria, and oculomotor abnormalities. Beyond cerebellar dysfunction, many SCA subtypes present with additional neurological features, including pyramidal signs, peripheral neuropathy, parkinsonism, cognitive impairment, and retinal degeneration, reflecting widespread neurodegeneration beyond the cerebellum. To date, more than 40 SCA subtypes have been identified, with considerable variability in age of onset, disease progression, and clinical severity. Epidemiologically, SCAs are rare disorders, with a combined prevalence estimated at approximately 1–5 per 100,000 individuals worldwide, although this varies significantly depending on geographic region and population-specific founder effects []. From a molecular perspective, SCAs can be clustered depending on the nature and location of the causative mutation. The majority of SCAs are caused by repeat expansion mutations located either in coding or non-coding regions (), while a minority (SCA5, SCA13, and SCA14) arise from conventional point mutations. In SCA1, SCA2, SCA3/MJD, SCA6, SCA7, and SCA17, repeat expansions of the CAG trinucleotide occur in a coding region of the gene of interest and, therefore, encode elongated polyQ tracts that promote protein misfolding, oligomerization, and aggregation. Together with Huntington’s disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA) and spinal and bulbar muscular atrophy (SBMA), which share the same pathogenic mechanism, they are collectively known as polyQ diseases []. At the cellular level, polyQ stretches form intranuclear or cytoplasmic inclusions that sequester transcription factors, chaperones, and components of the protein quality control machinery, including elements of the ubiquitin-proteasome system and autophagy pathways. This leads to widespread disruption of proteostasis, transcriptional dysregulation, mitochondrial dysfunction, and ultimately neuronal death. In contrast, non-coding SCAs arise from repeat expansions located in untranslated regions of the associated genes. Although the underlying pathogenic mechanisms have not yet been fully elucidated, current evidence suggests that these disorders are primarily driven by RNA gain-of-function toxicity, as observed in SCA8, SCA10, SCA31, SCA36, and SCA37. Indeed, expanded repeat transcripts can form stable secondary structures and accumulate as nuclear RNA foci that sequester RNA-binding proteins and other factors, thereby disrupting RNA metabolism. Additionally, repeat transcripts may undergo RAN translation, which generates toxic peptides in multiple reading frames, further contributing to neuronal toxicity []. Nevertheless, protein loss-of-function mechanisms resulting from repeat-induced transcriptional silencing may also contribute to the pathogenesis of non-coding ataxias. This is notably the case for