Jul 2026· Current Neurology and Neuroscience Reports· Vol 26· 0 citations· 95 references
Medicine
TL;DR
The findings on somatic instability in HD suggest that neurodegeneration in HD is an asynchronous DNA process for >95% of a neuron's life, with majority of neurons in all disease stages having a HTT gene which is not biologically harmful.
Abstract
Chorea is a symptom of numerous pathophysiologically and clinically heterogeneous genetic conditions. A number of developments have been made in this field over the last years linked to improved genomic testing, large cohort collaborations and improved understanding of the molecular mechanisms. This review aims to provide an update on the new genetic conditions and phenotypes linked to chorea disorders, their modification factors and pathophysiological background. Several novel genetic conditions have been linked to chorea over the last 3 years, including mutations in FTH1, NAA60, ACBD6 or TOR1AIP2. Also, novel phenotypes have been established and linked to chorea, such as Adult-onset Neurodegeneration in Nucleotide Excision Repair Disorder (NERD-ND). Major advances have been made in understanding of the pathophysiological role of somatic instability in HD. Striatal pallidal neurons (SPNs) with 150–500 + CAG repeats seem to lose positive and then negative features of neuronal identity, de-repress senescence/apoptosis genes, ultimately leading to cell death. Improved recognition of the genetic background of chorea leads to more effective diagnostic processes, better prognostication and improved personalized treatment. The findings on somatic instability in HD suggest that neurodegeneration in HD is an asynchronous DNA process for >95% of a neuron's life, with majority of neurons in all disease stages having a HTT gene which is not biologically harmful. This has potential major therapeutic implications not only in HD but also in other neurological repeat expansion disorders.
Four major themes are identified, encompassing genetic modifiers, epigenetic modifications, mosaicism, and environmental factors that may act independently or interactively to influence pathogenic burden and functional network balance, ultimately determining whether a pathogenic mutation manifests clinically.
Jiao-Jiao Xu, Dian-Fu Chen, Zhi-Ying Wu· Journal of genetics and geno...· 0 citations
The study provides an integrated framework linking genetic variation to molecular dysfunction and clinical outcomes, offering valuable insights for future research and therapeutic development in pediatric neurology.
Varada Vidya Rani, Suryanarayana Reddy Kovvuri, D. Arya· Genetics and Molecular Resea...· 0 citations
Subtle changes to the genetic code can result in profoundly debilitating and diverse pathologies. The hereditary nature of human traits has been described since classical times.
In the history of modern medicine, the first known genetic disorder, alkaptonuria, was described at the turn of the twentieth century, giving rise to the recognition of inborn errors of metabolism[1]. Diseases with their basis in mutations and alterations of the human genetic code represent a massive burden, and recognized genetic disorders affect more than 5% of live births and more than two-thirds of miscarriages[2].Beyond highly penetrant monogenic disorders and large-scale chromosomal alterations, the heritability of many common diseases has long suggested a genetic basis for more prevalent disorders such as cardiovascular disease [3].The prospect of passing genetic afflictions on to the next generation adds to the fear of these disorders. The first heritable alteration in a protein linked to disease was identified in sickle cell anemia in the late 1940s, with the discovery of altered shifts during electrophoresis, a change that corresponded with disease status among tested patients [5].
Subsequently, once the DNA code for amino acids was deciphered, scientists recognized the potential for alterations in DNA to cause alterations in enzymes and thus disease. Prior to the advent of DNA sequencing, the cause of Down syndrome, identified in 1959 as the chromosomal abnormality trisomy 21, was the first human genetic alteration found to be associated with disease . Beginning in the 1960s, hereditary metabolic disorders such as phenylketonuria could be screened for biochemically without the need to know the causative gene’s location or sequence[5]. The advent of Sanger sequencing and recombinant molecular biology in the 1970s and 1980s made the determination of DNA sequences widely accessible for the first time. The following decades, prior to the completion of the Human Genome Project in 2003, saw gene mapping consortia undergo herculean efforts to discover the causative genes in some of the most debilitating diseases, including the first mapped human genetic disorder, Huntington’s disease, in 1983 . With the diminishing costs of exome and whole-genome sequencing over the past 2 decades, genetic diagnosis has become increasingly feasible, even for conditions that were not previously recognized as genetic diseases[6].
Almustafa Qays Abdulkareem, Ahmed Adnan Abed, Dhaffar Alwan Majbil et al.· Adolescência e Saúde· 0 citations
CASK-related disorders may present with severe neurodevelopmental impairment and cerebral palsy–like phenotypes, even in the absence of characteristic neuroimaging findings, which should raise suspicion for CASK-related disorders.
I. Pacheva, Elena Timova, T. Todorov et al.· Frontiers in Psychiatry· 0 citations
Hypospadias is one of the most common birth defects in China and a key feature of differences in sex development (DSD), yet its genetic etiology remains largely unresolved. Current diagnostic approaches using DSD-targeted gene panels have a low rate of definitive diagnoses (5.5%), highlighting the need for more comprehensive genetic investigation. In this study, we performed next-generation sequencing (NGS) on the largest trio-based cohort of hypospadias to date, comprising 106 pediatric cases and their parents (92 trios). We achieved a definitive genetic diagnosis in 6.6% of patients, identifying pathogenic variants in canonical DSD genes such as AR, NR5A1 and WT1. By incorporating a broader spectrum of potentially clinically significant variants, we increased the overall genetic identification rate to 33.0% (35/106). Strikingly, trio analysis uncovered a significant burden of de novo loss-of-function (LoF) variants (2.2-fold enrichment, P=0.001), primarily driven by variants in genes associated with ciliopathies (10.35-fold, P=0.016), a previously underappreciated gene class in hypospadias. Furthermore, we identified and functionally validated two high-confidence risk genes, PRKCZ and HRNR, based on recurrent de novo variants. Functional assays confirmed that these variants disrupt key biological mechanisms, including cell proliferation, migration, and androgen signaling. Our large-scale trio approach substantially expands the genetic landscape of hypospadias, demonstrates the critical value of trio-based sequencing for improving diagnostic yield, and decisively implicates ciliary genes in its pathogenesis.
Yanqin You, Yingliu Luo, Honghui Zhou et al.· Science China Life Sciences· 0 citations
Spinal Muscular Atrophy (SMA) is a serious autosomal recessive neuromuscular disorder. In the past few years, the rapid progresses of molecular genetics and precision medicine have greatly pushed the understanding of disease cause and the making of treatment methods for SMA. This review systematically sums up the newest advances in molecular mechanisms and accurate therapies of SMA during the time from 2024 to 2026. It highlights the regulatory roles of SMN1/SMN2 genes, non-coding RNAs, and epigenetic modifications, as well as pathophysiological alterations and disease-modifying factors induced by SMN protein deficiency. Furthermore, the clinic significances of SMN gene examination, biology markers, imaging examination, and newborn screening are all narrated in this paper. The effect and security of many accurate treatment methods, including antisense oligonucleotides, AAV-mediated gene substitution, small-molecule splicing modulators, and gene editing, are also assessed. At present, the problems that exist include the off-target effects brought by gene editing, relatively expensive treatment expenses, restricted acquisition channels, and not enough long-term follow-up observation data. Future directions include optimization of technical strategies, combination therapy, and translational application of biomarkers.
C. Yan· Theoretical and Natural Scie...· 0 citations