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Annals of Clinical and Translational... Jun 2024While biallelic POLR3A loss-of-function variants are traditionally linked to hypomyelinating leukodystrophy, patients with a specific splice variant c.1909+22G>A...
While biallelic POLR3A loss-of-function variants are traditionally linked to hypomyelinating leukodystrophy, patients with a specific splice variant c.1909+22G>A manifest as adolescent-onset spastic ataxia without overt leukodystrophy. In this study, we reported eight new cases, POLR3A-related disorder with c.1909+22 variant. One of these patients showed expanded phenotypic spectrum of generalised dystonia and her sister remained asymptomatic except for hypodontia. Two patients with dystonic arm tremor responded to deep brain stimulation. In our systemic literature review, we found that POLR3A-related disorder with c.1909+22 variant has attenuated disease severity but frequency of dystonia and upper limb tremor did not differ among genotypes.
Topics: Humans; Female; Deep Brain Stimulation; RNA Polymerase III; Dystonia; Adolescent; Male; Muscle Spasticity; Adult; Spinocerebellar Ataxias; Young Adult; Child; Intellectual Disability; Optic Atrophy
PubMed: 38700104
DOI: 10.1002/acn3.52064 -
Zhongguo Yi Xue Ke Xue Yuan Xue Bao.... Apr 2024DNA is susceptible to various factors and and experience different forms of damage,among which double-strand break(DSB)is a deleterious form.To maintain the stability... (Review)
Review
DNA is susceptible to various factors and and experience different forms of damage,among which double-strand break(DSB)is a deleterious form.To maintain the stability of genetic information,organisms have developed multiple mechanisms to repair DNA damage.Among these mechanisms,homologous recombination(HR)is praised for the high accuracy.The MRE11-RAD50-NBS1(MRN)complex plays an important role in HR and is conserved across different species.The knowledge on the MRN complex mainly came from the previous studies in and ,while studies in the last decades have revealed the role of mammalian MRN complex in DNA repair of higher animals.In this review,we first introduces the MRN complex regarding the composition,structure,and roles in HR.In addition,we discuss the human diseases such as ataxia-telangiectasia-like disorder,Nijmegen breakage syndrome,and Nijmegen breakage syndrome-like disorder that are caused by dysfunctions in the MRN complex.Furthermore,we summarize the mouse models established to study the clinical phenotypes of the above diseases.
Topics: Humans; Acid Anhydride Hydrolases; MRE11 Homologue Protein; Cell Cycle Proteins; DNA-Binding Proteins; DNA Repair Enzymes; Nuclear Proteins; Animals; DNA Repair; Ataxia Telangiectasia; Nijmegen Breakage Syndrome
PubMed: 38686720
DOI: 10.3881/j.issn.1000-503X.15556 -
Developing a pathway to clinical trials for -related epilepsies: A patient organization perspective.Therapeutic Advances in Rare Disease 2024CACNA1A-related disorders are rare neurodevelopmental disorders linked to variants in the CACNA1A gene. This gene encodes the α1 subunit of the P/Q-type calcium channel... (Review)
Review
CACNA1A-related disorders are rare neurodevelopmental disorders linked to variants in the CACNA1A gene. This gene encodes the α1 subunit of the P/Q-type calcium channel Cav2.1, which is globally expressed in the brain and crucial for fast synaptic neurotransmission. The broad spectrum of CACNA1A-related neurological disorders includes developmental and epileptic encephalopathies, familial hemiplegic migraine type 1, episodic ataxia type 2, spinocerebellar ataxia type 6, together with unclassified presentations with developmental delay, ataxia, intellectual disability, autism spectrum disorder, and language impairment. The severity of each disorder is also highly variable. The spectrum of CACNA1A-related seizures is broad across both loss-of-function and gain-of-function variants and includes absence seizures, focal seizures with altered consciousness, generalized tonic-clonic seizures, tonic seizures, status epilepticus, and infantile spasms. Furthermore, over half of CACNA1A-related epilepsies are refractory to current therapies. To date, almost 1700 CACNA1A variants have been reported in ClinVar, with over 400 listed as Pathogenic or Likely Pathogenic, but with limited-to-no clinical or functional data. Robust genotype-phenotype studies and impacts of variants on protein structure and function have also yet to be established. As a result, there are few definitive treatment options for CACNA1A-related epilepsies. The CACNA1A Foundation has set out to change the landscape of available and effective treatments and improve the quality of life for those living with CACNA1A-related disorders, including epilepsy. Established in March 2020, the Foundation has built a robust preclinical toolbox that includes patient-derived induced pluripotent stem cells and novel disease models, launched clinical trial readiness initiatives, and organized a global CACNA1A Research Network. This Research Network is currently composed of over 60 scientists and clinicians committed to collaborating to accelerate the path to CACNA1A-specific treatments and one day, a cure.
PubMed: 38681799
DOI: 10.1177/26330040241245725 -
International Journal of Molecular... Apr 2024Polyglutamine (polyQ)-encoding CAG repeat expansions represent a common disease-causing mutation responsible for several dominant spinocerebellar ataxias (SCAs)....
Polyglutamine (polyQ)-encoding CAG repeat expansions represent a common disease-causing mutation responsible for several dominant spinocerebellar ataxias (SCAs). PolyQ-expanded SCA proteins are toxic for cerebellar neurons, with Purkinje cells (PCs) being the most vulnerable. RNA interference (RNAi) reagents targeting transcripts with expanded CAG reduce the level of various mutant SCA proteins in an allele-selective manner in vitro and represent promising universal tools for treating multiple CAG/polyQ SCAs. However, it remains unclear whether the therapeutic targeting of CAG expansion can be achieved in vivo and if it can ameliorate cerebellar functions. Here, using a mouse model of SCA7 expressing a mutant Atxn7 allele with 140 CAGs, we examined the efficacy of short hairpin RNAs (shRNAs) targeting CAG repeats expressed from PHP.eB adeno-associated virus vectors (AAVs), which were introduced into the brain via intravascular injection. We demonstrated that shRNAs carrying various mismatches with the CAG target sequence reduced the level of polyQ-expanded ATXN7 in the cerebellum, albeit with varying degrees of allele selectivity and safety profile. An shRNA named A4 potently reduced the level of polyQ-expanded ATXN7, with no effect on normal ATXN7 levels and no adverse side effects. Furthermore, A4 shRNA treatment improved a range of motor and behavioral parameters 23 weeks after AAV injection and attenuated the disease burden of PCs by preventing the downregulation of several PC-type-specific genes. Our results show the feasibility of the selective targeting of CAG expansion in the cerebellum using a blood-brain barrier-permeable vector to attenuate the disease phenotype in an SCA mouse model. Our study represents a significant advancement in developing CAG-targeting strategies as a potential therapy for SCA7 and possibly other CAG/polyQ SCAs.
Topics: Animals; Spinocerebellar Ataxias; Peptides; Disease Models, Animal; Dependovirus; Mice; Ataxin-7; Trinucleotide Repeat Expansion; RNA, Small Interfering; Phenotype; Genetic Vectors; Purkinje Cells; Mice, Transgenic; Cerebellum; Humans; Genetic Therapy; Alleles
PubMed: 38673939
DOI: 10.3390/ijms25084354 -
Journal of Veterinary Internal Medicine 2024In 2020, a novel neurologic disease was observed in juvenile Quarter Horses (QHs) in North America. It was unknown if this was an aberrant manifestation of another...
BACKGROUND
In 2020, a novel neurologic disease was observed in juvenile Quarter Horses (QHs) in North America. It was unknown if this was an aberrant manifestation of another previously described neurological disorder in foals, such as equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM).
HYPOTHESIS/OBJECTIVES
To describe the clinical findings, outcomes, and postmortem changes with Equine Juvenile Spinocerebellar Ataxia (EJSCA), differentiate the disease from other similar neurological disorders, and determine a mode of inheritance.
ANIMALS
Twelve neurologically affected QH foals and the dams.
METHODS
Genomic DNA was isolated and pedigrees were manually constructed.
RESULTS
All foals (n = 12/12) had a history of acute onset of neurological deficits with no history of trauma. Neurological deficits were characterized by asymmetrical spinal ataxia, with pelvic limbs more severely affected than thoracic limbs. Clinicopathological abnormalities included high serum activity of gamma-glutamyl transferase and hyperglycemia. All foals became recumbent (median, 3 days: [0-18 days]), which necessitated humane euthanasia (n = 11/12, 92%; the remaining case was found dead). Histological evaluation at postmortem revealed dilated myelin sheaths and digestion chambers within the spinal cord, most prominently in the dorsal spinocerebellar tracts. Pedigree analysis revealed a likely autosomal recessive mode of inheritance.
CONCLUSIONS AND CLINICAL IMPORTANCE
EJSCA is a uniformly fatal, rapidly progressive, likely autosomal recessive neurological disease of QHs <1 month of age in North America that is etiologically distinct from other clinically similar neurological disorders. Once the causative variant for EJSCA is validated, carriers can be identified through genetic testing to inform breeding decisions.
Topics: Animals; Horses; Horse Diseases; Pedigree; Male; Female; North America; Spinocerebellar Ataxias; Nervous System Diseases
PubMed: 38669583
DOI: 10.1111/jvim.17049 -
Nucleic Acids Research Jun 2024Nucleotide repeat expansion disorders, a group of genetic diseases characterized by the expansion of specific DNA sequences, pose significant challenges to treatment and...
Nucleotide repeat expansion disorders, a group of genetic diseases characterized by the expansion of specific DNA sequences, pose significant challenges to treatment and therapy development. Here, we present a precise and programmable method called prime editor-mediated correction of nucleotide repeat expansion (PE-CORE) for correcting pathogenic nucleotide repeat expansion. PE-CORE leverages a prime editor and paired pegRNAs to achieve targeted correction of repeat sequences. We demonstrate the effectiveness of PE-CORE in HEK293T cells and patient-derived induced pluripotent stem cells (iPSCs). Specifically, we focus on spinal and bulbar muscular atrophy and spinocerebellar ataxia type, two diseases associated with nucleotide repeat expansion. Our results demonstrate the successful correction of pathogenic expansions in iPSCs and subsequent differentiation into motor neurons. Specifically, we detect distinct downshifts in the size of both the mRNA and protein, confirming the functional correction of the iPSC-derived motor neurons. These findings highlight PE-CORE as a precision tool for addressing the intricate challenges of nucleotide repeat expansion disorders, paving the way for targeted therapies and potential clinical applications.
Topics: Humans; Induced Pluripotent Stem Cells; Gene Editing; HEK293 Cells; Motor Neurons; Cell Differentiation; DNA Repeat Expansion; Trinucleotide Repeat Expansion
PubMed: 38661210
DOI: 10.1093/nar/gkae310 -
Frontiers in Genetics 2024The article aims to provide genetic counseling to a family with two children who were experiencing growth and developmental delays. Clinical information of the proband...
The article aims to provide genetic counseling to a family with two children who were experiencing growth and developmental delays. Clinical information of the proband was collected. Peripheral blood was collected from core family members to identify the initial reason for growth and developmental delays by whole exome sequencing (WES) and Sanger sequencing. To ascertain the consequences of the newly discovered variants, details of the variants detected were analyzed by bioinformatic tools. Furthermore, we performed experimentation targeting gene expression to confirm whether the variants could alter the expression of . The proband had prenatal ultrasound findings that included flattened frontal bones, increased interocular distance, widened bilateral cerebral sulci, and shortened long bones, which resulted in subsequent postnatal developmental delays. The older sister also displayed growth developmental delays and poor muscle tone. WES identified compound heterozygous variants of c.712A>T (p.Arg238Ter) and .2744A>T (p.Gln915Leu) in the gene in these two children. Both are novel missense variant that originates from the father and mother, respectively. Sanger sequencing confirmed this result. Following the guideline of the American College of Medical Genetics and Genomics (ACMG), the c.712A>T (p.Arg238Ter) variant was predicted to be pathogenic (P), while the c.2744A>T (p.Gln915Leu) variant was predicted to be a variant of uncertain significance (VUS). The structural analysis revealed that the c.2744A>T (p.Gln915Leu) variant may impact the stability of the protein. experiments demonstrated that both variants reduced expression. The gene c.712A>T (p.Arg238Ter) and c.2744A>T (p.Gln915Leu) were identified as the genetic causes of growth and developmental delay in two affected children. This conclusion was based on the clinical presentations of the children, structural analysis of the mutant protein, and experimental validation. This discovery expands the range of gene variants and provides a foundation for genetic counseling and guidance for future pregnancies in the affected children's families.
PubMed: 38655056
DOI: 10.3389/fgene.2024.1379366 -
American Journal of Human Genetics May 2024Expanded CAG repeats in coding regions of different genes are the most common cause of dominantly inherited spinocerebellar ataxias (SCAs). These repeats are unstable...
Expanded CAG repeats in coding regions of different genes are the most common cause of dominantly inherited spinocerebellar ataxias (SCAs). These repeats are unstable through the germline, and larger repeats lead to earlier onset. We measured somatic expansion in blood samples collected from 30 SCA1, 50 SCA2, 74 SCA3, and 30 SCA7 individuals over a mean interval of 8.5 years, along with postmortem tissues and fetal tissues from SCA1, SCA3, and SCA7 individuals to examine somatic expansion at different stages of life. We showed that somatic mosaicism in the blood increases over time. Expansion levels are significantly different among SCAs and correlate with CAG repeat lengths. The level of expansion is greater in individuals with SCA7 who manifest disease compared to that of those who do not yet display symptoms. Brain tissues from SCA individuals have larger expansions compared to the blood. The cerebellum has the lowest mosaicism among the studied brain regions, along with a high expression of ATXNs and DNA repair genes. This was the opposite in cortices, with the highest mosaicism and lower expression of ATXNs and DNA repair genes. Fetal cortices did not show repeat instability. This study shows that CAG repeats are increasingly unstable during life in the blood and the brain of SCA individuals, with gene- and tissue-specific patterns.
Topics: Humans; Mosaicism; Spinocerebellar Ataxias; Trinucleotide Repeat Expansion; Female; Male; Adult; Middle Aged; Cerebellum; Aged; Brain; Ataxin-1
PubMed: 38626762
DOI: 10.1016/j.ajhg.2024.03.015 -
Computer Methods and Programs in... Jun 2024Metabolomics, the study of substrates and products of cellular metabolism, offers valuable insights into an organism's state under specific conditions and has the...
BACKGROUND
Metabolomics, the study of substrates and products of cellular metabolism, offers valuable insights into an organism's state under specific conditions and has the potential to revolutionise preventive healthcare and pharmaceutical research. However, analysing large metabolomics datasets remains challenging, with available methods relying on limited and incompletely annotated metabolic pathways.
METHODS
This study, inspired by well-established methods in drug discovery, employs machine learning on metabolite fingerprints to explore the relationship of their structure with responses in experimental conditions beyond known pathways, shedding light on metabolic processes. It evaluates fingerprinting effectiveness in representing metabolites, addressing challenges like class imbalance, data sparsity, high dimensionality, duplicate structural encoding, and interpretable features. Feature importance analysis is then applied to reveal key chemical configurations affecting classification, identifying related metabolite groups.
RESULTS
The approach is tested on two datasets: one on Ataxia Telangiectasia and another on endothelial cells under low oxygen. Machine learning on molecular fingerprints predicts metabolite responses effectively, and feature importance analysis aligns with known metabolic pathways, unveiling new affected metabolite groups for further study.
CONCLUSION
In conclusion, the presented approach leverages the strengths of drug discovery to address critical issues in metabolomics research and aims to bridge the gap between these two disciplines. This work lays the foundation for future research in this direction, possibly exploring alternative structural encodings and machine learning models.
Topics: Machine Learning; Metabolomics; Humans; Cell Line; Ataxia Telangiectasia; Cell Hypoxia
PubMed: 38626559
DOI: 10.1016/j.cmpb.2024.108163 -
Tremor and Other Hyperkinetic Movements... 2024Spinocerebellar ataxia 21 (SCA21) is a rare neurological disorder caused by heterozygous variants in . A growing, yet still limited number of reports suggested that... (Review)
Review
BACKGROUND
Spinocerebellar ataxia 21 (SCA21) is a rare neurological disorder caused by heterozygous variants in . A growing, yet still limited number of reports suggested that hyperkinetic movements should be considered a defining component of the disease.
CASE SERIES
We describe two newly identified families harboring the recurrent pathogenic p.Pro170Leu variant. Both index patients and the mother of the first proband developed movement disorders, manifesting as myoclonic dystonia and action-induced dystonia without co-occurring ataxia in one case, and pancerebellar syndrome complicated by action-induced dystonia in the other. We reviewed the literature on variants linked to hyperkinetic disorders, comparing our cases to described phenotypes.
DISCUSSION
Adding to prior preliminary observations, our series highlights the relevance of hyperkinetic movements as clinically meaningful features of SCA21. mutation should be included in the differential diagnosis of myoclonic dystonia and ataxia-dystonia syndromes.
Topics: Humans; Dystonia; Myoclonus; Hyperkinesis; Ataxia; Rare Diseases; Syndrome; Membrane Proteins; Spinocerebellar Degenerations; Dystonic Disorders
PubMed: 38617829
DOI: 10.5334/tohm.858