The FGF14 GAA repeat expansion is a major cause of ataxia in the Cypriot population DOI Creative Commons

Ioannis Livanos,

Christina Votsi, Kyriaki Michailidou

и другие.

Brain Communications, Год журнала: 2024, Номер 7(1)

Опубликована: Дек. 24, 2024

Abstract Dominantly inherited intronic GAA repeat expansions in the fibroblast growth factor 14 gene have recently been shown to cause spinocerebellar ataxia 27B. Currently, pathogenic threshold of (GAA)≥300 units is considered highly penetrant, while (GAA)250–299 likely with reduced penetrance. This study investigated frequency expansion and phenotypic profile a Cypriot cohort unresolved late-onset cerebellar ataxia. We analysed this trinucleotide 155 patients 227 non-neurological disease controls. The locus was examined by long-range PCR followed fragment analysis using capillary electrophoresis, agarose gel electrophoresis automated electrophoresis. A comprehensive comparison all three techniques conducted. Additionally, bidirectional repeat-primed PCRs Sanger sequencing were carried out confirm absence any interruptions or non-GAA motifs expanded alleles. (GAA)≥250 present 12 (7.7%) patients. average age at onset 60 ± 13.5 years. earliest observed patient (GAA)287 expansion, symptoms appearing 25 years age. All 27B displayed gait appendicular Nystagmus 41.7% patients, 58.3% exhibited dysarthria. Our findings indicate that represents predominant aetiology autosomal dominant population, as first type detected population. Given our results existing research, we propose including testing first-tier genetic diagnostic approach for

Язык: Английский

Recent Advances in the Genetics of Ataxias: An Update on Novel Autosomal Dominant Repeat Expansions DOI Creative Commons
David Pellerin, Pablo Iruzubieta,

Isaac Xu

и другие.

Current Neurology and Neuroscience Reports, Год журнала: 2025, Номер 25(1)

Опубликована: Янв. 16, 2025

Язык: Английский

Процитировано

1
Targeted Long‐Read Sequencing as a Single Assay Improves the Diagnosis of Spastic‐Ataxia Disorders DOI Creative Commons
Laura Ivete Rudaks, Igor Stevanovski, Dennis Yeow

и другие.

Annals of Clinical and Translational Neurology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 25, 2025

ABSTRACT Objective The hereditary spastic‐ataxia spectrum disorders are a group of disabling neurological diseases. traditional genetic testing pathway is complex, multistep and leaves many cases unsolved. We aim to streamline improve this process using long‐read sequencing. Methods developed targeted sequencing strategy with the capacity characterise variation all types sizes within 469 disease‐associated genes, in single assay. applied cohort 34 individuals unsolved spastic‐ataxia. An additional five known diagnosis were included as positive controls. Results identified causative pathogenic variants that would be sufficient for 14/34 (41%) participants. success rate was 5/11 (45%) those who naïve 9/23 (39%) undiagnosed after prior testing, completed on clinical basis. Short tandem repeat expansions FGF14 most common (7/34, 21%). Two (2/34, 6%) had biallelic RFC1 one individual monoallelic expansion ATXN8OS / ATXN8 . Causative sequence other than short found four individuals, including VCP , STUB1 ANO10 SPG7 Furthermore, controls identified. Interpretation Our results demonstrate utility evaluation patients disorders, highlighting both increase overall diagnostic yield by capturing causes

Язык: Английский

Процитировано

1
Neuroradiological findings in GAA-FGF14 ataxia (SCA27B): more than cerebellar atrophy. DOI

Shihan Chen,

Catherine Ashton, Rawan Sakalla

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Фев. 18, 2024

GAA-

Язык: Английский

Процитировано

4
Delayed Progression of Ataxia with a Static Cerebellar Lesion– Consider SCA27B DOI Creative Commons

Tsz Hang Wong,

Jamie Manuputty,

Tom van Seeters

и другие.

The Cerebellum, Год журнала: 2025, Номер 24(2)

Опубликована: Янв. 16, 2025

Язык: Английский

Процитировано

0
Study on the Modulation of NLRP1 by Natural Products in Neurodegenerative Diseases DOI Creative Commons
Tingting Wang, Xintong Zuo,

Ling Cheng

и другие.

Natural Product Communications, Год журнала: 2025, Номер 20(3)

Опубликована: Март 1, 2025

Neuronal pyroptosis is one of the crucial pathogenesis neurodegenerative diseases, and signaling pathway mediated by inflammasome main pyroptosis. Neuroinflammation not only a common feature, but also an essential basis for diagnosis diseases. important pathological feature nervous system diseases such as Alzheimer's disease (AD), Parkinson's (PD). NLRP1 plays role in activating inducing inflammatory response, so development drugs targeting regulation has become reasonable research direction treatment By analyzing current progress which affects process neuronal related Chinese medicine, natural products were docked with targets to find higher activity. The target CB-Dock molecular docking platform. Molecular results showed that silibinin, crocin, hyperoside had excellent binding affinity, most promising potential active compounds AD regulating NLRP1. This paper discusses feasibility rationality medicine on future.

Язык: Английский

Процитировано

0
The genetic landscape of sporadic adult-onset degenerative ataxia: a multi-modal genetic study of 377 consecutive patients from the longitudinal multi-centre SPORTAX cohort DOI
Danique Beijer, David Mengel,

Demet Önder

и другие.

EBioMedicine, Год журнала: 2025, Номер 115, С. 105715 - 105715

Опубликована: Апрель 23, 2025

Язык: Английский

Процитировано

0
Enhanced Detection and Genotyping of Disease-Associated Tandem Repeats Using HMMSTR and Targeted Long-Read Sequencing DOI Creative Commons
Kinsey Van Deynze, Camille Mumm, Connor J. Maltby

и другие.

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Май 3, 2024

Abstract Tandem repeat sequences comprise approximately 8% of the human genome and are linked to more than 50 neurodegenerative disorders. Accurate characterization disease-associated loci remains resource intensive often lacks high resolution genotype calls. We introduce a multiplexed, targeted nanopore sequencing panel HMMSTR, sequence-based tandem copy number caller. HMMSTR outperforms current signal- callers relative two assemblies we show it performs with accuracy in heterozygous regions at low read coverage. The flexible allows us capture disease associated an average coverage >150x. Using these tools, successfully characterize known or suspected expansions patient derived samples. In samples also identify unexpected expanded alleles not previously underlying diagnosis. This genotyping approach for is scalable, simple, flexible, accurate, offering significant potential diagnostic applications investigation expansion co-occurrence Figure

Язык: Английский

Процитировано

3
Clinical, Radiological and Pathological Features of a Large American Cohort of Spinocerebellar Ataxia (SCA27B) DOI Creative Commons
Widad Abou Chaar, Anirudh N. Eranki,

Hannah A. Stevens

и другие.

Annals of Neurology, Год журнала: 2024, Номер 96(6), С. 1092 - 1103

Опубликована: Сен. 12, 2024

Objectives Spinocerebellar ataxia 27B due to GAA repeat expansions in the fibroblast growth factor 14 ( FGF14 ) gene has recently been recognized as a common cause of late‐onset hereditary cerebellar ataxia. Here we present first report this disease US population, characterizing its clinical manifestations, progression, pathological abnormalities, and response 4‐aminopyridine cohort 102 patients bearing expansions. Methods We compiled series with SCA27B, recruited from 5 academic centers across United States. Clinical manifestations patient demographics were collected retrospectively records an unblinded approach using standardized form. Post‐mortem analysis was done on 4 brains genetically confirmed SCA27B. Results In our found that SCA27B (57 ± 12.5 years) slowly progressive episodic component 51% patients. Balance gait impairment almost always at onset. The principal finding post‐mortem examination brain specimens loss Purkinje neurons most severe vermis particularly anterior vermis. Similar European populations, high percent 21/28 (75%) reported positive treatment 4‐aminopyridine. Interpretation Our study further estimates prevalence expands clinical, imaging features while looking response, survival disease. Testing for should be considered all undiagnosed patients, especially those ANN NEUROL 2024;96:1092–1103

Язык: Английский

Процитировано

3
Characteristics of tandem repeat inheritance and sympathetic nerve involvement in GAA-FGF14 ataxia DOI Creative Commons

Ze-Hong Zheng,

Chun‐Yan Cao,

Bi Cheng

и другие.

Journal of Human Genetics, Год журнала: 2024, Номер 69(9), С. 433 - 440

Опубликована: Июнь 12, 2024

Intronic GAA repeat expansion ([GAA] ≥250) in FGF14 is associated with the late-onset neurodegenerative disorder, spinocerebellar ataxia 27B (SCA27B, GAA-FGF14 ataxia). We aim to determine prevalence of Chinese populations presenting cerebellar (LOCA) and evaluate characteristics tandem inheritance, radiological features sympathetic nerve involvement.

Язык: Английский

Процитировано

2
Genetic profiles of multiple system atrophy revealed by exome sequencing, long‐read sequencing and spinocerebellar ataxia repeat expansion analysis DOI Creative Commons
Xuying Li, Hong Lai, Xian Li

и другие.

European Journal of Neurology, Год журнала: 2024, Номер 31(12)

Опубликована: Авг. 17, 2024

Abstract Background and Purpose Multiple system atrophy (MSA) is a progressive, adult‐onset neurodegenerative disorder clinically characterized by combinations of autonomic failure, parkinsonism, cerebellar ataxia pyramidal signs. Although few genetic factors have been reported to contribute the disease, its mutational profiles not systemically studied. Methods To address diagnosed MSA patients, exome sequencing triplet repeat detection was conducted in 205 including one familial case. The pathogenicity variants determined according American College Medical Genetics Genomics Association for Molecular Pathology guidelines. Results In patient, novel heterozygous COQ2 pathogenic variant (p.Ala351Thr) identified pedigree. sporadic 29 were revealed 21 genes, PARK7 p.Ala104Thr significantly associated with ( p = 0.0018). Moreover, burden tests demonstrated that enriched ataxia‐related genes patients. Furthermore, expansion analyses two patients carried CAG CACNA1A gene (SCA6), patient (ACAGG)exp/(ACAGG)exp RFC1 GAA‐pure FGF14 gene. Conclusion conclusion, expansions CACNA1A, detected four MSA.

Язык: Английский

Процитировано

2