Substantia nigra degeneration in spinocerebellar ataxia 2 and 7 using neuromelanin‐sensitive imaging

European Journal of Neurology, Journal Year: 2025, Volume and Issue: 32(1)

Published: Jan. 1, 2025

Spinocerebellar ataxias (SCA) are neurodegenerative diseases with widespread lesions across the central nervous system. Ataxia and spasticity usually predominant, but patients may also present parkinsonism. We aimed to characterize substantia nigra pars compacta (SNc) degeneration in SCA2 7 using neuromelanin-sensitive imaging. Ataxic preataxic expansion carriers (n=15) SCA7 healthy controls (n=10) were prospectively recruited. Volume signal-to-noise ratio (SNR) values of SNc extracted from images. ROC curves used determine metrics that best differentiated SCA participants. Correlations between imaging measurements, clinical variables, plasma neurofilaments light chain (NfL) levels investigated. participants had lower SNR than (110.2 ± 1.3 versus 113.2 1.4; p < 0.001) those (112.5 2.1; 0.01). did not differ. In ataxic patients, volumes (0.13 0.04; = 0.06) (0.10 0.03, 0.02) compared (0.17 0.04). Signal decrease was detected at stage SCA2, SCA7. showed prominent involvement associative limbic nigral territories. discriminated (AUC ≥0.94). volume 1), ones. SCA7, correlations observed time onset, CAG repeats, severity scores, NfL. Neuromelanin-sensitive provides biomarkers SCAs, detectable which could potentially serve as outcome measures trials.

Language: Английский

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CAG Repeat Instability and Region-Specific Gene Expression Changes in the SCA12 Brain

The Cerebellum, Journal Year: 2025, Volume and Issue: 24(3)

Published: March 13, 2025

Language: Английский

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Mosaicism in Short Tandem Repeat Disorders: A Clinical Perspective

Genes, Journal Year: 2025, Volume and Issue: 16(2), P. 216 - 216

Published: Feb. 13, 2025

Fragile X, Huntington disease, and myotonic dystrophy type 1 are prototypical examples of human disorders caused by short tandem repeat variation, repetitive nucleotide stretches that highly mutable both in the germline somatic tissue. As repeats unstable, they can expand, contract, acquire lose epigenetic marks This means within an individual, genotype state at these loci vary considerably from cell to cell. mosaicism may play a key role clinical pathogenesis, yet, our understanding driving phenotypes is only just emerging. review focuses on three relatively well-studied where, given advent new technologies bioinformatic approaches, critical for coming into focus with respect cellular physiology phenotypes.

Language: Английский

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Uncontrolled CAG expansion in neurons susceptible to Huntington's disease

The Lancet Neurology, Journal Year: 2025, Volume and Issue: 24(4), P. 282 - 284

Published: March 20, 2025

Language: Английский

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Age-dependent somatic expansion of the ATXN3 CAG repeat in the blood and buccal swab DNA of individuals with spinocerebellar ataxia type 3/Machado-Joseph disease

Human Genetics, Journal Year: 2024, Volume and Issue: 143(11), P. 1363 - 1378

Published: Oct. 8, 2024

Abstract Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is caused by the expansion of a genetically unstable polyglutamine-encoding CAG repeat in ATXN3 . Longer alleles are generally associated with earlier onset and frequent intergenerational expansions mediate anticipation observed this disorder. Somatic has also been implicated slowing rate somatic proposed as therapeutic strategy. Here, we utilised high-throughput ultra-deep MiSeq amplicon sequencing to precisely define number sequence repeat, genotype an adjacent single nucleotide variant quantify blood buccal swab DNA cohort individuals SCA3 from Azores islands (Portugal). We revealed systematic mis-sizing high levels inaccuracy traditional fragment length analysis that have important implications for attempts identify modifiers clinical molecular phenotypes. Quantification multivariate regression expected effects age at sampling length, although effect was surprisingly modest much stronger associations age. association downstream rs12895357 expansion, higher level compared blood. These data suggest locus patients or might serve good biomarker trials testing suppressors peripheral exposure.

Language: Английский

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Insights into the causes and consequences of DNA repeat expansions from 700,000 biobank participants

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 26, 2024

Abstract Expansions and contractions of tandem DNA repeats are a source genetic variation in human populations tissues: some expanded cause inherited disorders, also somatically unstable. We analyzed sequence data, derived from the blood cells >700,000 participants UK Biobank All Us Research Program, developed new computational approaches to recognize, measure learn DNA-repeat instability at 15 highly polymorphic CAG-repeat loci. found that expansion contraction rates varied widely across these loci, even for alleles same length; different loci exhibited variable relative propensities mutate germline versus blood. The high somatic TCF4 enabled genome-wide association analysis identified seven which variants modulate repeat cells. Three implicated contained genes ( MSH3 , FAN1 PMS2 ) Huntington’s disease age-at-onset as well HTT blood; however, specific their effects (instability-increasing or-decreasing) appeared be tissue-specific repeat-specific, suggesting mutation tissues—or tissue—proceeds independently under control substantially variation. Additional modifier included damage response ATAD5 GADD45A . Analyzing expansions together with clinical data showed 5’ UTR glutaminase GLS) gene associated stage 5 chronic kidney (OR=14.0 [5.7–34.3]) liver diseases (OR=3.0 [1.5–5.9]). These other results point dynamics lifespan.

Language: Английский

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Somatic instability of theFGF14-SCA27B GAA·TTC repeat reveals a marked expansion bias in the cerebellum

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 3, 2024

Spinocerebellar ataxia 27B (SCA27B) is a common autosomal dominant caused by an intronic GAA•TTC repeat expansion in

Language: Английский

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Early-onset phenotype in a patient with an intermediate allele and a large SCA1 expansion: a case report

BMC Neurology, Journal Year: 2024, Volume and Issue: 24(1)

Published: Sept. 17, 2024

Language: Английский

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