Biomedical subjects

Mathilde Renaud

Publications and source records attributed to Mathilde Renaud.

3 recordsLinked to original sources

PubMed2026

Longitudinal progression, metrics, age-dependence, and modifiers of ataxia severity in SCA27B: a multicentre study of 219 patients.

BACKGROUND: Spinocerebellar Ataxia 27B (SCA27B) is a novel, frequent and likely treatable late-onset autosomal-dominant ataxia caused by GAA repeat-expansions in FGF14. For understanding disease evolution and imminent trial planning, metrics of the most widely used clinical outcome assessment (Scale for the Assessment and Rating of Ataxia/SARA), longitudinal progression and modifiers thereof are warranted. METHODS: Multicentre intercontinental observational study (2015-2024) of 661 assessments from 219 patients with SCA27B (age: 68 ± 10 years; SARA: 9 ± 6 points) with item-level distribution-based analyses to characterise SARA metrics relative to ageing-related impairment in 390 healthy controls; and linear mixed-effects modelling to determine longitudinal progression and demographic or genetic modifiers. FINDINGS: Ataxia severity in SCA27B as assessed by SARA was primarily attributable to gait, stance, and lower-limb impairment; other ataxia domains scored ≤1 SARA point in 79-94% of patients. Discrimination of SCA27B motor performance from controls decreased with age due to ageing-related motor variability captured by SARA, thus limiting potential metric response windows for symptomatic treatments. Disease progression was faster in the presence of interfering ageing-related comorbidities in 14 (6%) patients. Overall longitudinal progression of SCA27B was 0.54 SARA points/year [95% CI: 0.37-0.71]. Expansions of (GAA)> 180 repeats were frequent also on the shorter allele (n = 18 (8%), range: 196-348 repeats), and associated with faster progression (+1.6 SARA points/year, [95% CI: 0.9-2.2]), including also otherwise less affected ataxia domains speech and sitting. INTERPRETATION: Disease progression in SCA27B is characterised by mild progression, ageing-related motor variabilities and comorbidities, and associated with repeat size on both alleles. FUNDING: Else-Kröner-Fresenius-Stiftung, EU, DFG, BMBF, CIHR, NAF, Ataxia-UK, CSC.

Humans↗

PubMed2025

Type and position of repeat interruptions as determinants of disease severity and expansion size in Friedreich ataxia.

PURPOSE: In Friedreich ataxia (FRDA) the size of the smaller GAA expansion is a major determinant of disease severity; interruption motifs were identified after the discovery of the pathogenic expansions; however, their impact is only recently investigated. METHODS: 164 patients with FRDA with biallelic expansions and 15 patients without FRDA were analyzed for interruption(s) number, position, and motif. Expansion size and age at onset of ataxia (AAO) were determined for patients with FRDA. RESULTS: Three groups of patients with FRDA were identified by the simultaneous analysis of the precise distance ("depth") between the interruptions (mostly nontriplet) and the 3' end of the expansion (P < .001), the smaller expansion size (P < .001), and AAO (P < .001). Classical FRDA corresponds to absence of interruption or interruption depth < 8 repeats, with AAO often <15 years (area under the curve [AUC] = 0.90; 95% CI, 0.84-0.96); LOFA to interruption depth of 8 to 18 repeats (AUC = 0.97; 95% CI, 0.94-1), with AAO 15 to 34 years (AUC = 1; 95% CI, 1-1); and vLOFA to interruption depth > 18 (AUC = 0.97; 95% CI, 0.92-1), with AAO > 34 years. Multiple (>5) triplet interruptions hamper further expansion. CONCLUSION: This study provides the molecular basis for a novel classification of FRDA that should be recommended for correct diagnosis.

Humans↗

PubMed2025

Delineating the pathogenic threshold and phenotypic spectrum of SCA27B: findings from a large French-Canadian cohort.

BACKGROUND: Autosomal dominant spinocerebellar ataxia 27B (SCA27B), caused by an intronic (GAA•TTC) repeat expansion in FGF14, is a common cause of late-onset cerebellar ataxia, but its genotypic and phenotypic spectrum remains to be fully established. METHODS: We analysed the FGF14 (GAA•TTC) repeat expansion in a cohort of 134 patients with ataxia and 822 controls from Quebec. We conducted segregation study in large families to further characterize intergenerational repeat instability. RESULTS: We found a significant enrichment of (GAA•TTC)≥200 alleles in the ataxia cohort compared to controls (53.0%, 71/134, vs 3.6%, 30/822, p < 0.0001), including for (GAA•TTC)200-249 alleles (8.2% vs 2.6%, p = 0.0026). We identified 12 ataxic patients with a phenotype compatible with SCA27B carrying a (GAA•TTC)200-249 expansion supporting the pathogenicity of these alleles in some patients. We further delineated the phenotype of 125 symptomatic individuals from 69 families who carried an FGF14 (GAA•TTC)≥200 repeat expansion. Patients with (GAA•TTC)200-249, (GAA•TTC)250-299, and (GAA•TTC)≥300 had a similar phenotype. We observed that 14% of patients with episodic symptoms (13/92) had severe episodes that were initially misdiagnosed as stroke, vestibular neuritis, Wernicke's encephalopathy, or seizures. DISCUSSION AND CONCLUSION: This large cohort demonstrates that (GAA•TTC)200-249 alleles are enriched in patients with ataxia compared to controls and can be pathogenic for SCA27B, supporting the need to define a lower pathogenic threshold in the presence of specific clinical criteria.

Humans↗