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1.
Ann Neurol ; 2024 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-39096063

RESUMEN

OBJECTIVES: Spinocerebellar ataxia type 1 (SCA1) is a rare autosomal dominant neurodegenerative disease. Objective surrogate markers sensitive to detect changes in disease severity are needed to reduce sample sizes in interventional trials and identification of predictors of faster disease progression would facilitate patient selection, enrichment, or stratification in such trials. METHODS: We performed a prospective 1-year longitudinal, multimodal study in 34 ataxic SCA1 individuals and 21 healthy controls. We collected clinical, patient-reported outcomes, biochemical and magnetic resonance (MR) biomarkers at baseline and after 1 year. We determined 1-year progression and evaluated the potential predictive value of several baseline markers on 1-year disease progression. RESULTS: At baseline, multiple structural and spectroscopic MR markers in pons and cerebellum differentiated SCA1 from healthy controls and correlated with disease severity. Plasma and cerebrospinal fluid (CSF) neurofilament light (NfL) chain and CSF glial fibrillary acidic protein (GFAP) were elevated in SCA1. In longitudinal analysis, total brainstem and pontine volume change, inventory of non-ataxia signs (INAS) count, and SCA functional index (SCAFI) showed larger responsiveness compared to the Scale for Assessment and Rating of Ataxia (SARA). Longer disease duration, longer non-expanded CAG repeat length, and higher disease burden were associated with faster SARA increase after 1-year in the SCA1 group. Similarly, lower baseline brainstem, pontine, and cerebellar volumes, as well as lower levels of N-acetylaspartate and glutamate in the cerebellar white matter, were also associated with faster SARA increase. INTERPRETATION: Our results guide the selection of the most sensitive measures of disease progression in SCA1 and have identified features associated with accelerated progression that could inform the design of clinical trials. ANN NEUROL 2024.

2.
Mov Disord ; 39(9): 1636-1640, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38973070

RESUMEN

BACKGROUND: Monoallelic, pathogenic STUB1 variants cause autosomal dominant cerebellar ataxia (ATX-STUB1/SCA48). Recently, a genetic interaction between STUB1 variants and intermediate or high-normal CAG/CAA repeats in TBP was suggested, indicating digenic inheritance or a disease-modifying role for TBP expansions. OBJECTIVE: To determine the presence and impact of intermediate or high-normal TBP expansions in ataxic patients with heterozygous STUB1 variants. METHODS: We describe 21 patients with ataxia carrying a heterozygous STUB1 variant and determined TBP repeat length. RESULTS: A total of 15 of 21 patients (71%) carried a normal TBP <40 allele, 4 (19%) carried an intermediate TBP 41-42 allele, and two carried a high-normal TBP 40 allele (9.5%). Five of six carriers (83%) of both STUB1 variants and TBP 40-42 alleles showed marked cognitive impairment. CONCLUSIONS: SCA48 is predominantly a monogenic disorder, because most patients carried an isolated, heterozygous STUB1 variant and presented with the typical combined phenotype of ataxia and cognitive dysfunction. Still, co-occurrence of TBP 41-42 or high-normal TBP40 alleles was relatively frequent and associated with marked cognitive defects (28.5%), suggesting a modifying effect on clinical expression in some cases.


Asunto(s)
Proteína de Unión a TATA-Box , Ubiquitina-Proteína Ligasas , Humanos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Proteína de Unión a TATA-Box/genética , Ubiquitina-Proteína Ligasas/genética , Anciano , Ataxias Espinocerebelosas/genética , Expansión de Repetición de Trinucleótido/genética , Ataxia Cerebelosa/genética , Heterocigoto , Adulto Joven , Fenotipo
3.
J Neurol ; 269(6): 3094-3108, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-34806130

RESUMEN

Variants in CACNA1A are classically related to episodic ataxia type 2, familial hemiplegic migraine type 1, and spinocerebellar ataxia type 6. Over the years, CACNA1A has been associated with a broader spectrum of phenotypes. Targeted analysis and unbiased sequencing of CACNA1A result not only in clear molecular diagnoses, but also in large numbers of variants of uncertain significance (VUS), or likely pathogenic variants with a phenotype that does not directly match the CACNA1A spectrum. Over the last years, targeted and clinical exome sequencing in our center has identified 41 CACNA1A variants. Ultimately, variants were considered pathogenic or likely pathogenic in 23 cases, with most phenotypes ranging from episodic or progressive ataxia to more complex ataxia syndromes, as well as intellectual disability and epilepsy. In two cases, the causality of the variant was discarded based on non-segregation or an alternative diagnosis. In the remaining 16 cases, the variant was classified as uncertain, due to lack of opportunities for segregation analysis or uncertain association with a non-classic phenotype. Phenotypic variability and the large number of VUS make CACNA1A a challenging gene for neurogenetic diagnostics. Accessible functional read-outs are clearly needed, especially in cases with a non-classic phenotype.


Asunto(s)
Ataxia Cerebelosa , Migraña con Aura , Ataxias Espinocerebelosas , Ataxia/genética , Canales de Calcio/genética , Ataxia Cerebelosa/diagnóstico , Ataxia Cerebelosa/genética , Humanos , Fenotipo , Ataxias Espinocerebelosas/diagnóstico , Ataxias Espinocerebelosas/genética
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