Clinical and molecular studies in two new cases of ARSACS

Ricca, Ivana; Morani, Federica; Bacci, Giacomo Maria; Nesti, Claudia; Caputo, Roberto; Tessa, Alessandra; Santorelli, Filippo M.

doi:10.1007/s10048-019-00564-7

Cited by 17 publications

(16 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DNA samples were analysed at the neurogenetic laboratory of the IRCCS Fondazione Stella Maris (Pisa) through a TRP methodology (SureSelect, Agilent) that includes 273 genes related to hereditary ataxias using an Illumina NextSeq500 platform, previously described [ 9 ]. The Ingenuity Variant Analysis suite (QIAGEN) was used for variant annotation according to an in‐house validated pipeline; the impact of mutations on TMEM240 was determined in silico using 11 prediction tools [ 10 ].…”

Section: Methodsmentioning

confidence: 99%

A next generation sequencing‐based analysis of a large cohort of ataxic patients refines the clinical spectrum associated with spinocerebellar ataxia 21

Riso

Galatolo

Barghigiani

et al. 2021

Euro J of Neurology

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Methodsmentioning

confidence: 99%

A next generation sequencing‐based analysis of a large cohort of ataxic patients refines the clinical spectrum associated with spinocerebellar ataxia 21

Riso

Galatolo

Barghigiani

et al. 2021

Euro J of Neurology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Overall, our reference cohort included 235 patients from 235 unrelated pedigrees, 17 with familial and 218 with sporadic cerebellar ataxia; all of them had an age of onset ≥30 years, (mean ± SD 45 ± 25 years; median 48; range 30–71) and a mean age at examination of 51 ± 14 years (median 54, range 31–79). NGS investigations were performed in all 235 probands using previously reported methods and adopting whole‐exome sequencing in the 17 familial cases and a targeted multigene panel in the 218 sporadic cases. To analyse the data gathered from our study, a routine bioinformatics pipeline was used that adopts the Ingenuity Variant Analysis Suite (Qiagen, Hilden, Germany, https://apps.ingenuity.com).…”

Section: Methodsmentioning

confidence: 99%

The complex phenotype of spinocerebellar ataxia type 48 in eight unrelated Italian families

Lieto

Riso

Galatolo

et al. 2019

Euro J of Neurology

View full text Add to dashboard Cite

Background and purpose Heterozygous mutations in the STUB1 gene have recently been associated with an autosomal dominant form of spinocerebellar ataxia (SCA) associated with cerebellar cognitive‐affective syndrome (CCAS), named SCA48. Methods Molecular screening was performed in a cohort of 235 unrelated patients with adult‐onset, autosomal dominant (17) or sporadic (218) cerebellar ataxia, negative for pathological trinucleotide expansions in the common SCAs, FRDA and FXTAS loci, by using targeted multigene panels or whole‐exome sequencing. Bioinformatics analyses, detailed neurological phenotyping and family segregation studies corroborated the pathogenicity of the novel STUB1 mutations. Clinico‐diagnostic findings were reviewed to define the phenotypic spectrum. Results Eight heterozygous STUB1 mutations were identified, six of which were novel in 11 patients from eight index families, giving an estimated overall frequency of 3.4% (8/235) for SCA48 in our study cohort, rising to 23.5% (4/17) when considering only familial cases. All our SCA48 patients had cerebellar ataxia and dysarthria associated with cerebellar atrophy on brain magnetic resonance imaging; of note, many cases were also associated with parkinsonism, chorea and dystonia. CCAS also occurred frequently, whereas definite signs of pyramidal tract dysfunction and peripheral nervous system involvement were absent. One SCA48 patient presented with hypogonadism, associated with other autoimmune endocrine dysfunctions. Conclusions Our results support SCA48 as a significant cause of adult‐onset SCA. Besides CCAS, our SCA48 patients often showed movement disorders and other clinical manifestations previously described in SCAR16, linked to biallelic variants in the same gene, thus suggesting a continuous clinical spectrum and significant overlap amongst recessive and dominantly inherited mutations in STUB1.

show abstract

“…PN6a and PN6b, and PN8a and PN8b are siblings, and despite carriers of the same mutation, they present phenotypic variability (Table 1). (Baets et al, 2010); PN4 (Terracciano et al, 2009); PN5 (Ricca et al, 2019); PN7 (Masciullo et al, 2012)) (Fig. 1 and Table 1).…”

Section: Full-length Sacsin Protein Is Dramatically Reduced In Arsacs Patient Fibroblasts Regardless Of the Nature Of The Mutationmentioning

confidence: 97%

Sacsin cotranslational degradation causes autosomal recessive spastic ataxia of Charlevoix-Saguenay

Longo

Ritis

Miluzio

et al. 2021

Preprint

View full text Add to dashboard Cite

Autosomal recessive spastic ataxia of Charlevoix-Saguenay is caused by more than 200 different mutations in the SACS gene encoding sacsin, a huge multimodular protein of unknown function. ARSACS phenotypic spectrum is highly variable. Previous studies correlated the nature and position of SACS mutations with age of onset or disease severity, though the effects on protein stability were not considered. In this study, we explain mechanistically the lack of genotype-phenotype correlation in ARSACS, with important consequences for disease diagnosis and treatment. We found that sacsin is almost absent in ARSACS fibroblasts, regardless of the nature of the mutation. We did not detect sacsin in patients with truncating mutations, while we found it strikingly reduced or absent also in compound heterozygotes carrying diverse missense mutations. We excluded SACS mRNA decay, defective translation, or faster post-translational degradation as causes of protein reduction. Conversely, we demonstrated that nascent mutant sacsin protein undergoes preemptive cotranslational degradation, emerging as a novel cause of a human disease. Based on these findings, sacsin levels should be included in the diagnostic algorithm for ARSACS.

show abstract

Clinical and molecular studies in two new cases of ARSACS

Cited by 17 publications

References 20 publications

A next generation sequencing‐based analysis of a large cohort of ataxic patients refines the clinical spectrum associated with spinocerebellar ataxia 21

A next generation sequencing‐based analysis of a large cohort of ataxic patients refines the clinical spectrum associated with spinocerebellar ataxia 21

The complex phenotype of spinocerebellar ataxia type 48 in eight unrelated Italian families

Sacsin cotranslational degradation causes autosomal recessive spastic ataxia of Charlevoix-Saguenay

Contact Info

Product

Resources

About