Spinocerebellar ataxia 48 presenting with ataxia associated with cognitive, psychiatric, and extrapyramidal features: A report of two Italian families

Michele, G. De; Lieto, Maria; Galatolo, Daniele; Salvatore, Elena; Cocozza, Sirio; Barghigiani, Melissa; Tessa, Alessandra; Baldacci, Jacopo; Pappatà, Sabina; Filla, Alessandro; Santorelli, Filippo M.

doi:10.1016/j.parkreldis.2019.05.001

Cited by 50 publications

(54 citation statements)

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“…In our cohort, clinical phenotyping in 11 patients from eight kindred substantially confirms the SCA48 clinical picture described in previous reports [15,16]. Indeed, all of the newly identified patients manifest with adult-onset cerebellar ataxia and dysarthria, associated with a significant cerebellar atrophy, prevalently involving the vermis and lobules VI-VII.…”

Section: Discussionsupporting

confidence: 86%

“…Then three additional STUB1-mutated patients were detected upon family segregation studies ( Fig. 1, marked [16]) were also found. All mutations affected highly conserved residues variably distributed in the U-box domain but one (p.[Ala67Thr]) was located in the TRP domain ( Fig.…”

Section: Resultsmentioning

confidence: 91%

“…[Tyr230Cysfs*9] ; and c.823_824delCT/p. [Leu275fs*16] ) were also found. All mutations affected highly conserved residues variably distributed in the U‐box domain but one (p.[Ala67Thr]) was located in the TRP domain (Fig.…”

Section: Resultsmentioning

confidence: 94%

“…Following the results of NGS and segregation studies, detailed clinical phenotyping was performed in the 11 heterozygous STUB1-positive patients, further supporting a pathogenic role of the identified mutations and thus a diagnosis of SCA48 (Table 1). Indeed, all of them showed various additional features, including parkinsonism, dystonia, chorea, neuropsychiatric symptoms or endocrine dysfunction, shared with both SCA48 [15,16] and SCAR16 patients [5][6][7][8][9][10][11][12][13].…”

Section: Resultsmentioning

confidence: 99%

“…In contrast to SCAR16 patients [5,7,8,10], none of our SCA48 patients had major pyramidal tract signs, nor evidence of peripheral neuropathy. Regarding the latter issue, lack of peripheral nervous system involvement also characterizes STUB1-mutated patients so far described in the literature [5][6][7][8][9][10][11][12][13]15,16]. Accordingly, immunohistochemical studies in mouse models have documented the expression of CHIP only in the central nervous system [5].…”

Section: Discussionmentioning

confidence: 98%

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

Lieto

Riso

Galatolo

et al. 2019

Euro J of Neurology

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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.

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Section: Discussionsupporting

confidence: 86%

Section: Resultsmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

See 3 more Smart Citations

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

Lieto

Riso

Galatolo

et al. 2019

Euro J of Neurology

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Monochorea of the Upper Limb in a Patient with Spinocerebellar Ataxia Type 12

Bhattad

Rawat

Pandey

2021

Movement Disord Clin Pract

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Nomenclature of Genetic Movement Disorders: Recommendations of the International Parkinson and Movement Disorder Society Task Force – An Update

et al. 2022

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In 2016, the Movement Disorder Society Task Force for the Nomenclature of Genetic Movement Disorders presented a new system for naming genetically determined movement disorders and provided a criterion‐based list of confirmed monogenic movement disorders. Since then, a substantial number of novel disease‐causing genes have been described, which warrant classification using this system. In addition, with this update, we further refined the system and propose dissolving the imaging‐based categories of Primary Familial Brain Calcification and Neurodegeneration with Brain Iron Accumulation and reclassifying these genetic conditions according to their predominant phenotype. We also introduce the novel category of Mixed Movement Disorders (MxMD), which includes conditions linked to multiple equally prominent movement disorder phenotypes. In this article, we present updated lists of newly confirmed monogenic causes of movement disorders. We found a total of 89 different newly identified genes that warrant a prefix based on our criteria; 6 genes for parkinsonism, 21 for dystonia, 38 for dominant and recessive ataxia, 5 for chorea, 7 for myoclonus, 13 for spastic paraplegia, 3 for paroxysmal movement disorders, and 6 for mixed movement disorder phenotypes; 10 genes were linked to combined phenotypes and have been assigned two new prefixes. The updated lists represent a resource for clinicians and researchers alike and they have also been published on the website of the Task Force for the Nomenclature of Genetic Movement Disorders on the homepage of the International Parkinson and Movement Disorder Society (https://www.movementdisorders.org/MDS/About/Committees--Other-Groups/MDS-Task-Forces/Task-Force-on-Nomenclature-in-Movement-Disorders.htm). © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

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Spinocerebellar ataxia 48 presenting with ataxia associated with cognitive, psychiatric, and extrapyramidal features: A report of two Italian families

Cited by 50 publications

References 20 publications

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

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

Monochorea of the Upper Limb in a Patient with Spinocerebellar Ataxia Type 12

Nomenclature of Genetic Movement Disorders: Recommendations of the International Parkinson and Movement Disorder Society Task Force – An Update

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