Spectrin mutations in spinocerebellar ataxia (SCA)

Bauer, Péter; Schöls, Lüdger; Rieß, Olaf

doi:10.1002/bies.20443

Cited by 14 publications

(9 citation statements)

References 15 publications

(10 reference statements)

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“…Dominant missense or in-frame mutations in SPTBN2 cause spinocerebellar ataxia type 5 (SCA5) a relatively pure cerebellar disorder with little brainstem or spinocerebellar tract involvement. The disease onset is generally in the third or fourth decade of life, although the age of onset can be as young as 10 years of age and up to 68 years ( Bauer et al , 2006 ). Some juvenile-onset SCA5 patients have bulbar and pyramidal tract dysfunction, in conjunction with a weakened ability to cough, which may shorten lifespan ( Ikeda et al , 2006 ).…”

Section: Discussionmentioning

confidence: 99%

De novopoint mutations in patients diagnosed with ataxic cerebral palsy

Schnekenberg

Perkins

Miller

et al. 2015

Brain

134

121

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Section: Discussionmentioning

confidence: 99%

De novopoint mutations in patients diagnosed with ataxic cerebral palsy

Schnekenberg

Perkins

Miller

et al. 2015

Brain

134

121

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show abstract

“…Clinical features of SCA5 suggest a predominately cerebellar disease [36], whereas histopathological examination of SCA cases suggested limited cerebellum pathology, with degeneration of the brain stem and spinocerebellar tract involved in disease progression. This evidence suggests a different genetic cause for SCA and SCA5, although it is possible for different mutations in the same gene to result in variable phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Missense Mutation in CAPN1 Is Associated with Spinocerebellar Ataxia in the Parson Russell Terrier Dog Breed

2013

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Spinocerebellar ataxia (SCA) in the Parson Russell Terrier (PRT) dog breed is a disease of progressive incoordination of gait and loss of balance. Clinical signs usually become notable between 6 and 12 months of age with affected dogs presenting with symmetric spinocerebellar ataxia particularly evident in the pelvic limbs. The degree of truncal ataxia, pelvic limb hypermetria and impaired balance is progressive, particularly during the initial months of disease. A certain degree of stabilisation as well as intermittent worsening may occur. At the later stages of the disease ambulation often becomes difficult, with owners often electing to euthanise affected dogs on welfare grounds. Using a GWAS approach and target-enriched massively-parallel sequencing, a strongly associated non-synonymous SNP in the CAPN1 gene, encoding the calcium dependent cysteine protease calpain1 (mu-calpain), was identified. The SNP is a missense mutation causing a cysteine to tyrosine substitution at residue 115 of the CAPN1 protein. Cysteine 115 is a highly conserved residue and forms a key part of a catalytic triad of amino acids that are crucial to the enzymatic activity of cysteine proteases. The CAPN1 gene shows high levels of expression in the brain and nervous system and roles for the protein in both neuronal necrosis and maintenance have been suggested. Given the functional implications and high level of conservation observed across species, the CAPN1 variant represents a provocative candidate for the cause of SCA in the PRT and a novel potential cause of ataxia in humans.

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“…The clinical symptoms of SCA5 include ataxia, dysarthria, oculomotor dysfunction with downbeat nystagmus, facial myokymia, defects of the visual field, tremor, writer's cramp and decreased vibration sense (Table 1) [6]. Subsequent to its onset in childhood or adulthood, SCA5 progresses slowly and has no significant impact on life expectancy.…”

Section: Sca5mentioning

confidence: 98%

Brain pathology of spinocerebellar ataxias

et al. 2012

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The autosomal dominant cerebellar ataxias (ADCAs) represent a heterogeneous group of neurodegenerative diseases with progressive ataxia and cerebellar degeneration. The current classification of this disease group is based on the underlying genetic defects and their typical disease courses. According to this categorization, ADCAs are divided into the spinocerebellar ataxias (SCAs) with a progressive disease course, and the episodic ataxias (EA) with episodic occurrences of ataxia. The prominent disease symptoms of the currently known and genetically defined 31 SCA types result from damage to the cerebellum and interconnected brain grays and are often accompanied by more specific extra-cerebellar symptoms. In the present review, we report the genetic and clinical background of the known SCAs and present the state of neuropathological investigations of brain tissue from SCA patients in the final disease stages. Recent findings show that the brain is commonly seriously affected in the polyglutamine SCAs (i.e. SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17) and that the patterns of brain damage in these diseases overlap considerably in patients suffering from advanced disease stages. In the more rarely occurring non-polyglutamine SCAs, post-mortem neuropathological data currently are scanty and investigations have been primarily performed in vivo by means of MRI brain imaging. Only a minority of SCAs exhibit symptoms and degenerative patterns allowing for a clear and unambiguous diagnosis of the disease, e.g. retinal degeneration in SCA7, tau aggregation in SCA11, dentate calcification in SCA20, protein depositions in the Purkinje cell layer in SCA31, azoospermia in SCA32, and neurocutaneous phenotype in SCA34. The disease proteins of polyglutamine ataxias and some non-polyglutamine ataxias aggregate as cytoplasmic or intranuclear inclusions and serve as morphological markers. Although inclusions may impair axonal transport, bind transcription factors, and block protein quality control, detailed molecular and pathogenetic consequences remain to be determined.

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Spectrin mutations in spinocerebellar ataxia (SCA)

Cited by 14 publications

References 15 publications

De novopoint mutations in patients diagnosed with ataxic cerebral palsy

De novopoint mutations in patients diagnosed with ataxic cerebral palsy

Missense Mutation in CAPN1 Is Associated with Spinocerebellar Ataxia in the Parson Russell Terrier Dog Breed

Brain pathology of spinocerebellar ataxias

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