Refinement by linkage analysis in two large families of the candidate region of the third locus (SCA3) for autosomal dominant cerebellar ataxia type I

Verschuuren-Bemelmans, CC; Brunt, Erp; Mensink, Rgj; vanderMeulen, MA; Smit, Nh; Stoltedijkstra, [No Value]; Buys, Chcm; Scheffer, Hans; Burton, M.

doi:10.1007/bf00210301

Cited by 12 publications

(5 citation statements)

References 10 publications

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“…All of the patients, along with gait, stance and limb ataxia, suffered from dysarthria, saccadic smooth pursuits and dysmetrical horizontal saccades. Genetic investigation of the CAG trinucleotide expansion in the mutated alleles confirmed the clinical diagnosis in all of our SCA2, SCA3, SCA6 and SCA7 patients [1,3,5,8,11,39].…”

Section: Methodssupporting

confidence: 73%

Degeneration of ingestion‐related brainstem nuclei in spinocerebellar ataxia type 2, 3, 6 and 7

Rüb

Brunt

Petrasch‐Parwez

et al. 2006

Neuropathology Appl Neurobio

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Dysphagia, which can lead to nutritional deficiencies, weight loss and dehydration, represents a risk factor for aspiration pneumonia. Although clinical studies have reported the occurrence of dysphagia in patients with spinocerebellar ataxia type 2 (SCA2), type 3 (SCA3), type 6 (SCA6) and type 7 (SCA7), there are neither detailed clinical records concerning the kind of ingestive malfunctions which contribute to dysphagia nor systematic pathoanatomical studies of brainstem regions involved in the ingestive process. In the present study we performed a systematic post mortem study on thick serial tissue sections through the ingestion-related brainstem nuclei of 12 dysphagic patients who suffered from clinically diagnosed and genetically confirmed spinocerebellar ataxias assigned to the CAG-repeat or polyglutamine diseases (two SCA2, seven SCA3, one SCA6 and two SCA7 patients) and evaluated their medical records. Upon pathoanatomical examination in all of the SCA2, SCA3, SCA6 and SCA7 patients, a widespread neurodegeneration of the brainstem nuclei involved in the ingestive process was found. The clinical records revealed that all of the SCA patients were diagnosed with progressive dysphagia and showed dysfunctions detrimental to the preparatory phase of the ingestive process, as well as the lingual, pharyngeal and oesophageal phases of swallowing. The vast majority of the SCA patients suffered from aspiration pneumonia, which was the most frequent cause of death in our sample. The findings of the present study suggest (i) that dysphagia in SCA2, SCA3, SCA6 and SCA7 patients may be associated with widespread neurodegeneration of ingestion-related brainstem nuclei; (ii) that dysphagic SCA2, SCA3, SCA6 and SCA7 patients may suffer from dysfunctions detrimental to all phases of the ingestive process; and (iii) that rehabilitative swallow therapy which takes specific functional consequences of the underlying brainstem lesions into account might be helpful in preventing aspiration pneumonia, weight loss and dehydration in SCA2, SCA3, SCA6 and SCA7 patients.

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Section: Methodssupporting

confidence: 73%

Degeneration of ingestion‐related brainstem nuclei in spinocerebellar ataxia type 2, 3, 6 and 7

Rüb

Brunt

Petrasch‐Parwez

et al. 2006

Neuropathology Appl Neurobio

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“…Genetic investigation confirmed the clinical diagnosis of the SCA3 patients by showing the presence of sequences of 65–75 CAG repeats in the mutated allele [38] (Table 1), thereby identifying the patients as carriers of the mutated SCA3 gene.…”

Section: Methodsmentioning

confidence: 82%

Degeneration of the central vestibular system in spinocerebellar ataxia type 3 (SCA3) patients and its possible clinical significance

Rüb¹,

Brunt

Vos³

et al. 2004

Neuropathology Appl Neurobio

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Although the vestibular complex represents an important component of the neural circuits crucial for the maintenance of truncal and postural stability, and it is integrated into specialized oculomotor circuits, knowledge regarding the extent of the involvement of its nuclei and associated fibre tracts in cases with spinocerebellar ataxia type 3 (SCA3) is incomplete. Accordingly, we performed a pathoanatomical analysis of the vestibular complex and its associated fibre tracts in four clinically diagnosed and genetically confirmed SCA3 patients with the aim of providing more exact information as to the involvement of the vestibular system in this disorder. By means of unconventionally thick serial sections through the vestibular nuclei stained for lipofuscin pigment and Nissl material, we could show that all five nuclei of this complex (interstitial, lateral, medial, spinal, and superior vestibular nuclei) are subject to neurodegenerative processes in SCA3, whereby examination of thick serial sections stained for myelin revealed that all associated fibre tracts (ascending tract of Deiters, juxtarestiform body, lateral and medial vestibulospinal tracts, medial longitudinal fascicle, vestibular portion of the eighth cranial nerve) underwent atrophy and demyelinization in all four of the patients studied. The reported lesions can help to explain the truncal and postural instability as well as the impaired optokinetic nystagmus, vestibulo-ocular reaction, and horizontal gaze-holding present in SCA3 cases.

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“…Genetical diagnosis was carried out in all SCA3 patients by genotyping the DNA extracted from peripheral lymphocytes with polymorphic dinucleotide repeat sequences that flank the specific ataxin-3 gene loci [20, 50]. In the SCA3 patients studied, the length of the normal CAG-repeats varied from 14 to 27, while the pathologically expanded CAG-repeats varied from 62 to 81 (Table 1).…”

Section: Methodsmentioning

confidence: 99%

Axonal inclusions in spinocerebellar ataxia type 3

et al. 2010

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Protein aggregation is a major pathological hallmark of many neurodegenerative disorders including polyglutamine diseases. Aggregation of the mutated form of the disease protein ataxin-3 into neuronal nuclear inclusions is well described in the polyglutamine disorder spinocerebellar ataxia type 3 (SCA3 or Machado–Joseph disease), although these inclusions are not thought to be directly pathogenic. Neuropil aggregates have not yet been described in SCA3. We performed a systematic immunohistochemical study of serial thick sections through brains of seven clinically diagnosed and genetically confirmed SCA3 patients. Using antibodies against ataxin-3, p62, ubiquitin, the polyglutamine marker 1C2 as well as TDP-43, we analyzed neuronal localization, composition and distribution of aggregates within SCA3 brains. The analysis revealed widespread axonal aggregates in fiber tracts known to undergo neurodegeneration in SCA3. Similar to neuronal nuclear inclusions, the axonal aggregates were ubiquitinated and immunopositive for the proteasome and autophagy associated shuttle protein p62, indicating involvement of neuronal protein quality control mechanisms. Rare TDP-43 positive axonal inclusions were also observed. Based on the correlation between affected fiber tracts and degenerating neuronal nuclei, we hypothesize that these novel axonal inclusions may be detrimental to axonal transport mechanisms and thereby contribute to degeneration of nerve cells in SCA3.

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Refinement by linkage analysis in two large families of the candidate region of the third locus (SCA3) for autosomal dominant cerebellar ataxia type I

Cited by 12 publications

References 10 publications

Degeneration of ingestion‐related brainstem nuclei in spinocerebellar ataxia type 2, 3, 6 and 7

Degeneration of ingestion‐related brainstem nuclei in spinocerebellar ataxia type 2, 3, 6 and 7

Degeneration of the central vestibular system in spinocerebellar ataxia type 3 (SCA3) patients and its possible clinical significance

Axonal inclusions in spinocerebellar ataxia type 3

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