Small-expanded allele spinocerebellar ataxia 17: imaging and phenotypic variability

Spinocerebellar ataxia type 6 (SCA6) is the most recently identified mutation causing autosomal-dominant cerebellar ataxia without retinal degeneration (ADCA). The SCA6 mutation is allelic with episodic ataxia type 2(EA-2), but the two differ clinically because of the presence of progressive, rather than episodic, ataxia in SCA6. SCA6 accounts for 12% of families with ADCA in an ethnically heterogeneous population of patients. Clinical examination, quantitative eye movement testing, and imaging data show that the brainstem is normal in most patients with SCA6, especially within the first 10 years of symptoms. Most patients show progressive ataxia from the onset, but several patients show an episodic course resembling EA-2. Thus, SCA6 mutations not only account for patients with ADCA I and ADCA III phenotypes but also for some patients presenting with episodic features that are typical for EA-2. Interestingly, a compound heterozygote for the SCA6 expansion manifested an earlier onset and more rapid course than family members with the same larger expanded allele.

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Machado-Joseph disease versus hereditary spastic paraplegia: case report

Arquivos de Neuro-Psiquiatria ◽

10.1590/s0004-282x2001000500030 ◽

2001 ◽

Vol 59 (3B) ◽

pp. 809-811 ◽

Cited By ~ 14

Author(s):

Hélio A. Ghizoni Teive ◽

Fabio Massaiti Iwamoto ◽

Carlos Henrique Camargo ◽

Iscia Lopes-Cendes ◽

Lineu Cesar Werneck

Keyword(s):

Hereditary Spastic Paraplegia ◽

Autosomal Dominant ◽

Phenotypic Variability ◽

Spastic Paraparesis ◽

Japanese Patients ◽

Cag Repeats ◽

Spastic Paraplegia ◽

Expanded Allele ◽

Machado Joseph Disease ◽

Autosomal Dominant Spinocerebellar Ataxia

Machado-Joseph disease (MJD) is the most common autosomal dominant spinocerebellar ataxia and presents great phenotypic variability. MJD presenting with spastic paraparesis was recently described in Japanese patients. We report the case of 41-year-old woman with the phenotype of complicated hereditary spastic paraplegia. Her father died at the age of 56 years due to an undiagnosed progressive neurological disease that presented parkinsonism. She had an expanded allele with 66 CAG repeats and a normal allele with 22 repeats in the gene of MJD. MJD should be considered in the differential diagnosis of autosomal dominant complicated HSP. A patient with the phenotype of complicated HSP and relatives with other clinical features of a neurodegenerative disease should raise the suspicion of MJD.

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Intrafamilial phenotypic variability in Spinocerebellar ataxia type 8

Journal of the Neurological Sciences ◽

10.1016/j.jns.2015.08.903 ◽

2015 ◽

Vol 357 ◽

pp. e255

Author(s):

A. Antenora ◽

S. Peluso ◽

M. Esposito ◽

A. De Rosa ◽

A. Brusco ◽

...

Keyword(s):

Spinocerebellar Ataxia ◽

Phenotypic Variability ◽

Spinocerebellar Ataxia Type ◽

Intrafamilial Phenotypic Variability

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DNAzyme Cleavage of CAG Repeat RNA in Polyglutamine Diseases

Neurotherapeutics ◽

10.1007/s13311-021-01075-w ◽

2021 ◽

Author(s):

Nan Zhang ◽

Brittani Bewick ◽

Jason Schultz ◽

Anjana Tiwari ◽

Robert Krencik ◽

...

Keyword(s):

Spinocerebellar Ataxia ◽

Cag Repeat ◽

Spinocerebellar Ataxia Type ◽

Spinocerebellar Ataxia Type 3 ◽

Therapeutic Value ◽

Expanded Allele ◽

Allele Specific ◽

Aggresome Formation ◽

Polyq Diseases ◽

Type 3

AbstractCAG repeat expansion is the genetic cause of nine incurable polyglutamine (polyQ) diseases with neurodegenerative features. Silencing repeat RNA holds great therapeutic value. Here, we developed a repeat-based RNA-cleaving DNAzyme that catalyzes the destruction of expanded CAG repeat RNA of six polyQ diseases with high potency. DNAzyme preferentially cleaved the expanded allele in spinocerebellar ataxia type 1 (SCA1) cells. While cleavage was non-allele-specific for spinocerebellar ataxia type 3 (SCA3) cells, treatment of DNAzyme leads to improved cell viability without affecting mitochondrial metabolism or p62-dependent aggresome formation. DNAzyme appears to be stable in mouse brain for at least 1 month, and an intermediate dosage of DNAzyme in a SCA3 mouse model leads to a significant reduction of high molecular weight ATXN3 proteins. Our data suggest that DNAzyme is an effective RNA silencing molecule for potential treatment of multiple polyQ diseases.

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Prevalence of RFC1-Mediated Spinocerebellar Ataxia in a United States Ataxia Cohort

10.1101/790006 ◽

2019 ◽

Author(s):

Dona Aboud Syriani ◽

Darice Wong ◽

Claudio M. De Gusmao ◽

Sameer Andani ◽

Yuanming Mao ◽

...

Keyword(s):

United States ◽

Cerebellar Ataxia ◽

Spinocerebellar Ataxia ◽

The United States ◽

Tertiary Referral ◽

Expanded Allele ◽

Initial Cohort ◽

Heterozygous Sample ◽

Repeat Expansions ◽

Polymerase Chain

ABSTRACTObjectiveRepeat expansions in RFC1 and DAB1 have recently been identified as causing cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) and spinocerebellar ataxia 37 (SCA37), respectively. We evaluated the prevalence of these repeat-expansions in an undiagnosed ataxia cohort from the United States.MethodsA cohort of 596 patients with undiagnosed familial or sporadic cerebellar ataxia were evaluated at a tertiary referral ataxia center and excluded for common genetic causes of cerebellar ataxia. Patients were then screened for the presence of pathogenic repeat expansions in RFC1 (AAGGG) and DAB1 (ATTTC) using fluorescent repeat primed polymerase chain reaction (RP-PCR). Two additional undiagnosed ataxia cohorts from different centers, totaling 96 and 13 patients respectively, were subsequently screened for RFC1 resulting in a combined 705 subjects tested.ResultsIn the initial cohort, 42 samples were identified with one expanded allele in the RFC1 gene (7.0%), and 9 had two expanded alleles (1.5%). For the additional cohorts, we found 12 heterozygous samples (12.5%) and 7 biallelic samples (7.3%) in the larger cohort, and 1 heterozygous sample (7.7%) and 3 biallelic samples (23%) in the second. In total, 19 patients were identified with biallelic repeat expansions in RFC1 (2.7%). Of these 19 patients, 6 (32%) had a clinical diagnosis of CANVAS, 10 had cerebellar ataxia with neuropathy (53%), and 3 had spinocerebellar ataxia (16%). No patients were identified with expansions in the DAB1 gene.ConclusionIn a large undiagnosed ataxia cohort from the United States, biallelic pathogenic repeat expansion in RFC1 was observed in 2.7%. Testing should be strongly considered in ataxia patients, especially those with CANVAS or neuropathy.

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From Mild Ataxia to Huntington Disease Phenocopy: The Multiple Faces of Spinocerebellar Ataxia 17

Case Reports in Neurological Medicine ◽

10.1155/2014/643289 ◽

2014 ◽

Vol 2014 ◽

pp. 1-4 ◽

Cited By ~ 2

Author(s):

Georgios Koutsis ◽

Marios Panas ◽

George P. Paraskevas ◽

Anastasia M. Bougea ◽

Athina Kladi ◽

...

Keyword(s):

Spinocerebellar Ataxia ◽

Huntington Disease ◽

Autosomal Dominant ◽

Psychiatric Symptoms ◽

Phenotypic Variability ◽

Autosomal Dominant Cerebellar Ataxia ◽

Child Transmission ◽

Affective Symptoms ◽

Progressive Ataxia ◽

The Family

Introduction. Spinocerebellar ataxia 17 (SCA 17) is a rare autosomal dominant cerebellar ataxia (ADCA) caused by a CAG/CAA expansion in theTBPgene, reported from a limited number of countries. It is a very heterogeneous ADCA characterized by ataxia, cognitive decline, psychiatric symptoms, and involuntary movements, with some patients presenting with Huntington disease (HD) phenocopies. The SCA 17 expansion is stable during parent-child transmission and intrafamilial phenotypic homogeneity has been reported. However, significant phenotypic variability within families has also been observed.Report of the Family. We presently report a Greek family with a pathological expansion of 54 repeats at the SCA 17 locus that displayed remarkable phenotypic variability. Among 3 affected members, one presented with HD phenocopy; one with progressive ataxia, dementia, chorea, dystonia, and seizures, and one with mild slowly progressive ataxia with minor cognitive and affective symptoms.Conclusions. This is the first family with SCA 17 identified in Greece and highlights the multiple faces of this rare disorder, even within the same family.

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