TGM6 L517W is not a pathogenic variant for spinocerebellar ataxia type 35

ObjectiveTo investigate the pathogenicity of the TGM6 variant for spinocerebellar ataxia 35 (SCA35), which was previously reported to be caused by pathogenic mutations in the gene TGM6.MethodsNeurologic assessment and brain MRI were performed to provide detailed description of the phenotype. Whole-exome sequencing and dynamic mutation analysis were performed to identify the genotype.ResultsThe proband, presenting with myoclonic epilepsy, cognitive decline, and ataxia, harbored both the TGM6 p.L517W variant and expanded CAG repeats in gene ATN1. Further analysis of the other living family members in this pedigree revealed that the CAG repeat number was expanded in all the patients and within normal range in all the unaffected family members. However, the TGM6 p.L517W variant was absent in 2 affected family members, but present in 3 healthy individuals.ConclusionsThe nonsegregation of the TGM6 variant with phenotype does not support this variant as the disease-causing gene in this pedigree, questioning the pathogenicity of TGM6 in SCA35.

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Homozygous spinocerebellar ataxia type 3 in China: a case report

Journal of International Medical Research ◽

10.1177/03000605211021370 ◽

2021 ◽

Vol 49 (6) ◽

pp. 030006052110213

Author(s):

Yuchao Chen ◽

Dan Li ◽

Minger Wei ◽

Menglu Zhou ◽

Linan Zhang ◽

...

Keyword(s):

Spinocerebellar Ataxia ◽

Clinical Phenotype ◽

Gene Dosage ◽

Cag Repeat ◽

Cag Repeats ◽

Spinocerebellar Ataxia Type ◽

Contraction Pattern ◽

Spinocerebellar Ataxia Type 3 ◽

Type 3 ◽

Stable Transmission

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease caused by a heterozygous CAG repeat expansion in the ataxin 3 gene ( ATXN3). However, patients with homozygous SCA3 carrying expanded CAG repeats in both alleles of ATXN3 are extremely rare. Herein, we present a case of a 50-year-old female who had homozygous SCA3 with expansion of 62/62 repeats. Segregation analysis of the patient’s family showed both a contraction pattern of CAG repeat length and stable transmission. The present case demonstrated an earlier onset and more severe clinical phenotype than that seen in heterozygous individuals, suggesting that the gene dosage enhances disease severity.

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Expanded CAG repeats in Swedish spinocerebellar ataxia type 7 (SCA7) patients: effect of CAG repeat length on the clinical manifestation

Human Molecular Genetics ◽

10.1093/hmg/7.2.171 ◽

1998 ◽

Vol 7 (2) ◽

pp. 171-176 ◽

Cited By ~ 91

Author(s):

J Johansson

Keyword(s):

Spinocerebellar Ataxia ◽

Clinical Manifestation ◽

Repeat Length ◽

Cag Repeat ◽

Cag Repeats ◽

Spinocerebellar Ataxia Type ◽

Spinocerebellar Ataxia Type 7

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Clinical and molecular features of spinocerebellar ataxia type 6

Neurology ◽

10.1212/wnl.49.5.1243 ◽

1997 ◽

Vol 49 (5) ◽

pp. 1243-1246 ◽

Cited By ~ 77

Author(s):

G. Stevanin ◽

A. Dürr ◽

G. David ◽

O. Didierjean ◽

G. Cancel ◽

...

Keyword(s):

Cerebellar Ataxia ◽

Spinocerebellar Ataxia ◽

Age At Onset ◽

Cerebellar Atrophy ◽

Cag Repeat ◽

Cag Repeats ◽

Spinocerebellar Ataxia Type ◽

Olivopontocerebellar Atrophy ◽

Molecular Features ◽

Spinocerebellar Ataxia Type 6

The mutation involved in spinocerebellar ataxia type 6 (SCA6) is a small CAG expansion in the alpha-1A subunit of the voltage-dependent calcium channel gene. We looked for this mutation in 91 families with autosomal-dominant cerebellar ataxias and found that SCA6 is a minor locus in our series (2%) and is rare in France (1%). Furthermore, we did not detect the SCA6 mutation on 146 sporadic cases with isolated cerebellar ataxia or olivopontocerebellar atrophy. The normal and expanded alleles ranged from 4 to 15 and 22 to 28 CAG repeats, respectively, and age at onset was correlated to CAG repeat length (r = -0.87). In contrast with other SCA, the expanded allele was stable during transmission. Clinically, SCA6 patients (n = 12) presented with moderate to severe cerebellar ataxia with a lower frequency of associated signs compared with other SCA and a mean age at onset of 45± 14 years (range, 24 to 67). MRI showed extensive cerebellar atrophy but not of the brainstem or cerebral cortex.

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Spinocerebellar ataxia type 2 in China

Neurology ◽

10.1212/wnl.51.2.595 ◽

1998 ◽

Vol 51 (2) ◽

pp. 595-598 ◽

Cited By ~ 10

Author(s):

Y.-X. Zhou ◽

G.-X. Wang ◽

B.-S. Tang ◽

W.-D. Li ◽

D.-A. Wang ◽

...

Keyword(s):

Spinocerebellar Ataxia ◽

Disease Onset ◽

Inverse Correlation ◽

Cag Repeat ◽

Cag Repeats ◽

Spinocerebellar Ataxia Type ◽

Spinocerebellar Ataxia Type 2 ◽

Chinese Families ◽

Strong Inverse Correlation

Sixteen patients from nine Chinese families with spinocerebellar ataxia type 2 (SCA2) were heterozygous for a CAG repeat expansion in the SCA2 gene containing 37 to 56 repeats, whereas the normal alleles carried 14 to 28 repeats. One or two CAA triplets within the CAG tract were seen in normal, but not in the expanded alleles. A strong inverse correlation was established between the number of CAG repeats and the age of disease onset. SCA2 accounted for 12% of the known Chinese families with spinocerebellar ataxia.

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Brain stem and cerebellum volumetric analysis of Machado Joseph disease patients

Arquivos de Neuro-Psiquiatria ◽

10.1590/s0004-282x2011000300005 ◽

2011 ◽

Vol 69 (2b) ◽

pp. 292-296 ◽

Cited By ~ 8

Author(s):

S T Camargos ◽

W Marques-Jr ◽

A C Santos

Keyword(s):

Brain Stem ◽

Spinocerebellar Ataxia ◽

Disease Duration ◽

Volumetric Analysis ◽

Repeat Length ◽

Cag Repeat ◽

Clinical Severity ◽

Cag Repeats ◽

Spinocerebellar Ataxia Type ◽

Machado Joseph Disease

Machado-Joseph disease, or spinocerebellar ataxia type 3(MJD/SCA3), is the most frequent late onset spinocerebellar ataxia and results from a CAG repeat expansion in the ataxin-3 gene. Previous studies have found correlation between atrophy of cerebellum and brainstem with age and CAG repeats, although no such correlation has been found with disease duration and clinical manifestations. In this study we test the hypothesis that atrophy of cerebellum and brainstem in MJD/SCA3 is related to clinical severity, disease duration and CAG repeat length as well as to other variables such as age and ICARS (International Cooperative Ataxia Rating Scale). Whole brain high resolution MRI and volumetric measurement with cranial volume normalization were obtained from 15 MJD/SCA3 patients and 15 normal, age and sex-matchedcontrols. We applied ICARS and compared the score with volumes and CAG number, disease duration and age. We found significant correlation of both brain stem and cerebellar atrophy with CAG repeat length, age, disease duration and degree of disability. The Spearman rank correlation was stronger with volumetric reduction of the cerebellum than with brain stem. Our data allow us to conclude that volumetric analysis might reveal progressive degeneration after disease onset, which in turn is linked to both age and number of CAG repeat expansions in SCA 3.

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Sequence variation and size ranges of CAG repeats in the Machado-Joseph disease, spinocerebellar ataxia type 1 and androgen receptor genes

Human Molecular Genetics ◽

10.1093/hmg/4.9.1585 ◽

1995 ◽

Vol 4 (9) ◽

pp. 1585-1590 ◽

Cited By ~ 42

Author(s):

David C. Rubinsztein ◽

Jayne Leggo ◽

Gerhard A. Coetzee ◽

Ryan A. Irvine ◽

Michael Buckley ◽

...

Keyword(s):

Androgen Receptor ◽

Spinocerebellar Ataxia ◽

Sequence Variation ◽

Cag Repeats ◽

Spinocerebellar Ataxia Type ◽

Spinocerebellar Ataxia Type 1 ◽

Machado Joseph Disease

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Bovine CACNA1A gene and comparative analysis of the CAG repeats associated to human spinocerebellar ataxia type-6

Gene ◽

10.1016/j.gene.2006.06.003 ◽

2006 ◽

Vol 380 (1) ◽

pp. 54-61 ◽

Cited By ~ 2

Author(s):

Eva Andrés-Mateos ◽

Jesús Cruces ◽

Jaime Renart ◽

Luisa M. Solís-Garrido ◽

Rocío Serantes ◽

...

Keyword(s):

Comparative Analysis ◽

Spinocerebellar Ataxia ◽

Cag Repeats ◽

Spinocerebellar Ataxia Type ◽

Spinocerebellar Ataxia Type 6 ◽

Cacna1a Gene

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Dystonia in Patients with Spinocerebellar Ataxia 3 - Machado-Joseph disease: An Underestimated Diagnosis?

The Open Neurology Journal ◽

10.2174/1874205x01812010041 ◽

2018 ◽

Vol 12 (1) ◽

pp. 41-49 ◽

Cited By ~ 2

Author(s):

Ligia Maria Perrucci Catai ◽

Carlos Henrique Ferreira Camargo ◽

Adriana Moro ◽

Gustavo Ribas ◽

Salmo Raskin ◽

...

Keyword(s):

Spinocerebellar Ataxia ◽

Movement Disorders ◽

Disease Onset ◽

Cag Repeat ◽

Spinocerebellar Ataxia Type ◽

Spinocerebellar Ataxia Type 3 ◽

Generalized Dystonia ◽

Machado Joseph Disease ◽

Sca3 Patient ◽

Type 3

Background:Spinocerebellar Ataxia type 3 (SCA3) or Machado-Joseph Disease (MJD) is characterized by cerebellar, central and peripheral symptoms, including movement disorders. Dystonia can be classified as hereditary and neurodegenerative when present in SCA3.Objective:The objective of this study was to evaluate the dystonia characteristics in patients with MJD.Method:We identified all SCA3 patients with dystonia from the SCA3 HC-UFPR database, between December 2015 and December 2016.Their medical records were reviewed to verify the diagnosis of dystonia and obtain demographic and clinical data. Standardized evaluation was carried out through the classification of Movement Disorders Society of 2013 and Burke Fahn-Marsden scale (BFM).Results:Amongst the presenting some common characteristics, 381 patients with SCA3, 14 (3.7%) subjects presented dystonia: 5 blepharospasm, 1 cervical dystonia, 3 oromandibular, 3 multifocal and 2 generalized dystonia. Regarding dystonia's subtypes, 71.4% had SCA3 subtype I and 28.6% SCA3 subtype II. The average age of the disease onset was 40±10.7 years; the SCA3 disease duration was 11.86± 6.13 years; the CAG repeat lengths ranged from 75 to 78, and the BFM scores ranged from 1.0 to 40. There was no correlation between the dystonia severity and CAG repeat lengths or the SCA3 clinical evolution.Conclusion:Dystonia in SCA3 is frequent and displays highly variable clinical profiles and severity grades. Dystonia is therefore a present symptom in SCA3, which may precede the SCA3 classic symptoms. Dystonia diagnosis is yet to be properly recognized within SCA3 patient.

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Spinocerebellar ataxia type 6 in Brazil

Arquivos de Neuro-Psiquiatria ◽

10.1590/s0004-282x2008000500015 ◽

2008 ◽

Vol 66 (3b) ◽

pp. 691-694 ◽

Cited By ~ 13

Author(s):

Hélio A.G. Teive ◽

Renato Puppi Munhoz ◽

Salmo Raskin ◽

Lineu César Werneck

Keyword(s):

Cerebellar Ataxia ◽

Spinocerebellar Ataxia ◽

Late Onset ◽

Cag Repeat ◽

Autosomal Dominant Cerebellar Ataxia ◽

Spinocerebellar Ataxia Type ◽

Spinocerebellar Ataxia Type 6 ◽

Voltage Dependent ◽

Pure Cerebellar Ataxia ◽

Japanese Ancestry

Spinocerebellar ataxia type 6 (SCA 6) is an autosomal dominant cerebellar ataxia caused by CAG repeat expansion in the SCA6 gene, a alpha 1A voltage-dependent calcium channel subunit gene on chromosome 19p13. SCA-6 is characterized predominantly by slowly progressive pure cerebellar ataxia with late onset. We report three index patients, with pure, late onset, cerebellar ataxia, belonging to three different Brazilian families, all of them with Japanese ancestry, from Hokkaido island of Japan.

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