Brain stem and cerebellum volumetric analysis of Machado Joseph disease patients

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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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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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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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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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

Neurology ◽

10.1212/wnl.49.5.1238 ◽

1997 ◽

Vol 49 (5) ◽

pp. 1238-1243 ◽

Cited By ~ 101

Author(s):

R. Matsumura ◽

N. Futamura ◽

Y. Fujimoto ◽

S. Yanagimoto ◽

H. Horikawa ◽

...

Keyword(s):

Family History ◽

Cerebellar Ataxia ◽

Age At Onset ◽

Repeat Expansion ◽

Repeat Length ◽

Cag Repeat ◽

Cag Repeats ◽

Spinocerebellar Ataxia Type ◽

Cag Repeat Expansion ◽

Spinocerebellar Ataxia Type 6

Spinocerebellar ataxia type 6 (SCA6) is a newly classified autosomal-dominant cerebellar ataxia (ADCA) associated with CAG repeat expansion. We screened 111 patients with cerebellar ataxia for the SCA6 mutation. Of these, 35 patients were found to have expanded CAG repeats in the SCA6 gene, indicating that second to SCA3, SCA6 is the most common ADCA in Japan. Expanded alleles ranged from 21 to 29 repeats, whereas normal alleles had seven to 17 repeats. There was no change in the CAG repeat length during meiosis. The age at onset was inversely correlated with the repeat length. The main clinical feature of the 35 patients with SCA6 was slowly progressive cerebellar ataxia; multisystem involvement was not common. The 35 patients included nine cases without apparent family history of cerebellar ataxia. The sporadic cases had smaller CAG repeats (21 or 22 repeats) and a later age at onset (64.9 ± 4.9 years) than the other cases with established family history. We also identified one patient who was homozygous for the SCA6 repeat expansion. The homozygote showed an earlier age of onset and more severe clinical manifestations than her sister, a heterozygote carrying an expanded allele with the same repeat length as the homozygote. This finding suggests that the dosage of the CAG repeat expansion plays an important role in phenotypic expression in SCA6.

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Spinocerebellar ataxia type 6 in relation to CAG repeat length

Acta Neurologica Scandinavica ◽

10.1111/j.1600-0404.1999.tb07348.x ◽

1999 ◽

Vol 99 (4) ◽

pp. 209-212 ◽

Cited By ~ 6

Author(s):

Y. Kaseda ◽

H. Kawakami ◽

Z. Matsuyama ◽

R. Kumagai ◽

M. Toji ◽

...

Keyword(s):

Spinocerebellar Ataxia ◽

Repeat Length ◽

Cag Repeat ◽

Spinocerebellar Ataxia Type ◽

Spinocerebellar Ataxia Type 6

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CAG repeat length and disease duration in Machado-Joseph disease: a new clinical classification

Journal of the Neurological Sciences ◽

10.1016/s0022-510x(97)00155-x ◽

1997 ◽

Vol 152 (2) ◽

pp. 166-171 ◽

Cited By ~ 15

Author(s):

H Maruyama ◽

H Kawakami ◽

T Kohriyama ◽

T Sakai ◽

M Doyu ◽

...

Keyword(s):

Disease Duration ◽

Repeat Length ◽

Cag Repeat ◽

Clinical Classification ◽

Machado Joseph Disease

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CAG repeat length does not associate with the rate of cerebellar degeneration in spinocerebellar ataxia type 3

NeuroImage Clinical ◽

10.1016/j.nicl.2016.11.007 ◽

2017 ◽

Vol 13 ◽

pp. 97-105 ◽

Cited By ~ 8

Author(s):

Shang-Ran Huang ◽

Yu-Te Wu ◽

Chii-Wen Jao ◽

Bing-Wen Soong ◽

Jiing-Feng Lirng ◽

...

Keyword(s):

Spinocerebellar Ataxia ◽

Cerebellar Degeneration ◽

Repeat Length ◽

Cag Repeat ◽

Spinocerebellar Ataxia Type ◽

Spinocerebellar Ataxia Type 3 ◽

Type 3

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Genetic analysis of age at onset variation in spinocerebellar ataxia type 2

Neurology Genetics ◽

10.1212/nxg.0000000000000155 ◽

2017 ◽

Vol 3 (3) ◽

pp. e155 ◽

Cited By ~ 18

Author(s):

K.P. Figueroa ◽

Hilary Coon ◽

Nieves Santos ◽

Luis Velazquez ◽

Luis Almaguer Mederos ◽

...

Keyword(s):

Spinocerebellar Ataxia ◽

Age At Onset ◽

Repeat Length ◽

Cag Repeat ◽

Spinocerebellar Ataxia Type ◽

Spinocerebellar Ataxia Type 2 ◽

Entire Sample ◽

Sib Pairs ◽

Parent Child

Objective:To examine heritability of the residual variability of spinocerebellar ataxia type 2 (SCA2) age at onset (AO) after controlling for CAG repeat length.Methods:From 1955 to 2001, dates of birth, CAG repeat lengths, AO, sex, familial inheritances, and clinical manifestations were collected for a large Cuban SCA2 cohort of 382 affected individuals, including 129 parent-child pairs and 69 sibships. Analyses were performed with log-transformed AO in the GENMOD procedure to predict AO using repeat length, taking into account family structure. Because all relationships were first degree, the model was implemented with an exchangeable correlation matrix. Familial correlations were estimated using the Pedigree Analysis Package to control for similarity due to genetic relatedness.Results:For the entire sample, the mutant CAG repeat allele explained 69% of AO variance. When adjusted for pedigree structure, this decreased to 50%. Evidence for imprinting or sex-specific effects of the CAG repeat on AO was not found. For the entire sample, we determined an upper bound for heritability of the residual variance of 33% (p = 0.008). Heritability was higher in sib-sib pairs, especially in female sib-sib pairs, than in parent-child pairs.Conclusions:We established that a large proportion of AO variance in SCA2 was determined by genetic modifiers in addition to CAG repeat length. The genetic structure of heritability of the residual AO variance was surprisingly similar to Huntington disease, suggesting the presence of recessive modifying alleles and possibly X-chromosome–linked modifiers.

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