Reduced-penetrance Huntington’s disease-causing alleles with 39 CAG trinucleotide repeats could be a genetic factor of amyotrophic lateral sclerosis - genetic association study

Sep 29, 2026

Expanded HTT alleles with 40 or more CAG repeats have been reported as a rare cause within the frontotemporal dementia and amyotrophic lateral sclerosis (ALS) spectrum. This study investigates whether HTT repeat expansions contribute to ALS risk in a Taiwanese cohort. CAG repeat numbers in exon 1 of HTT were measured in 410 ALS patients and 1514 controls using polymerase chain reaction and amplicon fragment length analysis. Only one patient carried a reduced-penetrance HD-causing 39 CAG allele, suggesting a genetic susceptibility link to ALS.

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J Chin MedAssoc Original article Reduced-penetrance Huntington’s diseasecausing alleles with 39 CAG trinucleotide repeats could be a genetic factor of amyotrophic lateral sclerosis Kang-Yang Jiha,b,c, Kuan-Lin Laia,c,d, Kon-Ping Lina,c, Yi-Chu Liaoa,c,d, Yi-Chung Leea,c,d,* aDepartment of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC; bDepartment of Physiology, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan, ROC; cDepartment of Neurology, National Yang Ming Chiao Tung University School of Medicine, Taipei, Taiwan, ROC; dBrain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC Abstract Background: Expanded HTT alleles with 40 or more CAG repeats were recently found to be a rare cause of frontotemporal dementia and amyotrophic lateral sclerosis (ALS) spectrum diseases. The aim of this study was to investigate the role of HTT repeat expansions in a Taiwanese cohort with ALS. Methods: We analyzed the numbers of CAG repeats in exon 1 of HTT in a cohort of 410 Taiwanese patients with ALS and 1514 control individuals by utilizing polymerase chain reaction and amplicon fragment length analysis. Results: Only one of the 410 ALS patients carried a reduced-penetrance HD-causing allele with 39 CAG repeats, and none had an expanded HTT CAG repeats ≥40 . The patient presented with rapidly progressive bulbar-onset ALS with disease onset at the age of 64 years. He had neither chorea nor cognitive impairment. He had a family history of chorea, but no other family member manifested with ALS. None of the 1514 control individuals carried an HTT expanded allele with CAG repeats larger than 37 repeats. Conclusion: The HTT allele with 39 CAG repeats could be a genetic factor linked to ALS susceptibility. Keywords: Amyotrophic lateral sclerosis; Huntington’s disease; HTT; Polyglutamine expansion 1. INTRODUCTION Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that results in both upper and lower motor neuron loss. Clinically, ALS manifests with progressive limb weakness, muscle atrophy, and bulbar palsy. Most patients who suffer from ALS die of respiratory failure or other complications within 5 years of disease onset. To date, there are more than 40 ALS causative or associated genes reported in previous literature.1 A known ALS-associated gene can be identified in approximately 15% of sporadic ALS cases and 70% of familial cases.2 Short tandem repeat expansions account for a major group of disease-related variants of ALS, including the most common pathogenic mutations (GGGGCC hexanucleotide repeats in C9ORF72) .2 In addition, the CAG trinucleotide repeats in ATXN1 and ATXN2 as well as the CAG/CAA * Address correspondence. Dr. Yi-Chung Lee, Department of Neurology, Taipei Veterans General Hospital, 201, Section 2, Shi-Pai Road, Taipei 112, Taiwan, [ROC. E-mail address: ycli@vghtpe.gov.tw](ROC. E-mail address: ycli@vghtpe.gov.tw) (Y.-C. Lee). Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article. Journal of Chinese Medical Association. (2023) 86: 47-51. Received April 27, 2022; accepted September 9, 2022. doi: 10. 1097/JCMA.0000000000000837. Copyright © 2022, the Chinese Medical Association. This is an open access article under the CC BY-NC-ND license ([http://creativecommons.org/licenses/](http://creativecommons.org/licenses/)[ ](http://creativecommons.org/licenses/)[by-nc-nd/4.0/](by-nc-nd/4.0/)) trinucleotide repeats in TBP have also been implicated in ALS.3–5 The CAG repeat expansion of HTT, another pathogenic tandem repeat expansion, was once thought to be unassociated with ALS.6,7 However, a recent large-scale study based on two ALS and frontotemporal dementia (FTD) cohorts has provided new evidence supporting that pathogenic HTT repeat expansions are a rare cause of FTD and ALS spectrum diseases.8 The study

FAQs

What was the main aim of this study?

To investigate the role of HTT repeat expansions in a Taiwanese cohort with ALS.

How were CAG repeats in HTT measured in ALS patients and controls?

CAG repeat numbers in exon 1 of HTT were analyzed in 410 ALS patients and 1514 controls using polymerase chain reaction and amplicon fragment length analysis.

What proportion of ALS patients carried the reduced-penetrance 39 CAG allele?

Only one of 410 ALS patients carried a reduced-penetrance HD-causing allele with 39 CAG repeats, and none had expanded HTT CAG repeats of 40 or more.

Sep 29, 2026

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