TY - JOUR
T1 - Intermediate HTT CAG repeats worsen disease severity in amyotrophic lateral sclerosis
AU - Grassano, Maurizio
AU - Canosa, Antonio
AU - D’Alfonso, Sandra
AU - Corrado, Lucia
AU - Brodini, Giorgia
AU - Koumantakis, Emanuele
AU - Cugnasco, Paolo
AU - Manera, Umberto
AU - Vasta, Rosario
AU - Palumbo, Francesca
AU - Mazzini, Letizia
AU - Gallone, Salvatore
AU - Moglia, Cristina
AU - Dewan, Ramita
AU - Chia, Ruth
AU - Ding, Jinhui
AU - Dalgard, Clifton
AU - Gibbs, Raphael J.
AU - Scholz, Sonja
AU - Calvo, Andrea
AU - Traynor, Bryan
AU - Chio, Adriano
PY - 2024/12/16
Y1 - 2024/12/16
N2 - Recent research has indicated a connection between amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD), an inherited neurological condition caused by a trinucleotide CAG repeat expansion within exon 1 of the Huntingtin gene ( HTT ; MIM:613004).1 The same pathogenic CAG repeat expansions (40 or more CAG repeats) observed in patients with HD have been identified in patients with frontotemporal dementia (FTD)/ALS.1 Similarly, non-pathogenic intermediate-length CAG repeats in the ATXN2 gene are a well-established factor associated with increased ALS risk and faster disease progression.2 Given these observations, we investigated the impact of intermediate HTT alleles on survival in two cohorts of patients diagnosed with ALS.
### Discovery cohort
The study population consisted of 1181 patients with ALS identified through the Piemonte and Valle d’Aosta Register for ALS (PARALS) (online supplemental etable 1). Among these, 996 samples were part of the original report of HTT repeat expansions in individuals with FTD/ALS.3 The characteristics of the PARALS register are described in online supplemental materials. These subjects were negative for pathogenic mutations in C9orf72 , SOD1 , TARDBP and FUS .
### Supplementary data
[jnnp-2024-333998supp001.pdf]
### Replication cohort
As a replication cohort, we used clinical and genomic data from the Answer ALS database (https://dataportal.answerals.org/home). We retrieved whole-genome sequence data from 376 patients with ALS who did not have mutations in the four major ALS genes (online supplemental etable 1). The data processing pipeline is described in online supplemental materials.
### HTT CAG repeat analysis
We used ExpansionHunter (V.5.0.0) to estimate repeat lengths of HTT expansions from the whole-genome sequence data. HTT CAG alleles were deemed ‘fully penetrant’ if they carried 40 or more repeats, ‘incompletely penetrant’ if they carried between 36 and 39 repeats and were designated as ‘intermediate’ if they carried between 27 and 35 repeats. Healthy subjects typically have 26 or fewer CAG repeats.
### Statistical methods
Survival was calculated from symptom onset to …
AB - Recent research has indicated a connection between amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD), an inherited neurological condition caused by a trinucleotide CAG repeat expansion within exon 1 of the Huntingtin gene ( HTT ; MIM:613004).1 The same pathogenic CAG repeat expansions (40 or more CAG repeats) observed in patients with HD have been identified in patients with frontotemporal dementia (FTD)/ALS.1 Similarly, non-pathogenic intermediate-length CAG repeats in the ATXN2 gene are a well-established factor associated with increased ALS risk and faster disease progression.2 Given these observations, we investigated the impact of intermediate HTT alleles on survival in two cohorts of patients diagnosed with ALS.
### Discovery cohort
The study population consisted of 1181 patients with ALS identified through the Piemonte and Valle d’Aosta Register for ALS (PARALS) (online supplemental etable 1). Among these, 996 samples were part of the original report of HTT repeat expansions in individuals with FTD/ALS.3 The characteristics of the PARALS register are described in online supplemental materials. These subjects were negative for pathogenic mutations in C9orf72 , SOD1 , TARDBP and FUS .
### Supplementary data
[jnnp-2024-333998supp001.pdf]
### Replication cohort
As a replication cohort, we used clinical and genomic data from the Answer ALS database (https://dataportal.answerals.org/home). We retrieved whole-genome sequence data from 376 patients with ALS who did not have mutations in the four major ALS genes (online supplemental etable 1). The data processing pipeline is described in online supplemental materials.
### HTT CAG repeat analysis
We used ExpansionHunter (V.5.0.0) to estimate repeat lengths of HTT expansions from the whole-genome sequence data. HTT CAG alleles were deemed ‘fully penetrant’ if they carried 40 or more repeats, ‘incompletely penetrant’ if they carried between 36 and 39 repeats and were designated as ‘intermediate’ if they carried between 27 and 35 repeats. Healthy subjects typically have 26 or fewer CAG repeats.
### Statistical methods
Survival was calculated from symptom onset to …
UR - http://www.scopus.com/inward/record.url?scp=85204777565&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/a528622a-4407-3b4c-8962-c42ce32fd1c3/
U2 - 10.1136/jnnp-2024-333998
DO - 10.1136/jnnp-2024-333998
M3 - Article
C2 - 39242198
AN - SCOPUS:85204777565
SN - 0022-3050
VL - 96
SP - 100
EP - 102
JO - Journal of Neurology, Neurosurgery and Psychiatry
JF - Journal of Neurology, Neurosurgery and Psychiatry
IS - 1
ER -