Curation SCA1 ATXN1

A seven-generation autosomal dominant SCA kindred included 41 affected individuals, with 26 examined neurologically and 15 identified from medical records or family history; this is pre-ATXN1-repeat, chromosome 6p/HLA-linked SCA1-region evidence rather than repeat-specific genotyping.

Population genotyping of polyglutamine disease genes defined ATXN1 intermediate alleles as 36-38 CAG repeats and pathological alleles as 39-91 CAG repeats; among 13,668 long ATXN1 alleles, 636 were intermediate and 9 were in the pathological range (39-44), but CAT interruptions were not assessed.

In the same seven-generation kindred, linkage analysis of a 93-member pedigree showed strong linkage of the SCA1-region disease locus to HLA loci, with maximum LOD score 5.83 at recombination fraction 0.12; this supports segregation of the linked region, not direct repeat-level segregation.

These studies compare genetically confirmed SCA1 individuals with controls for balance, neuropsychological features, or longitudinal biomarkers, supporting the clinical phenotype and biomarker profile of genetically confirmed SCA1. While, these studies are not ideal case-control designs, collectively, they are supportive.

PMID 8358429 identified the disease-associated ATXN1-region CAG repeat within a transcribed sequence and showed the repeat is present in a ~10 kb mRNA expressed in multiple tissues, including brain and skeletal muscle; this is locus-level transcript evidence rather than direct biochemical function.

In symptomatic B05 SCA1 mice expressing polyglutamine-expanded human ATXN1, AAV-delivered human ATXN1L alone or combined with miS1 targeting mutant ATXN1 improved rotarod motor phenotypes and partially normalized disease-associated cerebellar gene-expression changes.