This study examined how loss-of-interruption (LOI) variants in the HTT CAG repeat affect somatic CAG expansion and medium spiny neuron (MSN) loss in Huntington's disease (HD) brain tissue, comparing MSN somatic expansion profiles between LOI carriers and non-carriers across disease duration.
MSNs with large (111–150 CAG) and very large (>150 CAG) somatic expansions were rare in early HD but accumulated with disease duration; in patients carrying the CAG-CCG LOI modifier, the proportion of MSNs with large and very large expansions was ~5-fold higher, and caudate MSN counts were reduced — despite paradoxically reduced small somatic expansions in blood.
Causal directionality between somatic expansion and MSN death cannot be fully established from this observational design; blood-based somatic expansion may not reliably reflect brain somatic expansion in LOI carriers; sample sizes for LOI subgroups were not specified in the abstract.
Clinicians evaluating HD patients should be aware that CAG-CCG LOI variants markedly amplify striatal somatic CAG expansion and MSN loss, likely accelerating disease onset — blood-based somatic expansion metrics may underestimate brain pathology in these patients.
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