Objective: To characterize a variant of adult Huntington’s disease (HD) with akinetic-rigid syndrome (ARS) as initial motor manifestation

Background: HD Cases have been reported with ARS and minimal chorea as the presenting motor phenotype. We assessed the frequency and characteristics of the adult-onset ARS presentation in Enroll-HD, a global longitudinal observational study with >16,000 HD participants.

Method: Manifest participants with following UHDRS motor sub-scores were included: (i) total chorea score ≤4, (ii) bradykinesia score ≥3 and (iii) rigidity score ≥1, while patients with age of onset ≤20 years, duration of motor symptoms ≥5 years, and taking anti-psychotic/anti-chorea medications were excluded. We compared ARS patients with (i) rest of the manifest group, (ii) age, CAG_n-matched manifest patients, and (iii) iatrogenic ARS cases.

Results: Mean age and M:F ratio of 10,947 manifest HD participants (mean, (SD)) was 53.0 (12. 8) years, and 1:1.2 respectively; mean expanded CAG length is 44.0 (3.9). Fourty-three manifest HD participants met ARS criteria, while 81 presumably iatrogenic ARS cases taking anti-psychotics (n=56) or tetrabenazine (n=25) were identified. Compared to the iatrogenic cases and rest of manifest HD patients, ARS cases are younger (ARS cases vs. rest of manifest and iatrogenic cases, respectively; years, 41.9 (14.0) vs. 51.1 (14.7) and 53.0 (12.8), p<0.001) and have higher CAG_n (48.0 (7.2) vs 44.8 (4.8) and 44.0 (3.9), p<0.001). Compared with age, CAG_n -matched controls, ARS cases are similar on age of onset (ARS vs. controls: 39.6 (14.0) vs. 39.5 (13.7))[SS1] , disease duration (2.3 (2.3) vs. 2.3 (2.5)) and total motor score (33.7 (15.9) vs. 32.1 (18.9)). ARS cases have higher BMI (cases vs. controls: 25.0 (5.0) vs 23.9 (3.5)), lower SDMT scores (23.4 (11.3) vs. 27.2 (11.7)) and total functional capacity (8.8 (3.4) vs. 9.8 (3.5)), but these were not statistically significant.

Conclusion: ARS as the presenting motor manifestation is uncommon in adult-onset HD, albeit more common with CAG_n higher than 45. Since ARS is a known presenting phenotype of juvenile HD, a link between higher CAG_n and ARS is likely. ARS cases are also distinct from the iatrogenic cases, which suggests a specific underlying pathogenic mechanism. Further characterization of their longitudinal progression and potential genetic determinants is planned.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/akinetic-rigid-motor-presentation-among-adult-onset-hd-participants-in-enroll-hd/