Objective: To identify clinical and genetic markers to differ JHD from adult Huntington disease (HD) and to monitor JHD progression

Background: JHD is a HD variant with onset >20 years of age. Such classification was based on a clinical observation before the mutation discovery. After that, several articles reported young cases associated with heterogeneous and atypical phenotypes and variable size of mutations, sometime overlapping the size of adult presentations. Considering the rarity of JHD, the obvious difficulty in assessing young children and the still missing validated scales, no longitudinal studies for comparison with adults neither clinical trials, are available

Methods: We stratified JHD cases according to mutation length, i.e. patients with high CAG expansion ≥60 [HE, mean=76.6 (60-120), n=22] and with low CAG expansion <60 (LE, mean CAG=51 (43-57), n=13), with a total of 35 cases. A subgroup of 10 HE patients completed a total motor score (TMS) assay with a 3-year follow-up from a basal visit for comparison to an adult HD cohort. Life span and adult HD data were available from our Registry and Enroll-HD databases. JMP12 software was adopted for statistics

Results: HE-JHD patients had an infantile onset (before the age of 10) in 54% cases, paternal inheritance occurred in 95% of them. Cognitive impairment (i.e. developmental delay in younger cases) largely featured HE patients (68%), that were affected by parkinsonism or dystonia since onset (36 and 27% respectively) or during follow-up (31 and 54% respectively), predominating on other motor manifestations. Compared to an adult HD sample, HE patients presented a higher mean TMS unit increase per year (p<0.05) at a longitudinal analysis and a lower life span in year (p<0.05). All LE patients had adolescent onset (between 11 and 20 years, 92%) and presented paternal inheritance in 75%. They manifested with predominant parkinsonisms (46% at motor onset) with chorea in 53% cases during the follow-up. Obsessions were frequently and constantly reported since the onset (69%)

Conclusions: JHD cases with large expansions may manifest a worsen HD progression, with atypical, non-adulthood, manifestations (i.e. psychic and motor developmental delay, missing chorea). A correct stratification of JHD cases based on mutation size, in addition to age at onset, may offer new clues on detecting biomarkers to transfer into clinics in such ultra-rare condition

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MDS Abstracts - https://www.mdsabstracts.org/abstract/juvenile-huntington-disease-jhd-subjects-stratification-according-to-the-mutation-length/