Reclassification of juvenile Huntington’s disease may be required
medwireNews: A retrospective analysis of a cohort of children and adolescents with Huntington’s disease points to the presence of two juvenile forms that have markedly different clinical features and prognosis.
Individuals with “large CAG expansions experienced different motor and non-motor symptoms at disease onset and throughout the disease course, showed a faster rate of disease progression and had reduced survival not previously reported in patients with Huntington’s disease”, say the researchers.
And although they highlight the preliminary nature of the study, the team believes that “the current classification of juvenile Huntington’s disease might need to be revised.”
The study authors drew on the REGISTRY and ENROLL-HD platforms and two institutional databases to identify 36 patients with Huntington’s disease that manifested at 20 years of age or younger; all patients had motor symptoms, either with or without disabling psychiatric symptoms.
Hierarchical clustering analysis identified two subgroups, termed the highly expanded (HE) and low expansion (LE) subgroups, which differed by median CAG length and age of onset, at 86 versus 61 repeats and 4.0 versus 16.5 years, respectively.
Patients in both subgroups tended to present with dystonia and parkinsonism, but the 10 patients in the HE subgroup were significantly more likely to also have gait disturbances at presentation, at 80% compared with 27% of the 26 patients in the LE subgroup, while loss of hand dexterity was significantly less common, at 0% versus 42%.
The differences between groups persisted over time, such that severe gait impairment (90 vs 35%), development delays (90 vs 0%) and seizures (80 vs 12%) were significantly more common in the HE than the LE cohort, whereas the incidence of chorea (0 vs 35%) and obsessional behaviour (20 vs 73%) was significantly lower.
Furthermore, using data on 121 deceased patients whose age at death was known, the team found that survival was significantly shorter for patients with juvenile presentation than for those with adult-onset Huntington’s disease (hazard ratio [HR]=2.18).
And among the juvenile patients, those with the HE form had significantly worse survival than patients with either the LE form (HR=4.35) or adult-onset disease (HR=5.62). By contrast, survival in the LE subgroup did not differ significantly from the adult-onset group.
In light of these observations, researcher Ferdinando Squitieri (IRCCS Casa Sollievo della Sofferenza Hospital, Rome, Italy) and co-workers summarise that patients with HE juvenile Huntingdon’s disease “should be regarded as having a pathogenic process that is more severe” than that of patients with LE juvenile or adult-onset disease.
However, they note the inherent challenges in comparing the clinical manifestations of the HE and LE subgroups given the differences in the age of onset.
“Unlike in adult-onset Huntington’s disease, disease processes in juvenile Huntington’s disease are overlaid on the natural process of brain development, complicating the interpretation of how symptoms manifest and change over time”, the investigators explain in The Lancet Neurology.
“Therefore, whether differences in presenting symptoms represent a difference in disease pathophysiology or are a consequence of the developmental processes is unknown”, they conclude.
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