Differences in Juvenile Huntington Disease Manifestations Identified

September 27, 2018

A retrospective analysis has established clinical distinctions between expressions of juvenile Huntington disease, suggesting a need for a reclassification.

Ferdinando Squitieri, MD, PhD

A new analysis has found that patients with highly expanded juvenile Huntington disease have clinical differences from those with low expansion juvenile or adult-onset forms of the condition, suggesting a need for a reclassification of the aggressive form of the disease.

Ultimately, there were several significant clinical distinctions between the groups, including gait disturbances, hand dexterity, development delays, and seizures, among others.1

Conducted by Ferdinando Squitieri, MD, PhD, the head of neurology at the CSS-Mendel Institute, and a scientific officer and co-founder of the Italian League of Huntington Research (LIRH) Foundation, and colleagues, the retrospective analysis sought to further characterize juvenile Huntington's disease by examining the effect of CAG repeat size on disease presentation, progression, and survival.

"The missing longitudinal data on juvenile-onset Huntington disease and the effect of large-sized CAG expanded mutations on the phenotype, together with the restricted inclusion criteria of experimental therapeutic trials to accept children with Huntington prompted this research," Squitieri told NeurologyLive.

In total, 233 patients were included in the analysis, with 36 patients meeting the definition of juvenile Huntington disease and 197 meeting the definition of adult-onset Huntington disease. As noted in an accompanying editorial2 by Julie C. Stout, MD, “most movement disorders specialists will care for only a handful of children with juvenile Huntington's disease during a lifetime of clinical practice,” making this study population of 36 children and adolescents not only impressive, but “a rich opportunity to examine key features of juvenile Huntington's disease.”

Analysis of caregiver reports revealed that for those in the highly expanded group (n = 10), gait disturbances were more often a first presenting symptom, present in 80% (n = 8) of patients. Comparatively, in the low expansion group (n = 26), only 27% (n = 7) experienced this as their first presenting symptom (P = .0071). Conversely, a loss of hand dexterity was more common for those in the low expansion group, occurring in 42% (n = 11) of patients compared to none in the highly expanded group (P = .0160).

"We have identified a new juvenile Huntington variant with pediatric-onset and large mutations above 80 CAG repeats," Squitieri said. "These children may manifest with atypical symptoms in dependence on the large-sized mutation length and show a more severe course and a shorter lifespan than adults and other juvenile cases with relatively smaller CAG mutations. The main implications of the identifications of the manifestations are related to the chance that the disease is related to a developmental delay—psychic and motor—and to a correct clinical interpretation for better estimating the frequency of juvenile cases and for therapeutically approaching them in a correct time in future."

With regard to developmental delay, it was much more common in the highly expanded group, occurring in 90% (n = 9) of patients compared to none in the low expansion group (P <.0001). The same was the case for severe gait impairment and seizures, prevailing over time in 90% (n = 9) and 80% (n = 8) of those in the highly expanded group, respectively, compared to 35% (n = 9; P <.0072) and 11% (n = 3; P <.0001) of those in the low expansion group, respectively.

Furthermore, those with juvenile Huntington (n = 14) experienced more rapid disease progression than those with adult-onset Huntington (n = 52; generalized estimating equation model P = .0003). Squitieri and colleagues noted that of 121 deceased patients observed from the study period of June 23, 2004, to March 31, 2018, the median survival was shorter in the juvenile group (n = 17) than the adult-onset cohort (n = 104), with a hazard ratio of 2.18 (95% CI, 1.08 to 4.40; P = .002).

“This study is also a reminder of how little is known about the clinical and biological manifestations of this form of Huntington's disease,” Stout noted in her editorial.

"We were very surprised to pick a completely different pattern of abnormalities in brains of HD children with large mutations," Squitieri said. "They showed an underdeveloped part of the brain, the striatum, relatively preserved brain cortex, and white matter, implying a developmental disorder before neurodegeneration. Theoretically, this is a model for other neurodegenerative diseases, including adult HD, where the developmental abnormalities may be present but less visible."

REFERENCES

1. Fusilli C, Migliore S, Mazza T, et al. Biological and clinical manifestations of juvenile Huntington's disease: a retrospective analysis. Lancet Neurol. Epub September 19, 2018. doi: 10.1016/S1474-4422(18)30294-1.

2. Stout JC. Juvenile Huntington’s disease: left behind? Lancet Neurol. Epub September 19, 2018. doi: 10.1016/S1474-4422(18)30334-X.