Based on the study’s findings, researchers have also suggested that a revision of the current classification of juvenile Huntington’s disease may be needed.
The study, “Biological and clinical manifestations of juvenile Huntington’s disease: a retrospective analysis,” was published in The Lancet Neurology.
In most cases, Huntington’s symptoms occur after the age of 30, known as adult-onset. However, disease symptoms can appear earlier — a condition called juvenile Huntington’s disease. The juvenile form of the disease is rare and accounts only for 4-10 percent of all cases.
Huntington’s is caused by excessive repeats of a portion of DNA, called CAG triplets, within the gene that provides instructions for the production of the huntingtin (HTT) protein.
Due to the rarity of juvenile Huntington’s disease, researchers’ understanding of its characteristics is still pretty limited. Questions that remain to be answered include what specific regions of the brain are affected, how the disease progresses, and overall life expectancy.
To help answer these questions, researchers performed a retrospective analysis of medical records of patients ages 20 or younger with juvenile Huntington’s disease and patients between the ages of 30 and 60 with adult-onset Huntington’s disease, carrying at least 40 CAG repeats, from two prospective, observational studies: the REGISTRY (NCT01590589) and the ENROLL-HD (NCT01574053) trials.
Both clinical studies recruited individuals who had mutations in the huntingtin (HTT) gene, regardless of whether or not they displayed any clinical signs of the disease. They also included family members (at-risk or confirmed non-mutation carriers) and a group of individuals without a family history of the disease used as controls.
Additional data was retrieved from two institutional databases, one in Italy at the Lega Italiana Ricerca Huntington (LIRH) Foundation and one in Argentina at the Instituto Neurociencias de Buenos Aires and the Sanatorio de la Trinidad Mitre.
Medical records analyzed were from the period between June 23, 2004, and March 31, 2018.
The team extracted information from patients with juvenile Huntington’s disease who exhibited disabling psychiatric symptoms with motor symptoms, or motor symptoms alone.
They included patients with adult-onset Huntington’s disease had motor symptoms, while those with psychiatric symptoms were excluded.
Participants were assessed at enrollment (baseline) and annually thereafter. At each visit, individuals had a broad range of clinical, motor, cognitive, behavioral, and quality of life assessments, and donated blood samples.
Patients with juvenile Huntington’s disease were divided in two subgroups — highly expanded and low expansion — according to the number of CAG repeats, disease progression at baseline, and patient age.
Disease progression was measured using the Unified Huntington’s Disease Rating Scale–Total Motor Score (UHDRS−TMS), a clinical rating scale that assesses four domains: motor function, cognitive function, behavioral abnormalities, and functional capacity. The total motor impairment score is the sum of all the individual motor ratings, with higher scores indicating more severe motor impairment.
They also compared disease progression and patient survival between juvenile and adult-onset disease.
From an initial pool of 580 patients, 36 met the definition of juvenile Huntington’s disease and 197 of adult-onset Huntington’s disease. In the juvenile group, the low expansion subgroup (26 patients) had a median CAG length of 61 repeats compared with 86 repeats in the highly expanded subgroup (10 patients).
Disease onset occurred at an early age — a mean of 4 years old — in patients in the highly expanded subgroup and at a more advanced age in the low expansion subgroup — mean age of 16.5 years.
Gait disturbance was seen as the first symptom in significantly more patients in the highly expanded subgroup (80%) than in the low expansion subgroup (27%).
In contrast, loss of hand dexterity (i.e., clumsiness) was reported as the first symptom in significantly more patients in the low expansion group (42%) than in the highly expanded group (0%)
According to patient medical records, the mean frequency of presenting motor symptoms did not differ between subgroups.
Dystonia, a condition where muscles contract uncontrollably, and parkinsonism — a condition that causes some symptoms of Parkinson’s disease — were the main neurological motor symptoms at disease onset.
According to the researchers, the main differences in clinical symptoms between both groups occurred as the disease progressed, with the highly expanded subgroup showing prevalence of development delay, severe gait impairment, and seizures, compared with the low expansion subgroup.
For example, none of the patients in the low expanded group showed signs of development delay against the majority (90%) of those in the highly expanded group.
The disease progressed more rapidly in juvenile Huntington’s disease patients than adult-onset patients, shown by an increase in the UHDRS−TMS score of 27.43 points over three years in the juvenile group compared with 13.52 points in the adult-onset group.
Median survival was also significantly shorter in the juvenile Huntington’s disease group than in the adult-onset Huntington’s disease group, shown by data retrieved from 121 deceased patients with an available age at death from the LIRH Foundation institutional database.
“The results from our study add to the existing evidence by confirming that the juvenile variant of Huntington’s disease is particularly aggressive and associated with an early symptom onset,” the researchers wrote.
“Furthermore, our results also suggest that the current classification of juvenile Huntington’s disease might need to be revised,” they added.
“Juvenile patients who have large CAG expansions (>80 CAG repeats) could be regarded as having a more severe form of Huntington’s disease than juvenile patients with smaller expanded repeat regions and from those with adult-onset Huntington’s disease,” the researchers concluded.
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