Name: SKY-0515 in Huntington's disease: Natural history, survival, and mortality
Published: 2026-09-16T18:00:43-04:00

Age at onset and prodromal phase

“The mean age of onset is approximately 45 years” (opens the source at this quote in a new tab)
“About two thirds of individuals first present with neurologic manifestations; others present with psychiatric changes.” (opens the source at this quote in a new tab)
“These subtle changes can occur as early as 15-20 years prior to the clinical onset of manifest HD.” (opens the source at this quote in a new tab)
“In approximately 25% of individuals with HD, the onset is delayed until after age 50 years, with some after age 70 years” (opens the source at this quote in a new tab)

Prodromal change detected before diagnosis: PREDICT-HD

“1078 individuals with a CAG expansion were included in this analysis. Participants were followed up for a mean of 5·1 years (SD 3·3, range 0·0-12·0). 225 (21%) of these participants received a motor diagnosis of Huntington's disease during the study.” (opens the source at this quote in a new tab)

“This work showed that measurable brain and behavioral changes can be detected up to 15 years before an HD diagnosis.” (opens the source at this quote in a new tab)

Disease stages: Huntington's Disease Integrated Staging System

“The HD-ISS characterises individuals for research purposes from birth, starting at Stage 0 (ie, individuals with the Huntington's disease genetic mutation without any detectable pathological change) by using a genetic definition of Huntington's disease. Huntington's disease progression is then marked by measurable indicators of underlying pathophysiology (Stage 1), a detectable clinical phenotype (Stage 2), and then decline in function (Stage 3).” (opens the source at this quote in a new tab)

Progression in premanifest and early disease: TRACK-HD

“In the preHD-B group, several quantitative motor and cognitive tasks showed significantly increased rates of decline at 36 months, compared with controls, whereas few had at 24 months.” (opens the source at this quote in a new tab)

“For either score, initial progression age and then acceleration rate were highly CAG repeat length dependent. The acceleration continues through at least stage II disease.” (opens the source at this quote in a new tab)

Survival after onset and age at death

“In late stages of HD, motor disability becomes severe, and the individual is often totally dependent, mute, and incontinent. The median survival time after onset is 15 to 18 years (range: 5 to >25 years). The average age at death is 54 to 58 years” (opens the source at this quote in a new tab)

“For these fully ascertained subjects, the range, mean, SD, and median of duration values were 0–46, 15.4, 6.8, and 15 years, respectively.” (opens the source at this quote in a new tab)
“We found that, as with clinical onset, HD age at death is determined by expanded CAG-repeat length and has no contribution from the normal CAG allele. Surprisingly, disease duration is independent of the mutation's length.” (opens the source at this quote in a new tab)

Mortality relative to the general population: UK cohort

“The KM survival curve (Figure 1) shows a median survival time of 12.4 years (95% CI 10.6–15.2). Median age at death in individuals with HD and controls was 71 (IQR 59–79) and 81 (IQR 73–86) years, respectively. Individuals with HD were at 4.5 times greater risk of death than controls (hazard ratio 4.51, 95% CI 3.36–6.06, p < 0.001) after multivariable adjustment of baseline covariates (Figure S1).” (opens the source at this quote in a new tab)

Age at death and causes of death: Norwegian national registries

“Mean age at death for individuals with HD was found to be 63.9 years (NCDR) and 61.7 years (CRD), compared to a mean of 76.9 years in the general population (NCDR).” (opens the source at this quote in a new tab)
“In 73.5% of individuals with HD, the underlying cause of death was HD, followed by cardiovascular diseases, cancer and respiratory diseases. The most common immediate cause of death was respiratory diseases (44.2%). Suicide was a more common cause of death in the population with HD (2.3%) compared to the general population (1.3%).” (opens the source at this quote in a new tab)

Causes of death: aspiration pneumonia

“Two hundred twenty four charts of deceased HD patients were reviewed, of which 216 (111/104 male/female, one unknown) had records available, 147 listed a cause of death (Table 1), which was pneumonia in 81 (55%) cases.” (opens the source at this quote in a new tab)
“The conclusion is that the majority (86.8%) of our HD patients where the cause of death could be identified died from aspiration pneumonia.” (opens the source at this quote in a new tab)

Suicide and suicidal ideation

“Incidence of suicidal ideation, suicide attempt, and suicide are higher among those with HD relative to the non-HD population.” (opens the source at this quote in a new tab)

“At baseline, 169 (8.0%) mutation carriers endorsed suicidal ideation.” (opens the source at this quote in a new tab)
“The 4-year cumulative incidence of suicidal ideation was 9.9%.” (opens the source at this quote in a new tab)

“The critical periods for suicide risk are just prior to receiving a diagnosis and later, when affected individuals experience a loss of independence” (opens the source at this quote in a new tab)

Juvenile Huntington's disease: progression and survival

“Disease progression of JHD is faster compared to AOHD and the disease duration is shorter, particularly in case of higher CAG repeat lengths.” (opens the source at this quote in a new tab)

“Disease progression was more rapid in juvenile Huntington's disease (n=14) than in adult-onset Huntington's disease (n=52; generalised estimating equation model, p=0·0003). Of 121 deceased patients, median survival was shorter in the juvenile Huntington's disease (n=17) cohort than in adult-onset Huntington's disease (n=104) cohort (hazard ratio 2·18 [95% CI 1·08-4·40]; p=0·002).” (opens the source at this quote in a new tab)