Clinical and Molecular Features of Late Onset Huntington Disease in a Peruvian Cohort

Abstract

Background: Late onset cases of Huntington disease (HD), with onset ≥60 years, account for up to 20% of HD cases worldwide. Clinical features include mild motor dysfunction with slow progression and cognitive impairment, frequent absence of family history and low number of CAG repeats. The clinical and molecular features of late onset HD is still understudied in Latin America. Objectives: To describe the clinical and molecular characteristics of late onset HD in a Peruvian cohort. Methods: An observational study was carried out by reviewing the HD registry at the Neurogenetics Research Center-INCN from 2000 to 2014. Genotyping of HTT gene was confirmed using standard PCR and PAGE in accordance to protocols previously established.Results: Thirty-one late onset HD cases from 27 pedigrees were identified (9.42% of total HD cases, n = 329), 51.61% were male. Mean age at onset was 64.1 ± 4.2 and CAG repeats mean was 42.5 ± 2.5. We did not find significant correlation between age at onset and CAG repeats. 33.3% of cases were traced back to Cañete valley. Twenty-two cases had a positive family history, 14 of them with paternal transmission. Choreic movements and cognitive impairment were the main existing manifestations reported in this cohort, with lower frequency of psychiatric disturbances. Conclusions: This report of late onset HD affected individuals shows a mild phenotype expression of the disease, associated with low range of CAG repeats and up to 30 % of cases with absence of clear family history. Cañete valley remains the region with more cases.

Late-onset Huntington’s disease with 40–42 CAG expansion

“…The definition of LO-HD itself is unclear. Indeed, some authors defined the late onset as ≥ 50 years [5,7,9,16] while recent studies identified the LO-HD as ≥ 60 years [4,11,12,15].…”

“…Among the CO-HD subgroup, 86.5% had an early stage of the disease (1-2) and 13.5% had an advanced disease stage (3)(4). In LO-HD subgroup, 75.9% had stage 1-2 and 24.1% had an advanced stage.…”

“…This subgroup, named late-onset HD (LO-HD), was defined with an onset after 49 years [7,9,18] or in more recent studies after 59 years [4,11,12,15]. LO-HD accounts between 4.4 and 25% in small cohorts [4,7,9,11,12,15,18] and 11.4% in a larger cohort [20]. LO-HD patients have frequently negative family history; consequentially, the diagnosis might be more difficult and the prevalence results underestimated.…”

Genetic aspects of Huntington's disease in Latin America. A systematic review

“…AO and correlations with the expanded CAG repeats, proportion of juvenile cases, and homozygote cases Twelve publications reported mean AO, and 10 of them estimated the correlation between AO and expanded (26) noted that AO association with the expanded repeat was stronger in those individuals with expansions longer than 50 repeats. Other reports did not stratify their samples in this way, and showed a single line across the entire range of CAG repeat lengths (32,40,41,43,48,50,52,54,55). Figure 2 illustrates some of these findings.…”

“…Twelve LA studies described the distribution of expanded CAG repeats among HD patients (Table S2). Excluding one outermost result likely to be due to ascertainment bias favoring early onset patients (48), the obtained average measurements varied from 41 to 47 CAG repeats (26,32,33,(40)(41)(42)(43)(49)(50)(51)(52).…”