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

Abstract

Introduction Huntington's disease (HD) is a rare autosomal dominant neurodegenerative disorder caused by a CAG expansion greater than 35 in the IT-15 gene. There is an inverse correlation between the number of pathological CAG and the age of onset. However, CAG repeats between 40 and 42 showed a wider onset variation. We aimed to investigate potential clinical differences between patients with age at onset ≥ 60 years (late onset-HD) and patients with age at onset between 30 and 59 years (commononset HD) in a cohort of patients with the same CAG expansions (40-42). Methods A retrospective analysis of 66 HD patients with 40-41-42 CAG expansion was performed. Patients were investigated with the Unified Huntington's Disease Rating Scale (subitems I-II-III and Total Functional Capacity, Functional Assessment and Stage of Disease). Data were analysed using χ 2 , Fisher's test, t test and Pearson's correlation coefficient. GENMOD analysis and Kaplan-Meier analysis were used to study the disease progression. Results The age of onset ranged from 39 to 59 years in the CO subgroup, whereas the LO subgroup showed an age of onset from 60 to 73 years. No family history was reported in 31% of the late-onset in comparison with 20% in common-onset HD (p = 0.04). No difference emerged in symptoms of onset, in clinical manifestations and in progression of disease between the two groups. Conclusion There were no clinical differences between CO and LO subgroups with 40-42 CAG expansion. There is a need of further studies on environmental as well genetic variables modifying the age at onset.

Emerging Roles of Exosomes in Huntington’s Disease

“…The CAG repeat range of 36–39 might be found in affected individuals as well as asymptomatic individuals (reduced penetrance alleles), whereas individuals with ≥40 repeats always develop the disorder (fully penetrant alleles) [ 32 ]. The number of CAG repeats is inversely correlated with the age of onset, longer repeats predict earlier onset of the disease and vice versa [ 36 , 37 ]. Predictive and diagnostic genetic testing is available to detect the expanded CAG repeats for the affected individuals as well as for individuals at risk [ 38 ].…”

Facial-onset sensory-motor neuronopathy, a rare variant of Huntington’s disease or chance association?

“…Once chorea appeared in our patient, the clinical presentation of HD was rather classic, with behavioral disorder and cognitive impairment. However, she had lateonset HD, which is known to be related to the limited HTT CAG expansion [11]. In patients with limited HTT repeat expansions and late HD, familial history is frequently lacking, leading to diagnostic errors or delays.…”

Purinergic Signaling in the Pathophysiology and Treatment of Huntington’s Disease

“…Huntington’s disease (HD) is a devastating, progressive, and fatal neurodegenerative disorder inherited in an autosomal dominant manner ( Smith-Dijak et al, 2019 ; Blumenstock and Dudanova, 2020 ). It is triggered by an expansion of a cytosine-adenine-guanine (CAG) triplet repeat in exon 1 of the huntingtin ( HTT ) gene, located on chromosome 4 ( The Huntington’s Disease Collaborative Research Group, 1993 ; Capiluppi et al, 2020 ). This change leads to an expanded polyglutamine (polyQ) region in the encoded HTT protein ( Bailus et al, 2017 ; Rai et al, 2019 ).…”

“…As a result, the expressed HTT protein is a mutant (mHTT; Cybulska et al, 2020 ). Individuals with up to 35 CAG repeats are usually considered healthy, while people with 36 to 39 CAG repeats may or may not develop the signs and symptoms of HD ( Shoulson and Young, 2011 ; Capiluppi et al, 2020 ). More than 50 CAG repeats always cause the disease ( Capiluppi et al, 2020 ).…”

“…Individuals with up to 35 CAG repeats are usually considered healthy, while people with 36 to 39 CAG repeats may or may not develop the signs and symptoms of HD ( Shoulson and Young, 2011 ; Capiluppi et al, 2020 ). More than 50 CAG repeats always cause the disease ( Capiluppi et al, 2020 ). There is an inverse correlation between the number of CAG repeats, age at onset, and the severity of HD symptoms ( Bates et al, 2015 ; Petersén and Weydt, 2019 ).…”