Many common disorders, including depression, dementia and obesity are for a large part heritable. Despite the fact that genome-wide association studies (GWAS) have contributed substantially to... Show moreMany common disorders, including depression, dementia and obesity are for a large part heritable. Despite the fact that genome-wide association studies (GWAS) have contributed substantially to unraveling the genetic architecture of these polygenetic disorders, a large amount of ‘missing heritability’ remains. A possible explanation is that GWAS, aside single-nucleotide polymorphisms cannot assess the contribution of other important genetic polymorphisms, especially tandem repeats. Tandem repeats constitute 3% of the human genome. Nine hereditary neurodegenerative diseases, known as polyglutamine diseases, including Huntington disease (HD), are the most prevalent disorders associated with tandem repeat variations. These diseases are caused by an elongated cytosine-adenine-guanine (CAG) repeat sequence in the respective polyglutamine disease-associated gene (PDAG). In this dissertation, we provide ample evidence that CAG repeat variations within the ‘normal’ range in PDAGs can affect various aspects of disease, including the age of onset in HD, cognitive function, depression and body mass index. Finally, we found a relatively large prevalence of intermediate and pathological PDAG alleles in the general population. Therefore, we provided support for the role of repetitive DNA polymorphisms in elucidating the ‘missing heritability’ of polygenetic disorders and emphasized the necessity to include these variations in future genetic research. Show less
Oosterloo, M.; Bijlsma, E.; Kuijk, S. van; Minkes, F.; Roos, R.; Die-Smulders, C.E.M. de 2019
Background The frequency of late-onset Huntington's disease ( > 59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and... Show moreBackground The frequency of late-onset Huntington's disease ( > 59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and inconclusive.Objective: Our aim is to study clinical characteristics of late-onset compared to common-onset HD patients in a large cohort of HD patients from the Registry database.Methods: Participants with late- and common-onset (30-50 years)were compared for first clinical symptoms, disease progression, CAG repeat size and family history. Participants with a missing CAG repeat size, a repeat size of <= 35 or a UHDRS motor score of <= 5 were excluded.Results: Of 6007 eligible participants, 687 had late-onset (11.4%) and 3216 (53.5%) common-onset HD. Late onset (n = 577) had significantly more gait and balance problems as first symptom compared to common-onset (n = 2408) (P < .001). Overall motor and cognitive performance (P < .001) were worse, however only disease motor progression was slower (coefficient, -0.58; SE 0.16; P < .001) compared to the common-onset group. Repeat size was significantly lower in the late-onset (n = 40.8; SD 1.6) compared to common-onset (n = 44.4; SD 2.8) (P < .001). Fewer late-onset patients (n = 451) had a positive family history compared to common onset (n = 2940) (P < .001).Conclusions: Late-onset patients present more frequently with gait and balance problems as first symptom, and disease progression is not milder compared to common-onset HD patients apart from motor progression. The family history is likely to be negative, which might make diagnosing HD more difficult in this population. However, the balance and gait problems might be helpful in diagnosing HD in elderly patients. Show less
Schat, A.; Noorden, M.S. van; Noom, M.J.; Giltay, E.J.; Wee, N.J.A. van der; Griaf, R. de; ... ; Zitman, F.G. 2016
