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- Heinzel, Sebastian, et al.
(författare)
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Clinical relevance and translational impact of reduced penetrance in genetic movement disorders
- 2022
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Ingår i: Medizinische Genetik. - : Walter de Gruyter. - 0936-5931 .- 1863-5490. ; 34:2, s. 151-156
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Tidskriftsartikel (refereegranskat)abstract
- Reduced penetrance is an important but underreported aspect in monogenic diseases. It refers to the phenomenon that carriers of pathogenic variants do not manifest with an overt disease. Clinical expressivity, on the other hand, describes the degree to which certain disease characteristics are present. In this article, we discuss the implications of reduced penetrance on genetic testing and counseling, outline how penetrance can be estimated in rare diseases using large cohorts and review the ethical, legal and social implications of studying non-manifesting carriers of pathogenic mutations. We highlight the interplay between reduced penetrance and the prodromal phase of a neurodegenerative disorder through the example of monogenic Parkinson's disease and discuss the therapeutic implications.
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- Volk, Alexander E., et al.
(författare)
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Current knowledge and recent insights into the genetic basis of amyotrophic lateral sclerosis
- 2018
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Ingår i: Medizinische Genetik. - : Springer Berlin/Heidelberg. - 1863-5490 .- 0936-5931. ; 30:2, s. 252-258
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease, affecting the upper and/or lower motor neurons. However, extramotor symptoms can also occur; cognitive deficits are present in more than 40% of patients and 5-8% of ALS patients develop frontotemporal dementia. There is no effective treatment for ALS and median survival is 2-3 years after onset.Amyotrophic lateral sclerosis is a genetically heterogeneous disorder with monogenic forms as well as complex genetic etiology. Currently, complex genetic risk factors are of minor interest for routine diagnostic testing or counseling of patients and their families. By contrast, a monogenic cause can be identified in 70% of familial and 10% of sporadic ALS cases. The most frequent genetic cause is a noncoding hexanucleotide repeat expansion in the C9orf72 gene. In recent years, high-throughput sequencing technologies have helped to identify additional monogenic and complex risk factors of ALS.Genetic counseling should be offered to all ALS patients and their first- and possibly second-degree relatives, and should include information about the possibilities and limitations of genetic testing. Routine diagnostic testing should at least encompass the most frequently mutated disease genes (C9orf72, SOD1, TDP-43, FUS). Targeted sequencing approaches including further disease genes may be applied. Caution is warranted as the C9orf72 repeat expansion cannot be detected by routine sequencing technologies and testing by polymerase chain reaction (PCR) is failure-prone.Predictive testing is possible in families in which a genetic cause has been identified, but the limitations of genetic testing (i.aEuroe., the problems of incomplete penetrance, variable expressivity and possible oligogenic inheritance) have to be explained to the families.
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- Winblad, Stefan, 1966, et al.
(författare)
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Subtle cognitive decline in Myotonic dystrophy type 1: a five-year follow up study
- 2009
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Ingår i: Medizinische genetik. - : Springer-verlag. - 0936-5931.
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Konferensbidrag (refereegranskat)abstract
- Objective: To characterize the progression of cognitive decline in classical DM1 at a five-year follow-up examination. Background: Previous studies have indicated decline in executive attention, in agree ment with frontal brain involvement. Methods: Repeated assessment was performed in 34 (mean age = 42, 18 female, 16 male) out of 47 DM1 patients in whom a previous neuropsychological assessment was performed five years earlier. Neuropsychological test included measurements of memory, attention, visuospatial function, arithmetic, verbal ability, speed and executive function. Statistical analysis was performed using the Wilcoxon signed-rank test. Results: Neuropsychological tests results associated with executive attention, visuoconstructive and verbal memory abilities were significantly worsened over time. The difference between results on separate test occasions, as measured by Cohen’s d, was mild to moderate. Notably, not a single patient showed severe decline (comparable to dementia) in any examined cognitive domain. Conclusion: Our data con firms a subtle decline in executive attention function. However, our data also shows that visuoconstructive and verbal memory abilities was worsened over time, indicating, not only frontal brain dysfunction but also the possible involvement of other cortical and subcortial brain areas. These findings indicate the need for further longitudinal studies on cognition in DM1 and the development of interventions, both including proper medication and rehabilitation modules as to mitigate the progress of cognitive dysfunction. Subsequent analysis of the present data will determine if factors such as CTG repeat expansion size and muscle function is important for the rate of cognitive decline over time.
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