10 research outputs found
Nextâgeneration sequencing in the diagnosis of Dementia and Huntingtonâs disease Phenocopy Syndromes
Dementia is a major cause of disability worldwide, especially in the elderly. While Mendelian causes of dementia only account for a small proportion of cases, their role in elucidating the pathophysiology has been paramount. Genetically defined cohorts also offer opportunities for trials of diseaseâmodifying treatments, even before the onset of symptoms. Previously, only a small number of genes could be selected for genetic testing because of costârestrictions, but the advent of nextâgeneration sequencing has enabled its more widespread use. This thesis explored the use of nextâgeneration sequencing in patients living with dementia and HD phenocopy (HDPC) syndromes, who include patients with mixed presentations of dementia and motor symptoms. Using a validated 17 gene Dementia Gene panel supplemented by C9orf72 expansion testing and Apolipoprotein (ApoE) genotyping in over 3000 patients and controls, I determined the success rate of genetic panel testing in dementia; I developed an algorithm for the selection of patients for genetic testing based on the clinical presentation and common predictors of genetic causes of dementia. A detailed analysis of the ApoE data in the frontotemporal dementia cohort revealed strong effects of ApoE4 on age at onset in the subset with proven or suspected tau neuropathology, as well as opposite effects of amyloidâbeta pathology. In order to improve the definition and diagnostic rate of HDPC syndromes, patients who were referred for HD testing from two clinics were compared based on their clinical presentation; patients could not be distinguished based on clinical presentation alone, even if analysed as patterns. Given the low success rate of dementia gene panel testing in the HDPC cohort, 50 patients were selected for wholeâgenome sequencing based on their HDâlikeness and their likelihood of harbouring a Mendelian variant. The results revealed a number of variants of interest but require replication
Evaluating the causality of novel sequence variants in the prion protein gene by example
The estimation of pathogenicity and penetrance of novel prion protein gene (PRNP) variants presents significant challenges, particularly in the absence of family history, which precludes the application of Mendelian segregation. Moreover, the ambiguities of prion disease pathophysiology renders conventional in silico predictions inconclusive. Here, we describe 2 patients with rapid cognitive decline progressing to akinetic mutism and death within 10Â weeks of symptom onset, both of whom possessed the novel T201S variant in PRNP. Clinically, both satisfied diagnostic criteria for probable sporadic Creutzfeldt-Jakob disease and in one, the diagnosis was confirmed by neuropathology. While computational analyses predicted that T201S was possibly deleterious, molecular strain typing, prion protein structural considerations, and calculations leveraging large-scale population data (gnomAD) indicate that T201S is at best either of low penetrance or nonpathogenic. Thus, we illustrate the utility of harnessing multiple lines of prion disease-specific evidence in the evaluation of the T201S variant, which may be similarly applied to assess other novel variants in PRNP
ApoE4 lowers age at onset in patients with frontotemporal dementia and tauopathy independent of amyloid-ÎČ copathology.
INTRODUCTION: Apolipoprotein E (ApoE) is the most important genetic risk factor for Alzheimer's disease (AD), with ApoE4 thought to enhance and accelerate amyloid-ÎČ (AÎČ) pathology. ApoE4 has recently been described to increase neurodegeneration in a mouse model of frontotemporal dementia (FTD), in vitro, and in patients, demonstrating that ApoE4 modifies tauopathy independently of AÎČ. This raises the question whether ApoE genotype also modifies the clinical phenotype in patients with FTD with tau pathology. METHODS: We analyzed 704 patients with FTD, including a genetically and neuropathologically confirmed subset, and 452 healthy elderly controls. We compared ApoE4 genotype frequency and age at onset in tau+ or TDP43+ FTD patients with or without AÎČ copathology. RESULTS: The ApoE4 genotype lowered age at onset in patients with FTD and tau pathology, particularly once accounting for confounding effects of AÎČ pathology. DISCUSSION: We conclude that ApoE4 accelerates neurodegeneration in FTD patients with MAPT mutations or FTLD-tau pathology, independent of AÎČ
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ApoE4 lowers age at onset in patients with frontotemporal dementia and tauopathy independent of amyloid-ÎČ copathology.
Introduction: Apolipoprotein E (ApoE) is the most important genetic risk factor for Alzheimer's disease (AD), with ApoE4 thought to enhance and accelerate amyloid-ÎČ (AÎČ) pathology. ApoE4 has recently been described to increase neurodegeneration in a mouse model of frontotemporal dementia (FTD), in vitro, and in patients, demonstrating that ApoE4 modifies tauopathy independently of AÎČ. This raises the question whether ApoE genotype also modifies the clinical phenotype in patients with FTD with tau pathology. Methods: We analyzed 704 patients with FTD, including a genetically and neuropathologically confirmed subset, and 452 healthy elderly controls. We compared ApoE4 genotype frequency and age at onset in tau+ or TDP43+ FTD patients with or without AÎČ copathology. Results: The ApoE4 genotype lowered age at onset in patients with FTD and tau pathology, particularly once accounting for confounding effects of AÎČ pathology. Discussion: We conclude that ApoE4 accelerates neurodegeneration in FTD patients with MAPT mutations or FTLD-tau pathology, independent of AÎČ